Phase 1 study of lintuzumab-Ac225 combined with CLAG-M salvage therapy in relapsed/refractory acute myeloid leukemia

Phase 1 study of lintuzumab-Ac225 combined with CLAG-M salvage therapy in relapsed/refractory acute myeloid leukemia | 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 Article Phase 1 study of lintuzumab-Ac225 combined with CLAG-M salvage therapy in relapsed/refractory acute myeloid leukemia Sameem Abedin, Guru Subramanian Guru Murthy, Mehdi Hamadani, Karen Carlson, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5368989/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Feb, 2025 Read the published version in Leukemia → Version 1 posted 9 You are reading this latest preprint version Abstract Lintuzumab-Ac255 is an humanized anti-CD33 antibody linked to Actinium-225 that delivers high-energy alpha-particles to tumor cells, leading to double-strand DNA breaks and cell death. This phase 1 study assessed the safety and efficacy of lintuzumab-Ac225 after CLAG-M salvage therapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Primary objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and safety profile. Using a 3+3 dose-escalation design, 21 patients were enrolled sequentially into 4 cohorts to receive a lintuzumab-Ac225 infusion (0.25-1.0 µCi/kg) 7 (+2) days after CLAG-M (days 1-6); 5 additional patients received the RP2D. Of 23 efficacy-evaluable patients, 86.7% had high-risk disease. The MTD was 1.0 µCi/kg; the RP2D was 0.75 µCi/kg. The most common grade 3/4 adverse events were febrile neutropenia (65.4%), decreased white blood cells (50%), and decreased neutrophil count (42.3%). The composite complete remission rates (CR/CR with incomplete count recovery) were 56.6% overall, 50% in patients with mutated TP53 , and 38.5% in prior venetoclax-treated patients. Measurable residual disease (MRD)-negativity occurred in 75% of 12 evaluable patients. Lintuzumab-Ac225 plus CLAG-M was well tolerated with expected, manageable toxicities, while yielding deep responses characterized by high rates of MRD-negativity including in high-risk R/R AML populations. Health sciences/Diseases/Cancer/Haematological cancer/Leukaemia/Acute myeloid leukaemia Health sciences/Health care/Therapeutics/Drug therapy/Combination drug therapy Figures Figure 1 Figure 2 Introduction Acute myeloid leukemia (AML) is the most common acute leukemia in US adults, causing the majority of leukemia deaths [ 1 ]. Although advances in understanding the pathophysiology of AML have led to improvements in treatment, only 35%-40% of patients younger than 60 years and 5%-15% of older patients can be cured of AML with current treatment strategies [ 2 ]. Up to half of patients with AML relapse after initial treatment and up to one-third fail to achieve a complete remission (CR) after intensive induction therapy and are deemed to have primary refractory disease [ 3 ]. These patients have a similar poor prognosis. Failure to achieve remission is almost always fatal, and relapsed or refractory (R/R) AML poses a therapeutic challenge. Allogeneic hematopoietic cell transplantation (alloHCT) is the only treatment with curative potential for most patients who relapse after chemotherapy, with an estimated OS of 15–25% 5-years post-transplantation [ 1 , 2 , 4 ]. Salvage therapy is required before alloHCT to reduce the leukemia load [ 4 ] but patients with active disease or measurable residual disease (MRD) at transplantation and those with high-risk cytogenetic and molecular abnormalities have high risks of post-transplant relapse [ 1 , 5 ]. Therefore, a critical need exists for more effective salvage treatment to enable more patients to become eligible for successful alloHCT. Lintuzumab-Ac225 (HuM195) is a humanized anti-CD33 antibody conjugated to the alpha-emitting isotope Actinium-225 [ 6 ]. CD33 is expressed on the majority of AML blasts, and at much higher levels than on myeloid progenitors of healthy individuals [ 7 ]. The micrometer-range, high-energy alpha particles are delivered to tumor cells, leading to double-stranded DNA breaks that cause target cell death while the surrounding normal cells are spared. The 10-day half-life of Ac225 allows adequate time for it to reach target cells and its short path length means patients do not require special isolation after administration. Unconjugated lintuzumab exhibited antibody-dependent cellular cytotoxicity and antileukemic activity [ 8 ] but its potency and efficacy were not sufficient for use as a monotherapy. In a phase 1 study in patients with R/R AML, lintuzumab-Ac225 monotherapy demonstrated anti-AML activity through bone marrow blast reduction in 67% of patients, and an acceptable safety profile [ 6 ]. The maximum tolerated dose (MTD) for a single lintuzumab-Ac225 infusion was 111 kBq/kg (3.0 µCi/kg), with myelosuppression and infectious complications being dose limiting. There is no consensus regarding the optimal salvage regimen for R/R AML [ 9 ]. The most common salvage regimens used to achieve remission in patients with R/R AML are FLAG-Ida (fludarabine, high-dose cytarabine, granulocyte colony stimulating factor, and idarubicin), MEC (mitoxantrone, etoposide, high-dose cytarabine), and CLAG-M (cladribine, cytarabine, granulocyte-colony stimulating factor, and mitoxantrone) [ 10 – 12 ]. CLAG-M has acceptable tolerability and led to CR rates of 58% [ 13 ] and 30% [ 14 ] in patients with R/R AML, with 55% of patients undergoing alloHCT [ 14 ]. Enhancing the efficacy of CLAG-M is a rational approach to improving R/R AML outcomes. We hypothesized that lintuzumab-Ac225 could eliminate residual or resistant AML when given after salvage chemotherapy at lower doses that reduce prolonged myelosuppression, to increase chances of successful bridging to alloHCT. This dose escalation study was conducted to determine the safety, tolerability, pharmacokinetics (PK), and clinical activity of lintuzumab-Ac225 after CLAG-M in patients with R/R AML. Methods Patients Eligible patients were aged ≥ 18 years and had morphologically documented de novo or secondary AML in first or subsequent relapse, or refractory AML after ≥ 1 prior therapy, including prior alloHCT. More than 25% of marrow blasts in a baseline bone marrow aspirate/biopsy had to be CD33-positive by either immunohistochemistry staining or flow cytometry. The patients had to have an Eastern Cooperative Oncology Group performance score of 0–2 and adequate organ function, defined as total bilirubin ≤ 2×the upper limit of the normal range (ULN); alanine aminotransferase and aspartate aminotransferase ≤ 2.5×ULN; creatinine clearance ≥ 50 mL/minute; and a resting left ventricular ejection fraction > 40%. Exclusion criteria included acute promyelocytic leukemia, active severe infection not well controlled by antibacterial or antiviral therapy, known infection with human immunodeficiency virus, documented pulmonary disease, pregnancy or breastfeeding, prior chemotherapy or radiotherapy within 14 days of study entry, and active malignancy within 2 years of entry, except previously treated grade ≤ 2 melanoma, non-melanoma skin cancer, carcinoma in situ, or cervical intraepithelial neoplasia, and organ-confined prostate cancer with no evidence of progressive disease. Study design This was a prospective investigator-initiated phase 1 single-center dose escalation study (NCT03441048). The primary objectives and endpoints were to establish the MTD and recommended phase 2 dose (RP2D) of lintuzumab-Ac225 in combinations with CLAG-M, and to determine the safety profile of this combination. Secondary objectives and endpoints included determining the rates of CR, CR with incomplete count recovery (CRi), morphologic leukemia-free state (MLFS), MRD-negative CR/CRi; median OS; the proportion of transplant-eligible patients who proceeded to transplant; and the PK profile of lintuzumab-Ac225 when administered after CLAG-M. Using a standard 3 + 3 dose-escalation design, patients were enrolled sequentially into 4 cohorts to receive a single infusion of lintuzumab-Ac225 at doses ranging from 0.25 to 1.0 µCi/kg, with CLAG-M salvage therapy administered at a fixed dose and schedule (G-CSF at 300 µg/day on days 1–6, cladribine 5 mg/m 2 IV over 2 hours on days 2–6, cytarabine 2 g/m 2 IV over 3 hours on days 2–6 starting 2 hours after completion of the cladribine infusion, and mitoxantrone 10 mg/m 2 IV on days 2–4). On day 7 (+ 2), a single dose of lintuzumab-Ac225 was administered IV over 0.5 hours to patients in each cohort at escalating doses of 0.25 (n = 3), 0.5 (n = 9), 0.75 (n = 4), and 1.0 (n = 5) µCi/kg (Fig. 1 ). After administration, the patients could return to the ward without any requirement for isolation. The MTD was defined as the highest dose level at which no more than 1 of 6 treated patients experienced a dose-limiting toxicity (DLT, defined in Supplementary Table 1). The first patient at each new dose level was observed for ≥ 28 days (the DLT observation period) for occurrence of non-hematologic adverse events (AE) before treating the second patient at that dose level. After the RP2D (defined as the dose level below the dose at which ≥ 2 DLTs were observed) had been determined, an additional 5 patients were enrolled into an RP2D expansion cohort, and received CLAG-M followed by lintuzumab Ac225 at the RP2D. PK were evaluated in the expansion cohort receiving the RP2D. Treatment response was evaluated 28–42 days after treatment initiation by blood sample and bone marrow evaluation. Response categorization was based on European LeukemiaNet (ELN) 2017 criteria (Supplementary Table 2) [ 15 ]. Surviving patients were followed for 2 years for OS analyses. The study was conducted in accordance with the ethical principles originating in the Declaration of Helsinki as stated in 21 CFR § 312.120(c)(4), consistent with Good Clinical Practices and all applicable regulatory requirements. All participants provided written informed consent to participate in the study. The trial was approved by the Medical College of Wisconsin Institutional Review Board. Safety and efficacy assessments Safety analyses included all patients who received lintuzumab-Ac225 (the safety population). The National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03 was used to grade non-hematologic adverse events (AE); modified criteria were used to grade hematologic AE. Efficacy was assessed in the full analysis dataset that comprised all patients