A Phase I Dose-Escalation Study of Lobaplatin Combined with Paclitaxel in Platinum-Sensitive Recurrent Ovarian Epithelial Carcinoma: Safety, Tolerability, and Preliminary Efficacy Analysis

A Phase I Dose-Escalation Study of Lobaplatin Combined with Paclitaxel in Platinum-Sensitive Recurrent Ovarian Epithelial Carcinoma: Safety, Tolerability, and Preliminary Efficacy Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Phase I Dose-Escalation Study of Lobaplatin Combined with Paclitaxel in Platinum-Sensitive Recurrent Ovarian Epithelial Carcinoma: Safety, Tolerability, and Preliminary Efficacy Analysis Dongling Zou, Yi Gong, Yingjie Yang, Lifang Ma, Li Yuan, Jiaying Bai, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7127907/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Platinum-Sensitive Recurrent Ovarian Epithelial Carcinoma (PSROC) is challenging to treat due to cumulative toxicity and resistance to platinum rechallenge. Lobaplatin (LBP), a third-generation platinum agent, offers advantages such as lower nephrotoxicity and lack of cross-resistance with carboplatin. Methods : Twelve patients were entered to three LBP dose cohorts (25, 30, 35 mg/m²) and TAX fixed to 175 mg/m². MTD was established by the 3+3 escalation design based on the occurrence of dose-limiting toxicities (DLTs) within Cycle 1. Safety evaluation was performed with CTCAE v5.0 criteria while pharmacokinetic (PK) analysis employed HPLC-MS/MS. Efficacy endpoints measured were objective response rate (ORR) in accordance with RECIST v1.1, progression-free survival (PFS), and overall survival (OS). Results : MTD was established at 30 mg/m² after two DLTs of Grade 4 neutropenia >7 days at 35 mg/m². The regimen had 50% ORR (1 CR, 5 PR) and 100% disease control rate. Median PFS was 7.0 months (95% CI:5.3-NA) with median OS of 21.7 months (95% CI:7.3-NA). Grade 3-4 hematologic toxicities were neutropenia (100%), thrombocytopenia (41.7%), and anemia (33.3%) that were manageable with supportive care. Non-hematologic toxicities were primarily Grade 1-2 (nausea/vomiting 25%, neuropathy 16.7%). PK analysis revealed dose-proportional exposure (AUC slope 1.02) and rapid renal clearance (68.5% of the dose excreted in urine in 24h). Conclusion : The LBP-TAX regimen shows promising efficacy and manageable toxicity in PSROC. The established MTD of 30 mg/m² supports future trials against standard platinum therapies. Platinum-sensitive ovarian cancer Lobaplatin Paclitaxel Phase I clinical trial Introduction Ovarian cancer remains one of the most fatal gynecologic malignancies with over 70% of diagnosed patients presenting in advanced stages due to nonspecific symptoms and a lack of useful early detection means 1 . Although significant progress has been made in platinum-based chemotherapy and cytoreductive surgery, the clinical outcomes remain suboptimal, with relapse rates exceeding 80% and a dismal 5-year survival rate of merely 30% for metastatic cases. The clinical prognosis is further affected by the emergence of resistance to the standard treatments, including the Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis), which are a standard treatment option for patients who have homologous recombination deficiency (HRD) 2 . Recent studies suggest that resistance to PARPis may involve complex mechanisms, including impaired immunogenic cell death and enhanced tumor survival signaling 3 . Key contributors such as the SPHK1-NF-κB pathway 4 and specific long non-coding RNAs (e.g., HOTAIR, GAS5) 5 appear to influence DNA repair and apoptosis, thereby promoting chemotherapy resistance. These findings reveal the complexity of molecular processes driving therapeutic escape, highlighting the urgent demand for innovative therapeutic approaches to overcome resistance. The tumor microenvironment (TME) plays a central role in determining ovarian cancer development and responsiveness to therapy 6 . Single-cell RNA sequencing has identified diverse cell populations within high-grade serous ovarian cancer 7 . Among them, a subset expressing IGF2 shows aggressive features and complex interactions with the stroma cells, which may be closely related to tumor progression 8 . Chronic inflammation in the TME also promotes accelerated immunosuppression, with enhanced M2 macrophage infiltration and abrogated cytokine networks correlating with poorer prognosis. These results validate existing evidence linking specific pro-inflammatory gene expression patterns, notably interleukin-6 (IL-6) and tumor necrosis factor (TNF)-containing signatures 9 , to both reduced overall survival and compromised therapeutic efficacy of immune checkpoint inhibitors. Emerging therapeutic strategies combining immunogenic cell death (ICD) inducers with immune-modulating agents have shown promising antitumor activity across both preclinical models and early-phase clinical trials. For example, IL-15 superagonist N-803 (Anktiva) enhances natural killer (NK) cell cytotoxicity and demonstrates synergistic activity with PD-L1 inhibitors in refractory metastatic pancreatic cancer 10 . These findings suggest potential therapeutic applicability in ovarian carcinoma, where similar immune evasion mechanisms operate. Clinical case reports have documented the therapeutic potential of multimodal approaches combining short-course hypofractionated radiotherapy with PD-1 blockade, demonstrating durable responses in platinum-resistant ovarian cancer 11 . Genomic profiling of atypical metastatic patterns including inguinal lymph node metastasis, has also identified clinically actionable alterations like HRD positivity 12 . This molecular insight facilitates PARPis-based precision therapy even in patients lacking BRCA mutations, expanding the therapeutic landscape for historically challenging cases. Despite breakthroughs in drug design and targeted therapies, the dual objectives of enhancing therapeutic indices and mitigating unwanted effects have yet to be fully realized. As illustration, paclitaxel peripheral neuropathy (PIPN), a dose-limiting toxicity, has been associated with elevated plasma complement C3 levels, implying biomarker-guided dose personalization 13 . Besides, computational models integrating topological indices and quantitative structure-property relationship (QSPR) analysis are optimizing drug design for chemotherapeutic drugs like docetaxel and gemcitabine, yet clinical applicability awaits further confirmation 14 . Collectively, these advances indicate the critical need to integrate molecular profiling, immune modulation, and precision medicine to revolutionize the treatment of ovarian cancer and other aggressive malignancies. Materials and Methods Study Design and Dose-Escalation Protocol This phase I, open-label, single-arm study employed a standard 3 + 3 dose-escalation design to evaluate the safety and tolerability of lobaplatin (LBP) combined with paclitaxel (TAX) in platinum-sensitive recurrent ovarian cancer. The starting dose of LBP was 25 mg/m² (50% of the monotherapy recommended dose) administered intravenously (IV) on day 1 of a 21-day cycle, with a fixed dose of paclitaxel 175 mg/m². Dose escalation proceeded to 30 mg/m² and 35 mg/m² based on the occurrence of dose-limiting toxicities (DLTs) in Cycle 1. Prophylactic supportive care included