A Phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)

A Phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301) Pavlina Spiliopoulou, Farasat Kazmi, Francesca Aroldi, Thomas Holmes, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3593277/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Apr, 2024 Read the published version in Journal of Experimental & Clinical Cancer Research → Version 1 posted 5 You are reading this latest preprint version Abstract Purpose 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR‑MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. Patients and Methods: NUC‑3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28‑day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC‑3373. Secondary objectives included pharmacokinetics (PK), and anti‑tumor activity. Results Fifty-nine patients received NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. Conclusion NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m 2 NUC‑3373 weekly. NUC-3373 is currently in combination treatment studies. Trial registration: Clinicaltrials.gov registry number NCT02723240. Trial registered on 8 th December 2015. https://clinicaltrials.gov/study/NCT02723240 NUC-3373 5-FU 5-fluorouracil fluoropyrimidines thymidylate synthase resistant cancer Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Fluoropyrimidines, such as 5-fluorouracil (5-FU), are widely utilized anti-cancer agents that can be given as monotherapy or more commonly in combination therapy for the treatment of a range of tumor types, including colorectal, stomach, head and neck, pancreatic, and breast cancers [ 1 ]. The anti-cancer activity of 5-FU, and its other forms floxuridine (FUDR®) and capecitabine (Xeloda®), is largely attributed to the active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP or FdUMP), which inhibits the enzyme thymidylate synthase (TS), a critical enzyme in de novo nucleotide synthesis and cell survival [ 2 ]. However, due to multiple limitations, 5-FU is not efficiently converted to FUDR-MP. More than 85% of administered 5FU is degraded by the enzyme dihydropyrimidine dehydrogenase (DPD) in the liver; therefore, most of the drug is catabolized before it has an opportunity to exert any therapeutic effect [3]. 5-FU also requires the presence of nucleobase transporters for intracellular transfer and, once inside the cell, requires complex enzymatic processing to generate FUDR-MP [4]. These key limitations impacting breakdown, transport, and activation have been linked to poorer outcomes in patients receiving 5-FU [5]. Additionally, the generation of RNA-directed metabolites by fluoropyrimidines, such as fluorouridine triphosphate (FUTP), is responsible for a number of dose-limiting toxicities (DLTs), including neutropenia, diarrhoea and mucositis, impacting patient safety [6]. Although various strategies have been investigated to counter these limitations, such as biochemical modulation with leucovorin (LV) to enhance TS binding or increased infusion durations, none have successfully addressed these shortcomings in a comprehensive manner. NUC-3373, a phosphoramidate nucleotide analog, is the first such agent specifically designed to overcome the limitations and pharmacologic challenges associated with 5-FU and other fluoropyrimidines [ 7 ]. NUC-3373 is a pre-activated and protected form of FUDR, one of a new class of anti-cancer agents (ProTides) being developed to improve efficacy, safety and pharmacokinetic profiles of nucleoside analog drugs. ProTides contain a phosphate that is protected by a phosphoramidate group (consisting of an aryl, an ester, and an amino acid) with unique structural properties that stabilize the compound and protect it against enzymatic breakdown. Preclinical studies have shown that NUC-3373 is resistant to breakdown by DPD [ 8 ] and does not require nucleobase transporters to enter cancer cells [ 9 ]. As NUC-3373 contains the active anti-cancer metabolite FUDRMP, it does not rely on phosphorylation by thymidine kinase (TK) [ 8 , 9 ]. As a result of these properties, NUC-3373 generates substantially higher intracellular levels of FUDR-MP and is a more potent inhibitor of TS than 5FU in vitro , while generating markedly lower levels of the toxic metabolite FUTP (Fig. 1 ) [10]. In human colorectal cancer mouse xenograft models, NUC-3373 showed greater tumor inhibition than 5-FU [8]. Here we describe the first-in-human study of NUC-3373 given as monotherapy to patients with advanced solid tumors (NuTide:301). The study was conducted to determine the MTD, schedule, and recommended Phase II dose (RP2D) of NUC-3373 and to assess its safety, pharmacokinetics (PK) and anti-tumor activity. Patients and Methods Study Design and Objectives This Phase I, open-label, two-part, dose-escalation study was designed to evaluate the safety, PK, and anti-cancer activity of single-agent NUC‑3373, in addition to establishing its MTD, schedule and RP2D, in patients with advanced solid tumors. The primary objective was to determine the MTD and RP2D when given weekly on Days 1, 8, 15 and 22 (Part 1) or alternate weekly on Days 1 and 15 (Part 2) of 28-day cycles, until disease progression or unacceptable toxicity. In standard treatment, 5-FU has typically been administered on a weekly or alternate weekly schedule. Therefore, both schedules were selected for this study in order to allow for an efficient characterization of each schedule’s ability to produce sustained drug exposures that may be associated with biologic effect, while addressing safety questions. Secondary objectives included safety and tolerability, PK, and evaluation of anti-tumor activity through assessment of disease control and tumor response. Patients were enrolled sequentially into dose-escalation cohorts using a modified 3+3 design. The study was conducted at three clinical centres in the United Kingdom: the Churchill Hospital, Oxford; The Beatson West of Scotland Cancer Centre, Glasgow; and the Patrick G. Johnston Centre for Cancer Research, Belfast. The study was performed in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice [11]. The protocol was approved by the South Central - Oxford C Research Ethics Committee [15/SC/0644] and all patients provided written informed consent before undergoing any study procedures. Patients Patients ≥18 years of age with a histologically‑confirmed solid tumor not amenable or refractory to standard therapies, or for which standard therapy did not exist, were eligible for the study. Other inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2, adequate organ function, measurable disease on radiological imaging (in accordance with Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), and/or evaluable disease [12]. Exclusion criteria included prior allergy or cardiac events attributed to 5-FU or capecitabine, active hepatitis B, C or HIV and symptomatic central nervous system metastases. Treatment NUC‑3373 was administered via central or peripheral venous access device as an infusion lasting 30 minutes (for doses ≤750 mg/m 2 ), 2 hours (for doses ≤1500 mg/m 2 ) or 4 hours (for doses >1500 mg/m 2 ). A starting dose of 125 mg/m 2 NUC-3373 was selected for the first 3 patients (Part 1) and was escalated sequentially in cohorts of 3 to 6 patients using a modified 3+3 design. Dose‑escalation stopped when the MTD was determined. The MTD was defined as the highest dose level for which fewer than 2 out of 6 (or <33%) patients experienced DLTs. Following recruitment to the third dose group in Part 2, the Trial Management Group (TMG) agreed that this schedule would be stopped, and recruitment would instead resume in Part 1, to determine the RP2D for the weekly schedule. This decision was partially based on the Part 1 safety profile, which indicated that weekly dosing was tolerable. Thus, the weekly schedule was investigated as a priority to maximize dose intensity and potential activity. Furthermore, the number of dose-escalation cohorts required in Part 1 was higher than anticipated and the planned sample size was reached before completion of Part 2. Dose intensity (DI) was calculated for each patient per cycle using actual DI/allocated DI, where allocated DI was [4 x dose assigned (mg/m 2 )] / 28 days for the weekly schedule and [2 x dose assigned (mg/m 2 )] / 28 days for the alternate weekly schedule, and the actual DI was [sum of all doses received in a cycle (mg/m 2 )] / [Duration of cycle in days including any delays before starting]. Assessment All patients who received at least one dose of NUC-3373 were included in the safety analysis population. Safety parameters were continually assessed and based on treatment-emergent adverse events (TEAEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [13], along with clinical laboratory data and physical examinations. Due to the association of 5-FU to cardiac toxicity, echocardiograms and electrocardiograms (ECG) were conducted at baseline, at the end of study participation and during the study if clinically indicated. Patients were defined as evaluable for DLT assessment if they had received at least 75% (Part 1) or 100% (Part 2) of the intended treatment with NUC-3373 during Cycle 1 or if they experienced a DLT. A DLT was defined as any of the following occurring during the first treatment cycle: Grade 3 or higher non‑haematological toxicity (excluding nausea/vomiting/diarrhoea or rash that responded to standard medical treatment), Grade 3 or higher infusion reaction, Grade 3 or higher nausea/vomiting/diarrhoea or rash that occurred despite standard medical treatment, Grade 4 neutropenia, febrile neutropenia (any grade), Grade 4 thrombocytopenia, any toxicity related to NUC‑3373 that was unresolved after a treatment delay of >14 days, or isolated/recurrent toxicity that was judged by the Investigators to be a DLT. Tumor response assessments were performed for the safety population. Computed tomography (CT) based tumor assessments were conducted according to RECIST 1.1 [12] at screening and every 8 weeks until progression. Responses from all available post-baseline scans were used for derivation of the best overall response (BOR) and disease control rate (DCR). A response of stable disease was only considered if the scan was taken at least 6 weeks after the baseline scan. The highest reduction of the sum of diameters of target lesions was selected and reported for each patient with available post-baseline scan. This was expressed as a percentage change from baseline. Median progression free survival was estimated in the safety population using the Kaplan-Meier method, event times were from date of cycle 1 day 1, a PFS event was all progressions or death if death occurred without progression. The restricted mean survival time (RMST) for progression-free survival is also reported. Plasma NUC‑3373 concentrations were measured using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods and standard PK parameters were calculated using a non-compartmental analysis approach with Certara Phoenix 8.3 WinNonlin software. PK parameters were generated from available data for a subset of study patients. Blood samples were collected at set timepoints on Cycle 1 Day 1 and Cycle 1 Day 15 with timepoints dependent on the NUC-3373 infusion duration. For those who received NUC-3373 over 30 minutes to 2 hours (doses <1500 mg/m 2 ), PK samples were collected pre-dose, at end of infusion, and at 15, 30 and 45 mins, and 1, 1.5, 2, 4, 6, 24 and 48 h after the end of infusion. For those who received NUC-3373 over 4 hours (doses ≥1500 mg/m 2 ), samples were collected pre-dose and at 45 mins and 2, 4, 4.5, 4.75, 5, 6, 7, 8, 24 and 48 h after the start of infusion. Statistical analysis Descriptive analyses were carried out using STATA 16.1 (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC). Median (range) and numbers (with percentages) were used to summarize continuous and categorical variables, respectively. Sample size calculations were based on a Fleming design [14]. No formal statistical analyses were planned or performed on safety, PK or efficacy data. With respect to primary objectives and endpoints, no specific hypotheses were tested statistically. The primary focus was on determining the MTD and RP2D, evaluating the safety and PK profiles, and identifying a range of biologically active doses in patients with advanced cancers. Data availability The data generated in this study are available upon request to researchers who provide a methodologically sound proposal to the corresponding author. To gain access, data requestors will need to sign a data access agreement. Results Patient characteristics Between 22 February 2016 and 13 October 2020, 100 patients were screened for the study and 62 eligible patients were enrolled. Of the 62 patients in the intention-to-treat (ITT) population, 59 received at least one dose of NUC-3373 and were included in the safety analysis population. A total of 43 patients were treated across 9 dosing cohorts in Part 1 (weekly) and 16 patients were treated across 3 dosing cohorts in Part 2 (alternate weekly), as shown in Figure 2 . Overall, 51 patients were evaluable for DLT assessment, including 37 patients in Part 1 and 14 patients in Part 2. At the time of database lock (06 August 2021), no patients remained on study, all having discontinued treatment. The most common reasons for treatment discontinuation were progressive disease (75%) and adverse events (12%). Patient baseline characteristics in the ITT population are presented in Table 1. Across both parts of the study, patients had a median age of 59.5 years (range 20 - 77) and all had a good performance status (48% ECOG PS 0 and 52% PS 1). The most common tumor types were cancers of the colon (31%), rectum (15%), oesophageal/gastroesophageal junction (10%), pancreas (7%) and stomach (5%), and the majority of patients had a histology of adenocarcinoma (74%). Patients had received a median of 3 prior lines of treatment (range 0‑11). The majority of patients (74%) had received prior therapy with fluoropyrimidines, with 52% of patients having received 5-FU, 52% capecitabine, and 15% tipiracil/trifluridine. Table 1 Patient baseline characteristics Characteristic Part 1 (n=46) Part 2 (n=16) Total (n=62) Median age, years [range] 59.5 [20, 77] 59.5 [20, 77] 59.5 [20, 77] Sex, n (%) Female 18 (39) 7 (44) 25 (40) Male 28 (61) 9 (56) 37 (60) Histological type, n (%) Adenocarcinoma 35 (76) 11 (69) 46 (74.2) Adenosquamous Carcinoma 0 1 (6) 1 (1.6) Alveolar Rhabdomyosarcoma 0 1 (6) 1 (1.6) Basal Cell Carcinoma 0 1 (6) 1 (1.6) Low Grade Endometrioid Adenocarcinoma 0 1 (6) 1 (1.6) Mesothelioma 1 (2) 0 1 (1.6) Metastatic Melanoma 1 (2) 0 1 (1.6) Sarcoma 1 (2) 0 1 (1.6) Spindle Cell Carcinoma 1 (2) 0 1 (1.6) Squamous Cell 4 (9) 0 4 (6.5) Undifferentiated 0 1 (6) 1 (1.6) Histology not specified 3 (7) 0 3 (4.8) Performance Status, n (%) 0 23 (50) 7 (44) 30 (48) 1 23 (50) 9 (56) 32 (52) Cancer Type, n (%) Colon 16 (35) 3 (19) 19 (31) Rectum 8 (17) 1 (6) 9 (15) Oesophageal/gastroesophageal junction 3 (7) 3 (19) 6 (10) Pancreas 2 (4) 2 (13) 4 (7) Cervix 1 (2) 1 (6) 2 (3) Other 16 (35) 6 (38) 22 (35) Prior therapies Prior systemic therapy, median [range] 3 [0, 6] 3 [1, 11] 3 [0, 11] Prior fluoropyrimidine therapy a , n (%) 37 (80) 9 (56) 46 (74) Prior 5-FU 27 (59) 5 (31) 32 (52) Prior capecitabine 26 (57) 6 (38) 32 (52) Prior tipiracil / trifluridine 7 (15) 2 (13) 9 (15) Median BSA, m 2 [range] 1.84 [1.4, 2.6] 1.88 [1.5, 2.4] 1.86 [1.4, 2.6] Abbreviations: BSA=body surface area. a Prior fluoropyrimidine therapy includes systemic 5-FU and/or capecitabine and/or tipiracil/trifluridine. Treatment exposure Patient exposure to NUC-3373 in Parts 1 and 2 is presented in Table 2. Across all cohorts, patients received a median of 2 cycles of treatment, with a median duration of exposure of 8 weeks, in both parts of the study. A higher proportion of patients had dose modifications (70% vs 50%) or dose reductions (19% vs 6%) in Part 1 than in Part 2. Table 2 NUC-3373 treatment exposure Characteristic Part 1 Cohorts (Q1W) 125 mg/m 2 (n=4) 250 mg/m 2 (n=7) 500 mg/m 2 (n=8) 750 mg/m 2 (n=4) 1125 mg/m 2 (n=3) 1500 mg/m 2 (n=3) 1875 mg/m 2 (n=6) 2500 mg/m 2 (n=7) 3250 mg/m 2 (n=4) Started treatment, n 3 6 8 4 3 3 6 6 4 Did not start treatment, n 1 1 0 0 0 0 0 1 0 Median duration of exposure, weeks [range] 7.3 [7.3, 8.1] 4.8 [2, 7.7] 8 [2, 16] 7.5 [6.9, 11] 18.9 [17, 48] 15 [8.1, 41] 8.7 [4.1, 16.3] 8.1 [4.9, 16] 9.9 [2.3, 17.9] Median completed cycles, n [range] 2 [1.8, 2] 1.1 [0.3, 2] 1.9 [0.5, 4] 1.9 [1.8, 2.5] 4 [3.3, 11.8] 3.5 [2, 9.3] 2.1 [1, 4] 2 [1.3, 4] 2 [0.5, 4.3] Patients completing 6 cycles, n (%) 0 0 0 0 1 (33.3) 1 (33.3) 0 0 0 Patients with a dose modification a , n (%) 1 (33.3) 5 (83.3) 5 (62.5) 3 (75) 2 (66.7) 2 (66.7) 3 (50) 5 (83.3) 4 (100) Patients with a dose reduction, n (%) 0 0 1 (12.5) 2 (50) 1 (33.3) 0 1 (16.7) 0 3 (75) Characteristic Part 2 Cohorts (Q2W) 1500 mg/m 2 (n=4) 1875 mg/m 2 (n=6) 2500 mg/m 2 (n=6) Started treatment, n 4 6 6 Did not start treatment, n 0 0 0 Median duration of exposure, weeks [range] 12.2 [6.9, 44.6] 7.9 [6.3, 16.9] 6.9 [3, 8.9] Median completed cycles, n [range] 3 [1.5, 9.5] 2 [1.5, 4] 1.75 [0.5, 2] Patients completing 6 cycles, n (%) 1 (25) 0 0 Patients with a dose modification a , n (%) 3 (75) 2 (33.3) 3 (50) Patients with a dose reduction, n (%) 1 (25) 0 0 Abbreviations: Q1W=weekly; Q2W=alternate weekly. Percentages are based on the number of patients in the safety population (started treatment). a Dose modifications include missed, reduced or delayed doses. Safety Patients were sequentially recruited into the study as shown in Figure 2. Of the 59 patients in the safety population, 51 (86%) were evaluable for DLT assessment, including 37/43 patients (86%) in Part 1 and 14/16 patients (88%) in Part 2. In the Part 1 weekly dosing cohorts, 4 patients (9%) had DLTs: one patient each in the 500 mg/m 2 and 1875 mg/m 2 cohorts had DLTs of raised Grade 3 transaminases; 1 patient in the 3250 mg/m 2 cohort had a DLT of Grade 2 headache; and 1 patient in the 3250 mg/m 2 cohort had a DLT of Grade 3 hypotension (transient). Based on this, the MTD and RP2D was defined as 2500 mg/m 2 NUC‑3373 given weekly. The MTD was not reached in Part 2 as recruitment to this schedule was stopped after the third dose group due to sample size restrictions and prioritization of the weekly schedule to maximize dose intensity and potential activity. No DLTs were observed in Part 2. In Part 1, all 43 patients in the safety analysis population experienced TEAEs. The most common Grade 1‑2 TEAEs observed across all dose cohorts were fatigue (58%), diarrhoea (42%), nausea (42%), infusion-related reaction (35%), constipation (33%), and abdominal pain (26%). The most common Grade 1‑2 TEAEs that were considered related to NUC-3373 were fatigue (54%), nausea (37%), infusion-related reactions (35%), and diarrhoea (33%) (Table 3). The most common Grade 3 TEAEs were fatigue (9%), intravascular device-related infection (5%), ALT increased (5%), blood alkaline phosphatase increased (5%), and transaminases increased (5%). The most common Grade 3 TEAEs that were considered related to NUC-3373 were increased ALT (5%) and transaminases (5%). No Grade 4 TEAEs were reported. A total of 15 patients (35%) had serious adverse events (SAEs), 9 (21%) of whom had Grade 3 SAEs and one (2%) of whom had a Grade 5 AE (unrelated to NUC-3373) of pulmonary haemorrhage. Five patients (12%) had treatment-related SAEs, 2 patients with chest pain attributed to coronary vasospasm, 1 with pyrexia, 1 with drug hypersensitivity, and 1 with posterior reversible encephalopathy syndrome (PRES). In Part 2, all 16 patients in the safety analysis population experienced TEAEs. The most common Grade 1‑2 TEAEs observed across all dose cohorts were fatigue (56%), diarrhoea (44%), nausea (44%), vomiting (38%), anaemia (38%), and infusion-related reactions (38%). The most common Grade 1‑2 TEAEs that were considered related to NUC-3373 were fatigue (44%), nausea (38%), infusion-related reactions (38%), and diarrhoea (31%) (Table 3). Recurring infusion related reactions were mitigated with prophylactic treatment with antihistamine and steroid treatment prior to subsequent dosing. The most common Grade 3-4 TEAE reported was anaemia (13%). All other Grade 3-4 TEAEs were reported in only 1 patient (6%) each. Two patients had Grade 3 TEAEs that were considered related to NUC-3373, 1 patient with herpes zoster and 1 patient with increased hepatic enzymes and aspartate aminotransferase (AST) increased. No Grade 4 TEAEs were considered to be related to NUC-3373. Of note, one patient had an infusion reaction to study drug preventing further treatment. The reaction was graded as G2 but the treatment was discontinued as per patient’s preference. A total of 7 patients (44%) had SAEs, 5 (31%) of whom had Grade 3 SAEs and one (6%) of whom had a Grade 4 SAE of hypercalcemia. Two patients had treatment-related SAEs, one with herpes zoster infection and another with increased hepatic enzymes. Table 3 Treatment-related adverse events SOC PT Part 1 (n=43) Part 2 (n=16) Grade 1-2 n (%) Grade 3-4 n (%) Grade 1-2 n (%) Grade 3-4 n (%) Blood and lymphatic system disorders Anaemia 6 (13.9) 0 3 (18.8) 0 Platelet count decreased 3 (6.9) 0 0 0 Cardiac disorders Palpitations 0 0 1 (6.3) 0 Tachycardia 0 0 1 (6.3) 0 Gastrointestinal disorders Nausea 16 (37.2) 0 6 (37.5) 0 Diarrhoea 14 (32.6) 0 5 (31.3) 0 Vomiting 6 (13.9) 0 4 (25.0) 0 Constipation 4 (9.3) 0 3 (18.8) 0 Abdominal pain 2 (4.7) 0 1 (6.3) 0 Dyspepsia 0 0 1 (6.3) 0 Flatulence 0 0 1 (6.3) 0 General disorders and administration site conditions Fatigue 23 (53.5) 1 (2.3) 7 (43.8) 0 Pyrexia 4 (9.3) 0 0 0 Mucositis 3 (6.9) 0 0 0 Chest pain 0 1 (2.3) 1 (6.3) 0 Gait disturbance 0 0 1 (6.3) 0 Infections Herpes zoster 0 0 0 1 (6.3) Injury, poisoning and procedural complications Infusion-related reaction 15 (34.9) 0 6 (37.5) 0 Investigations ALT increased 4 (9.3) 2 (4.7) 2 (12.5) 0 AST increased 4 (9.3) 1 (2.3) 1 (6.3) 1 (6.3) ALT and AST increased 4 (9.3) 2 (4.7) 0 0 Blood ALP increased 2 (4.7) 0 0 0 Blood bilirubin increased 2 (4.7) 0 0 0 GGT increased 0 1 (2.3) 0 0 Hepatic enzyme increased 0 0 0 1 (6.3) Metabolism and nutrition disorders Hyperglycaemia 3 (6.9) 0 0 0 Decreased appetite 2 (4.7) 0 4 (25.0) 0 Hypophosphatemia 2 (4.7) 0 0 0 Musculoskeletal and connective tissue disorders Myalgia 2 (4.7) 0 0 0 Muscle spasms 0 0 1 (6.3) 0 Nervous system disorders Dysgeusia 7 (16.3) 0 0 0 Headache 4 (9.3) 0 2 (12.5) 0 Neuropathy peripheral 4 (9.3) 0 0 0 Lethargy 3 (6.9) 0 1 (6.3) 0 Posterior reversible encephalopathy syndrome 0 1 (2.3) 0 0 Respiratory, thoracic and mediastinal disorders Dyspnoea 3 (6.9) 0 1 (6.3) 0 Throat irritation 2 (4.7) 0 0 0 Dyspnoea exertional 0 0 1 (6.3) 0 Dysphonia 0 0 1 (6.3) 0 Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome 2 (4.7) 0 0 0 Rash 0 0 1 (6.3) 0 Vascular disorders Flushing 5 (11.6) 0 0 0 Hypotension 0 1 (2.3) 0 0 Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; n=number of patients; PT=preferred term; SOC=system organ class. Percentages are based on the total number of patients in the respective safety population. Pharmacokinetics Pharmacokinetic parameters were calculated from individual plasma NUC-3373 concentrations following IV administration of 500-3250 mg/m 2 NUC-3373 on a weekly or alternate weekly schedule. Thirty-one patients had evaluable PK samples: 500 mg/m 2 weekly (n=5), 1125 mg/m 2 weekly (n=3), 1875 mg/m 2 weekly (n=6), 1875 mg/m 2 alternate weekly (n=3), 2500 mg/m 2 weekly (n=6), 2500 mg/m 2 alternate weekly (n=5), and 3250 mg/m 2 weekly (n=3). A dose-proportional increase in NUC-3373 AUC was observed across the concentration range assessed (Table 4). Table 4 NUC-3373 plasma PK parameters on Day 1 and Day 15 Dose / infusion duration/ Regimen Parameter C max (mg/mL) AUC last (h*mg/L) AUC (0-∞) (h*mg/L) T 1/2 (h) AUC last_D (h*mg/L/mg) AUC (0-∞)_D (h*mg/L/mg) Day 1 500 mg/m 2 30 mins Q1W N 5 5 5 5 5 5 Geometric mean 32.54 56.68 70.83 12.21 0.057 0.072 Geo lower 1SD 22.47 33.08 44.05 4.65 0.033 0.044 Geo upper 1SD 47.14 97.12 113.89 32.06 0.100 0.117 1125 mg/m 2 2 hours Q1W N 3 3 3 3 3 3 Geometric mean 38.66 72.31 77.47 12.51 0.038 0.041 Geo lower 1SD 29.65 47.40 51.31 9.61 0.026 0.028 Geo upper 1SD 50.39 110.31 116.97 16.27 0.056 0.061 1875 mg/m 2 4 hours Q1W N 6 6 6 6 6 6 Geometric mean 25.50 105.59 111.25 8.74 0.032 0.033 Geo lower 1SD 18.36 60.27 60.67 3.43 0.019 0.019 Geo upper 1SD 35.43 184.97 204.01 22.28 0.052 0.058 1875 mg/m 2 4 hours Q2W N 3 3 3 3 3 3 Geometric mean 29.05 123.84 125.49 3.39 0.038 0.038 Geo lower 1SD 26.01 96.77 97.22 1.13 0.033 0.033 Geo upper 1SD 32.44 158.47 161.98 10.19 0.044 0.045 2500 mg/m 2 4 hours Q1W N 6 6 6 6 6 6 Geometric mean 38.11 172.47 174.21 3.77 0.038 0.038 Geo lower 1SD 28.80 116.50 116.72 1.74 0.024 0.024 Geo upper 1SD 50.44 255.33 260.01 8.17 0.059 0.060 2500 mg/m 2 4 hours Q2W N 5 5 5 5 4 4 Geometric mean 43.48 201.76 204.93 5.91 0.046 0.047 Geo lower 1SD 30.64 124.32 124.14 4.46 0.027 0.026 Geo upper 1SD 61.71 327.44 338.27 7.85 0.081 0.083 3250 mg/m 2 4 hours Q1W N 3 3 3 3 3 3 Geometric mean 35.50 150.98 151.75 3.71 0.024 0.024 Geo lower 1SD 22.46 90.69 91.38 3.05 0.014 0.014 Geo upper 1SD 56.11 251.36 251.99 4.53 0.041 0.041 Day 15 1875 mg/m 2 4 hours Q1W N 6 6 6 6 6 6 Geometric mean 29.68 126.38 130.22 5.59 0.040 0.041 Geo lower 1SD 21.13 88.19 86.37 3.64 0.025 0.025 Geo upper 1SD 41.68 181.11 196.34 8.59 0.063 0.068 1875 mg/m 2 4 hours Q2W N 3 3 3 3 3 3 Geometric mean 27.05 116.39 117.87 2.82 0.036 0.036 Geo lower 1SD 22.09 73.36 73.74 0.97 0.024 0.025 Geo upper 1SD 33.13 184.66 188.41 8.22 0.052 0.053 2500 mg/m 2 4 hours Q1W N 6 6 6 6 6 6 Geometric mean 39.65 170.48 176.93 4.47 0.037 0.039 Geo lower 1SD 28.58 112.15 113.84 1.93 0.023 0.024 Geo upper 1SD 55.02 259.17 275.01 10.32 0.060 0.063 2500 mg/m 2 4 hours Q2W N 3 3 3 3 3 3 Geometric mean 37.36 177.94 180.17 4.95 0.040 0.040 Geo lower 1SD 23.39 91.64 91.69 4.54 0.021 0.021 Geo upper 1SD 59.64 345.51 354.00 5.40 0.076 0.078 3250 mg/m 2 4 hours Q2W N 2 2 1 1 2 1 Geometric mean 36.92 136.67 164.37 4.59 0.021 0.026 Geo lower 1SD 32.91 105.64 - - 0.016 - Geo upper 1SD 41.42 176.83 - - 0.028 - Abbreviations: AUC (0-∞) =area under the plasma concentration-time curve from time 0 to infinity; AUC (0-∞)_D =dose normalized AUC (0-∞) ; AUC last =area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration; AUC last_D = dose normalized AUC last ; C max =maximum plasma concentration; Q1W=weekly; Q2W=alternate weekly; T 1/2 =half-life. Geo lower and Geo upper 1SD – 68% range of the geometric mean. The last observed concentrations were between 24 and 48 hours for most patients. The estimated half-life of NUC-3373 showed some inherent variability and ranged from 3-10 hours with a geometric mean of 5.61 hours, which is considerably longer than the reported half-life of 5-FU (8-14 minutes). Limited samples were available at the later timepoints, which impacted the typical terminal elimination half-life; however, a longer half-life was observed in patients who had a later PK sample collection timepoint. When comparing dose normalized exposure, all treatment regimens were comparable regardless of whether they were weekly or alternate weekly, with a difference of less than 15% in all comparisons based on the geometric mean ratios. Comparisons of the Day 1 and Day 15 geometric mean ratios were also similar regardless of whether they were weekly or alternate weekly and did not exceed a 15% difference. Efficacy Radiological response to treatment was determined according to RECIST v1.1 using CT scans conducted every 8 weeks and compared to baseline scans. Of the 43 patients in the Part 1 safety population, 16 had a BOR of stable disease resulting in a DCR of 37% and 18 (42%) had progressive disease (Table 5). When considering only the 34 patients who had at least one post-baseline scan, a DCR of 47% was observed. Of the 16 patients in the Part 2 safety population, 4 had a BOR of stable disease resulting in a DCR of 25% and 10 (63%) had progressive disease (Table 5). When considering only the 14 patients who had at least one post-baseline scan, a DCR of 29% was observed. Across both parts of the study, the overall DCR was 34% in the safety population and 42% in the population who had at least one post-baseline scan. No complete or partial responses were observed in this population of patients who had exhausted all other treatment options. Table 5 Anti-tumor activity of NUC-3373 Part 1 Cohorts 125 mg/m 2 (n=3) 250 mg/m 2 (n=6) 500 mg/m 2 (n=8) 750 mg/m 2 (n=4) 1125 mg/m 2 (n=3) 1500 mg/m 2 (n=3) 1875 mg/m 2 (n=6) 2500 mg/m 2 (n=6) 3250 mg/m 2 (n=4) Total (n=43) Best overall response, n (%) Complete response 0 0 0 0 0 0 0 0 0 0 Partial response 0 0 0 0 0 0 0 0 0 0 Stable disease 0 0 3 (37.5) 1 (25.0) 3 (100) 2 (66.7) 2 (33.3) 2 (33.3) 3 (75) 16 (37.2) Progressive disease 3 (100) 3 (50) 2 (25) 2 (50) 0 1 (33.3) 4 (66.7) 3 (50) 0 18 (41.9) Response rate a 0 0 0 0 0 0 0 0 0 0 Disease control rate b 0 0 3 (37.5) 1 (25.0) 3 (100) 2 (66.7) 2 (33.3) 2 (33.3) 3 (75) 16 (37.2) Part 2 Cohorts 1500 mg/m 2 (n=4) 1875 mg/m 2 (n=6) 2500 mg/m 2 (n=6) Total (n=16) Best overall response, n (%) Complete response 0 0 0 0 Partial response 0 0 0 0 Stable disease 3 (75) 1 (16.7) 0 4 (25) Progressive disease 1 (25) 5 (83.3) 4 (66.7) 10 (62.5) Response rate a 0 0 0 0 Disease control rate b 3 (75) 1 (16.7) 0 4 (25) a Response rate = confirmed CR + confirmed PR b Disease control rate = confirmed CR + confirmed PR + confirmed SD Abbreviations: CR=complete response; PR=partial response; SD=stable disease. The overall median duration of exposure was 8 weeks across both parts of the study. In Part 1, 10 patients remained on treatment for ≥3 months, with 2 of these patients completing ≥9 months of treatment (Figure 3). One of the patients completing ≥9 months had colorectal cancer and had received 6 prior lines of therapy, including 5 prior lines of fluoropyrimidine-based therapy (progressed within 2 months on third-line treatment with capecitabine plus oxaliplatin, progressed within 8 months on fourth-line treatment with FOLFIRI, and progressed within 3 months on fifth-line treatment with tipiracil/trifluridine). This patient received 1500 mg/m 2 NUC-3373 weekly and achieved stable disease for 9 months before choosing to suspend treatment to go on an extended vacation. The other patient completing ≥9 months had cholangiocarcinoma and progressed within 6 months of first-line therapy (gemcitabine in combination with cisplatin). This patient received 1125 mg/m 2 NUC-3373 weekly and achieved stable disease for 11 months. In Part 2, 3 patients remained on treatment for ≥3 months, with 1 of these patients completing ≥9 months (Figure 3). This patient had metastatic basal cell carcinoma, had received 2 prior lines of therapy, and had progressed within 3 months of the last line. This patient received 1500 mg/m2 NUC-3373 every two weeks and achieved stable disease for 10 months. For part 1, estimated median progression free survival was 7.1 weeks (95% CI 7.0 to 14.7 weeks). The restricted mean progression-free survival time was 12.9 weeks (95% CI 8.8 to 16.9 weeks). For part 2, estimated median progression free survival was 6.9 weeks (95% CI 6.0 to 7.1 weeks). The restricted mean progression-free survival time was 10.8 weeks (95% CI 5.3 to 16.4 weeks). Visualisation of patients’ responses over time is shown in Figure 4 . It is worth noting that the majority of the patients in this study received lower doses than the established RP2D and this phase I study was not designed to examine efficacy per se. Discussion NUC-3373 is a phosphoramidate modification of FUDR specifically designed to overcome the limitations and pharmacologic challenges associated with 5-FU and other fluoropyrimidines. In this first-in-human clinical study, single-agent NUC-3373 demonstrated a favorable safety and PK profile, compared to historical 5-FU data, in patients with advanced solid tumors. NUC-3373 also showed encouraging signs of anti-tumor activity in heavily pre-treated patients, including those who had progressed on multiple lines of prior fluoropyrimidine-based combination therapies. In this study, NUC-3373 was well-tolerated at doses up to the MTD of 2500 mg/m 2 weekly. The most common treatment-related TEAEs were fatigue, nausea, infusion-related reactions and diarrhoea; most of which are also commonly observed with 5-FU. These were mitigated with supportive medications; prophylactic administration of steroid and antihistamine treatment was introduced prior to subsequent dosing for patients with infusion related reactions. Interestingly, other typical 5-FU-related adverse events (such as neutropenia, mucositis and hand-foot syndrome) were either not observed in those receiving NUC-3373 or were observed at a lower incidence and reduced severity when compared with historical data for 5-FU or capecitabine [15, 16]. These findings are consistent with nonclinical data indicating that NUC-3373 generates lower levels of toxic by-products [10], which are implicated in hand-foot syndrome as well as 5-FU-induced hematological and gastrointestinal toxicities through misincorporation into the RNA of normal cells [6]. Across both parts of the study, a total of 7 patients (12%) experienced treatment-related SAEs. The SAEs observed were consistent with the overall TEAE profile and with the type of adverse reactions typically associated with 5-FU, including the rare SAE of PRES which was experienced by one patient in this study and was considered to be possibly related to NUC-3373. In addition to reducing the generation of toxic metabolites, NUC-3373’s resistance to DPD‑mediated breakdown may contribute to its PK; the estimated plasma half-life of NUC‑3373 was 3-10 hours compared to the reported 5-FU half-life of 8-14 minutes. The calculated half-life of NUC-3373 in this study was shorter than previously reported [17], and this is very likely due to limited sampling at later timepoints which impacts the determination of terminal elimination half-life. Nonetheless, the longer half-life compared to 5‑FU is anticipated to prolong the exposure of tumor cells to FUDR-MP, potentially resulting in enhanced activity. It also allows a much shorter administration schedule (1‑4 hours, depending on the selected dose) compared to the prolonged infusion times (up to 48 hours) required for 5-FU. Overall, NUC-3373 PK showed no tendency of non-linearity and the dose-related PK parameters increased with increasing doses. The PK of NUC-3373 were also