who received lintuzumab-Ac225 and had disease evaluation post treatment. Response was assessed up to 60 days after treatment initiation or at hematologic recovery, whichever was earlier. Treatment response was evaluated according to published International Working Group criteria [ 16 ]. Measurable residual disease assessment MRD was assessed using the first specimen of the bone marrow aspirate for patients with a CR or CRi, using multiparameter flow cytometry. Briefly, EDTA-anticoagulated bone marrow aspirates were lysed and cell suspensions were prepared for incubation with 8 different fluorochrome-labeled antibodies per tube. Antibodies analyzed across multiple tubes included CD7, CD11b, CD13, CD14, CD15, CD22, CD33, CD34, CD36, CD38, CD45, CD56, CD64, CD117, and HLA-DR. At least 200,000 events were collected per tube on a FACS CANTO cytometer (BD Biosciences) and analyzed with Paint-A-Gate software (BD Biosciences). Blasts were identified using cluster analysis, based on reproducible forward and light scatter properties and CD45 staining across tubes, along with identification of other cell populations. Aberrant blast immunophenotypes were identified based on comparison with reproducible, known blast antigen expression patterns. Comparisons were also made to previous leukemic blast immunophenotypes, when available. MRD was defined as a ≥ 0.01% population of aberrant myeloblasts in the absence of morphologic evidence of disease. CD33 single nucleotide polymorphism assay All enrolled patients underwent pre-treatment testing for CD33 single nucleotide polymorphisms (SNP) to determine whether these potential lintuzumab-Ac225 binding site abnormalities would impact treatment response. The CD33 SNP assay was performed using peripheral blood from patients with peripheral blood blasts, or on bone marrow aspirates, by Hematologics (Seattle, WA). Specimens were tested for the presence of a C > T, pA14V single nucleotide polymorphism in CD33 . Pharmacokinetic analysis Blood samples for measurement of total radioactivity concentrations were obtained from patients in the RP2D expansion cohort approximately 30 minutes prior to dosing with lintuzumab-Ac225, at 5 and 30 minutes after the end of the infusion, and at 1, 2, 6, 24, 48, 144, and 312 hours after the end of the infusion. Summary PK statistics included the arithmetic mean, standard deviation (SD), geometric mean, coefficient of variation (CV) of geometric mean, median, minimum, maximum, and number of acceptable observations (n), and number of patients (N) for concentrations and all PK parameters (except t last and t max where geometric mean and CV of geometric mean were not reported). Terminal elimination t 1/2 and distribution t 1/2 were calculated and reported. The parameters C max , AUC 0 − tlast , and AUC 0−∞ were determined from total radioactivity concentrations in units of µCi/g in addition to those determined with ngEq/g concentrations. Summary statistics were performed for patients included in the PK analysis population using the validated software Phoenix WinNonlin Versions 8.1.1 and 8.3.5. Statistical analysis The proportion of patients in each dose cohort, their baseline characteristics, adverse event (AE) profile, and rate of CR and MRD negativity were described using descriptive statistics. The Kaplan-Meier method and log rank test were used to determine OS, defined as the time from treatment initiation until death due to any cause. In cases of patient withdrawal from the study, the final observation recorded was used as the patient’s endpoint during analysis. All analyses were carried out with two-sided P < 0.05 as significant. The data were analyzed by the statistical analysis team at Actinium Pharmaceuticals. Results Patient characteristics Twenty-six eligible patients were enrolled at Froedtert &Medical College of Wisconsin, of whom 21 received treatment in dose escalation cohorts and 5 received treatment in the RP2D expansion cohort (Fig. 1 ). The full analysis dataset for efficacy comprised 23 patients who received lintuzumab-Ac225 and had post-treatment disease evaluation; these patients had a median age of 62 years (range 20–73 years) and their other baseline characteristics are summarized in Table 1 . The majority (95.7%) had an ECOG PS of 0–1 and 43.5% were female. Twenty patients (86.7%) had high-risk disease (defined as patients with AML having adverse risk genetic features and/or patients with relapsed/refractory disease after venetoclax-based therapies), 18 (78%) had ELN 2017 adverse risk disease, 12 (52.2%) had a TP53 mutation, and 13 (56.5%) had received prior venetoclax treatment. Table 1 Baseline characteristics in the full analysis dataset a Characteristic N = 23 Age, median (range) 62 years (20–73 years) EGOG Performance Status, n (%) 0 1 2 1 (4.3%) 21 (91.4%) 1 (4.3%) Female, n (%) 10 (43.5%) AML type at screen, n (%) Relapsed Refractory 5 (21.7%) 18 (78.3%) 2017 ELN cytogenetic risk at screening, n (%) Favorable Intermediate Adverse 2 (8.7%) 3 (13%) 18 (78.3%) TP53 mutation 12 (52.2%) Prior therapies, median (range) Prior allogeneic transplant, n (%) Prior venetoclax combination, n (%) 2 (1–5) 13 (56.5%) 13 (56.5%) Blasts expressing CD33, median (range) 82% (29–100%) ECOG, Eastern Cooperative Oncology Group; ELN, European LeukemiaNet risk stratification system for acute myeloid leukemia. a Patients who received lintuzumab-Ac225 and had post-treatment disease evaluation. DLTs and MTD determination Initially, the DLT criterion of prolonged neutropenia was defined as an absolute neutrophil count (ANC) < 0.5×10 9 /L lasting ≥ 42 days; this was modified based on U.S. FDA guidance to ANC < 0.5×10 9 /L lasting ≥ 49 days in the absence of AML. No DLTs occurred in the 0.25 µCi/kg lintuzumab-Ac225 cohort (n = 3) (Fig. 1 ). In the 0.50 µCi/kg lintuzumab-Ac225 cohort (n = 9), DLTs occurred in 3 of the first 6 patients enrolled: ANC < 0.5×10 9 /L at day 42 (n = 2), and grade 4 tumor lysis syndrome (n = 1). After this criterion was modified to neutropenia lasting ≥ 49 days in the absence of AML, an additional 3 patients were treated in cohort 2, with no DLTs. In the 0.75 µCi/kg lintuzumab-Ac225 cohort (n = 4), 1 patient was not evaluable for dose escalation due to not completing treatment. The other 3 patients receiving 0.75 µCi/kg did not experience a DLT. In the final cohort, in which patients received a dose of 1.00 µCi/kg lintuzumab-Ac225 (n = 5), 2 patients were not evaluable for dose escalation (1 did not complete CLAG-M treatment and 1 had a lintuzumab-Ac255 dose delay). Of the other 3 evaluable patients, 2 patients experienced DLTs: ANC < 0.5×10 9 /L at day 49, and grade 4 mucositis. The MTD was therefore 1.00 µCi/kg and the RP2D was 0.75 µCi/kg lintuzumab-Ac225. Among the 26 patients who received lintuzumab-Ac225, the median time to neutrophil recovery (ANC > 1.0×10 9 /L) was 34 days (range, 25–61 days), and platelet recovery (platelets > 50×10 9 /L) occurred at a median of 39 days (range, 25–56 days) after study treatment. Safety The safety population included 26 patients who received lintuzumab-Ac225. Every patient in each dose cohort (100%) experienced at least one treatment-emergent adverse event (TEAE). TEAE were primarily hematologic, including anemia, neutropenia, and thrombocytopenia. The incidence of grade 3 and 4 TEAE occurring in ≥ 20% of patients are summarized in Table 2 . The five most common grade 3/4 TEAE were all hematologic: febrile neutropenia in 17 of 26 patients (65.4%), white blood cells decreased in 13 patients (50%), neutrophil count decreased in 11 patients (42.3%), platelet count decreased in 8 patients (30.8%), and anemia in 6 patients (23.1%). Other 3/4 TEAE occurred less frequently and most occurred at the highest lintuzumab-Ac225 dose (1.0 µCi/kg). No patients discontinued study treatment due to AE. Table 2 Incidence (≥ 20%) of Grade 3 and 4 treatment-emergent adverse events in the safety population Adverse event Lintuzumab-Ac225 dose Total safety population (N = 26) n (%) 0.25 µCi/kg (n = 3) n (%) 0.5 µCi/kg (n = 9) a n (%) 0.75 µCi/kg (n = 9) b n (%) 1.00 µCi/kg (n = 5) n (%) Febrile neutropenia 3 (100) 7 (77.8) 3 (33.3) 4 (80) 17 (65.4) White blood cell decreased 2 (66.7) 5 (55.6) 6 (66.7) 0 13 (50) Neutrophil count decreased 1 (33.3) 5 (55.6) 4 (44.4) 1 (20) 11 (42.3) Platelet count decreased 1 (33.3) 4 (44.4) 3 (33.3) 0 8 (30.8) Anemia 0 3 (33.3) 2 (22.2) 1 (20) 6 (23.1) Rash-maculopapular 0 2 (22.2) 1 (11.1) 0 3 (11.5) Skin infection 0 1 (11.1) 0 1 (20) 2 (7.7) Hypokalemia 0 1 (11.1) 0 1 (20) 2 (7.7) Colitis 0 0 1 (11.1) 1 (20) 2 (7.7) Typhlitis 0 0 1 (11.1) 1 (20) 2 (7.7) Blood bilirubin increased 0 0 0 1 (20) 1 (3.8) Mucositis oral 0 0 0 1 (20) 1 (3.8) Hyperglycemia 0 0 0 1 (20) 1 (3.8) Dysphagia 0 0 0 1 (20) 1 (3.8) Hypophosphatemia 1 (33.3) 0 0 0 1 (3.8) Tumor lysis syndrome 0 1 (20) 0 0 1 (3.8) Hypoxia 0 0 0 1 (20) 1 (3.8) Respiratory failure 0 0 0 1 (20) 1 (3.8) Hypertension 0 0 0 1 (20) 1(3.8) Hypotension 0 0 0 1 (20) 1 (3.8) Adrenal insufficiency 0 0 0 1 (20) 1 (3.8) Vascular access complication 1 (33.3) 0 0 0 1 (3.8) a Additional patients enrolled after DLT criterion changed based on U.S. FDA recommendation. b Includes 5 patients from the RPD2 PK expansion cohort. Two patients died within 30 days after study treatment due to progressive underlying disease. Pharmacokinetics The PK parameters for lintuzumab-Ac255 at the RP2D of 0.75 µCi/kg lintuzumab-Ac225 are summarized in Table 3 and Fig. 2 . Following the 0.5-hour lintuzumab-Ac255 infusion, the t max was observed at a median of 0.633 hours (range, 0.617–0.650) after the start of infusion, corresponding to the first sample collection time point post-infusion. After reaching C max , concentrations decreased in a bi-phasic manner with a geometric mean terminal t 1/2 of 8.25 hours. Total radioactivity in whole blood remained quantifiable for a median of 24.5 hours (range 23.5–48.1 hours) post infusion. Table 3 PK parameters of lintuzumab-Ac225 at the RP2D 4.7 µg/kg at 0.75 µCi/kg (n = 5) AUC 0 − tlast , h*ngEq/g 87.8 (39.4) AUC 0−∞ , h*ngEq/g 96.9 (36.0) C max , ngEq/g 24.7 (33.0) t max , h, median (range) 0.633 (0.617–0.650) t last , h, median (range) 24.5 (23.5–48.1) Terminal elimination t 1/2 , h 8.25 (32.0) Distribution t 1/2 , h 1.58 (16.9) CL, L/h 3.15 (36.2) V z , L 37.5 (41.0) C max , µCi/g 0.00398 (33.3) AUC 0 − tlast , h*µCi /g 0.0142 (36.9) AUC 0−∞ , h*µCi /g 0.0157 (33.2) Geometric mean (CV%) data are presented unless otherwise indicated. AUC 0 − tlast , area under the concentrationtime curve from time zero to the last quantifiable concentration; AUC 0−∞ , area under the concentrationtime curve from time zero extrapolated to infinity; CL, total clearance; C max , maximum observed concentration; CV, coefficient of variation; N, number of patients; RP2D, recommended phase 2 dose; t 1/2 , halflife; t last , time of last quantifiable concentration; t max , time of the maximum observed concentration; V z , volume of distribution during the terminal phase. Efficacy The composite complete remission (CRc) rate (CR/CRi) for all 23 patients in the full analysis dataset was 56.5%, and was 62.5% at the RP2D of 0.75 µCi/kg lintuzumab-Ac225 (Table 4 ). The overall response rate (ORR) was 65.2% for all patients, and 75% at the RP2D. The CRc rate and ORR were both 79% in 14 patients who received 1 or 2 prior therapy lines, and 22% and 44%, respectively, in 9 patients who had received ≥ 3 prior therapies, including 6 patients who had received a prior high-intensity salvage regimen. In the 20 patients with high-risk AML, the CRc rate was 50% and the ORR was 60%. CRc rates and ORRs were 50% and 66.7%, respectively, in 12 patients with mutated TP53 , and 38.5% and 53.8% in 13 patients previously treated with a venetoclax combination regimen. Among 13 patients achieving CR/CRi on study, MRD was evaluable in 12. Of these, 75% were MRD-negative. Table 4 Efficacy of CLAG-M followed by lintuzumab-Ac225 in the full dataset Patient group CRc (CR/CRi), n (%) ORR (CR/CRi/ MLFS), n (%) Median OS, months (95% CI) Patients undergoing alloHCT, n Median OS in patients undergoing alloHCT, months Full analysis set (n = 23) 13 (56.5) 15 (65.2) 7.16 (4.04, 18.37) 6 24.05 (18.37, NE) RP2D cohort (n = 8) 5 (62.5) 6 (75.0) 6.74 (2.07, NE) 1 NE Prior treatment lines a 1 or 2 (n = 14) ≥ 3 (n = 9) 11 (79) 2 (22) 11 (79) 4 (44) 18.37 (4.04, NE) 6.54 (1.45, 11.93) 6 0 24.05 (18.37, NE) NE High-risk AML (n = 20) 10 (50.0) 12 (60.0) 7.21 (2.46, 18.37) 4 24.05 (18.37, NE) ELN adverse risk (n = 18) 8 (44.4) 10 (55.6) 7.05 (2.46, 14.16) 4 24.05 (18.37, NE) TP53 mutated (n = 12) 6 (50.0) 8 (66.7) 9.55 (1.97, 18.37) 3 18.73 (18.37, NE) Prior venetoclax (n = 13) 5 (38.5) 7 (53.8) 7.26 (2.07, 18.73) 3 18.73 (18.37, NE) a Included targeted therapy, low-intensity chemotherapy and high-intensity salvage chemotherapy CR, complete remission; CRc, composite complete remission; CRi, complete remission with incomplete count recovery; ELN, European LeukemiaNet; MLFS, morphologic leukemia-free state; NE, not estimable; ORR, overall response rate; OS, overall survival; RP2D, recommended phase 2 dose. A C > T, pA14V SNP in CD33 was detected in 15 patients, of whom 9 (60%) achieved CR at the end of treatment. The median OS was 7.16 months (95% CI 4.04–18.37) in the full analysis dataset. Among patients who received 1 or 2 prior lines of therapy, the median OS was 18.37 months (95% CI 4.04-not estimable [NE]), and in those who received ≥ 3 prior lines the median OS was 6.54 months (95% CI 1.45, 11.93). The median OS was 7.21 months in the total high-risk population, 9.55 months in patients with TP53 mutation, and 7.26 months among those with prior venetoclax exposure. After achieving remission, 7 patients were deemed eligible for a first alloHCT, and 5 of these 7 patients (71.4%) were successfully bridged. The median OS in the patients who underwent alloHCT was 24.05 months (95% CI 18.37-NE). Discussion This is the first study to evaluate the safety and tolerability of a radioimmunotherapy agent, lintuzumab-Ac225, in combination with CLAG-M for R/R AML. The MTD was 1.0 µCi/kg and the RP2D was 0.75 µCi/kg. Overall, lintuzumab-Ac225 in combination CLAG-M was safe and well tolerated at the RP2D. The most common grade 3/4 TEAE were hematologic, as commonly seen with salvage chemotherapy treatment in this patient population. Myelosuppression was difficult to evaluate in these patients due to coexisting baseline suppression of hematopoiesis by active AML. However, with a CRc rate of 56.5% and a MRD negativity rate of 75% among evaluable subjects, the combination of lintuzumab-Ac225 with CLAG-M yielded preliminary evidence of considerable improvement in these clinically significant endpoints compared with CLAG-M alone [ 17 ]. Among patients in whom 1 or 2 prior lines of therapy had failed, 79% achieved CRc, along with a favorable median OS of 18.8 months. Importantly, this phase 1 study also showed encouraging clinical responses in patients with high-risk R/R AML, who comprised 87% of the study population and continue to present a significant treatment challenge. The median OS in 26% of the study cohort who had CRc and proceeded to alloHCT was 24.1 months. TP53 mutations are associated with a very poor prognosis and define a unique disease subgroup within AML [ 18 ]. Survival with TP53 -mutated AML is approximately 6 months from initial diagnosis [ 18 ]. Outcomes following failure of first-line venetoclax plus hypomethylating agent therapy are also poor, with OS ranging from 2.4–4.6 months [ 19 , 20 ]. In this study, CRc rates were 66.7% and 53.8% in patients with TP53 mutation and prior venetoclax failure, respectively. The median OS was 9.6 and 7.3 months in these respective subgroups. Notably, preclinical studies have shown that lintuzumab-Ac225 depletes the anti-apoptotic protein MCL-1, which may benefit patients with venetoclax-resistant disease [ 21 ]. The t max at the RP2D of lintuzumab-Ac225 occurred at a median of 0.6 hours and the t 1/2 8.3 hours after the start of infusion. Total radioactivity in whole blood remained quantifiable for a median of 24.5 hours. Collectively, these findings indicate that lintuzumab-Ac225 is rapidly cleared after administration. Dose-dependent PK will be assessed in future studies. Gemtuzumab ozogamicin (GO), aCD33-directed antibody-drug conjugate, has demonstrated modest activity in patients with newly diagnosed and R/R AML [ 22 ]. A meta-analysis of 8 studies evaluating GO showed that its addition to induction chemotherapy had no significant effect on the rate of CR/CRi [ 22 ]. Previous studies have also demonstrated that GO may be vulnerable to resistance through multidrug resistance p-glycoprotein efflux pumps [ 23 ]. Lintuzumab-Ac225 provides several potential advantages over GO, which requires calicheamicin internalization followed by DNA binding for effect. Lintuzumab-Ac225 does not require internalization after binding for effect, and is thus is less vulnerable to these resistance mechanisms. GO activity was decreased in leukemia with CD33 binding-site mutations [ 24 , 25 ], but our study showed that there was no correlation between the presence of the C > T, pA14V SNP in CD33 and response, given that the CRc rate was 60% in the patients with this abnormality. Furthermore, unlike with GO, hepatic toxicity including veno-occlusive disorder was not detected amongst patients in this study. In conclusion, lintuzumab-Ac225 in combination with CLAG-M had a tolerable safety profile with expected, manageable toxicities and demonstrated promising efficacy in patients with R/R AML, even in high-risk patient subgroups such as those with TP53 mutation and prior venetoclax treatment. These phase 1 results provide compelling evidence to investigate lintuzumab-Ac225 following salvage chemotherapy further in patients with R/R AML. Declarations Acknowledgments This study was supported in part by research funding from Actinium Pharmaceuticals to the Medical College of Wisconsin. The authors thank Dr. Madhuri Vusirikala for review of the manuscript. Samantha Santangelo, PhD, a medical writer at Santangelo Consulting LLC, Newton, MA, US, provided drafts and editorial assistance to the authors during preparation of this manuscript, supported by funding from Actinium Pharmaceuticals. Author contributions SA and EA designed the research; SA, EA and MMC wrote the manuscript; KL and KG performed the statistical analyses; SA, MMC, KLL, and MR created the figures; SA, GSGM, MH, LCM, KC, LR, AH, and ELA contributed to the patient enrollment; SA, GSGM, MH, LCM, KC, LR, KG, AGD, MMC, KLL, MR, US, AH, and ELA contributed to the literature review, data interpretation, and final draft writing. All authors reviewed and approved the final manuscript. Data sharing Individual participant data will not be shared. The study protocol is included as a data supplement available with the online version of this article. References Koenig K, Mims A, Levis MJ, Horowitz MM. the changing landscape of treatment in acute myeloid leukemia. American Society of Clinical Oncology Educational Book. 2020(40):343–54. Atallah EL. Why isn't there a one-size-fits-all approach for relapsed/refractory acute myeloid leukemia? Insights into different variables for decision-making. Best Pract Res Clin Haematol. 2021;34(1):101240. Ferguson P, Hills RK, Grech A, Betteridge S, Kjeldsen L, Dennis M, et al. An operational definition of primary refractory acute myeloid leukemia allowing early identification of patients who may benefit from allogeneic stem cell transplantation. Haematologica. 2016;101(11):1351–8. Thol F, Heuser M. Treatment for relapsed/refractory acute myeloid leukemia. Hemasphere. 2021;5(6):e572. Chen X, Xie H, Wood BL, Walter RB, Pagel JM, Becker PS, et al. Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J Clin Oncol. 2015;33(11):1258–64. Rosenblat TL, McDevitt MR, Carrasquillo JA, Pandit-Taskar N, Frattini MG, Maslak PG, et al. Treatment of patients with acute myeloid leukemia with the targeted alpha-particle nanogenerator actinium-225-lintuzumab. Clin Cancer Res. 2022;28(10):2030–7. Ehninger A, Kramer M, Röllig C, Thiede C, Bornhäuser M, von Bonin M, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer Journal. 2014;4(6):e218-e. Feldman EJ, Brandwein J, Stone R, Kalaycio M, Moore J, O'Connor J, et al. Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J Clin Oncol. 2005;23(18):4110–6. Silva WFD, Rosa LID, Seguro FS, Silveira DRA, Bendit I, Buccheri V, et al. Salvage treatment for refractory or relapsed acute myeloid leukemia: a 10-year single-center experience. Clinics (Sao Paulo). 2020;75:e1566. da Silva WF, da Rosa LI, Seguro FS, Silveira DRA, Bendit I, Buccheri V, et al. Salvage treatment for refractory or relapsed acute myeloid leukemia: a 10-year single-center experience. Clinics. 