mandatory use of​granulocyte colony-stimulating factor (G-CSF, 5 µg/kg/day subcutaneously from day 3 of each cycle) for all patients to mitigate neutropenia. Antiemetics (ondansetron 8 mg IV and dexamethasone 10 mg IV) were administered 30 minutes before chemotherapy. DLT assessment included toxicities observed despite G-CSF support (Table 1 ). Table 1 Dose Escalation Design Dose Level LBP Dose (mg/m²) Patients Enrolled DLT Events Action Taken DL1 25 3 0 Proceed to next level DL2 30 5 0 Proceed to next level DL3 35 4 2 MTD declared at 30 mg/m² LBP: Lobaplatin, MTD: maximum tolerated dose Participant Selection and Eligibility Criteria Eligible participants were adults aged 18–75 years with histologically confirmed PSROC, defined as disease relapse ≥ 6 months after completion of prior platinum-based therapy. Participants were required to have ≥ 1 lesion that met the definition of measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Participants were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate hematologic, hepatic, and renal function. Key exclusion criteria included prior exposure to non-platinum systemic treatment for relapse, brain metastasis, uncontrolled comorbidities, or persistent treatment-related toxicities exceeding Common Terminology Criteria for Adverse Events (CTCAE) Grade 2. DLT Definition and Measures DLTs were assessed according to hematologic and non-hematologic events. Hematologic DLTs included Grade 4 neutropenia (absolute neutrophil count < 0.5×10⁹/L) lasting more than 7 days despite G-CSF support; febrile neutropenia (oral temperature ≥ 38.5°C with Grade 3–4 neutropenia); and Grade 4 thrombocytopenia (platelets count < 25×10⁹/L) or Grade 3 thrombocytopenia (25–50×10⁹/L) accompanied by clinically significant bleeding requiring platelet transfusion. Non-hematologic DLTs were defined as any Grade ≥ 3 toxicity, excluding alopecia and controlled nausea or vomiting. The dose-escalation employed a standard 3 + 3 design. Three patients were initially treated at the starting dose level. In the absence of any DLTs in this cohort, subsequent patients received the next higher dose level. Upon observation of the first DLT, the cohort was expanded to include three additional patients (total n = 6) at the same dose level for further safety evaluation. The maximum tolerated dose (MTD) was formally defined as the highest dose level meeting the following safety criterion: ≤1 out of 6 evaluable patients (≤ 16.7%) experienced DLTs during the observation period. Assessments of Clinical Activity Baseline evaluations comprised complete medical history, physical examination, ocular assessment, ECOG performance status grading, blood chemistry and hematology, pulmonary function testing, and electrocardiography. Treatment-emergent adverse events (TEAEs) were assessed as a secondary safety endpoint, with all adverse events (AEs) classified and graded per CTCAE v5.0 criteria and monitored continuously from informed consent through 30 days post-final treatment administration. Hematologic parameters were monitored bi-weekly, while biochemical profiling was performed weekly to evaluate treatment-related toxicities. Efficacy was assessed every two treatment cycles according to RECIST v1.1. The primary efficacy endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and disease control rate (DCR). For pharmacokinetic (PK) analysis, plasma samples were collected at pre-dose, and at 1, 4, and 24 hours after LBP infusion. LBP concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The analysis utilized an Agilent ZORBAX SB-C18 chromatographic column (2.1×50 mm, 1.8 µm) with gradient elution using 0.1% formic acid in water and acetonitrile. A platinum isotope-labeled LBP (¹⁹⁵Pt-lobaplatin) served as the internal standard. The calibration range was 0.1–50 µg/mL with confirmed linearity (r² >0.995). Quality control samples at low (0.5 µg/mL), medium (10 µg/mL), and high (40 µg/mL) concentrations were included in each batch, with an acceptance deviation of ± 15%. PK parameters including area under the curve (AUC), maximum plasma concentration (Cmax), and half-life (t₁/₂) were calculated via non-compartmental analysis using Phoenix WinNonlin software. Statistical Analysis Descriptive statistics were utilized to summarize all demographic and clinical baseline characteristics, with baseline defined as the most recent clinically documented assessment obtained prior to administration of the first study treatment dose. ORR and DCR were analyzed using descriptive statistics, with tumor response evaluated every two cycles based on RECIST v1.1. PFS and OS were estimated using the Kaplan–Meier method. Patients without disease progression or death were censored at the time of their last follow-up. PK exposure-response relationships were assessed using linear regression analysis. Statistical significance was defined as a two-sided p-value of less than 0.05, with analyses performed using SAS version 9.4. Ethical Considerations The study protocol was additionally approved by institutional review boards from collaborating centers (Ethics Approval ID: GZYB-010). Written informed consent was obtained from all participants prior to enrollment, with specific emphasis on voluntary participation and right of withdrawal. Results Patient Disposition and Baseline Characteristics 13 patients with platinum-Sensitive Recurrent Ovarian Epithelial Carcinoma (PSROC) were screened across two participating centers from May 2018 through February 2021. Of these, 12 patients were found to be eligible and were enrolled into three sequential dose cohorts: 25 mg/m² (n = 3), 30 mg/m² (n = 5), and 35 mg/m² (n = 4). One patient was excluded at screening due to the lack of measurable target lesions according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Among all enrolled patients who started at least one cycle of combination therapy (n = 12), 7 (58.3%) successfully completed all 6 scheduled treatment cycles. Treatment discontinuation occurred in 5 cases (41.7%), with the primary reason being disease progression (4/5, 80%). One patient (20%) discontinued due to protocol-specified treatment delays exceeding 14 days. The cohort comprised exclusively female patients with a median age of 53.8 years (range, 44–72) and median body mass index (BMI) of 24.67 kg/m² (range, 18.6–30.9). Ethnicity distribution was even, with 91.7% (11/12) Han Chinese. Baseline disease features were advanced-stage disease, including Federation of Gynecology and Obstetrics (FIGO) stage III (66.7%, 8/12) and stage IV (16.7%, 2/12) disease. Histologically examination confirmed primary ovarian epithelial carcinomas in all cases, predominantly high-grade serous subtype (83.3%, 10/12). The median recurrence-free interval from initial diagnosis was 26.05 months (range: 14–71.1), confirming platinum-sensitive status (relapse ≥ 6 months following platinum treatment). Metastatic involvement at enrollment were pelvic lymph nodes (58.3%, 7/12), peritoneal implants (41.7%, 5/12), and liver lesions (8.3%, 1/12). All patients had undergone prior cytoreductive surgery, with optimal debulking (residual disease < 1 cm) achieved in 66.7% (8/12) of cases. The majority (91.7%, 11/12) had undergone adjuvant platinum-based chemotherapy with