comparable on different days of administration and were similar regardless of whether the administration schedule was weekly or alternate weekly. NUC-3373’s lack of dependency on DPD for its metabolism may favour its use in the estimated 5% population who have DPYD gene mutations and are at heightened risk of toxicity from standard fluoropyrimidines. DPD testing was not conducted on participants in the NuTide:301 study, and it was not routinely conducted as standard of care at the time of the study. However, as 74% study patients had received, and tolerated, multiple prior fluoropyrimidine-containing regimens, it is unlikely that any of the patients were DPD-deficient. Patients who received NUC-3373 at the MTD (2500 mg/m 2 ) or below were able to maintain treatment intensity across both the weekly (Part 1) and alternate weekly (Part 2) dosing schedules, with patients in Part 1 generally achieving higher dosing intensities for longer durations. This was associated with a higher median DCR in Part 1 than in Part 2 for both the safety analysis population (37% vs 25%) and a larger number of patients who remained on study beyond one post-baseline scan (47% vs 29%). Notably, the highest DCRs were observed in the 1125 mg/m 2 (100%), 1500 mg/m 2 (67%), and 3250 mg/m 2 (75%) weekly cohorts and the 1500 mg/m 2 alternate weekly cohort (75%), in which patients remained on treatment for a median of 19, 15, 10, and 12 weeks, respectively, compared to the overall median of 8 weeks. Observations of prolonged disease control across both parts of the study are encouraging in this population of patients who received NUC-3373 as a monotherapy after exhausting all current standards of care, including 5-FU and other fluoropyrimidine-based therapies. Notably, we observed tumour regression/stability in patients who had previously progressed to 5-FU treatment ( Figure 4 ), supporting the hypothesis that NUC-3373 can circumvent 5-FU resistance mechanisms. The main limitations of this study were the small sample size and the heterogenous nature of the patient population, who had a wide variety of tumor types and had received a range of prior treatment regimens. In addition, patients with the cancers represented in this study are typically treated with 5-FU combination chemotherapy, whereas NUC-3373 was given as monotherapy. Finally, this was a single-arm study and while comparisons with historical 5-FU data may be informative, future studies should include a direct randomized comparison of NUC‑3373 versus 5-FU. In conclusion, NUC-3373 has demonstrated favorable safety, tolerability and PK as well as promising clinical activity in patients with advanced solid tumors who had exhausted standard treatment options. It is anticipated that NUC-3373 will overcome the key limitations associated with 5‑FU, thereby offering a more effective and tolerable treatment option with a more convenient administration schedule. NUC-3373 is currently being evaluated in combination with other agents in ongoing clinical studies [NCT05678257 and NCT05714553]. Declarations Financial support: The study was sponsored by the University of Oxford and funded by NuCana plc. Corresponding Author: Dr Sarah Patricia Blagden, Professor of Experimental Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, Oxford, OX3 7DQ, UK. Telephone: +44 (0)1865 617409, Email: [email protected] Prior Presentation: This study has been presented in partat AACR (2016) and ESMO (2017, 2018, 2021) annual meetings. Conflicts of Interest: DJH receives salary support and research funding from NuCana plc. FA & CQ are currently employed by AstraZeneca but were not at the time of the study. The other authors have no conflicts of interest to disclose. Disclosure: Independent data monitoring was conducted during the study and data gathered was independently reviewed. All authors had full access to the data and signed confidentiality agreements regarding the data. All authors have reviewed and provided feedback on the manuscript, the first draft of which was written by the corresponding author. The corresponding author had final responsibility for the decision to submit for publication. All authors vouch for the completeness and accuracy of the data presented and confirm that the study was conducted and reported with fidelity to the protocol. Statement of Translational Relevance: The anti-cancer activity of 5-FU, and other fluoropyrimidines, is largely attributed to the active metabolite, FUDR-MP, which inhibits thymidylate synthase, a critical enzyme in nucleotide synthesis and cell survival. However, 5-FU is often inefficiently converted to FUDR-MP. NUC‑3373, a phosphoramidate modification of 5-FU, is designed to bypass this initial monophosphorylation step and deliver FUDR-MP into cells; it is subsequently metabolized independent of dihydropyrimidine dehydrogenase (DPD). This Phase I study demonstrated that NUC-3373 given as monotherapy had a longer half-life than what has been observed with 5-FU, was well-tolerated and showed evidence of anti-cancer activity in patients with advanced cancers, the majority of whom had been extensively pre-treated with fluoropyrimidines. These properties indicate that NUC-3373 may prove to be an alternative to 5-FU, that is quicker to deliver with fewer side effects, especially in patients with DPD deficiency. Studies of NUC-3373 in combination with other chemotherapeutics and targeted therapies are ongoing. Acknowledgments The authors would like to thank the patients, their families and all healthcare professionals involved in this study. The study was designed by the lead investigators and the sponsor (University of Oxford). The sponsor collected and analysed the data in conjunction with the authors. The centres that conducted this study are National Institute for Health and Care Research (NIHR) Biomedical Research Centres that also receive institutional funding as Cancer Research UK (CRUK) and Experimental Cancer Medicine Centres (ECMC). The study was funded and the investigational drug NUC-3373 was supplied by NuCana plc. The study was reviewed and given a favourable opinion by the South Central Oxford C Research Ethics Committee and authorised by the Medicines and Healthcare products Regulatory Agency. This study has been conducted as part of the portfolio of trials in the registered UKCRC Oxford Clinical Trials Research Unit (OCTRU) at the University of Oxford. It has followed their Standard Operating Procedures ensuring compliance with the principles of Good Clinical Practice and the Declaration of Helsinki and any applicable regulatory requirements. We are grateful to Danielle McLean for support in writing this manuscript and the late Professor Chris McGuigan for the initial development of NUC-3373. References Grem JL. 5-fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs 2000; 18:299-313. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003; 3:330–338. Diasio RB & Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 1989; 16:215–237. Parker WB. Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chem Rev 2009; 109:2880-2893. Longley DB & Johnston PG. Molecular mechanisms of drug resistance. J Pathol 2005 ; 205:275-292. Brutcher E, Christensen D, Smith MH, et al . 5‑fluorouracil and capecitabine: Assessment and treatment of uncommon early-onset severe toxicities associated with administration. Clin J Oncol Nursing 2018; 22:627‑634. Vande Voorde J, Liekens S, McGuigan C, et al . The cytostatic activity of NUC-3073, a phosphoramidate prodrug of 5 fluoro-2'-deoxyuridine, is independent of activation by thymidine kinase and insensitive to degradation by phosphorolytic enzymes. Biochem Pharmacol 2011; 82:441–452. Blagden SP, Slusarczyk M, Serpi M, et al . First in human Phase I study of NUC-3373, a nucleotide analogue designed to overcome fluoropyrimidine drug resistance mechanisms. AACR Annual Meeting 2016. Cancer Research; 76 (suppl 14). McGuigan C, Murziani P, Slusarczyk M, et al. Phosphoramidate ProTides of the anticancer agent FUDR successfully deliver the preformed bioactive monophosphate in cells and confer advantage over the parent nucleoside. J Med Chem 2011; 27:7247–7258. Bre J, Dickson AL, Read OJ, et al . NUC-3373 has a more targeted DNA mode of action than 5-FU. AACR Annual Meeting 2022. Cancer Research ; 82 (suppl 12). Vijayananthan A & Nawani O. The importance of Good Clinical Practice guidelines and its role in clinical trials. Biomed Imaging Interv J 2008; 3:e5. Eisenhauer EA, Therasse P, Bogaerts J, et al . New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03, 2010. Available from: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982; 38:143-151. Campostar Prescribing Information, 2014. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020571s048lbl.pdf Xeloda Prescribing Information, 2015. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020896s037lbl.pdf Coveler AL, Kazmi F, Ciombor KK, et al . NuTide:302: A Phase Ib study of NUC-3373 in combination with standard therapies in advanced/metastatic colorectal cancer. ASCO GI annual meeting 2021. J Clin Oncol 39 (suppl 3). Cite Share Download PDF Status: Published Journal Publication published 02 Apr, 2024 Read the published version in Journal of Experimental & Clinical Cancer Research → Version 1 posted Editorial decision: Major revision 27 Dec, 2023 Reviewers agreed at journal 11 Dec, 2023 Reviewers invited by journal 13 Nov, 2023 Editor assigned by journal 13 Nov, 2023 First submitted to journal 09 Nov, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3593277","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":249064503,"identity":"051b1c51-aff0-42f6-9a68-9e99bbe1a602","order_by":0,"name":"Pavlina Spiliopoulou","email":"data:image/png;base64,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","orcid":"","institution":"University of Glasgow Institute of Cancer Sciences","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Pavlina","middleName":"","lastName":"Spiliopoulou","suffix":""},{"id":249064504,"identity":"e5bd2509-05f2-452a-8233-f88331d15c99","order_by":1,"name":"Farasat Kazmi","email":"","orcid":"","institution":"University of Oxford Medical Sciences Division","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Farasat","middleName":"","lastName":"Kazmi","suffix":""},{"id":249064505,"identity":"5879d871-bf98-476d-99ca-93817f3698b0","order_by":2,"name":"Francesca Aroldi","email":"","orcid":"","institution":"University of Oxford Medical Sciences Division","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Aroldi","suffix":""},{"id":249064506,"identity":"56b3f833-7083-440d-9852-8ec22f76014e","order_by":3,"name":"Thomas Holmes","email":"","orcid":"","institution":"University of Oxford Medical Sciences Division","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Holmes","suffix":""},{"id":249064507,"identity":"9469c6e1-2321-4057-8015-0dcdcb425b33","order_by":4,"name":"David Thompson","email":"","orcid":"","institution":"University of Oxford Medical Sciences Division","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Thompson","suffix":""},{"id":249064508,"identity":"66fa6211-5fb8-4098-8840-393b948186c3","order_by":5,"name":"Lucy Griffiths","email":"","orcid":"","institution":"University of Oxford Medical Sciences Division","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lucy","middleName":"","lastName":"Griffiths","suffix":""},{"id":249064509,"identity":"b92f7f56-9a5b-4ab4-b668-762659bc98e4","order_by":6,"name":"Cathy Qi","email":"","orcid":"","institution":"University of Oxford Department of Statistics","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cathy","middleName":"","lastName":"Qi","suffix":""},{"id":249064510,"identity":"0a7a9e3a-7387-41d0-b28b-8bf19b030d1e","order_by":7,"name":"Matthew Parkes","email":"","orcid":"","institution":"University of Oxford Department of Statistics","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Matthew","middleName":"","lastName":"Parkes","suffix":""},{"id":249064511,"identity":"2f3a3903-3a82-41ed-a118-7ce5c1ce079a","order_by":8,"name":"Simon Lord","email":"","orcid":"","institution":"University of Oxford Medical Sciences Division","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Simon","middleName":"","lastName":"Lord","suffix":""},{"id":249064512,"identity":"d5068e6d-5380-48ca-8909-881fa5bba12d","order_by":9,"name":"Gareth Veal","email":"","orcid":"","institution":"Newcastle Cancer Centre: Newcastle University Centre for Cancer","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gareth","middleName":"","lastName":"Veal","suffix":""},{"id":249064513,"identity":"fd65948d-d719-4233-ba84-127fb7248c73","order_by":10,"name":"David Harrison","email":"","orcid":"","institution":"University of St Andrews Bute Medical School: University of St Andrews School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Harrison","suffix":""},{"id":249064514,"identity":"9c03f02a-0a0d-4aad-9fb4-06b2b5a4486e","order_by":11,"name":"Vicky Coyle","email":"","orcid":"","institution":"Queen's University Belfast","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vicky","middleName":"","lastName":"Coyle","suffix":""},{"id":249064515,"identity":"b44245ef-a491-4a9e-9127-fb783b8b1190","order_by":12,"name":"Jill Graham","email":"","orcid":"","institution":"Beatson West of Scotland Cancer Centre","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jill","middleName":"","lastName":"Graham","suffix":""},{"id":249064516,"identity":"f315c397-5eb6-4afc-9811-e54a0507ec54","order_by":13,"name":"Jeffry Thomas Evans","email":"","orcid":"","institution":"University of Glasgow Institute of Cancer Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jeffry","middleName":"Thomas","lastName":"Evans","suffix":""},{"id":249064517,"identity":"805ec34d-485f-4473-b202-626457e587ca","order_by":14,"name":"Sarah Blagden","email":"","orcid":"","institution":"University of Oxford Medical Sciences Division","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Blagden","suffix":""}],"badges":[],"createdAt":"2023-11-10 22:18:51","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3593277/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3593277/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13046-024-03010-1","type":"published","date":"2024-04-02T15:01:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":46514715,"identity":"d85be0b3-61e0-445e-aa11-8d88056b1a8d","added_by":"auto","created_at":"2023-11-15 21:31:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":284137,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNUC-3373 and 5-fluorouracil mechanisms of action\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: 5-FU= 5-fluorouracil; DPD= dihydropyrimidine dehydrogenase; DHFU= dihydrofluorouracil; FBAL= alpha-fluoro-beta-alanine; FUDR= fluorodeoxyuridine; FUDR-DP= fluorodeoxyuridine diphosphate; FUDR-TP= fluorodeoxyuridine triphosphate; OPRT= orotate phosphoribosyl transferase; RR= ribonucleotide reductase; TK= thymidine kinase; TP= thymidine phosphorylase; FUMP= fluorouridine monophosphate; FUDP= fluorouridine diphosphate; FUTP= fluorouridine triphosphate.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3593277/v1/f27910a42301b20e6da7c6cd.png"},{"id":46514713,"identity":"f57fabfe-3c05-40e2-b167-f8e840c2c811","added_by":"auto","created_at":"2023-11-15 21:31:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":121160,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient disposition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e \u0026nbsp;A total of 46 patients were enrolled in Part 1; however, 3 patients (1 patient each in the 125, 250 and 2500 mg/m\u003csup\u003e2\u003c/sup\u003e cohorts) did not receive any study treatment with NUC-3373.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Six patients in Part 1 were not evaluable for DLT assessment: 5 patients withdrew in Cycle 1 (3 patients in the 250 mg/m\u003csup\u003e2\u003c/sup\u003e cohort and 2 patients in the 500 mg/m\u003csup\u003e2\u003c/sup\u003e cohort) and 1 patient in the 750 mg/m\u003csup\u003e2\u003c/sup\u003e cohort received less than 3 doses of NUC-3373 (the required 75% of Cycle 1 doses).\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003e Two patients in Part 2 were not evaluable for DLT assessment: 1 patient withdrew in Cycle 1 and 1 patient received less than 2 doses of NUC-3373, both in the 2500 mg/m\u003csup\u003e2\u003c/sup\u003e cohort.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ed\u003c/sup\u003e One patient discontinued at the discretion of the Investigator due to declining performance status (ECOG 3).\u003c/p\u003e\n\u003cp\u003eAbbreviations: AE=adverse event; DLT=dose-limiting toxicity; ITT=intention-to-treat; PD=progressive disease; Q1W=weekly; Q2W=alternate weekly.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3593277/v1/ae66198194ba51d8f1431b56.png"},{"id":46514712,"identity":"f9591ce0-e502-408c-a2d0-e72fb75e6e67","added_by":"auto","created_at":"2023-11-15 21:31:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":32241,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient time on treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003eDetails presented in text.