2020;75:e1566. Xu J, Lv TT, Zhou XF, Huang Y, Liu DD, Yuan GL. Efficacy of common salvage chemotherapy regimens in patients with refractory or relapsed acute myeloid leukemia: A retrospective cohort study. Medicine (Baltimore). 2018;97(39):e12102. Price SL, Lancet JE, George TJ, Wetzstein GA, List AF, Ho VQ, et al. Salvage chemotherapy regimens for acute myeloid leukemia: Is one better? Efficacy comparison between CLAG and MEC regimens. Leuk Res. 2011;35(3):301–4. Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Hołowiecki J, et al. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008;80(2):115–26. Halpern AB, Megan O, Emily MH, Bart LS, Paul CH, Mary-Elizabeth MP, et al. Phase I/II trial of cladribine, high-dose cytarabine, mitoxantrone, and G-CSF with dose-escalated mitoxantrone for relapsed/refractory acute myeloid leukemia and other high-grade myeloid neoplasms. Haematologica. 2019;104(4):e143-e6. Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345–77. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21(24):4642–9. Mushtaq MU, Harrington AM, Chaudhary SG, Michaelis LC, Carlson KB, Abedin S, et al. Comparison of salvage chemotherapy regimens and prognostic significance of minimal residual disease in relapsed/refractory acute myeloid leukemia. Leuk Lymphoma. 2021;62(1):158–66. Daver NG, Iqbal S, Huang J, Renard C, Lin J, Pan Y, et al. Clinical characteristics and overall survival among acute myeloid leukemia patients with TP53 gene mutation or chromosome 17p deletion. Am J Hematol. 2023;98(8):1176–84. Maiti A, Rausch CR, Cortes JE, Pemmaraju N, Daver NG, Ravandi F, et al. Outcomes of relapsed or refractory acute myeloid leukemia after frontline hypomethylating agent and venetoclax regimens. Haematologica. 2021;106(3):894–8. Gangat N, Ilyas R, Johnson IM, McCullough K, Al-Kali A, Alkhateeb HB, et al. Outcome of patients with acute myeloid leukemia following failure of frontline venetoclax plus hypomethylating agent therapy. Haematologica. 2023;108(11):3170–4. Abedin S, Guru Murthy GS, Szabo A, Hamadani M, Michaelis LC, Carlson K-S, et al. Lintuzumab-Ac225 with Combination with Intensive Chemotherapy Yields High Response Rate and MRD Negativity in R/R AML with Adverse Features. Blood. 2022;140(Supplement 1):157–8. Guo Y, Deng L, Qiao Y, Liu B. Efficacy and safety of adding gemtuzumab ozogamicin to conventional chemotherapy for adult acute myeloid leukemia: a systematic review and meta-analysis. Hematology. 2022;27(1):53–64. Takeshita A. Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia. Int J Hematol. 2013;97(6):703–16. Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29(4):369–77. Pollard JA, Alonzo TA, Loken M, Gerbing RB, Ho PA, Bernstein ID, et al. Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML. Blood. 2012;119(16):3705–11. Additional Declarations Yes there is potential conflict of interest. Supplementary Files Ac225ClagMSupplData17Oct2024.pdf LintuzumabProtocolv102921.pdf Cite Share Download PDF Status: Published Journal Publication published 15 Feb, 2025 Read the published version in Leukemia → Version 1 posted Editorial decision: revise 18 Nov, 2024 Review # 2 received at journal 17 Nov, 2024 Review # 1 received at journal 15 Nov, 2024 Reviewer # 2 agreed at journal 02 Nov, 2024 Reviewer # 1 agreed at journal 02 Nov, 2024 Reviewers invited by journal 02 Nov, 2024 Editor assigned by journal 01 Nov, 2024 Submission checks completed at journal 01 Nov, 2024 First submitted to journal 31 Oct, 2024 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. 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Michaelis","email":"","orcid":"https://orcid.org/0000-0002-1798-9658","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Michaelis","suffix":""}],"badges":[],"createdAt":"2024-10-31 19:55:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5368989/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5368989/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41375-025-02528-3","type":"published","date":"2025-02-15T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70286009,"identity":"eb930e17-82ee-45a1-88b1-bb4ea0be5c4d","added_by":"auto","created_at":"2024-12-01 16:27:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":79954,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient enrollment and disposition by dose cohort. \u003c/strong\u003e*Initial dose-limiting toxicity (DLT) criteria defined prolonged neutropenia as absolute neutrophil count (ANC) \u0026lt;0.5×10\u003csup\u003e9\u003c/sup\u003e/L lasting ≥42 days; this was later modified per U. S. FDA guidance to ANC \u0026lt;0.5×10\u003csup\u003e9\u003c/sup\u003e/L lasting ≥49 days in the absence of AML.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5368989/v1/91a8eec67f30210587fa5826.png"},{"id":70286007,"identity":"30569c8e-3b7a-4b83-af3f-6fff4ca5ba75","added_by":"auto","created_at":"2024-12-01 16:27:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":34644,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePK profile after 0.75 µCi/kg lintuzumab-Ac225 in patients with RR-AML \u003c/strong\u003eIndividual concentration-time profiles for total radioactivity following a single 0.5-hour IV infusion of 0.75 µCi/kg lintuzumab-Ac225 in the 5 patients in the RP2D PK expansion cohort\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5368989/v1/4374fabeaa129885feda86de.png"},{"id":76384974,"identity":"818795d1-c04f-4e9b-afb4-3c0f34f17ea7","added_by":"auto","created_at":"2025-02-16 08:05:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1073783,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5368989/v1/0ac26a21-96f4-42e2-a21a-647bcebc3db2.pdf"},{"id":70286011,"identity":"696f735f-9c18-4818-9581-3d293d074a22","added_by":"auto","created_at":"2024-12-01 16:27:19","extension":"pdf","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":147756,"visible":true,"origin":"","legend":"","description":"","filename":"Ac225ClagMSupplData17Oct2024.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5368989/v1/90f0dcbac4029dceb08a4a30.pdf"},{"id":70286010,"identity":"691816d8-39ff-4a7b-bb0c-fc1b2137c255","added_by":"auto","created_at":"2024-12-01 16:27:19","extension":"pdf","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":1008544,"visible":true,"origin":"","legend":"","description":"","filename":"LintuzumabProtocolv102921.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5368989/v1/237c3b41faddb4455ec43bd0.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential conflict of interest.","formattedTitle":"Phase 1 study of lintuzumab-Ac225 combined with CLAG-M salvage therapy in relapsed/refractory acute myeloid leukemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute myeloid leukemia (AML) is the most common acute leukemia in US adults, causing the majority of leukemia deaths [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although advances in understanding the pathophysiology of AML have led to improvements in treatment, only 35%-40% of patients younger than 60 years and 5%-15% of older patients can be cured of AML with current treatment strategies [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Up to half of patients with AML relapse after initial treatment and up to one-third fail to achieve a complete remission (CR) after intensive induction therapy and are deemed to have primary refractory disease [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These patients have a similar poor prognosis. Failure to achieve remission is almost always fatal, and relapsed or refractory (R/R) AML poses a therapeutic challenge.\u003c/p\u003e \u003cp\u003eAllogeneic hematopoietic cell transplantation (alloHCT) is the only treatment with curative potential for most patients who relapse after chemotherapy, with an estimated OS of 15\u0026ndash;25% 5-years post-transplantation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Salvage therapy is required before alloHCT to reduce the leukemia load [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] but patients with active disease or measurable residual disease (MRD) at transplantation and those with high-risk cytogenetic and molecular abnormalities have high risks of post-transplant relapse [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Therefore, a critical need exists for more effective salvage treatment to enable more patients to become eligible for successful alloHCT.\u003c/p\u003e \u003cp\u003eLintuzumab-Ac225 (HuM195) is a humanized anti-CD33 antibody conjugated to the alpha-emitting isotope Actinium-225 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. CD33 is expressed on the majority of AML blasts, and at much higher levels than on myeloid progenitors of healthy individuals [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The micrometer-range, high-energy alpha particles are delivered to tumor cells, leading to double-stranded DNA breaks that cause target cell death while the surrounding normal cells are spared. The 10-day half-life of Ac225 allows adequate time for it to reach target cells and its short path length means patients do not require special isolation after administration.\u003c/p\u003e \u003cp\u003eUnconjugated lintuzumab exhibited antibody-dependent cellular cytotoxicity and antileukemic activity [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] but its potency and efficacy were not sufficient for use as a monotherapy. In a phase 1 study in patients with R/R AML, lintuzumab-Ac225 monotherapy demonstrated anti-AML activity through bone marrow blast reduction in 67% of patients, and an acceptable safety profile [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The maximum tolerated dose (MTD) for a single lintuzumab-Ac225 infusion was 111 kBq/kg (3.0 \u0026micro;Ci/kg), with myelosuppression and infectious complications being dose limiting.\u003c/p\u003e \u003cp\u003eThere is no consensus regarding the optimal salvage regimen for R/R AML [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The most common salvage regimens used to achieve remission in patients with R/R AML are FLAG-Ida (fludarabine, high-dose cytarabine, granulocyte colony stimulating factor, and idarubicin), MEC (mitoxantrone, etoposide, high-dose cytarabine), and CLAG-M (cladribine, cytarabine, granulocyte-colony stimulating factor, and mitoxantrone) [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. CLAG-M has acceptable tolerability and led to CR rates of 58% [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and 30% [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] in patients with R/R AML, with 55% of patients undergoing alloHCT [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Enhancing the efficacy of CLAG-M is a rational approach to improving R/R AML outcomes.