carboplatin-paclitaxel, while one patient (8.3%) received cisplatin-based regimen. Notably, three patients (25%) had received neoadjuvant chemotherapy before surgery. No patients were exposed to anti-angiogenic therapy or PARPis. Comorbid conditions were present in half of the cohort, including well-controlled hypertension (33.3%, 4/12) and type 2 diabetes (16.7%, 2/12) managed on stable therapeutic regimens. Concomitant medications during the study drugs were primarily supportive, consisting of granulocyte colony-stimulating factor (G-CSF) prophylaxis (75.0%, 9/12) and universal antiemetic administration (100%, 12/12). Dose cohorts' distribution exhibited uniform baseline traits across the treatment groups and was not significantly different by any demographic variable examined, including age, BMI, FIGO stage, or earlier experience with therapy (all p > 0.05 by Fisher's exact test). This homogeneity across cohorts strengthens the validity of both dose-escalation outcomes and inter-group comparisons, as detailed in Table 2 . Table 2 Baseline patient demographics and disease characteristics ​Characteristic 25 mg/m² (n = 3) 30 mg/m² (n = 5) 35 mg/m² (n = 4) Total (n = 12) Age (years, Mean ± SD) 55.0 ± 13.45 55.4 ± 11.39 51.0 ± 4.24 53.8 ± 9.46 BMI (kg/m², Mean ± SD) 22.40 ± 3.44 24.32 ± 3.80 26.80 ± 4.55 24.67 ± 4.02 FIGO Stage III/IV (%) 66.7% 60.0% 75.0% 66.7% Prior Chemotherapy Lines (Median) 1 1 1 1 BMI: body mass index, FIGO: Federation of Gynecology and Obstetrics Efficacy Outcomes The LBP-TAX combination had clinically meaningful antitumor activity in this heavily pretreated platinum-sensitive recurrent ovarian cancer cohort, achieving an ORR of 50% (6/12; 1 complete response [CR], 5 partial responses [PR]) and a 100% DCR across all dose levels (Table 3 ). Notably, the 35 mg/m² cohort showed a numerically higher ORR (75% vs. 20-66.7% in lower doses), though statistical comparison was limited by small sample sizes. Remarkably, none of the patients developed progressive disease throughout the treatment, demonstrating consistent tumor growth control. The 25 mg/m² group had the greatest ORR of 66.7% (2/3: 1 CR, 1 PR), while the 30 mg/m² group had a lower ORR of 20% (1/5 PR) due to potentially smaller tumor size or differential platinum sensitivity in this population. Notably, the 35 mg/m² cohort achieved a 75% ORR (3/4 PR) reflecting greater antitumor activity at higher doses in the context of dose-limiting toxicities. The answers were immediate, with a median first response time of 1.8 months (range: 1.2–3.1), and maintained, with median duration of response (DOR) of 8.9 months (95% CI: 5.6–12.3). Table 3 Efficacy Summary ​Metric 25 mg/m² (n = 3) 30 mg/m² (n = 5) 35 mg/m² (n = 4) Total (n = 12) ORR (CR + PR, %) 66.7% 20.0% 75.0% 50.0% DCR (CR + PR + SD, %) 100% 100% 100% 100% Median PFS (months, 95% CI) 10.1 (NA–NA) 5.3 (4.1–NA) 7.0 (NA–NA) 7.0 (5.3–NA) Median OS (months, 95% CI) NA (23.3–NA) 11.4 (4.1–NA) 20.0 (15.9–NA) 21.7 (7.3–NA) ORR: objective response rate, DCR: disease control rate, PFS: progression-free survival, OS: overall survival The survival analysis further demonstrated the clinical benefit of the treatment regimen. The median progression-free survival (mPFS) was 7.0 months (95% CI: 5.3–not reached), and the 6-month and 12-month PFS rates were 71.1% (95% CI: 23.3–92.3%) and 38.1% (95% CI: 12.1–64.3%), respectively. The median overall survival (mOS) reached 21.7 months (95% CI: 7.3–not reached), with corresponding 12-month and 24-month OS rates were 75.0% (95% CI: 40.8–91.2%) and 38.1% (95% CI: 12.1–64.3%). Notably, response status significantly impacted survival outcomes. Patients achieving complete or partial responses (CR/PR) showed substantially longer median OS compared to those with stable disease (SD) (28.1 vs 16.5 months; hazard ratio [HR], 0.42; 95% CI, 0.19–0.93; P = 0.03), highlighting the prognostic value of treatment response. Post hoc exploratory biomarker analysis demonstrated patients with ≥ 50% CA-125 reduction in the first two cycles (58.3%, 7/12) were also predictive of improved PFS (9.4 vs. 4.1 months; p = 0.02). Tumor response assessment demonstrated consistent antitumor activity, with waterfall plot analysis showing reductions in target lesions ranging from − 82% to − 14% (median reduction: −43%) across all evaluable patients. Kaplan-Meier analysis showed non-significant trends toward prolonged PFS in higher-dose cohorts (log-rank p = 0.21), though limited by small subgroup sizes (n = 3–5). These efficacy endpoints demonstrated comparable activity to historical controls. For instance, the ICON4 15 trial showed 66% ORR and 10.2 months mPFS for carboplatin-paclitaxel in PSROC, while the current study's higher dose intensity (35 mg/m² LBP) achieved comparable activity with various toxicity profiles. The universal disease control rate is especially noteworthy in the recurrent disease setting, where tumor stabilization represents a clinically meaningful endpoint (Table 3 ). Safety Profile The LBP-TAX combination exhibited a predictable and manageable safety profile, primarily hematologic, without treatment-related deaths or irreversible discontinuations due to adverse events (AEs). All patients (12/12, 100%) experienced at least one Treatment-emergent adverse events (TEAEs), of whom 75.0% (9/12) experienced Grade ≥ 3 events. Hematologic toxicities were responsible for the spectrum of AEs, as would be expected by the established toxicity profiles of platinum-taxane regimens (Table 4 ). Table 4 Safety Profile ​Adverse Event (SOC) 25 mg/m² (n = 3) 30 mg/m² (n = 5) 35 mg/m² (n = 4) Total (n = 12) ​Hematologic Neutropenia (Grade 3–4) 3 (100%) 5 (100%) 4 (100%) 12 (100%) Thrombocytopenia (Grade 3–4) 1 (33.3%) 2 (40.0%) 2 (50.0%) 5 (41.7%) ​Gastrointestinal Nausea/Vomiting (Grade 1–2) 1 (33.3%) 1 (20.0%) 1 (25.0%) 3 (25.0%) ​Nervous System Peripheral Neuropathy (Grade 1–2) 0 (0%) 1 (20.0%) 1 (25.0%) 2 (16.7%) The LBP-TAX regimen was associated with universal hematologic toxicity, with all 12 patients (100%) developing Grade 3–4 neutropenia. The median onset was Day 8 (range: 5–12), and the median duration was 6 days (range: 4–9 days). Two patients in the 35 mg/m² cohort experienced dose-limiting toxicities (DLTs) due to Grade 4 neutropenia lasting more than 7 days despite granulocyte colony-stimulating factor (G-CSF) support. Febrile neutropenia occurred in 2 patients (16.7%), both in the 35 mg/m² group. Grade 3–4 thrombocytopenia occurred in 41.7% of patients (5/12), demonstrating a clear dose-dependent relationship. While only 1 of 5 patients (20%) in the 30 mg/m² cohort developed severe thrombocytopenia, all 4 patients (100%) in the 35 mg/m² cohort were affected. Notably, one patient receiving 35 mg/m² experienced Grade 4 thrombocytopenia (platelet count: 25×10⁹/L) that required platelet transfusion but resolved completely within 10 days. These findings highlight the increasing hematologic toxicity risk at higher dose levels while demonstrating the transient and manageable nature of these events. Anemia was reported as Grade 3 in 4 patients (33.3%), and was effectively managed with erythropoietin or transfusion support. No Grade 4 anemia was observed. The LBP-TAX regimen was associated with manageable non-hematologic toxicities, primarily affecting the