\u003c/p\u003e\n\u003cp\u003ePart 1 = weekly NUC-3373 dosing on Days 1, 8, 15 and 22 of 28-day cycles\u003c/p\u003e\n\u003cp\u003ePart 2 = alternate weekly NUC-3373 dosing on Days 1 and 15 of 28-day cycles\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3593277/v1/276676cd09c5c7d880722fde.png"},{"id":46514714,"identity":"63a2a197-11fc-4e67-bade-c2a222c68853","added_by":"auto","created_at":"2023-11-15 21:31:38","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":179970,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSpider plots depicting tumour responses to treatment.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUpper panel: Part 1, lower panel: Part 2\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3593277/v1/d35446f916c47682b991cc0d.png"},{"id":54303765,"identity":"86759789-1930-477b-b0ae-10463f2dc01e","added_by":"auto","created_at":"2024-04-08 15:11:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1408461,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3593277/v1/6dcb407e-f9b8-4f75-8d1c-91d9a6d203a6.pdf"}],"financialInterests":"","formattedTitle":"A Phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFluoropyrimidines, such as 5-fluorouracil (5-FU), are widely utilized anti-cancer agents that can be given as monotherapy or more commonly in combination therapy for the treatment of a range of tumor types, including colorectal, stomach, head and neck, pancreatic, and breast cancers [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The anti-cancer activity of 5-FU, and its other forms floxuridine (FUDR\u0026reg;) and capecitabine (Xeloda\u0026reg;), is largely attributed to the active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP or FdUMP), which inhibits the enzyme thymidylate synthase (TS), a critical enzyme in \u003cem\u003ede novo\u003c/em\u003e nucleotide synthesis and cell survival [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, due to multiple limitations, 5-FU is not efficiently converted to FUDR-MP. More than 85% of administered 5FU is degraded by the enzyme dihydropyrimidine dehydrogenase (DPD) in the liver; therefore, most of the drug is catabolized before it has an opportunity to exert any therapeutic effect [3]. 5-FU also requires the presence of nucleobase transporters for intracellular transfer and, once inside the cell, requires complex enzymatic processing to generate FUDR-MP [4]. These key limitations impacting breakdown, transport, and activation have been linked to poorer outcomes in patients receiving 5-FU [5]. Additionally, the generation of RNA-directed metabolites by fluoropyrimidines, such as fluorouridine triphosphate (FUTP), is responsible for a number of dose-limiting toxicities (DLTs), including neutropenia, diarrhoea and mucositis, impacting patient safety [6].\u003c/p\u003e \u003cp\u003eAlthough various strategies have been investigated to counter these limitations, such as biochemical modulation with leucovorin (LV) to enhance TS binding or increased infusion durations, none have successfully addressed these shortcomings in a comprehensive manner. NUC-3373, a phosphoramidate nucleotide analog, is the first such agent specifically designed to overcome the limitations and pharmacologic challenges associated with 5-FU and other fluoropyrimidines [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. NUC-3373 is a pre-activated and protected form of FUDR, one of a new class of anti-cancer agents (ProTides) being developed to improve efficacy, safety and pharmacokinetic profiles of nucleoside analog drugs. ProTides contain a phosphate that is protected by a phosphoramidate group (consisting of an aryl, an ester, and an amino acid) with unique structural properties that stabilize the compound and protect it against enzymatic breakdown.\u003c/p\u003e \u003cp\u003ePreclinical studies have shown that NUC-3373 is resistant to breakdown by DPD [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and does not require nucleobase transporters to enter cancer cells [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. As NUC-3373 contains the active anti-cancer metabolite FUDRMP, it does not rely on phosphorylation by thymidine kinase (TK) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. As a result of these properties, NUC-3373 generates substantially higher intracellular levels of FUDR-MP and is a more potent inhibitor of TS than 5FU \u003cem\u003ein vitro\u003c/em\u003e, while generating markedly lower levels of the toxic metabolite FUTP (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [10]. In human colorectal cancer mouse xenograft models, NUC-3373 showed greater tumor inhibition than 5-FU [8].\u003c/p\u003e \u003cp\u003eHere we describe the first-in-human study of NUC-3373 given as monotherapy to patients with advanced solid tumors (NuTide:301). The study was conducted to determine the MTD, schedule, and recommended Phase II dose (RP2D) of NUC-3373 and to assess its safety, pharmacokinetics (PK) and anti-tumor activity.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy Design and Objectives\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis Phase I, open-label, two-part, dose-escalation study was designed to evaluate the safety, PK, and anti-cancer activity of single-agent NUC‑3373, in addition to establishing its MTD, schedule and RP2D, in patients with advanced solid tumors. The primary objective was\u0026nbsp;to determine the MTD and RP2D when given weekly on Days 1, 8, 15 and 22 (Part 1) or alternate weekly on Days 1 and 15 (Part 2) of 28-day cycles, until disease progression or unacceptable toxicity. In standard treatment, 5-FU has typically been administered on a weekly or alternate weekly schedule. Therefore, both schedules were selected for this study in order to allow for an efficient characterization of each schedule’s ability to produce sustained drug exposures that may be associated with biologic effect, while addressing safety questions. Secondary objectives included safety and tolerability, PK, and evaluation of anti-tumor activity through assessment of disease control and tumor response. Patients were enrolled sequentially into dose-escalation cohorts using a modified 3+3 design.\u0026nbsp;The study was conducted at three clinical centres in the United Kingdom: the Churchill Hospital, Oxford; The Beatson West of Scotland Cancer Centre, Glasgow; and the Patrick G. Johnston Centre for Cancer Research, Belfast. The study was performed in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice [11]. The protocol was approved by the South Central - Oxford C Research Ethics Committee [15/SC/0644] and all patients provided written informed consent before undergoing any study procedures.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatients\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients ≥18 years of age with a histologically‑confirmed solid tumor not amenable or refractory to standard therapies, or for which standard therapy did not exist, were eligible for the study. Other inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2, adequate organ function, measurable disease on radiological imaging (in accordance with\u0026nbsp;Response Evaluation Criteria in Solid Tumors\u0026nbsp;[RECIST] v1.1), and/or evaluable disease [12]. Exclusion criteria included\u0026nbsp;prior\u0026nbsp;allergy or cardiac events attributed to 5-FU or capecitabine, active hepatitis B, C or HIV and symptomatic central nervous system metastases.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTreatment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNUC‑3373 was administered via central or peripheral venous access device as an infusion lasting 30 minutes (for doses ≤750 mg/m\u003csup\u003e2\u003c/sup\u003e), 2 hours (for doses ≤1500 mg/m\u003csup\u003e2\u003c/sup\u003e) or 4 hours (for doses \u0026gt;1500 mg/m\u003csup\u003e2\u003c/sup\u003e). A starting dose of 125 mg/m\u003csup\u003e2\u003c/sup\u003e NUC-3373 was selected for the first 3 patients (Part 1) and was escalated sequentially in cohorts of 3 to 6 patients using a modified 3+3 design. Dose‑escalation stopped when the MTD was determined. The MTD was defined as the highest dose level for which fewer than 2 out of 6 (or \u0026lt;33%) patients experienced DLTs. Following recruitment to the third dose group in Part 2, the Trial Management Group (TMG) agreed that this schedule would be stopped, and recruitment would instead resume in Part 1, to determine the RP2D for the weekly schedule. This decision was partially based on the Part 1 safety profile, which indicated that weekly dosing was tolerable. Thus, the weekly schedule was investigated as a priority to maximize dose intensity and potential activity. Furthermore, the number of dose-escalation cohorts required in Part 1 was higher than anticipated and the planned sample size was reached before completion of Part 2. Dose intensity (DI) was calculated for each patient per cycle using actual DI/allocated DI, where allocated DI was [4 x dose assigned (mg/m\u003csup\u003e2\u003c/sup\u003e)] / 28 days for the weekly schedule and [2\u0026nbsp;x dose assigned (mg/m\u003csup\u003e2\u003c/sup\u003e)] / 28 days for the alternate weekly schedule, and the actual DI was [sum of all doses received in a cycle (mg/m\u003csup\u003e2\u003c/sup\u003e)] / [Duration of cycle in days including any delays before starting]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAssessment\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients who received at least one dose of NUC-3373 were included in the safety analysis population. Safety parameters were continually assessed and based on treatment-emergent adverse events (TEAEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [13], along with clinical laboratory data and physical examinations. Due to the association of 5-FU to cardiac toxicity, echocardiograms and electrocardiograms (ECG) were conducted at baseline, at the end of study participation and during the study if clinically indicated. Patients were defined as evaluable for DLT assessment if they had received at least 75% (Part 1) or 100% (Part 2) of the intended treatment with NUC-3373 during Cycle 1 or if they experienced a DLT. A DLT was defined as any of the following occurring during the first treatment cycle: Grade 3 or higher non‑haematological toxicity (excluding nausea/vomiting/diarrhoea or rash that responded to standard medical treatment), Grade 3 or higher infusion reaction, Grade 3 or higher nausea/vomiting/diarrhoea or rash that occurred despite standard medical treatment, Grade 4 neutropenia, febrile neutropenia (any grade), Grade 4 thrombocytopenia, any toxicity related to NUC‑3373 that was unresolved after a treatment delay of \u0026gt;14 days, or isolated/recurrent toxicity that was judged by the Investigators to be a DLT.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTumor response assessments were performed for the safety population. Computed tomography (CT) based tumor assessments were conducted according to RECIST\u0026nbsp;1.1 [12] at screening and every 8 weeks until progression. Responses from all available post-baseline scans were used for derivation of the best overall response (BOR) and disease control rate (DCR). A response of stable disease was only considered if the scan was taken at least 6 weeks after the baseline scan. The highest reduction of the sum of diameters of target lesions was selected and reported for each patient with available post-baseline scan. This was expressed as a percentage change from baseline. Median progression free survival was estimated in the safety population using the Kaplan-Meier method, event times were from date of cycle 1 day 1, a PFS event was all progressions or death if death occurred without progression. The restricted mean survival time (RMST) for progression-free survival is also reported.\u003c/p\u003e\n\u003cp\u003ePlasma NUC‑3373 concentrations were measured using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods and standard PK parameters were calculated using a non-compartmental analysis approach with Certara Phoenix 8.3 WinNonlin software. PK parameters were generated from available data for a subset of study patients. Blood samples were collected at set timepoints on Cycle\u0026nbsp;1 Day 1 and Cycle 1 Day 15 with timepoints dependent on the NUC-3373 infusion duration. For those who received NUC-3373 over 30 minutes to 2 hours (doses \u0026lt;1500 mg/m\u003csup\u003e2\u003c/sup\u003e), PK samples were collected pre-dose, at end of infusion, and at 15, 30 and 45\u0026nbsp;mins, and 1, 1.5, 2, 4, 6, 24 and 48 h after the end of infusion. For those who received NUC-3373 over 4 hours (doses ≥1500 mg/m\u003csup\u003e2\u003c/sup\u003e), samples were collected pre-dose and at 45 mins and 2, 4, 4.5, 4.75, 5, 6, 7, 8, 24 and 48 h after the start of infusion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDescriptive analyses were carried out using STATA 16.1 (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC). Median (range) and numbers (with percentages) were used to summarize continuous and categorical variables, respectively. Sample size calculations were based on a Fleming design [14]. No formal statistical analyses were planned or performed on safety, PK or efficacy data. With respect to primary objectives and endpoints, no specific hypotheses were tested statistically. The primary focus was on determining the MTD and RP2D, evaluating the safety and PK profiles, and identifying a range of biologically active doses in patients with advanced cancers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data generated in this study are available upon request to researchers who provide a methodologically sound proposal to the corresponding author. To gain access, data requestors will need to sign a data access agreement.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween 22 February 2016 and 13 October 2020, 100 patients were screened for the study and 62 eligible patients were enrolled. Of the 62 patients in the intention-to-treat (ITT) population, 59 received at least one dose of NUC-3373 and were included in the safety analysis population. A total of 43 patients were treated across 9 dosing cohorts in Part 1 (weekly) and 16 patients were treated across 3 dosing cohorts in Part 2 (alternate weekly), as shown in \u003cstrong\u003eFigure 2\u003c/strong\u003e. Overall, 51 patients were evaluable for DLT assessment, including 37 patients in Part 1 and 14 patients in Part 2. At the time of database lock (06 August 2021), no patients remained on study, all having discontinued treatment. The most common reasons for treatment discontinuation were progressive disease (75%) and adverse events (12%). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatient baseline characteristics in the ITT population are presented in Table 1. Across both parts of the study, patients had a median age of 59.5 years (range 20 - 77) and all had a good performance status (48% ECOG PS 0 and 52% PS 1). The most common tumor types were cancers of the colon (31%), rectum (15%), oesophageal/gastroesophageal junction (10%), pancreas (7%) and stomach (5%), and the majority of patients had a histology of adenocarcinoma (74%). Patients had received a median of 3 prior lines of treatment (range 0‑11). The majority of patients (74%) had received prior therapy with fluoropyrimidines, with 52% of patients having received 5-FU, 52% capecitabine, and 15% tipiracil/trifluridine.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp; Patient baseline characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePart 1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=46)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePart 2\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=62)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eMedian age, years [range]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e59.5 [20, 77]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e59.5 [20, 77]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e59.5 [20, 77]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\"\u003e\n \u003cp\u003eSex, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e18 (39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e7 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e25 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e28 (61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e9 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e37 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\"\u003e\n \u003cp\u003eHistological type, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eAdenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e35 (76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e11 (69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e46 (74.