\u003c/p\u003e \u003cp\u003eWe hypothesized that lintuzumab-Ac225 could eliminate residual or resistant AML when given after salvage chemotherapy at lower doses that reduce prolonged myelosuppression, to increase chances of successful bridging to alloHCT. This dose escalation study was conducted to determine the safety, tolerability, pharmacokinetics (PK), and clinical activity of lintuzumab-Ac225 after CLAG-M in patients with R/R AML.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eEligible patients were aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years and had morphologically documented de novo or secondary AML in first or subsequent relapse, or refractory AML after \u0026ge;\u0026thinsp;1 prior therapy, including prior alloHCT. More than 25% of marrow blasts in a baseline bone marrow aspirate/biopsy had to be CD33-positive by either immunohistochemistry staining or flow cytometry. The patients had to have an Eastern Cooperative Oncology Group performance score of 0\u0026ndash;2 and adequate organ function, defined as total bilirubin\u0026thinsp;\u0026le;\u0026thinsp;2\u0026times;the upper limit of the normal range (ULN); alanine aminotransferase and aspartate aminotransferase\u0026thinsp;\u0026le;\u0026thinsp;2.5\u0026times;ULN; creatinine clearance\u0026thinsp;\u0026ge;\u0026thinsp;50 mL/minute; and a resting left ventricular ejection fraction\u0026thinsp;\u0026gt;\u0026thinsp;40%.\u003c/p\u003e \u003cp\u003eExclusion criteria included acute promyelocytic leukemia, active severe infection not well controlled by antibacterial or antiviral therapy, known infection with human immunodeficiency virus, documented pulmonary disease, pregnancy or breastfeeding, prior chemotherapy or radiotherapy within 14 days of study entry, and active malignancy within 2 years of entry, except previously treated grade\u0026thinsp;\u0026le;\u0026thinsp;2 melanoma, non-melanoma skin cancer, carcinoma in situ, or cervical intraepithelial neoplasia, and organ-confined prostate cancer with no evidence of progressive disease.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eThis was a prospective investigator-initiated phase 1 single-center dose escalation study (NCT03441048).\u003c/p\u003e \u003cp\u003eThe primary objectives and endpoints were to establish the MTD and recommended phase 2 dose (RP2D) of lintuzumab-Ac225 in combinations with CLAG-M, and to determine the safety profile of this combination. Secondary objectives and endpoints included determining the rates of CR, CR with incomplete count recovery (CRi), morphologic leukemia-free state (MLFS), MRD-negative CR/CRi; median OS; the proportion of transplant-eligible patients who proceeded to transplant; and the PK profile of lintuzumab-Ac225 when administered after CLAG-M.\u003c/p\u003e \u003cp\u003eUsing a standard 3\u0026thinsp;+\u0026thinsp;3 dose-escalation design, patients were enrolled sequentially into 4 cohorts to receive a single infusion of lintuzumab-Ac225 at doses ranging from 0.25 to 1.0 \u0026micro;Ci/kg, with CLAG-M salvage therapy administered at a fixed dose and schedule (G-CSF at 300 \u0026micro;g/day on days 1\u0026ndash;6, cladribine 5 mg/m\u003csup\u003e2\u003c/sup\u003e IV over 2 hours on days 2\u0026ndash;6, cytarabine 2 g/m\u003csup\u003e2\u003c/sup\u003e IV over 3 hours on days 2\u0026ndash;6 starting 2 hours after completion of the cladribine infusion, and mitoxantrone 10 mg/m\u003csup\u003e2\u003c/sup\u003e IV on days 2\u0026ndash;4). On day 7 (+\u0026thinsp;2), a single dose of lintuzumab-Ac225 was administered IV over 0.5 hours to patients in each cohort at escalating doses of 0.25 (n\u0026thinsp;=\u0026thinsp;3), 0.5 (n\u0026thinsp;=\u0026thinsp;9), 0.75 (n\u0026thinsp;=\u0026thinsp;4), and 1.0 (n\u0026thinsp;=\u0026thinsp;5) \u0026micro;Ci/kg (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). After administration, the patients could return to the ward without any requirement for isolation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe MTD was defined as the highest dose level at which no more than 1 of 6 treated patients experienced a dose-limiting toxicity (DLT, defined in Supplementary Table\u0026nbsp;1). The first patient at each new dose level was observed for \u0026ge;\u0026thinsp;28 days (the DLT observation period) for occurrence of non-hematologic adverse events (AE) before treating the second patient at that dose level. After the RP2D (defined as the dose level below the dose at which\u0026thinsp;\u0026ge;\u0026thinsp;2 DLTs were observed) had been determined, an additional 5 patients were enrolled into an RP2D expansion cohort, and received CLAG-M followed by lintuzumab Ac225 at the RP2D.\u003c/p\u003e \u003cp\u003ePK were evaluated in the expansion cohort receiving the RP2D. Treatment response was evaluated 28\u0026ndash;42 days after treatment initiation by blood sample and bone marrow evaluation. Response categorization was based on European LeukemiaNet (ELN) 2017 criteria (Supplementary Table\u0026nbsp;2) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Surviving patients were followed for 2 years for OS analyses.\u003c/p\u003e \u003cp\u003e The study was conducted in accordance with the ethical principles originating in the Declaration of Helsinki as stated in 21 CFR \u0026sect;\u0026nbsp;312.120(c)(4), consistent with Good Clinical Practices and all applicable regulatory requirements. All participants provided written informed consent to participate in the study. The trial was approved by the Medical College of Wisconsin Institutional Review Board.\u003c/p\u003e\n\u003ch3\u003eSafety and efficacy assessments\u003c/h3\u003e\n\u003cp\u003eSafety analyses included all patients who received lintuzumab-Ac225 (the safety population). The National Cancer Institute\u0026rsquo;s Common Terminology Criteria for Adverse Events, version 4.03 was used to grade non-hematologic adverse events (AE); modified criteria were used to grade hematologic AE.\u003c/p\u003e \u003cp\u003eEfficacy was assessed in the full analysis dataset that comprised all patients who received lintuzumab-Ac225 and had disease evaluation post treatment. Response was assessed up to 60 days after treatment initiation or at hematologic recovery, whichever was earlier. Treatment response was evaluated according to published International Working Group criteria [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eMeasurable residual disease assessment\u003c/h3\u003e\n\u003cp\u003eMRD was assessed using the first specimen of the bone marrow aspirate for patients with a CR or CRi, using multiparameter flow cytometry. Briefly, EDTA-anticoagulated bone marrow aspirates were lysed and cell suspensions were prepared for incubation with 8 different fluorochrome-labeled antibodies per tube. Antibodies analyzed across multiple tubes included CD7, CD11b, CD13, CD14, CD15, CD22, CD33, CD34, CD36, CD38, CD45, CD56, CD64, CD117, and HLA-DR. At least 200,000 events were collected per tube on a FACS CANTO cytometer (BD Biosciences) and analyzed with Paint-A-Gate software (BD Biosciences). Blasts were identified using cluster analysis, based on reproducible forward and light scatter properties and CD45 staining across tubes, along with identification of other cell populations. Aberrant blast immunophenotypes were identified based on comparison with reproducible, known blast antigen expression patterns. Comparisons were also made to previous leukemic blast immunophenotypes, when available. MRD was defined as a\u0026thinsp;\u0026ge;\u0026thinsp;0.01% population of aberrant myeloblasts in the absence of morphologic evidence of disease.\u003c/p\u003e\n\u003ch3\u003eCD33 single nucleotide polymorphism assay\u003c/h3\u003e\n\u003cp\u003eAll enrolled patients underwent pre-treatment testing for \u003cem\u003eCD33\u003c/em\u003e single nucleotide polymorphisms (SNP) to determine whether these potential lintuzumab-Ac225 binding site abnormalities would impact treatment response. The CD33 SNP assay was performed using peripheral blood from patients with peripheral blood blasts, or on bone marrow aspirates, by Hematologics (Seattle, WA). Specimens were tested for the presence of a C\u0026thinsp;\u0026gt;\u0026thinsp;T, pA14V single nucleotide polymorphism in \u003cem\u003eCD33\u003c/em\u003e.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePharmacokinetic analysis\u003c/h2\u003e \u003cp\u003eBlood samples for measurement of total radioactivity concentrations were obtained from patients in the RP2D expansion cohort approximately 30 minutes prior to dosing with lintuzumab-Ac225, at 5 and 30 minutes after the end of the infusion, and at 1, 2, 6, 24, 48, 144, and 312 hours after the end of the infusion.\u003c/p\u003e \u003cp\u003eSummary PK statistics included the arithmetic mean, standard deviation (SD), geometric mean, coefficient of variation (CV) of geometric mean, median, minimum, maximum, and number of acceptable observations (n), and number of patients (N) for concentrations and all PK parameters (except t\u003csub\u003elast\u003c/sub\u003e and t\u003csub\u003emax\u003c/sub\u003e where geometric mean and CV of geometric mean were not reported). Terminal elimination t\u003csub\u003e1/2\u003c/sub\u003e and distribution t\u003csub\u003e1/2\u003c/sub\u003e were calculated and reported. The parameters C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;tlast\u003c/sub\u003e, and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e were determined from total radioactivity concentrations in units of \u0026micro;Ci/g in addition to those determined with ngEq/g concentrations. Summary statistics were performed for patients included in the PK analysis population using the validated software Phoenix WinNonlin Versions 8.1.1 and 8.3.5.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe proportion of patients in each dose cohort, their baseline characteristics, adverse event (AE) profile, and rate of CR and MRD negativity were described using descriptive statistics. The Kaplan-Meier method and log rank test were used to determine OS, defined as the time from treatment initiation until death due to any cause. In cases of patient withdrawal from the study, the final observation recorded was used as the patient\u0026rsquo;s endpoint during analysis. All analyses were carried out with two-sided \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 as significant.