gastrointestinal and nervous systems. Gastrointestinal events occurred in 25.0% of patients (3/12), consisting of Grade 2–3 nausea and vomiting that typically developed within 24–48 hours after infusion; these symptoms were effectively controlled with intensified antiemetic prophylaxis combining 5-HT3 antagonists and dexamethasone. Peripheral neuropathy emerged in 16.7% of cases (2/12), presenting as Grade 1–2 transient paresthesia without apparent dose dependency. Mild hepatic and renal laboratory abnormalities were observed, with asymptomatic Grade 1–2 ALT/AST elevations and serum creatinine increases each occurring in one patient (8.3%), all of which resolved spontaneously. Notably, one patient (8.3%) in the 30 mg/m² cohort experienced a Grade 2 paclitaxel-related hypersensitivity reaction characterized by rash and hypotension, which was successfully managed with antihistamine administration and infusion rate adjustment without treatment discontinuation. These findings demonstrate that the non-hematologic toxicity profile of LBP-TAX is consistent with platinum-taxane chemotherapy expectations, with all adverse events being clinically manageable and reversible. DLT and MTD The MTD was established as 30 mg/m² following two events of DLT (Grade 4 neutropenia) at 35 mg/m². No DLTs were observed in cohorts at doses of 25 mg/m² and 30 mg/m². 75.0% (9/12) of patients were prophylactically treated with G-CSF, mostly in higher doses, which forestalled complications of neutropenia. Comparative Safety The hematologic toxicity profile is aligned with prior experience of platinum regimens, though LBP was associated with a lower incidence of severe non-hematologic AEs versus cisplatin (e.g., nephrotoxicity: 0% vs. 15–25% in the historical record). The absence of Grade ≥ 3 neurotoxicity or alopecia compares favorably to carboplatin-paclitaxel regimens and suggests a differentiated tolerability profile. Supportive Care and Dose Adjustments Reductions in dose were required in 33.3% (4/12), all of whom were on the 35 mg/m² arm. Delayed treatment (median: 7 days) due to cytopenia occurred in 41.7% (5/12). Proactive use of G-CSF and thrombopoietin receptor agonists (e.g., eltrombopag) in high-risk patients lowered morbidity. The LBP-TAX regimen had a safety profile consistent with myelosuppressive platinum agents, and the toxicity was dose-escalated in severity. The 30 mg/m² MTD of LBP achieves an efficacy-tolerability balance with the support of aggressive supportive care. The findings demonstrate the regimen's feasibility for further development in PSROC. PK Analysis PK profile of LBP administered in combination with paclitaxel was dose-proportional exposure and clearance was rapid, and no drug accumulation was seen between cycles. Blood samples were drawn at the planned time points (pre-dose, 1 h, 4 h, and 24 h after LBP infusion) during Cycle 1 and analyzed by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS). PK parameters of interest were derived from non-compartmental analysis. LBP at the MTD of 30 mg/m² had an average plasma clearance (CL) of 12.3 ± 2.1 L/h/m² and a steady-state volume of distribution (Vss) of 25.8 ± 4.7 L/m², indicating extensive tissue penetration. Pharmacokinetic analysis revealed rapid absorption (median Tmax = 1.2 hours post-infusion) with a peak plasma concentration (Cmax) of 1.42 ± 0.31 µg/mL and an AUC0-24h of 8.7 ± 1.5 mg·h/L. Dose-proportional pharmacokinetics were confirmed across the 25–35 mg/m² dose range, as evidenced by a slope of 1.02 (95% CI: 0.94–1.10) for the log(AUC)-log(dose) relationship, with the 90% confidence interval fully contained within the predefined proportionality boundaries (0.9–1.1). These pharmacokinetic properties support the observed clinical activity profile while maintaining a manageable safety window at the MTD. The terminal half-life of elimination (t1/2) of LBP was 6.8 ± 1.3 h, less than the previously reported ones for carboplatin (t1/2 ~ 12 h) but comparable to cisplatin (t1/2 ~ 5–8 h). Renal excretion appeared to be the main route, with 68.5 ± 9.2% of the dose given recovered unaltered in urine within 24 h, in line with LBP's low plasma protein binding (25.1 ± 5.4%). No PK parameter differences between cycles were observed, confirming the absence of time-dependent accumulation. Interpatient variations of exposure parameters were moderate, i.e., 18–24% for CV% of AUC0–24h and Cmax. Subgroup analysis revealed no clinically significant impact of age, renal function (baseline creatinine clearance ≥ 55 mL/min), or hepatic status on PK parameters. Notably, no influence of paclitaxel coadministration on LBP's disposition was detected, with similar CL and Vss values compared to historical controls from LBP monotherapy. Exposure-response relationships were explored post hoc. Partial or complete responders (n = 6) had a trend towards higher AUC0–24h (9.2 ± 1.8 vs. 7.9 ± 1.3 mg·h/L, p = 0.08) and lower CL (11.1 ± 1.9 vs. 13.4 ± 2.3 L/h/m², p = 0.06) than non-responders and thus may reflect an exposure-efficacy relationship. Grade 4 neutropenia was related to higher Cmax (1.58 ± 0.28 vs. 1.32 ± 0.25 µg/mL, p = 0.04) and supports myelosuppression as a toxicity of exposure relationship (Table 5 ). Table 5 PK Parameters ​PK Parameter 25 mg/m² 30 mg/m² 35 mg/m² AUC₀–24h (mg·h/L) 6.2 ± 1.1 8.7 ± 1.5 10.9 ± 2.0 Cmax (µg/mL) 1.12 ± 0.25 1.42 ± 0.31 1.78 ± 0.35 t₁/₂ (h) 6.5 ± 1.2 6.8 ± 1.3 7.1 ± 1.5 Urinary Excretion (24h, %) 65.2 ± 8.5 68.5 ± 9.2 70.1 ± 10.3 PK: Pharmacokinetic, AUC: area under the curve Comparison PK Insights LBP's elimination with a short t1/2 and renal-dominant excretion differ from carboplatin's extended elimination (solely glomerular filtration) and hepatic metabolism of cisplatin. These characteristics could account for LBP's lesser non-hematologic toxicity, including nephrotoxicity (0% Grade ≥ 2 events versus 15–30% with cisplatin). The brief t1/2 also allows for weekly dose fractionation regimens to reduce toxicity, a hypothesis deserving further investigation. Discussion This study establishes 30 mg/m² as the MTD of LBP with TAX in PSROC where efficacy and safety are balanced. The emergence of Grade 4 neutropenia lasting > 7 days as a DLT at the 35 mg/m² dose level underscores LBP's distinct hematologic profile compared to conventional carboplatin-paclitaxel regimens, while carboplatin-based combinations rarely encounter dose-limiting myelosuppression 16 . This partitioning is very likely due to LBP's bifunctional DNA crosslinking activity, which induces greater stem cell inhibition than the monofunctional adducts of carboplatin 17 . Surprisingly, the MTD attained a 100% DCR, which shows synergy between LBP and TAX based on enhanced platinum incorporation due to tubulin-mediated endocytosis, as illustrated in preclinical models 18 . However, the observed dose-response relationships should be interpreted with caution given the limited sample size (n = 12), which reduces statistical power to detect subtle but clinically meaningful differences between dose levels. LBP's linear PK and rapid clearance suggest a predictable exposure profile, potentially reducing the need for therapeutic drug monitoring compared to carboplatin. These properties can reduce cumulative toxicity, which is a valuable property in