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eAdenosquamous Carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eAlveolar Rhabdomyosarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eBasal Cell Carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eLow Grade Endometrioid Adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eMesothelioma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eMetastatic Melanoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eSarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eSpindle Cell Carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eSquamous Cell\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e4 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e4 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eUndifferentiated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eHistology not specified \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e3 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e3 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\"\u003e\n \u003cp\u003ePerformance Status, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e23 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e7 (44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e30 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e23 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e9 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e32 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\"\u003e\n \u003cp\u003eCancer Type, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eColon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e16 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e3 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e19 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eRectum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e8 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e9 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eOesophageal/gastroesophageal junction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e3 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e3 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e6 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003ePancreas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e2 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e2 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e4 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eCervix\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e2 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e16 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e6 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e22 (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\"\u003e\n \u003cp\u003ePrior therapies\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003ePrior systemic therapy, median [range]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e3 [0, 6]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e3 [1, 11]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e3 [0, 11]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003ePrior fluoropyrimidine therapy \u003csup\u003ea\u003c/sup\u003e, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e37 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e9 (56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e46 (74)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003ePrior 5-FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e27 (59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e5 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e32 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003ePrior capecitabine\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e26 (57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e6 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e32 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003ePrior tipiracil / trifluridine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e7 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e2 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e9 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.42424242424242%\"\u003e\n \u003cp\u003eMedian BSA, m\u003csup\u003e2\u003c/sup\u003e [range]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1.84 [1.4, 2.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1.88 [1.5, 2.4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\"\u003e\n \u003cp\u003e1.86 [1.4, 2.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\"\u003e\n \u003cp\u003eAbbreviations: BSA=body surface area.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003ePrior fluoropyrimidine therapy includes systemic 5-FU and/or capecitabine and/or tipiracil/trifluridine.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment exposure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient exposure to NUC-3373 in Parts 1 and 2 is presented in Table 2. Across all cohorts, patients received a median of 2 cycles of treatment, with a median duration of exposure of 8\u0026nbsp;weeks, in both parts of the study. A higher proportion of patients had dose modifications (70% vs 50%) or dose reductions (19% vs 6%) in Part 1 than in Part\u0026nbsp;2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp; NUC-3373 treatment exposure\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.79797979797979%\" colspan=\"9\"\u003e\n \u003cp\u003e\u003cstrong\u003ePart 1 Cohorts (Q1W)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.11111111111111%\"\u003e\n \u003cp\u003e\u003cstrong\u003e125 mg/m\u003csup\u003e2\u003c/sup\u003e (n=4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.11111111111111%\"\u003e\n \u003cp\u003e\u003cstrong\u003e250 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.11111111111111%\"\u003e\n \u003cp\u003e\u003cstrong\u003e500 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.11111111111111%\"\u003e\n \u003cp\u003e\u003cstrong\u003e750 mg/m\u003csup\u003e2\u003c/sup\u003e (n=4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.11111111111111%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1125 mg/m\u003csup\u003e2\u003c/sup\u003e (n=3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.11111111111111%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1500 mg/m\u003csup\u003e2\u003c/sup\u003e (n=3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.11111111111111%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1875 mg/m\u003csup\u003e2\u003c/sup\u003e\u0026nbsp; (n=6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.11111111111111%\"\u003e\n \u003cp\u003e\u003cstrong\u003e2500 mg/m\u003csup\u003e2\u003c/sup\u003e (n=7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.11111111111111%\"\u003e\n \u003cp\u003e\u003cstrong\u003e3250 mg/m\u003csup\u003e2\u003c/sup\u003e (n=4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.73913043478261%\"\u003e\n \u003cp\u003eStarted treatment, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.73913043478261%\"\u003e\n \u003cp\u003eDid not start treatment, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.73913043478261%\"\u003e\n \u003cp\u003eMedian duration of exposure, weeks [range]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003cp\u003e[7.3, 8.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e4.8\u003c/p\u003e\n \u003cp\u003e[2, 7.7]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e[2, 16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003cp\u003e[6.9, 11]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e18.9\u003c/p\u003e\n \u003cp\u003e[17, 48]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e[8.1, 41]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e8.7\u003c/p\u003e\n \u003cp\u003e[4.1, 16.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e8.1\u003c/p\u003e\n \u003cp\u003e[4.9, 16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e9.9\u003c/p\u003e\n \u003cp\u003e[2.3, 17.9]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.73913043478261%\"\u003e\n \u003cp\u003eMedian completed cycles, n [range]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e2\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e[1.8, 2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003cp\u003e[0.3, 2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e1.9\u003c/p\u003e\n \u003cp\u003e[0.5, 4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e1.9\u003c/p\u003e\n \u003cp\u003e[1.8, 2.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e[3.3, 11.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003cp\u003e[2, 9.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e2.1\u003c/p\u003e\n \u003cp\u003e[1, 4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e[1.3, 4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e[0.5, 4.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.73913043478261%\"\u003e\n \u003cp\u003ePatients completing 6\u0026nbsp;cycles, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e1 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e1 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003ePatients with a dose modification \u003csup\u003ea\u003c/sup\u003e, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e1 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e5 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e5 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e3 (75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e2 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e2 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e3 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e5 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e4 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.73913043478261%\" valign=\"top\"\u003e\n \u003cp\u003ePatients with a dose reduction, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e1 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e2 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e1 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.695652173913043%\"\u003e\n \u003cp\u003e3 (75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.79797979797979%\" colspan=\"9\"\u003e\n \u003cp\u003e\u003cstrong\u003ePart 2 Cohorts (Q2W)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e1500 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e1875 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e2500 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.408163265306122%\"\u003e\n \u003cp\u003eStarted treatment, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.408163265306122%\"\u003e\n \u003cp\u003eDid not start treatment, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.408163265306122%\"\u003e\n \u003cp\u003eMedian duration of exposure, weeks [range]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e12.2 [6.9, 44.6]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e7.9 [6.3, 16.9]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e6.9 [3, 8.9]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.408163265306122%\"\u003e\n \u003cp\u003eMedian completed cycles, n [range]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e3 [1.5, 9.5]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e2 [1.5, 4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e1.75 [0.5, 2]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.408163265306122%\"\u003e\n \u003cp\u003ePatients completing 6\u0026nbsp;cycles, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e1 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.408163265306122%\" valign=\"top\"\u003e\n \u003cp\u003ePatients with a dose modification \u003csup\u003ea\u003c/sup\u003e, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e3 (75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e2 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e3 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.408163265306122%\" valign=\"top\"\u003e\n \u003cp\u003ePatients with a dose reduction, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e1 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.53061224489796%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"10\"\u003e\n \u003cp\u003eAbbreviations: \u0026nbsp;Q1W=weekly; Q2W=alternate weekly.\u003c/p\u003e\n \u003cp\u003ePercentages are based on the number of patients in the safety population (started treatment).\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Dose modifications include missed, reduced or delayed doses.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were sequentially recruited into the study as shown in Figure 2. Of the 59 patients in the safety population, 51 (86%) were evaluable for DLT assessment, including 37/43 patients (86%) in Part\u0026nbsp;1 and 14/16 patients (88%) in Part 2. In the Part 1 weekly dosing cohorts, 4 patients (9%) had DLTs: one patient each in the 500\u0026nbsp;mg/m\u003csup\u003e2\u003c/sup\u003e and 1875 mg/m\u003csup\u003e2\u003c/sup\u003e cohorts had DLTs of raised Grade 3 transaminases; 1 patient in the 3250 mg/m\u003csup\u003e2\u003c/sup\u003e cohort had a DLT of Grade 2 headache; and 1 patient in the 3250 mg/m\u003csup\u003e2\u003c/sup\u003e cohort had a DLT of Grade 3 hypotension (transient). Based on this, the MTD and RP2D was defined as 2500 mg/m\u003csup\u003e2\u003c/sup\u003e NUC‑3373 given weekly. The MTD was not reached in Part 2 as recruitment to this schedule was stopped after the third dose group due to sample size restrictions and prioritization of the weekly schedule to maximize dose intensity and potential activity. No DLTs were observed in Part 2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn Part 1, all 43 patients in the safety analysis population experienced TEAEs. The most common Grade 1‑2 TEAEs observed across all dose cohorts were fatigue (58%), diarrhoea (42%), nausea (42%), infusion-related reaction (35%), constipation (33%), and abdominal pain (26%). The most common Grade 1‑2 TEAEs that were considered related to NUC-3373 were fatigue (54%), nausea (37%), infusion-related reactions (35%), and diarrhoea (33%) (Table 3). The most common Grade 3 TEAEs were fatigue (9%), intravascular device-related infection (5%), ALT increased (5%), blood alkaline phosphatase increased (5%), and transaminases increased (5%). \u0026nbsp;The most common Grade 3 TEAEs that were considered related to NUC-3373 were increased ALT (5%) and transaminases (5%). No Grade 4 TEAEs were reported.\u003c/p\u003e\n\u003cp\u003eA total of 15 patients (35%) had serious adverse events (SAEs), 9 (21%) of whom had Grade 3 SAEs and one (2%) of whom had a Grade 5 AE (unrelated to NUC-3373) of pulmonary haemorrhage. Five patients (12%) had treatment-related SAEs, 2 patients with chest pain attributed to coronary vasospasm, 1 with pyrexia, 1 with drug hypersensitivity, and 1 with posterior reversible encephalopathy syndrome (PRES). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn Part 2, all 16 patients in the safety analysis population experienced TEAEs. The most common Grade\u0026nbsp;1‑2 TEAEs observed across all dose cohorts were fatigue (56%), diarrhoea (44%), nausea (44%), vomiting (38%), anaemia (38%), and infusion-related reactions (38%). The most common Grade\u0026nbsp;1‑2 TEAEs that were considered related to NUC-3373 were fatigue (44%), nausea (38%), infusion-related reactions (38%), and diarrhoea (31%) (Table 3). Recurring infusion related reactions were mitigated with prophylactic treatment with antihistamine and steroid treatment prior to subsequent dosing. The most common Grade 3-4 TEAE reported was anaemia (13%). All other Grade 3-4 TEAEs were reported in only 1 patient (6%) each. Two patients had Grade 3 TEAEs that were considered related to NUC-3373, 1 patient with herpes zoster and 1 patient with increased hepatic enzymes and aspartate aminotransferase (AST) increased. No Grade 4 TEAEs were considered to be related to NUC-3373. Of note, one patient had an infusion reaction to study drug preventing further treatment. The reaction was graded as G2 but the treatment was discontinued as per patient\u0026rsquo;s preference.\u003c/p\u003e\n\u003cp\u003eA total of 7 patients (44%) had SAEs, 5 (31%) of whom had Grade 3 SAEs and one (6%) of whom had a Grade 4 SAE of hypercalcemia. Two patients had treatment-related SAEs, one with herpes zoster infection and another with increased hepatic enzymes. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Treatment-related adverse events\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSOC\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003ePT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.70764119601329%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePart 1 (n=43)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.2093023255814%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePart 2 (n=16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.272727272727273%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 1-2\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.059866962305986%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 3-4\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.272727272727273%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 1-2\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.394678492239468%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 3-4\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eBlood and lymphatic system disorders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eAnaemia\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e6 (13.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e3 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003ePlatelet count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e3 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eCardiac disorders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003ePalpitations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eTachycardia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eGastrointestinal disorders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e16 (37.