\u003c/p\u003e \u003cp\u003eThe data were analyzed by the statistical analysis team at Actinium Pharmaceuticals.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eTwenty-six eligible patients were enrolled at Froedtert \u0026amp;Medical College of Wisconsin, of whom 21 received treatment in dose escalation cohorts and 5 received treatment in the RP2D expansion cohort (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The full analysis dataset for efficacy comprised 23 patients who received lintuzumab-Ac225 and had post-treatment disease evaluation; these patients had a median age of 62 years (range 20\u0026ndash;73 years) and their other baseline characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The majority (95.7%) had an ECOG PS of 0\u0026ndash;1 and 43.5% were female. Twenty patients (86.7%) had high-risk disease (defined as patients with AML having adverse risk genetic features and/or patients with relapsed/refractory disease after venetoclax-based therapies), 18 (78%) had ELN 2017 adverse risk disease, 12 (52.2%) had a \u003cem\u003eTP53\u003c/em\u003e mutation, and 13 (56.5%) had received prior venetoclax treatment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics in the full analysis dataset\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;23\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 years (20\u0026ndash;73 years)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEGOG Performance Status, n (%)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4.3%)\u003c/p\u003e \u003cp\u003e21 (91.4%)\u003c/p\u003e \u003cp\u003e1 (4.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (43.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAML type at screen, n (%)\u003c/p\u003e \u003cp\u003eRelapsed\u003c/p\u003e \u003cp\u003eRefractory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (21.7%)\u003c/p\u003e \u003cp\u003e18 (78.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2017 ELN cytogenetic risk at screening, n (%)\u003c/p\u003e \u003cp\u003eFavorable\u003c/p\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003cp\u003eAdverse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (8.7%)\u003c/p\u003e \u003cp\u003e3 (13%)\u003c/p\u003e \u003cp\u003e18 (78.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTP53\u003c/em\u003e mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (52.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior therapies, median (range)\u003c/p\u003e \u003cp\u003ePrior allogeneic transplant, n (%)\u003c/p\u003e \u003cp\u003ePrior venetoclax combination, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1\u0026ndash;5)\u003c/p\u003e \u003cp\u003e13 (56.5%)\u003c/p\u003e \u003cp\u003e13 (56.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlasts expressing CD33, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82% (29\u0026ndash;100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eECOG, Eastern Cooperative Oncology Group; ELN, European LeukemiaNet risk stratification system for acute myeloid leukemia.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003ea\u003c/sup\u003ePatients who received lintuzumab-Ac225 and had post-treatment disease evaluation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDLTs and MTD determination\u003c/h2\u003e \u003cp\u003eInitially, the DLT criterion of prolonged neutropenia was defined as an absolute neutrophil count (ANC)\u0026thinsp;\u0026lt;\u0026thinsp;0.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L lasting\u0026thinsp;\u0026ge;\u0026thinsp;42 days; this was modified based on U.S. FDA guidance to ANC\u0026thinsp;\u0026lt;\u0026thinsp;0.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L lasting\u0026thinsp;\u0026ge;\u0026thinsp;49 days in the absence of AML.\u003c/p\u003e \u003cp\u003eNo DLTs occurred in the 0.25 \u0026micro;Ci/kg lintuzumab-Ac225 cohort (n\u0026thinsp;=\u0026thinsp;3) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In the 0.50 \u0026micro;Ci/kg lintuzumab-Ac225 cohort (n\u0026thinsp;=\u0026thinsp;9), DLTs occurred in 3 of the first 6 patients enrolled: ANC\u0026thinsp;\u0026lt;\u0026thinsp;0.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L at day 42 (n\u0026thinsp;=\u0026thinsp;2), and grade 4 tumor lysis syndrome (n\u0026thinsp;=\u0026thinsp;1). After this criterion was modified to neutropenia lasting\u0026thinsp;\u0026ge;\u0026thinsp;49 days in the absence of AML, an additional 3 patients were treated in cohort 2, with no DLTs. In the 0.75 \u0026micro;Ci/kg lintuzumab-Ac225 cohort (n\u0026thinsp;=\u0026thinsp;4), 1 patient was not evaluable for dose escalation due to not completing treatment. The other 3 patients receiving 0.75 \u0026micro;Ci/kg did not experience a DLT. In the final cohort, in which patients received a dose of 1.00 \u0026micro;Ci/kg lintuzumab-Ac225 (n\u0026thinsp;=\u0026thinsp;5), 2 patients were not evaluable for dose escalation (1 did not complete CLAG-M treatment and 1 had a lintuzumab-Ac255 dose delay). Of the other 3 evaluable patients, 2 patients experienced DLTs: ANC\u0026thinsp;\u0026lt;\u0026thinsp;0.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L at day 49, and grade 4 mucositis. The MTD was therefore 1.00 \u0026micro;Ci/kg and the RP2D was 0.75 \u0026micro;Ci/kg lintuzumab-Ac225.\u003c/p\u003e \u003cp\u003eAmong the 26 patients who received lintuzumab-Ac225, the median time to neutrophil recovery (ANC\u0026thinsp;\u0026gt;\u0026thinsp;1.0\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L) was 34 days (range, 25\u0026ndash;61 days), and platelet recovery (platelets\u0026thinsp;\u0026gt;\u0026thinsp;50\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L) occurred at a median of 39 days (range, 25\u0026ndash;56 days) after study treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eThe safety population included 26 patients who received lintuzumab-Ac225. Every patient in each dose cohort (100%) experienced at least one treatment-emergent adverse event (TEAE). TEAE were primarily hematologic, including anemia, neutropenia, and thrombocytopenia. The incidence of grade 3 and 4 TEAE occurring in \u0026ge;\u0026thinsp;20% of patients are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The five most common grade 3/4 TEAE were all hematologic: febrile neutropenia in 17 of 26 patients (65.4%), white blood cells decreased in 13 patients (50%), neutrophil count decreased in 11 patients (42.3%), platelet count decreased in 8 patients (30.8%), and anemia in 6 patients (23.1%). Other 3/4 TEAE occurred less frequently and most occurred at the highest lintuzumab-Ac225 dose (1.0 \u0026micro;Ci/kg). No patients discontinued study treatment due to AE.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIncidence (\u0026ge;\u0026thinsp;20%) of Grade 3 and 4 treatment-emergent adverse events in the safety population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eLintuzumab-Ac225 dose\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTotal safety population\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.25 \u0026micro;Ci/kg\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5 \u0026micro;Ci/kg\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;9)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75 \u0026micro;Ci/kg\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;9)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.00 \u0026micro;Ci/kg\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFebrile neutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (77.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17 (65.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite blood cell decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (55.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13 (50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophil count decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (55.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11 (42.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet count decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8 (30.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6 (23.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRash-maculopapular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (11.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypokalemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTyphlitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood bilirubin increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucositis oral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperglycemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysphagia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypophosphatemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor lysis syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypoxia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1(3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypotension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdrenal insufficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVascular access complication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003ea\u003c/sup\u003eAdditional patients enrolled after DLT criterion changed based on U.S. FDA recommendation.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003eb\u003c/sup\u003eIncludes 5 patients from the RPD2 PK expansion cohort.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTwo patients died within 30 days after study treatment due to progressive underlying disease.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePharmacokinetics\u003c/h2\u003e \u003cp\u003eThe PK parameters for lintuzumab-Ac255 at the RP2D of 0.75 \u0026micro;Ci/kg lintuzumab-Ac225 are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Following the 0.5-hour lintuzumab-Ac255 infusion, the t\u003csub\u003emax\u003c/sub\u003e was observed at a median of 0.633 hours (range, 0.617\u0026ndash;0.650) after the start of infusion, corresponding to the first sample collection time point post-infusion. After reaching C\u003csub\u003emax\u003c/sub\u003e, concentrations decreased in a bi-phasic manner with a geometric mean terminal t\u003csub\u003e1/2\u003c/sub\u003e of 8.25 hours. Total radioactivity in whole blood remained quantifiable for a median of 24.5 hours (range 23.5\u0026ndash;48.1 hours) post infusion.