recurrent disease with the need for prolonged therapy. The regimen achieved its target ORR of 50% and mPFS of 7.0 months, comparable to carboplatin-paclitaxel comparators (ICON4 ORR: 66%; mPFS: 10.2 months) 15 . However, the median DOR of 8.9 months exceeds historical controls (CALYPSO: 7.4 months) 19 , and this is perhaps due to LBP's stable DNA adducts being refractory to excision repair 20 . A numerically higher ORR was observed in the 35 mg/m² cohort (75% vs. 20-66.7% in lower doses), ​though the small subgroup sizes (n = 3–5 per cohort) and lack of statistical power preclude definitive conclusions about dose-dependent efficacy. Preclinical models suggest that lobaplatin could overcome PARPi resistance via PARP-independent mechanisms 21 , but the clinical relevance of this hypothesis remains to be tested in BRCA-stratified cohorts. While our study was not powered to detect biomarker-defined subgroups, future trials should prioritize integrating HRD/BRCA testing to explore predictive biomarkers for LBP-TAX. In this exploratory analysis, we observed an association between early CA-125 reduction (≥ 50% within two cycles) and prolonged PFS (9.4 vs.4.1 months; p = 0.02). ​However, this finding should be interpreted as hypothesis-generating due to the small sample size (n = 7 patients with CA-125 response), which increases the risk of type I error. Prospective validation in larger cohorts is required before clinical application. aligning with prior studies suggesting CA-125 kinetics as a surrogate for treatment response in ovarian cancer 22 . While promising, these findings require validation in larger cohorts to confirm their utility as predictive biomarkers. Future trials could integrate CA-125-driven adaptive dosing strategies, potentially enabling early escalation or de-escalation based on molecular response. Furthermore, the observed trend between higher LBP exposure (AUC) and clinical response (p = 0.08) warrants pharmacokinetic-pharmacodynamic modeling in expanded studies to optimize dose individualization. One of the major findings is the low incidence of peripheral neuropathy (16.7% Grade 1–2 as opposed to 68% in carboplatin-paclitaxel regimens) 23 . This is because of LBP's polar nature and rapid clearance, preventing dorsal root ganglion accumulation 24 . In this small cohort, the absence of Grade ≥ 3 neuropathy (0%) and manageable hematologic toxicity allowed 83.3% of patients to complete ≥ 4 cycles, contrasting with historical carboplatin-paclitaxel regimens where Grade ≥ 2 neuropathy occurred in 68% of patients and often limited treatment duration 23 . Additionally, the lack of nephrotoxicity (0% Grade ≥ 2 events) may broaden applicability to patients with preexisting renal impairment. Furthermore, the lack of nephrotoxicity (0% Grade ≥ 2 events vs 15–30% with cisplatin) enhances the likelihood of candidacy in frail or elderly patients. ​However, direct comparative inferences are limited by the restricted sample size and single-arm study design. Although such initial results have been encouraging for clinical activity, some limitations exist. Most important among them is that the cohort is of small size (n = 12), which restricts statistical power to detect clinically relevant differences and makes subgroup analyses inaccurate. This constraint manifests itself in three general features: first, the reported dose-response tendencies (e.g., higher ORR at 35 mg/m 2 ) can result from stochastic fluctuation and not true pharmacodynamic effects; second, our exploratory biomarker analysis of CA-125 reduction as an indicator of PFS extension (9.4 vs. 4.1 months; p = 0.02) requires verification in larger populations because of the small number of responders (n = 7); third, the borderline pharmacokinetic-pharmacodynamic associations (e.g., AUC-response trend with p = 0.08) should be read as hypothesis-generating and not confirmatory, particularly without adjustment for multiplicity for multiple testing. Single-arm design introduces additional uncertainty because historical controls rather than concurrent comparators were used in efficacy benchmarking. Maturation of survival data is still ongoing (median OS 21.7 months; 95% CI 7.3-NA), and longer follow-up is needed to confirm durability of response. Furthermore, exclusion of patients with a history of PARPis exposure limits generalizability to contemporary treatment settings. Future validation would have three highest priorities: 1) confirmation of the MTD in big phase Ib expansion cohorts (n ≥ 30) with PK follow-up; 2) establishment of CA-125 kinetic thresholds by pre-specified adaptive biomarker designs; 3) mechanistic evaluation of LBP's claimed neuroprotective activity compared to conventional platinum analogs in randomized settings. Parallel translational studies investigating homologous recombination repair status and inflammatory microenvironment signatures can also contribute to further refining patient selection criteria. Conclusion This trial positions LBP-TAX as a potentially useful regimen for PSROC with unique benefits in terms of response durability, neuroprotection, and renal safety. The established MTD and exposure-response correlations offer a platform for biomarker-guided confirmatory trials. Abbreviations AEs: adverse events AUC: area under the curve BMI: body mass index CR/PR: complete or partial responses CTCAE: Common Terminology Criteria for Adverse Events DCR: disease control rate DOR: duration of response DLTs: dose-limiting toxicities ECOG: Eastern Cooperative Oncology Group FIGO: Federation of Gynecology and Obstetrics G-CSF: granulocyte colony-stimulating factor HPLC-MS/MS: high-performance liquid chromatography-tandem mass spectrometry HR: hazard ratio HRD: homologous recombination deficiency ICD: immunogenic cell death IV: intravenously LBP: Lobaplatin MTD: maximum tolerated dose NK: natural killer ORR: objective response rate OS: overall survival PARPis: Poly(ADP-ribose) polymerase (PARP) inhibitors PFS: progression-free survival PK: pharmacokinetic PIPN: paclitaxel peripheral neuropathy PSROC: Platinum-Sensitive Recurrent Ovarian Epithelial Carcinoma QSPR: quantitative structure-property relationship RECIST v1.1: Response Evaluation Criteria in Solid Tumors version 1.1 SD: stable disease TAX: paclitaxel TEAEs: treatment-emergent adverse events TME: tumor microenvironment TNF: tumor necrosis factor Vss: volume of distribution Declarations Author Contribution Dongling Zou and Yi Gong wrote the main manuscript text. Yingjie Yang and Lifang Ma prepared tables. Li Yuan, Jiaying Bai and Qi Zhou revised the manuscript.All authors reviewed the manuscript. References Konstantinopoulos PA, Matulonis UA. Clinical and translational advances in ovarian cancer therapy. Nat Cancer . 2023; 4: 1239-1257. O'Malley DM, Krivak TC, Kabil N, Munley J, Moore KN. PARP Inhibitors in Ovarian Cancer: A Review. Target Oncol . 2023; 18: 471-503. Li H, Liu ZY, Wu N, Chen YC, Cheng Q, Wang J. PARP inhibitor resistance: the underlying mechanisms and clinical implications. Mol Cancer . 2020; 19: 107. Chen K, Pan Q, Gao Y, et al. DMS triggers apoptosis associated with the inhibition of SPHK1/NF-κB activation and increase in intracellular Ca2+ concentration in human cancer cells. Int J Mol Med . 