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e6 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eDiarrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e14 (32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e5 (31.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e6 (13.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e4 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e4 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e3 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eAbdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e2 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eDyspepsia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eFlatulence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eGeneral disorders and administration site conditions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e23 (53.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e1 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e7 (43.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003ePyrexia\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e4 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eMucositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e3 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eChest pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e1 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eGait disturbance\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eInfections\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eHerpes zoster\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eInjury, poisoning and procedural complications\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eInfusion-related reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e15 (34.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e6 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eInvestigations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eALT increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e4 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e2 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e2 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eAST increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e4 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e1 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eALT and AST increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e4 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e2 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eBlood ALP increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e2 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eBlood bilirubin increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e2 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eGGT increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e1 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eHepatic enzyme increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetabolism and nutrition disorders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eHyperglycaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e3 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eDecreased appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e2 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e4 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eHypophosphatemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e2 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eMusculoskeletal and connective tissue disorders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eMyalgia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e2 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eMuscle spasms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eNervous system disorders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eDysgeusia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e7 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e4 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e2 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eNeuropathy peripheral\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e4 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eLethargy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e3 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003ePosterior reversible encephalopathy syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e1 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eRespiratory, thoracic and mediastinal disorders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eDyspnoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e3 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eThroat irritation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e2 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eDyspnoea exertional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eDysphonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eSkin and subcutaneous tissue disorders\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003ePalmar-plantar erythrodysesthesia syndrome\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e2 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eVascular disorders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eFlushing\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e5 (11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.083056478405314%\"\u003e\n \u003cp\u003eHypotension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.27574750830565%\"\u003e\n \u003cp\u003e1 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.431893687707642%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.777408637873755%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003eAbbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; n=number of patients; PT=preferred term; SOC=system organ class.\u003c/p\u003e\n \u003cp\u003ePercentages are based on the total number of patients in the respective safety population.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePharmacokinetics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePharmacokinetic parameters were calculated from individual plasma NUC-3373 concentrations following IV administration of 500-3250 mg/m\u003csup\u003e2\u003c/sup\u003e NUC-3373 on a weekly or alternate weekly schedule. Thirty-one patients had evaluable PK samples: 500 mg/m\u003csup\u003e2\u003c/sup\u003e weekly (n=5), 1125 mg/m\u003csup\u003e2\u003c/sup\u003e weekly (n=3), 1875 mg/m\u003csup\u003e2\u003c/sup\u003e weekly (n=6), 1875 mg/m\u003csup\u003e2\u003c/sup\u003e alternate weekly (n=3), 2500 mg/m\u003csup\u003e2\u003c/sup\u003e weekly (n=6), 2500 mg/m\u003csup\u003e2\u003c/sup\u003e alternate weekly (n=5), and 3250 mg/m\u003csup\u003e2\u003c/sup\u003e weekly (n=3). A dose-proportional increase in NUC-3373 AUC was observed across the concentration range assessed (Table 4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp; NUC-3373 plasma PK parameters on Day 1 and Day 15\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDose / infusion duration/ Regimen\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e\u003cstrong\u003eC\u003csub\u003emax\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(mg/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAUC\u003csub\u003elast\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(h*mg/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAUC\u003csub\u003e(0-\u0026infin;)\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(h*mg/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eT\u003csub\u003e1/2\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(h)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAUC\u003csub\u003elast_D\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(h*mg/L/mg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAUC\u003csub\u003e(0-\u0026infin;)_D\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(h*mg/L/mg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e500 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e30 mins\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eQ1W\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeometric mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e32.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e56.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e70.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e12.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.072\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo lower 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e22.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e33.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e44.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e4.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo upper 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e47.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e97.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e113.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e32.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.117\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e1125 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2 hours\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eQ1W\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeometric mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e38.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e72.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e77.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e12.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo lower 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e29.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e47.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e51.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e9.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo upper 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e50.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e110.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e116.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e16.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.056\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.061\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e1875 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4 hours\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eQ1W\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeometric mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e25.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e105.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e111.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e8.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.032\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo lower 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e18.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e60.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e60.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e3.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo upper 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e35.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e184.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e204.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e22.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.052\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e1875 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4 hours\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eQ2W\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeometric mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e29.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e123.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e125.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e3.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo lower 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e26.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e96.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e97.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e1.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo upper 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e32.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e158.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e161.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e10.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e2500 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4 hours\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eQ1W\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeometric mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e38.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e172.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e174.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e3.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo lower 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e28.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e116.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e116.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e1.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo upper 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e50.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e255.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e260.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e8.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e2500 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4 hours\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eQ2W\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeometric mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e43.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e201.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e204.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e5.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.046\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo lower 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e30.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e124.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e124.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e4.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.027\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo upper 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e61.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e327.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e338.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e7.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.081\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.083\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e3250 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4 hours Q1W\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeometric mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e35.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e150.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e151.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e3.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo lower 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e22.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e90.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e91.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e3.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo upper 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e56.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e251.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e251.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e4.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e1875 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4 hours\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eQ1W\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeometric mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e29.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e126.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e130.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e5.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo lower 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e21.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e88.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e86.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e3.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo upper 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e41.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e181.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e196.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e8.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.063\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.068\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e1875 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4 hours\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eQ2W\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeometric mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e27.