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePK parameters of lintuzumab-Ac225 at the RP2D\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.7 \u0026micro;g/kg at 0.75 \u0026micro;Ci/kg\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;tlast\u003c/sub\u003e, h*ngEq/g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e87.8 (39.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e, h*ngEq/g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e96.9 (36.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e, ngEq/g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24.7 (33.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003et\u003csub\u003emax\u003c/sub\u003e, h, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.633 (0.617\u0026ndash;0.650)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003et\u003csub\u003elast\u003c/sub\u003e, h, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24.5 (23.5\u0026ndash;48.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTerminal elimination t\u003csub\u003e1/2\u003c/sub\u003e, h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.25 (32.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistribution t\u003csub\u003e1/2\u003c/sub\u003e, h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.58 (16.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCL, L/h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.15 (36.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003csub\u003ez\u003c/sub\u003e, L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37.5 (41.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e, \u0026micro;Ci/g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.00398 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;tlast\u003c/sub\u003e, h*\u0026micro;Ci /g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0142 (36.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e, h*\u0026micro;Ci /g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0157 (33.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eGeometric mean (CV%) data are presented unless otherwise indicated.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;tlast\u003c/sub\u003e, area under the concentrationtime curve from time zero to the last quantifiable concentration; AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e, area under the concentrationtime curve from time zero extrapolated to infinity; CL, total clearance; C\u003csub\u003emax\u003c/sub\u003e, maximum observed concentration; CV, coefficient of variation; N, number of patients; RP2D, recommended phase 2 dose; t\u003csub\u003e1/2\u003c/sub\u003e, halflife; t\u003csub\u003elast\u003c/sub\u003e, time of last quantifiable concentration; t\u003csub\u003emax\u003c/sub\u003e, time of the maximum observed concentration; V\u003csub\u003ez\u003c/sub\u003e, volume of distribution during the terminal phase.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy\u003c/h2\u003e \u003cp\u003eThe composite complete remission (CRc) rate (CR/CRi) for all 23 patients in the full analysis dataset was 56.5%, and was 62.5% at the RP2D of 0.75 \u0026micro;Ci/kg lintuzumab-Ac225 (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The overall response rate (ORR) was 65.2% for all patients, and 75% at the RP2D. The CRc rate and ORR were both 79% in 14 patients who received 1 or 2 prior therapy lines, and 22% and 44%, respectively, in 9 patients who had received\u0026thinsp;\u0026ge;\u0026thinsp;3 prior therapies, including 6 patients who had received a prior high-intensity salvage regimen. In the 20 patients with high-risk AML, the CRc rate was 50% and the ORR was 60%. CRc rates and ORRs were 50% and 66.7%, respectively, in 12 patients with mutated \u003cem\u003eTP53\u003c/em\u003e, and 38.5% and 53.8% in 13 patients previously treated with a venetoclax combination regimen. Among 13 patients achieving CR/CRi on study, MRD was evaluable in 12. Of these, 75% were MRD-negative.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEfficacy of CLAG-M followed by lintuzumab-Ac225 in the full dataset\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCRc (CR/CRi), n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eORR (CR/CRi/ MLFS), n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian OS, months (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePatients undergoing alloHCT, n\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMedian OS in patients undergoing alloHCT, months\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFull analysis set (n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13 (56.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15 (65.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.16 (4.04, 18.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24.05 (18.37, NE)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRP2D cohort (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (62.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.74 (2.07, NE)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNE\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior treatment lines\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e1 or 2 (n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3 (n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (79)\u003c/p\u003e \u003cp\u003e2 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (79)\u003c/p\u003e \u003cp\u003e4 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.37 (4.04, NE)\u003c/p\u003e \u003cp\u003e6.54 (1.45, 11.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24.05 (18.37, NE)\u003c/p\u003e \u003cp\u003eNE\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-risk AML (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12 (60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.21 (2.46, 18.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24.05 (18.37, NE)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eELN adverse risk (n\u0026thinsp;=\u0026thinsp;18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (55.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.05 (2.46, 14.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24.05 (18.37, NE)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTP53\u003c/em\u003e mutated (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.55 (1.97, 18.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18.73 (18.37, NE)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior venetoclax (n\u0026thinsp;=\u0026thinsp;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (38.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (53.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.26 (2.07, 18.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18.73 (18.37, NE)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003ea\u003c/sup\u003eIncluded targeted therapy, low-intensity chemotherapy and high-intensity salvage chemotherapy\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eCR, complete remission; CRc, composite complete remission; CRi, complete remission with incomplete count recovery; ELN, European LeukemiaNet; MLFS, morphologic leukemia-free state; NE, not estimable; ORR, overall response rate; OS, overall survival; RP2D, recommended phase 2 dose.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eA C\u0026thinsp;\u0026gt;\u0026thinsp;T, pA14V SNP in \u003cem\u003eCD33\u003c/em\u003e was detected in 15 patients, of whom 9 (60%) achieved CR at the end of treatment.\u003c/p\u003e \u003cp\u003eThe median OS was 7.16 months (95% CI 4.04\u0026ndash;18.37) in the full analysis dataset. Among patients who received 1 or 2 prior lines of therapy, the median OS was 18.37 months (95% CI 4.04-not estimable [NE]), and in those who received\u0026thinsp;\u0026ge;\u0026thinsp;3 prior lines the median OS was 6.54 months (95% CI 1.45, 11.93). The median OS was 7.21 months in the total high-risk population, 9.55 months in patients with \u003cem\u003eTP53\u003c/em\u003e mutation, and 7.26 months among those with prior venetoclax exposure.\u003c/p\u003e \u003cp\u003eAfter achieving remission, 7 patients were deemed eligible for a first alloHCT, and 5 of these 7 patients (71.4%) were successfully bridged. The median OS in the patients who underwent alloHCT was 24.05 months (95% CI 18.37-NE).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first study to evaluate the safety and tolerability of a radioimmunotherapy agent, lintuzumab-Ac225, in combination with CLAG-M for R/R AML. The MTD was 1.0 \u0026micro;Ci/kg and the RP2D was 0.75 \u0026micro;Ci/kg. Overall, lintuzumab-Ac225 in combination CLAG-M was safe and well tolerated at the RP2D. The most common grade 3/4 TEAE were hematologic, as commonly seen with salvage chemotherapy treatment in this patient population. Myelosuppression was difficult to evaluate in these patients due to coexisting baseline suppression of hematopoiesis by active AML. However, with a CRc rate of 56.5% and a MRD negativity rate of 75% among evaluable subjects, the combination of lintuzumab-Ac225 with CLAG-M yielded preliminary evidence of considerable improvement in these clinically significant endpoints compared with CLAG-M alone [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Among patients in whom 1 or 2 prior lines of therapy had failed, 79% achieved CRc, along with a favorable median OS of 18.8 months. Importantly, this phase 1 study also showed encouraging clinical responses in patients with high-risk R/R AML, who comprised 87% of the study population and continue to present a significant treatment challenge. The median OS in 26% of the study cohort who had CRc and proceeded to alloHCT was 24.1 months.