2014; 33: 17-24. Chen Y, Li Z, Chen X, Zhang S. Long non-coding RNAs: From disease code to drug role. Acta Pharm Sin B . 2021; 11: 340-354. Jiang Y, Wang C, Zhou S. Targeting tumor microenvironment in ovarian cancer: Premise and promise. Biochim Biophys Acta Rev Cancer . 2020; 1873: 188361. Izar B, Tirosh I, Stover EH, et al. A single-cell landscape of high-grade serous ovarian cancer. Nat Med . 2020; 26: 1271-1279. Zhao F, Jiang X, Li Y, et al. Characterizing tumor biology and immune microenvironment in high-grade serous ovarian cancer via single-cell RNA sequencing: insights for targeted and personalized immunotherapy strategies. Front Immunol . 2024; 15: 1500153. Multhoff G, Molls M, Radons J. Chronic inflammation in cancer development. Front Immunol . 2011; 2: 98. Seery T, Sender L, Jafari O, et al. Case report: PD-L1-targeted high-affinity natural killer cells and IL-15 superagonist N-803-based therapy extend overall survival of advanced metastatic pancreatic cancer patients. Front Oncol . 2025; 15: 1472714. Zhao L, Chen X, Wu H, He Q, Ding L, Yang B. Strategies to synergize PD-1/PD-L1 targeted cancer immunotherapies to enhance antitumor responses in ovarian cancer. Biochem Pharmacol . 2023; 215: 115724. Stecklein SR, Sharma P. Tumor homologous recombination deficiency assays: another step closer to clinical application? Breast Cancer Res . 2014; 16: 409. Xu J, Huang P, Bie B, et al. Complement Receptor C3aR1 Contributes to Paclitaxel-Induced Peripheral Neuropathic Pain in Mice and Rats. J Immunol . 2023; 211: 1736-1746. Arockiaraj M, Jeni Godlin JJ, Radha S, Aziz T, Al-Harbi M. Comparative study of degree, neighborhood and reverse degree based indices for drugs used in lung cancer treatment through QSPR analysis. Sci Rep . 2025; 15: 3639. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet . 2003; 361: 2099-2106. McKeage MJ. Lobaplatin: a new antitumour platinum drug. Expert Opin Investig Drugs . 2001; 10: 119-128. Zhang J, Liu D, Li Y, Sun J, Wang L, Zang A. Status of non-classical mononuclear platinum anticancer drug development. Mini Rev Med Chem . 2009; 9: 1357-1366. Tsvetkova D, Ivanova S. Application of Approved Cisplatin Derivatives in Combination Therapy against Different Cancer Diseases. Molecules . 2022; 27. Gladieff L, Ferrero A, De Rauglaudre G, et al. Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in partially platinum-sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase III trial. Ann Oncol . 2012; 23: 1185-1189. Jiang S, Pan AW, Lin TY, et al. Paclitaxel Enhances Carboplatin-DNA Adduct Formation and Cytotoxicity. Chem Res Toxicol . 2015; 28: 2250-2252. Sun X, Lou LG, Sui DH, Wu XH. Preclinical activity of lobaplatin as a single agent and in combination with taxanes for ovarian carcinoma cells. Asian Pac J Cancer Prev . 2014; 15: 9939-9943. You B, Robelin P, Tod M, et al. CA-125 ELIMination Rate Constant K (KELIM) Is a Marker of Chemosensitivity in Patients with Ovarian Cancer: Results from the Phase II CHIVA Trial. Clin Cancer Res . 2020; 26: 4625-4632. Lee CK, Gurney H, Brown C, et al. Carboplatin-paclitaxel-induced leukopenia and neuropathy predict progression-free survival in recurrent ovarian cancer. Br J Cancer . 2011; 105: 360-365. Elfarnawany A, Dehghani F. Palmitoylethanolamide Mitigates Paclitaxel Toxicity in Primary Dorsal Root Ganglion Neurons. Biomolecules . 2022; 12. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7127907","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":487043067,"identity":"b23d0559-8093-4235-a84b-892056ee680f","order_by":0,"name":"Dongling Zou","email":"","orcid":"","institution":"Chongqing Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dongling","middleName":"","lastName":"Zou","suffix":""},{"id":487043069,"identity":"638c1245-2d5a-424e-b26c-006b3b405fe7","order_by":1,"name":"Yi Gong","email":"","orcid":"","institution":"Chongqing Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Gong","suffix":""},{"id":487043071,"identity":"d738a9ac-0c9f-4e03-a398-772095a584c5","order_by":2,"name":"Yingjie Yang","email":"","orcid":"","institution":"Guizhou Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yingjie","middleName":"","lastName":"Yang","suffix":""},{"id":487043072,"identity":"2d64a27e-0920-4cd8-a927-47aebb3b660b","order_by":3,"name":"Lifang Ma","email":"","orcid":"","institution":"Chongqing Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lifang","middleName":"","lastName":"Ma","suffix":""},{"id":487043074,"identity":"d48f4f8c-7beb-4a15-bdd5-4ed3b415ddfb","order_by":4,"name":"Li Yuan","email":"","orcid":"","institution":"Chongqing Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Yuan","suffix":""},{"id":487043075,"identity":"898564e2-474e-4aff-bb66-6cc1e7a22cd1","order_by":5,"name":"Jiaying Bai","email":"","orcid":"","institution":"Guizhou Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jiaying","middleName":"","lastName":"Bai","suffix":""},{"id":487043076,"identity":"6faabc16-885d-42fe-868c-5cd99abdad92","order_by":6,"name":"Qi Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIiWNgGAWjYDACZgY2IGnDw8/efODAhx/Ea0mTkew5lnhwZg9x9oC0HLYxuJFjfJiDjQj1fMfZnz342HaYh+HMmQ+HGXgY5PnFDuDXInmYId1wZls6D2N774bDBRYMhjNnJ+DXYnCY4Zg0b5s1DzPP2Q2HZ/AwJBjcJqiFsQ2ohZmHTSLnwWEeNqK0MLMBtTjz8EjkMBCnRfIwG5vkjHNpPBI8xwyAgSxB2C98548/k/hQZmNvf7z58YcPP2zk+aUJaGE4gMqVIKAci5ZRMApGwSgYBZgAAPBARBvaHkCFAAAAAElFTkSuQmCC","orcid":"","institution":"Chongqing Cancer Hospital","correspondingAuthor":true,"prefix":"","firstName":"Qi","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2025-07-15 08:08:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7127907/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7127907/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87590613,"identity":"78218581-385e-45a1-9629-2b9fa6dc54ee","added_by":"auto","created_at":"2025-07-25 14:46:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":777974,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7127907/v1/97ea6687-6eed-4028-876b-4d35fc55ce6d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Phase I Dose-Escalation Study of Lobaplatin Combined with Paclitaxel in Platinum-Sensitive Recurrent Ovarian Epithelial Carcinoma: Safety, Tolerability, and Preliminary Efficacy Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOvarian cancer remains one of the most fatal gynecologic malignancies with over 70% of diagnosed patients presenting in advanced stages due to nonspecific symptoms and a lack of useful early detection means\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Although significant progress has been made in platinum-based chemotherapy and cytoreductive surgery, the clinical outcomes remain suboptimal, with relapse rates exceeding 80% and a dismal 5-year survival rate of merely 30% for metastatic cases. The clinical prognosis is further affected by the emergence of resistance to the standard treatments, including the Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis), which are a standard treatment option for patients who have homologous recombination deficiency (HRD)\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Recent studies suggest that resistance to PARPis may involve complex mechanisms, including impaired immunogenic cell death and enhanced tumor survival signaling\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Key contributors such as the SPHK1-NF-κB pathway\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e and specific long non-coding RNAs (e.g., HOTAIR, GAS5)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e appear to influence DNA repair and apoptosis, thereby promoting chemotherapy resistance. These findings reveal the complexity of molecular processes driving therapeutic escape, highlighting the urgent demand for innovative therapeutic approaches to overcome resistance.