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e116.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e117.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e2.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.036\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.036\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo lower 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e22.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e73.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e73.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo upper 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e33.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e184.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e188.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e8.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.052\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e2500 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4 hours\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eQ1W\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeometric mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e39.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e170.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e176.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e4.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.039\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo lower 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e28.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e112.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e113.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e1.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo upper 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e55.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e259.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e275.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e10.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.063\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e2500 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4 hours\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eQ2W\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeometric mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e37.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e177.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e180.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e4.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo lower 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e23.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e91.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e91.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e4.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo upper 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e59.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e345.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e354.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e5.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.076\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.078\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.583333333333334%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e3250 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4 hours Q2W\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.416666666666666%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeometric mean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e36.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e136.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e164.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e4.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo lower 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e32.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e105.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003eGeo upper 1SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.195121951219512%\"\u003e\n \u003cp\u003e41.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.414634146341463%\"\u003e\n \u003cp\u003e176.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.536585365853659%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.29268292682927%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\"\u003e\n \u003cp\u003eAbbreviations: AUC\u003csub\u003e(0-\u0026infin;)\u003c/sub\u003e=area under the plasma concentration-time curve from time 0 to infinity; AUC\u003csub\u003e(0-\u0026infin;)_D\u003c/sub\u003e=dose normalized AUC\u003csub\u003e(0-\u0026infin;)\u003c/sub\u003e; AUC\u003csub\u003elast\u003c/sub\u003e=area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration; AUC\u003csub\u003elast_D\u003c/sub\u003e= dose normalized AUC\u003csub\u003elast\u003c/sub\u003e; C\u003csub\u003emax\u003c/sub\u003e=maximum plasma concentration; Q1W=weekly; Q2W=alternate weekly; T\u003csub\u003e1/2\u003c/sub\u003e=half-life.\u003c/p\u003e\n \u003cp\u003eGeo lower and Geo upper 1SD \u0026ndash; 68% range of the geometric mean.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe last observed concentrations were between 24 and 48 hours for most patients. The estimated half-life of NUC-3373 showed some inherent variability and ranged from 3-10 hours with a geometric mean of 5.61 hours, which is considerably longer than the reported half-life of 5-FU (8-14 minutes). Limited samples were available at the later timepoints, which impacted the typical terminal elimination half-life; however, a longer half-life\u003csub\u003e\u0026nbsp;\u003c/sub\u003ewas observed in patients who had a later PK sample collection timepoint. When comparing dose normalized exposure, all treatment regimens were comparable regardless of whether they were weekly or alternate weekly, with a difference of less than 15% in all comparisons based on the geometric mean ratios. Comparisons of the Day 1 and Day 15 geometric mean ratios were also similar regardless of whether they were weekly or alternate weekly and did not exceed a 15% difference. \u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEfficacy\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRadiological response to treatment was determined according to RECIST\u0026nbsp;v1.1 using CT scans conducted every 8 weeks and compared to baseline scans. Of the 43\u0026nbsp;patients in the Part 1 safety population, 16 had a BOR of stable disease resulting in a DCR of 37% and 18 (42%) had progressive disease (Table 5). When considering only the 34 patients who had at least one post-baseline scan, a DCR of 47% was observed. Of the 16 patients in the Part 2 safety population, 4 had a BOR of stable disease resulting in a DCR of 25% and 10 (63%) had progressive disease (Table 5). When considering only the 14 patients who had at least one post-baseline scan, a DCR of 29% was observed. Across both parts of the study, the overall DCR was 34% in the safety population and 42% in the population who had at least one post-baseline scan. No complete or partial responses were observed in this population of patients who had exhausted all other treatment options.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Anti-tumor activity of NUC-3373\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.171717171717173%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.82828282828282%\" colspan=\"15\"\u003e\n \u003cp\u003e\u003cstrong\u003ePart 1 Cohorts\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.6923076923076925%\"\u003e\n \u003cp\u003e\u003cstrong\u003e125 mg/m\u003csup\u003e2\u003c/sup\u003e (n=3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.256410256410257%\"\u003e\n \u003cp\u003e\u003cstrong\u003e250 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.256410256410257%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e500 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.256410256410257%\"\u003e\n \u003cp\u003e\u003cstrong\u003e750 mg/m\u003csup\u003e2\u003c/sup\u003e (n=4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.256410256410257%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1125 mg/m\u003csup\u003e2\u003c/sup\u003e (n=3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.256410256410257%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e1500 mg/m\u003csup\u003e2\u003c/sup\u003e (n=3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.256410256410257%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1875 mg/m\u003csup\u003e2\u003c/sup\u003e\u0026nbsp; (n=6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.256410256410257%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e2500 mg/m\u003csup\u003e2\u003c/sup\u003e (n=6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.256410256410257%\"\u003e\n \u003cp\u003e\u003cstrong\u003e3250 mg/m\u003csup\u003e2\u003c/sup\u003e (n=4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.256410256410257%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (n=43)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"16\"\u003e\n \u003cp\u003e\u003cstrong\u003eBest overall response, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.894736842105264%\"\u003e\n \u003cp\u003eComplete response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.894736842105264%\"\u003e\n \u003cp\u003ePartial response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.894736842105264%\"\u003e\n \u003cp\u003eStable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"3\"\u003e\n \u003cp\u003e3 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e1 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"2\"\u003e\n \u003cp\u003e2 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e2 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"3\"\u003e\n \u003cp\u003e2 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e3 (75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e16 (37.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.894736842105264%\"\u003e\n \u003cp\u003eProgressive disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e3 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"3\"\u003e\n \u003cp\u003e2 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e2 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"2\"\u003e\n \u003cp\u003e1 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e4 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"3\"\u003e\n \u003cp\u003e3 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e18 (41.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.894736842105264%\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse rate\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.894736842105264%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisease control rate\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e3 (37.5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1 (25.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u003cstrong\u003e3 (100)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 (66.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 (33.3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 (33.3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u003cstrong\u003e3 (75)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u003cstrong\u003e16 (37.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.171717171717173%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.82828282828282%\" colspan=\"15\"\u003e\n \u003cp\u003e\u003cstrong\u003ePart 2 Cohorts\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.75%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e1500 mg/m\u003csup\u003e2\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e1875 mg/m\u003csup\u003e2\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e2500 mg/m\u003csup\u003e2\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.25%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"16\"\u003e\n \u003cp\u003e\u003cstrong\u003eBest overall response, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.171717171717173%\"\u003e\n \u003cp\u003eComplete response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" colspan=\"4\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"4\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"4\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.171717171717173%\"\u003e\n \u003cp\u003ePartial response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" colspan=\"4\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"4\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"4\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"3\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.171717171717173%\"\u003e\n \u003cp\u003eStable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" colspan=\"4\"\u003e\n \u003cp\u003e3 (75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"4\"\u003e\n \u003cp\u003e1 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"4\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"3\"\u003e\n \u003cp\u003e4 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.171717171717173%\"\u003e\n \u003cp\u003eProgressive disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" colspan=\"4\"\u003e\n \u003cp\u003e1 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"4\"\u003e\n \u003cp\u003e5 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"4\"\u003e\n \u003cp\u003e4 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"3\"\u003e\n \u003cp\u003e10 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.171717171717173%\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse rate\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.171717171717173%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisease control rate\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.19191919191919%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e3 (75)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e1 (16.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.21212121212121%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e4 (25)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"16\"\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Response rate = confirmed CR + confirmed PR\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Disease control rate = confirmed CR + confirmed PR + confirmed SD\u003c/p\u003e\n \u003cp\u003eAbbreviations: CR=complete response; PR=partial response; SD=stable disease.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe overall median duration of exposure was 8 weeks across both parts of the study. In Part 1, 10 patients remained on treatment for \u0026ge;3 months, with 2 of these patients completing \u0026ge;9 months of treatment (Figure 3). One of the patients completing \u0026ge;9 months had colorectal cancer and had received 6 prior lines of therapy, including 5 prior lines of fluoropyrimidine-based therapy (progressed within 2 months on third-line treatment with capecitabine plus oxaliplatin, progressed within 8 months on fourth-line treatment with FOLFIRI, and progressed within 3 months on fifth-line treatment with tipiracil/trifluridine). This patient received 1500 mg/m\u003csup\u003e2\u003c/sup\u003e NUC-3373 weekly and achieved stable disease for 9 months before choosing to suspend treatment to go on an extended vacation. The other patient completing \u0026ge;9 months had cholangiocarcinoma and progressed within 6 months of first-line therapy (gemcitabine in combination with cisplatin). This patient received 1125 mg/m\u003csup\u003e2\u003c/sup\u003e NUC-3373 weekly and achieved stable disease for 11 months.\u003c/p\u003e\n\u003cp\u003eIn Part 2, 3 patients remained on treatment for \u0026ge;3 months, with 1 of these patients completing \u0026ge;9 months (Figure 3). This patient had metastatic basal cell carcinoma, had received 2 prior lines of therapy, and had progressed within 3 months of the last line. This patient received 1500 mg/m2 NUC-3373 every two weeks and achieved stable disease for 10 months. For part 1, estimated median progression free survival was 7.1 weeks (95% CI 7.0 to 14.7 weeks). The restricted mean progression-free survival time was 12.9 weeks (95% CI 8.8 to 16.9 weeks). For part 2, estimated median progression free survival was 6.9 weeks (95% CI 6.0 to 7.1 weeks). The restricted mean progression-free survival time was 10.8 weeks (95% CI 5.3 to 16.4 weeks). Visualisation of patients\u0026rsquo; responses over time is shown in \u003cstrong\u003eFigure 4\u003c/strong\u003e. It is worth noting that the majority of the patients in this study received lower doses than the established RP2D and this phase I study was not designed to examine efficacy per se.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eNUC-3373 is a phosphoramidate modification of FUDR specifically designed to overcome the limitations and pharmacologic challenges associated with 5-FU and other fluoropyrimidines. In this first-in-human clinical study, single-agent NUC-3373 demonstrated a favorable safety and PK profile, compared to historical 5-FU data, in patients with advanced solid tumors. NUC-3373 also showed encouraging signs of anti-tumor activity in heavily pre-treated patients, including those who had progressed on multiple lines of prior fluoropyrimidine-based combination therapies. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this study, NUC-3373 was well-tolerated at doses up to the MTD of 2500 mg/m\u003csup\u003e2\u003c/sup\u003e weekly. The most common treatment-related TEAEs were fatigue, nausea, infusion-related reactions and diarrhoea; most of which are also commonly observed with 5-FU. These were mitigated with supportive medications; prophylactic administration of steroid and antihistamine treatment was introduced prior to subsequent dosing for patients with infusion related reactions. Interestingly, other typical 5-FU-related adverse events (such as neutropenia, mucositis and hand-foot syndrome) were either not observed in those receiving NUC-3373 or were observed at a lower incidence and reduced severity when compared with historical data for 5-FU or capecitabine [15, 16]. These findings are consistent with nonclinical data\u0026nbsp;indicating that NUC-3373 generates lower levels of toxic by-products [10], which are implicated in hand-foot syndrome as well as 5-FU-induced hematological and gastrointestinal toxicities through misincorporation into the RNA of normal cells\u0026nbsp;[6].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcross both parts of the study, a total of 7 patients (12%) experienced treatment-related SAEs. The SAEs observed were consistent with the overall TEAE profile and with the type of adverse reactions typically associated with 5-FU, including the rare SAE of PRES which was experienced by one patient in this study and was considered to be possibly related to NUC-3373.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn addition to reducing the generation of toxic metabolites, NUC-3373\u0026rsquo;s resistance to DPD‑mediated breakdown may contribute to its PK; the estimated plasma half-life of NUC‑3373 was 3-10 hours compared to the reported 5-FU half-life of 8-14 minutes. The calculated half-life of NUC-3373 in this study was shorter than previously reported [17], and this is very likely due to limited sampling at later timepoints which impacts the determination of terminal elimination half-life. Nonetheless, the longer half-life compared to 5‑FU is anticipated to prolong the exposure of tumor cells to FUDR-MP, potentially resulting in enhanced activity. It also allows a much shorter administration schedule (1‑4 hours, depending on the selected dose) compared to the prolonged infusion times (up to 48 hours) required for 5-FU. Overall, NUC-3373 PK showed no tendency of non-linearity and the dose-related PK parameters increased with increasing doses. The PK of NUC-3373 were also comparable on different days of administration and were similar regardless of whether the administration schedule was weekly or alternate weekly.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNUC-3373\u0026rsquo;s lack of dependency on DPD for its metabolism may favour its use in the estimated 5% population who have \u003cem\u003eDPYD\u003c/em\u003e gene mutations and are at heightened risk of toxicity from standard fluoropyrimidines. DPD testing was not conducted on participants in the NuTide:301 study, and it was not routinely conducted as standard of care at the time of the study. However, as 74% study patients had received, and tolerated, multiple prior fluoropyrimidine-containing regimens, it is unlikely that any of the patients were DPD-deficient. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients who received NUC-3373 at the MTD (2500 mg/m\u003csup\u003e2\u003c/sup\u003e) or below were able to maintain treatment intensity across both the weekly (Part 1) and alternate weekly (Part\u0026nbsp;2) dosing schedules, with patients in Part 1 generally achieving higher dosing intensities for longer durations. This was associated with a higher median DCR in Part\u0026nbsp;1 than in Part 2 for both the safety analysis population (37% vs 25%) and a larger number of patients who remained on study beyond one post-baseline scan (47% vs 29%). Notably, the highest DCRs were observed in the 1125 mg/m\u003csup\u003e2\u003c/sup\u003e (100%), 1500 mg/m\u003csup\u003e2\u003c/sup\u003e (67%), and 3250 mg/m\u003csup\u003e2\u003c/sup\u003e (75%) weekly cohorts and the 1500 mg/m\u003csup\u003e2\u0026nbsp;\u003c/sup\u003ealternate weekly cohort (75%), in which patients remained on treatment for a median of 19, 15, 10, and 12 weeks, respectively, compared to the overall median of 8 weeks. Observations of prolonged disease control across both parts of the study are encouraging in this population of patients who received NUC-3373 as a monotherapy after exhausting all current standards of care, including 5-FU and other fluoropyrimidine-based therapies. Notably, we observed tumour regression/stability in patients who had previously progressed to 5-FU treatment (\u003cstrong\u003eFigure 4\u003c/strong\u003e), supporting the hypothesis that NUC-3373 can circumvent 5-FU resistance mechanisms.\u003c/p\u003e\n\u003cp\u003eThe main limitations of this study were the small sample size and the heterogenous nature of the patient population, who had a wide variety of tumor types and had received a range of prior treatment regimens. In addition, patients with the cancers represented in this study are typically treated with 5-FU combination chemotherapy, whereas NUC-3373 was given as monotherapy. Finally, this was a single-arm study and while comparisons with historical 5-FU data may be informative, future studies should include a direct randomized comparison of NUC‑3373 versus 5-FU.\u003c/p\u003e\n\u003cp\u003eIn conclusion, NUC-3373 has demonstrated favorable safety, tolerability and PK as well as promising clinical activity in patients with advanced solid tumors who had exhausted standard treatment options. It is anticipated that NUC-3373 will overcome the key limitations associated with 5‑FU, thereby offering a more effective and tolerable treatment option with a more convenient administration schedule. NUC-3373 is currently being evaluated in combination with other agents in ongoing clinical studies [NCT05678257 and NCT05714553].\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFinancial support:\u003c/strong\u003e The study was sponsored by the University of Oxford and funded by NuCana plc.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding Author:\u003c/strong\u003e Dr Sarah Patricia Blagden, Professor of Experimental Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, Oxford, OX3 7DQ, UK. Telephone: +44 (0)1865 617409, Email: [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrior Presentation:\u0026nbsp;\u003c/strong\u003eThis study has been presented in partat AACR (2016) and ESMO (2017, 2018, 2021) annual meetings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e DJH receives salary support and research funding from NuCana plc. FA \u0026amp; CQ are currently employed by AstraZeneca but were not at the time of the study. The other authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure:\u0026nbsp;\u003c/strong\u003eIndependent data monitoring was conducted during the study and data gathered was independently reviewed. \u0026nbsp;All authors had full access to the data and signed confidentiality agreements regarding the data. \u0026nbsp;All authors have reviewed and provided feedback on the manuscript, the first draft of which was written by the corresponding author. The corresponding author had final responsibility for the decision to submit for publication. All authors vouch for the completeness and accuracy of the data presented and confirm that the study was conducted and reported with fidelity to the protocol.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of Translational Relevance:\u003c/strong\u003e The anti-cancer activity of 5-FU, and other fluoropyrimidines, is largely attributed to the active metabolite, FUDR-MP, which inhibits thymidylate synthase, a critical enzyme in nucleotide synthesis and cell survival. However, 5-FU is often inefficiently converted to FUDR-MP. NUC‑3373, a phosphoramidate modification of 5-FU, is designed to bypass this initial monophosphorylation step and deliver FUDR-MP into cells; it is subsequently metabolized independent of dihydropyrimidine dehydrogenase (DPD). This Phase I study demonstrated that NUC-3373 given as monotherapy had a longer half-life than what has been observed with 5-FU, was well-tolerated and showed evidence of anti-cancer activity in patients with advanced cancers, the majority of whom had been extensively pre-treated with fluoropyrimidines. These properties indicate that NUC-3373 may prove to be an alternative to 5-FU, that is quicker to deliver with fewer side effects, especially in patients with DPD deficiency. Studies of NUC-3373 in combination with other chemotherapeutics and targeted therapies are ongoing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the patients, their families and all healthcare professionals involved in this study. The study was designed by the lead investigators and the sponsor (University of Oxford). The sponsor collected and analysed the data in conjunction with the authors. The centres that conducted this study are National Institute for Health and Care Research (NIHR) Biomedical Research Centres that also receive institutional funding as Cancer Research UK (CRUK) and Experimental Cancer Medicine Centres (ECMC). The study was funded and the investigational drug NUC-3373 was supplied by NuCana plc. The study was reviewed and given a favourable opinion by the South Central Oxford C Research Ethics Committee and authorised by the Medicines and Healthcare products Regulatory Agency. This study has been conducted as part of the portfolio of trials in the registered UKCRC Oxford Clinical Trials Research Unit (OCTRU) at the University of Oxford. It has followed their Standard Operating Procedures ensuring compliance with the principles of Good Clinical Practice and the Declaration of Helsinki and any applicable regulatory requirements. We are grateful to Danielle McLean for support in writing this manuscript and the late Professor Chris McGuigan for the initial development of NUC-3373.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGrem JL. 5-fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development. \u003cem\u003eInvest New Drugs\u003c/em\u003e 2000; 18:299-313.\u003c/li\u003e\n\u003cli\u003eLongley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. \u003cem\u003eNat Rev Cancer \u003c/em\u003e2003; 3:330\u0026ndash;338.\u003c/li\u003e\n\u003cli\u003eDiasio RB \u0026amp; Harris BE. Clinical pharmacology of 5-fluorouracil. \u003cem\u003eClin Pharmacokinet \u003c/em\u003e1989; 16:215\u0026ndash;237.\u003c/li\u003e\n\u003cli\u003eParker WB. Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. \u003cem\u003eChem Rev\u003c/em\u003e 2009; 109:2880-2893.\u003c/li\u003e\n\u003cli\u003eLongley DB \u0026amp; Johnston PG. Molecular mechanisms of drug resistance. \u003cem\u003eJ Pathol 2005\u003c/em\u003e; 205:275-292.\u003c/li\u003e\n\u003cli\u003eBrutcher E, Christensen D, Smith MH, \u003cem\u003eet al\u003c/em\u003e. 5‑fluorouracil and capecitabine: Assessment and treatment of uncommon early-onset severe toxicities associated with administration. \u003cem\u003eClin J Oncol Nursing \u003c/em\u003e2018; 22:627‑634.\u003c/li\u003e\n\u003cli\u003eVande Voorde J, Liekens S, McGuigan C, \u003cem\u003eet al\u003c/em\u003e. The cytostatic activity of NUC-3073, a phosphoramidate prodrug of 5 fluoro-2\u0026apos;-deoxyuridine, is independent of activation by thymidine kinase and insensitive to degradation by phosphorolytic enzymes. \u003cem\u003eBiochem Pharmacol \u003c/em\u003e2011; 82:441\u0026ndash;452.\u003c/li\u003e\n\u003cli\u003eBlagden SP, Slusarczyk M, Serpi M, \u003cem\u003eet al\u003c/em\u003e. First in human Phase I study of NUC-3373, a nucleotide analogue designed to overcome fluoropyrimidine drug resistance mechanisms. AACR Annual Meeting 2016. Cancer Research; 76 (suppl 14).\u003c/li\u003e\n\u003cli\u003eMcGuigan C, Murziani P, Slusarczyk M, \u003cem\u003eet al. \u003c/em\u003ePhosphoramidate ProTides of the anticancer agent FUDR successfully deliver the preformed bioactive monophosphate in cells and confer advantage over the parent nucleoside. \u003cem\u003eJ Med Chem \u003c/em\u003e2011; 27:7247\u0026ndash;7258.\u003c/li\u003e\n\u003cli\u003eBre J, Dickson AL, Read OJ, \u003cem\u003eet al\u003c/em\u003e. NUC-3373 has a more targeted DNA mode of action than 5-FU. AACR Annual Meeting 2022. \u003cem\u003eCancer Research\u003c/em\u003e; 82 (suppl 12). \u003c/li\u003e\n\u003cli\u003eVijayananthan A \u0026amp; Nawani O. The importance of Good Clinical Practice guidelines and its role in clinical trials. \u003cem\u003eBiomed Imaging Interv J\u003c/em\u003e 2008; 3:e5. \u003c/li\u003e\n\u003cli\u003eEisenhauer EA, Therasse P, Bogaerts J, \u003cem\u003eet al\u003c/em\u003e. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). \u003cem\u003eEur J Cancer\u003c/em\u003e 2009; 45: 228\u0026ndash;247.\u003c/li\u003e\n\u003cli\u003eUS Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03, 2010. Available from: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf\u003c/li\u003e\n\u003cli\u003eFleming TR. One-sample multiple testing procedure for phase II clinical trials. \u003cem\u003eBiometrics\u003c/em\u003e 1982; 38:143-151.\u003c/li\u003e\n\u003cli\u003eCampostar Prescribing Information, 2014. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020571s048lbl.pdf\u003c/li\u003e\n\u003cli\u003eXeloda Prescribing Information, 2015. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020896s037lbl.pdf\u003c/li\u003e\n\u003cli\u003eCoveler AL, Kazmi F, Ciombor KK, \u003cem\u003eet al\u003c/em\u003e. NuTide:302: A Phase Ib study of NUC-3373 in combination with standard therapies in advanced/metastatic colorectal cancer. ASCO GI annual meeting 2021. \u003cem\u003eJ Clin Oncol\u003c/em\u003e 39 (suppl 3).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-experimental-and-clinical-cancer-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jecc","sideBox":"Learn more about [Journal of Experimental \u0026 Clinical Cancer Research](http://jeccr.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/jecc/default.aspx","title":"Journal of Experimental \u0026 Clinical Cancer Research","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"NUC-3373, 5-FU, 5-fluorouracil, fluoropyrimidines, thymidylate synthase, resistant cancer","lastPublishedDoi":"10.21203/rs.3.rs-3593277/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3593277/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR‑MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and Methods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNUC‑3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28‑day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC‑3373. Secondary objectives included pharmacokinetics (PK), and anti‑tumor activity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFifty-nine patients received NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment related G3 adverse event of raised transaminases occurred in \u0026lt; 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m\u003csup\u003e2\u003c/sup\u003e NUC‑3373 weekly. NUC-3373 is currently in combination treatment studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u0026nbsp;\u003c/strong\u003eClinicaltrials.gov registry number\u0026nbsp;NCT02723240. Trial registered on 8\u003csup\u003eth\u003c/sup\u003e\u0026nbsp;December 2015.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ehttps://clinicaltrials.gov/study/NCT02723240\u003c/p\u003e","manuscriptTitle":"A Phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-15 21:31:33","doi":"10.21203/rs.3.rs-3593277/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-12-27T13:09:55+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2023-12-12T00:48:59+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-11-13T09:19:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-11-13T09:10:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Experimental \u0026 Clinical Cancer Research","date":"2023-11-09T10:36:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-experimental-and-clinical-cancer-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jecc","sideBox":"Learn more about [Journal of Experimental \u0026 Clinical Cancer Research](http://jeccr.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/jecc/default.aspx","title":"Journal of Experimental \u0026 Clinical Cancer Research","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7ceab3bd-8285-4b94-82d1-1632d7306b66","owner":[],"postedDate":"November 15th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-04-08T15:03:52+00:00","versionOfRecord":{"articleIdentity":"rs-3593277","link":"https://doi.org/10.1186/s13046-024-03010-1","journal":{"identity":"journal-of-experimental-and-clinical-cancer-research","isVorOnly":false,"title":"Journal of Experimental \u0026 Clinical Cancer Research"},"publishedOn":"2024-04-02 15:01:00","publishedOnDateReadable":"April 2nd, 2024"},"versionCreatedAt":"2023-11-15 21:31:33","video":"","vorDoi":"10.1186/s13046-024-03010-1","vorDoiUrl":"https://doi.org/10.1186/s13046-024-03010-1","workflowStages":[]},"version":"v1","identity":"rs-3593277","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3593277","identity":"rs-3593277","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}