\u003c/p\u003e \u003cp\u003e \u003cem\u003eTP53\u003c/em\u003e mutations are associated with a very poor prognosis and define a unique disease subgroup within AML [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Survival with \u003cem\u003eTP53\u003c/em\u003e-mutated AML is approximately 6 months from initial diagnosis [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Outcomes following failure of first-line venetoclax plus hypomethylating agent therapy are also poor, with OS ranging from 2.4\u0026ndash;4.6 months [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In this study, CRc rates were 66.7% and 53.8% in patients with \u003cem\u003eTP53\u003c/em\u003e mutation and prior venetoclax failure, respectively. The median OS was 9.6 and 7.3 months in these respective subgroups. Notably, preclinical studies have shown that lintuzumab-Ac225 depletes the anti-apoptotic protein MCL-1, which may benefit patients with venetoclax-resistant disease [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe t\u003csub\u003emax\u003c/sub\u003e at the RP2D of lintuzumab-Ac225 occurred at a median of 0.6 hours and the t\u003csub\u003e1/2\u003c/sub\u003e 8.3 hours after the start of infusion. Total radioactivity in whole blood remained quantifiable for a median of 24.5 hours. Collectively, these findings indicate that lintuzumab-Ac225 is rapidly cleared after administration. Dose-dependent PK will be assessed in future studies.\u003c/p\u003e \u003cp\u003eGemtuzumab ozogamicin (GO), aCD33-directed antibody-drug conjugate, has demonstrated modest activity in patients with newly diagnosed and R/R AML [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A meta-analysis of 8 studies evaluating GO showed that its addition to induction chemotherapy had no significant effect on the rate of CR/CRi [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Previous studies have also demonstrated that GO may be vulnerable to resistance through multidrug resistance p-glycoprotein efflux pumps [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Lintuzumab-Ac225 provides several potential advantages over GO, which requires calicheamicin internalization followed by DNA binding for effect. Lintuzumab-Ac225 does not require internalization after binding for effect, and is thus is less vulnerable to these resistance mechanisms. GO activity was decreased in leukemia with CD33 binding-site mutations [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], but our study showed that there was no correlation between the presence of the C\u0026thinsp;\u0026gt;\u0026thinsp;T, pA14V SNP in \u003cem\u003eCD33\u003c/em\u003e and response, given that the CRc rate was 60% in the patients with this abnormality. Furthermore, unlike with GO, hepatic toxicity including veno-occlusive disorder was not detected amongst patients in this study.\u003c/p\u003e \u003cp\u003eIn conclusion, lintuzumab-Ac225 in combination with CLAG-M had a tolerable safety profile with expected, manageable toxicities and demonstrated promising efficacy in patients with R/R AML, even in high-risk patient subgroups such as those with \u003cem\u003eTP53\u003c/em\u003e mutation and prior venetoclax treatment. These phase 1 results provide compelling evidence to investigate lintuzumab-Ac225 following salvage chemotherapy further in patients with R/R AML.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported in part by research funding from Actinium Pharmaceuticals to the Medical College of Wisconsin. The authors thank Dr. Madhuri Vusirikala for review of the manuscript. Samantha Santangelo, PhD, a medical writer at Santangelo Consulting LLC, Newton, MA, US, provided drafts and editorial assistance to the authors during preparation of this manuscript, supported by funding from Actinium Pharmaceuticals.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SA and EA designed the research; SA, EA and MMC wrote the manuscript; KL and KG performed the statistical analyses; SA, MMC, KLL, and MR created the figures; SA, GSGM, MH, LCM, KC, LR, AH, and ELA contributed to the patient enrollment; SA, GSGM, \u0026nbsp;MH, LCM, KC, LR, KG, AGD, MMC, KLL, MR, US, AH, and ELA contributed to the literature review, data interpretation, and final draft writing. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData sharing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIndividual participant data will not be shared. The study protocol is included as a data supplement available with the online version of this article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKoenig K, Mims A, Levis MJ, Horowitz MM. the changing landscape of treatment in acute myeloid leukemia. American Society of Clinical Oncology Educational Book. 2020(40):343\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAtallah EL. Why isn't there a one-size-fits-all approach for relapsed/refractory acute myeloid leukemia? Insights into different variables for decision-making. Best Pract Res Clin Haematol. 2021;34(1):101240.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerguson P, Hills RK, Grech A, Betteridge S, Kjeldsen L, Dennis M, et al. An operational definition of primary refractory acute myeloid leukemia allowing early identification of patients who may benefit from allogeneic stem cell transplantation. 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Clinical characteristics and overall survival among acute myeloid leukemia patients with TP53 gene mutation or chromosome 17p deletion. Am J Hematol. 2023;98(8):1176\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaiti A, Rausch CR, Cortes JE, Pemmaraju N, Daver NG, Ravandi F, et al. Outcomes of relapsed or refractory acute myeloid leukemia after frontline hypomethylating agent and venetoclax regimens. Haematologica. 2021;106(3):894\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGangat N, Ilyas R, Johnson IM, McCullough K, Al-Kali A, Alkhateeb HB, et al. Outcome of patients with acute myeloid leukemia following failure of frontline venetoclax plus hypomethylating agent therapy. Haematologica. 2023;108(11):3170\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbedin S, Guru Murthy GS, Szabo A, Hamadani M, Michaelis LC, Carlson K-S, et al. Lintuzumab-Ac225 with Combination with Intensive Chemotherapy Yields High Response Rate and MRD Negativity in R/R AML with Adverse Features. Blood. 2022;140(Supplement 1):157\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo Y, Deng L, Qiao Y, Liu B. Efficacy and safety of adding gemtuzumab ozogamicin to conventional chemotherapy for adult acute myeloid leukemia: a systematic review and meta-analysis. Hematology. 2022;27(1):53\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakeshita A. Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia. Int J Hematol. 2013;97(6):703\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29(4):369\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePollard JA, Alonzo TA, Loken M, Gerbing RB, Ho PA, Bernstein ID, et al. Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML. Blood. 2012;119(16):3705\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"leukemia","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"leu","sideBox":"Learn more about [Leukemia](http://www.nature.com/leu/)","snPcode":"41375","submissionUrl":"https://mts-leu.nature.com/cgi-bin/main.plex","title":"Leukemia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5368989/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5368989/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLintuzumab-Ac255 is an humanized anti-CD33 antibody linked to Actinium-225 that delivers high-energy alpha-particles to tumor cells, leading to double-strand DNA breaks and cell death. This phase 1 study assessed the safety and efficacy of lintuzumab-Ac225 after CLAG-M salvage therapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). \u0026nbsp;Primary objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and safety profile. Using a 3+3 dose-escalation design, 21 patients were enrolled sequentially into 4 cohorts to receive a lintuzumab-Ac225 infusion (0.25-1.0 µCi/kg) 7 (+2) days after CLAG-M (days 1-6); 5 additional patients received the RP2D. Of 23 efficacy-evaluable patients, 86.7% had high-risk disease. The MTD was 1.0 µCi/kg; the RP2D was 0.75 µCi/kg. The most common grade 3/4 adverse events were febrile neutropenia (65.4%), decreased white blood cells (50%), and decreased neutrophil count (42.3%). The composite complete remission rates (CR/CR with incomplete count recovery) were 56.6% overall, 50% in patients with mutated \u003cem\u003eTP53\u003c/em\u003e, and 38.5% in prior venetoclax-treated patients. Measurable residual disease (MRD)-negativity occurred in 75% of 12 evaluable patients. Lintuzumab-Ac225 plus CLAG-M was well tolerated with expected, manageable toxicities, while yielding deep responses characterized by high rates of MRD-negativity including in high-risk R/R AML populations.\u003c/p\u003e","manuscriptTitle":"Phase 1 study of lintuzumab-Ac225 combined with CLAG-M salvage therapy in relapsed/refractory acute myeloid leukemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-01 16:27:14","doi":"10.21203/rs.3.rs-5368989/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-11-18T14:45:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-11-18T00:21:34+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-11-15T19:08:20+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-11-02T23:28:59+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-11-02T09:37:17+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-11-02T04:30:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-01T11:12:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-01T11:10:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Leukemia","date":"2024-10-31T19:50:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"leukemia","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"leu","sideBox":"Learn more about [Leukemia](http://www.nature.com/leu/)","snPcode":"41375","submissionUrl":"https://mts-leu.nature.com/cgi-bin/main.plex","title":"Leukemia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4bfdbfd4-52c1-45ac-8b30-e37224a12253","owner":[],"postedDate":"December 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":39725166,"name":"Health sciences/Diseases/Cancer/Haematological cancer/Leukaemia/Acute myeloid leukaemia"},{"id":39725167,"name":"Health sciences/Health care/Therapeutics/Drug therapy/Combination drug therapy"}],"tags":[],"updatedAt":"2025-02-16T08:05:11+00:00","versionOfRecord":{"articleIdentity":"rs-5368989","link":"https://doi.org/10.1038/s41375-025-02528-3","journal":{"identity":"leukemia","isVorOnly":false,"title":"Leukemia"},"publishedOn":"2025-02-15 05:00:00","publishedOnDateReadable":"February 15th, 2025"},"versionCreatedAt":"2024-12-01 16:27:14","video":"","vorDoi":"10.1038/s41375-025-02528-3","vorDoiUrl":"https://doi.org/10.1038/s41375-025-02528-3","workflowStages":[]},"version":"v1","identity":"rs-5368989","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5368989","identity":"rs-5368989","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}