\u003c/p\u003e\u003cp\u003eThe tumor microenvironment (TME) plays a central role in determining ovarian cancer development and responsiveness to therapy\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Single-cell RNA sequencing has identified diverse cell populations within high-grade serous ovarian cancer\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Among them, a subset expressing IGF2 shows aggressive features and complex interactions with the stroma cells, which may be closely related to tumor progression\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Chronic inflammation in the TME also promotes accelerated immunosuppression, with enhanced M2 macrophage infiltration and abrogated cytokine networks correlating with poorer prognosis. These results validate existing evidence linking specific pro-inflammatory gene expression patterns, notably interleukin-6 (IL-6) and tumor necrosis factor (TNF)-containing signatures\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, to both reduced overall survival and compromised therapeutic efficacy of immune checkpoint inhibitors.\u003c/p\u003e\u003cp\u003eEmerging therapeutic strategies combining immunogenic cell death (ICD) inducers with immune-modulating agents have shown promising antitumor activity across both preclinical models and early-phase clinical trials. For example, IL-15 superagonist N-803 (Anktiva) enhances natural killer (NK) cell cytotoxicity and demonstrates synergistic activity with PD-L1 inhibitors in refractory metastatic pancreatic cancer\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. These findings suggest potential therapeutic applicability in ovarian carcinoma, where similar immune evasion mechanisms operate. Clinical case reports have documented the therapeutic potential of multimodal approaches combining short-course hypofractionated radiotherapy with PD-1 blockade, demonstrating durable responses in platinum-resistant ovarian cancer\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Genomic profiling of atypical metastatic patterns including inguinal lymph node metastasis, has also identified clinically actionable alterations like HRD positivity\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. This molecular insight facilitates PARPis-based precision therapy even in patients lacking BRCA mutations, expanding the therapeutic landscape for historically challenging cases.\u003c/p\u003e\u003cp\u003eDespite breakthroughs in drug design and targeted therapies, the dual objectives of enhancing therapeutic indices and mitigating unwanted effects have yet to be fully realized. As illustration, paclitaxel peripheral neuropathy (PIPN), a dose-limiting toxicity, has been associated with elevated plasma complement C3 levels, implying biomarker-guided dose personalization\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Besides, computational models integrating topological indices and quantitative structure-property relationship (QSPR) analysis are optimizing drug design for chemotherapeutic drugs like docetaxel and gemcitabine, yet clinical applicability awaits further confirmation\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Collectively, these advances indicate the critical need to integrate molecular profiling, immune modulation, and precision medicine to revolutionize the treatment of ovarian cancer and other aggressive malignancies.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cb\u003eStudy Design and Dose-Escalation Protocol\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis phase I, open-label, single-arm study employed a standard 3\u0026thinsp;+\u0026thinsp;3 dose-escalation design to evaluate the safety and tolerability of lobaplatin (LBP) combined with paclitaxel (TAX) in platinum-sensitive recurrent ovarian cancer. The starting dose of LBP was 25 mg/m\u0026sup2; (50% of the monotherapy recommended dose) administered intravenously (IV) on day 1 of a 21-day cycle, with a fixed dose of paclitaxel 175 mg/m\u0026sup2;. Dose escalation proceeded to 30 mg/m\u0026sup2; and 35 mg/m\u0026sup2; based on the occurrence of dose-limiting toxicities (DLTs) in Cycle 1. Prophylactic supportive care included mandatory use of​granulocyte colony-stimulating factor (G-CSF, 5 \u0026micro;g/kg/day subcutaneously from day 3 of each cycle) for all patients to mitigate neutropenia. Antiemetics (ondansetron 8 mg IV and dexamethasone 10 mg IV) were administered 30 minutes before chemotherapy. DLT assessment included toxicities observed despite G-CSF support (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\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\u003eDose Escalation Design\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDose Level\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLBP Dose (mg/m\u0026sup2;)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePatients Enrolled\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDLT Events\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAction Taken\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDL1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProceed to next level\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDL2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProceed to next level\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDL3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMTD declared at 30 mg/m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eLBP: Lobaplatin, MTD: maximum tolerated dose\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eParticipant Selection and Eligibility Criteria\u003c/b\u003e\u003c/p\u003e\u003cp\u003eEligible participants were adults aged 18\u0026ndash;75 years with histologically confirmed PSROC, defined as disease relapse\u0026thinsp;\u0026ge;\u0026thinsp;6 months after completion of prior platinum-based therapy. Participants were required to have \u0026ge;\u0026thinsp;1 lesion that met the definition of measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Participants were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate hematologic, hepatic, and renal function. Key exclusion criteria included prior exposure to non-platinum systemic treatment for relapse, brain metastasis, uncontrolled comorbidities, or persistent treatment-related toxicities exceeding Common Terminology Criteria for Adverse Events (CTCAE) Grade 2.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDLT Definition and Measures\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDLTs were assessed according to hematologic and non-hematologic events. Hematologic DLTs included Grade 4 neutropenia (absolute neutrophil count\u0026thinsp;\u0026lt;\u0026thinsp;0.5\u0026times;10⁹/L) lasting more than 7 days despite G-CSF support; febrile neutropenia (oral temperature\u0026thinsp;\u0026ge;\u0026thinsp;38.5\u0026deg;C with Grade 3\u0026ndash;4 neutropenia); and Grade 4 thrombocytopenia (platelets count\u0026thinsp;\u0026lt;\u0026thinsp;25\u0026times;10⁹/L) or Grade 3 thrombocytopenia (25\u0026ndash;50\u0026times;10⁹/L) accompanied by clinically significant bleeding requiring platelet transfusion. Non-hematologic DLTs were defined as any Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 toxicity, excluding alopecia and controlled nausea or vomiting. The dose-escalation employed a standard 3\u0026thinsp;+\u0026thinsp;3 design. Three patients were initially treated at the starting dose level. In the absence of any DLTs in this cohort, subsequent patients received the next higher dose level. Upon observation of the first DLT, the cohort was expanded to include three additional patients (total n\u0026thinsp;=\u0026thinsp;6) at the same dose level for further safety evaluation. The maximum tolerated dose (MTD) was formally defined as the highest dose level meeting the following safety criterion: \u0026le;1 out of 6 evaluable patients (\u0026le;\u0026thinsp;16.7%) experienced DLTs during the observation period.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAssessments of Clinical Activity\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBaseline evaluations comprised complete medical history, physical examination, ocular assessment, ECOG performance status grading, blood chemistry and hematology, pulmonary function testing, and electrocardiography. Treatment-emergent adverse events (TEAEs) were assessed as a secondary safety endpoint, with all adverse events (AEs) classified and graded per CTCAE v5.0 criteria and monitored continuously from informed consent through 30 days post-final treatment administration. Hematologic parameters were monitored bi-weekly, while biochemical profiling was performed weekly to evaluate treatment-related toxicities. Efficacy was assessed every two treatment cycles according to RECIST v1.1. The primary efficacy endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and disease control rate (DCR).\u003c/p\u003e\u003cp\u003eFor pharmacokinetic (PK) analysis, plasma samples were collected at pre-dose, and at 1, 4, and 24 hours after LBP infusion. LBP concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The analysis utilized an Agilent ZORBAX SB-C18 chromatographic column (2.1\u0026times;50 mm, 1.8 \u0026micro;m) with gradient elution using 0.1% formic acid in water and acetonitrile. A platinum isotope-labeled LBP (\u0026sup1;⁹⁵Pt-lobaplatin) served as the internal standard. The calibration range was 0.1\u0026ndash;50 \u0026micro;g/mL with confirmed linearity (r\u0026sup2; \u0026gt;0.995). Quality control samples at low (0.5 \u0026micro;g/mL), medium (10 \u0026micro;g/mL), and high (40 \u0026micro;g/mL) concentrations were included in each batch, with an acceptance deviation of \u0026plusmn;\u0026thinsp;15%. PK parameters including area under the curve (AUC), maximum plasma concentration (Cmax), and half-life (t₁/₂) were calculated via non-compartmental analysis using Phoenix WinNonlin software.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eDescriptive statistics were utilized to summarize all demographic and clinical baseline characteristics, with baseline defined as the most recent clinically documented assessment obtained prior to administration of the first study treatment dose. ORR and DCR were analyzed using descriptive statistics, with tumor response evaluated every two cycles based on RECIST v1.1. PFS and OS were estimated using the Kaplan\u0026ndash;Meier method. Patients without disease progression or death were censored at the time of their last follow-up. PK exposure-response relationships were assessed using linear regression analysis. Statistical significance was defined as a two-sided p-value of less than 0.05, with analyses performed using SAS version 9.4.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEthical Considerations\u003c/b\u003e\u003c/p\u003e\u003cp\u003e The study protocol was additionally approved by institutional review boards from collaborating centers (Ethics Approval ID: GZYB-010). Written informed consent was obtained from all participants prior to enrollment, with specific emphasis on voluntary participation and right of withdrawal.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003ePatient Disposition and Baseline Characteristics\u003c/b\u003e\u003c/p\u003e\u003cp\u003e13 patients with platinum-Sensitive Recurrent Ovarian Epithelial Carcinoma (PSROC) were screened across two participating centers from May 2018 through February 2021. Of these, 12 patients were found to be eligible and were enrolled into three sequential dose cohorts: 25 mg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;3), 30 mg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;5), and 35 mg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;4). One patient was excluded at screening due to the lack of measurable target lesions according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Among all enrolled patients who started at least one cycle of combination therapy (n\u0026thinsp;=\u0026thinsp;12), 7 (58.3%) successfully completed all 6 scheduled treatment cycles. Treatment discontinuation occurred in 5 cases (41.7%), with the primary reason being disease progression (4/5, 80%). One patient (20%) discontinued due to protocol-specified treatment delays exceeding 14 days.\u003c/p\u003e\u003cp\u003eThe cohort comprised exclusively female patients with a median age of 53.8 years (range, 44\u0026ndash;72) and median body mass index (BMI) of 24.67 kg/m\u0026sup2; (range, 18.6\u0026ndash;30.9). Ethnicity distribution was even, with 91.7% (11/12) Han Chinese. Baseline disease features were advanced-stage disease, including Federation of Gynecology and Obstetrics (FIGO) stage III (66.7%, 8/12) and stage IV (16.7%, 2/12) disease. Histologically examination confirmed primary ovarian epithelial carcinomas in all cases, predominantly high-grade serous subtype (83.3%, 10/12). The median recurrence-free interval from initial diagnosis was 26.05 months (range: 14\u0026ndash;71.1), confirming platinum-sensitive status (relapse\u0026thinsp;\u0026ge;\u0026thinsp;6 months following platinum treatment). Metastatic involvement at enrollment were pelvic lymph nodes (58.3%, 7/12), peritoneal implants (41.7%, 5/12), and liver lesions (8.3%, 1/12).\u003c/p\u003e\u003cp\u003eAll patients had undergone prior cytoreductive surgery, with optimal debulking (residual disease\u0026thinsp;\u0026lt;\u0026thinsp;1 cm) achieved in 66.7% (8/12) of cases. The majority (91.7%, 11/12) had undergone adjuvant platinum-based chemotherapy with carboplatin-paclitaxel, while one patient (8.3%) received cisplatin-based regimen. Notably, three patients (25%) had received neoadjuvant chemotherapy before surgery. No patients were exposed to anti-angiogenic therapy or PARPis. Comorbid conditions were present in half of the cohort, including well-controlled hypertension (33.3%, 4/12) and type 2 diabetes (16.7%, 2/12) managed on stable therapeutic regimens. Concomitant medications during the study drugs were primarily supportive, consisting of granulocyte colony-stimulating factor (G-CSF) prophylaxis (75.0%, 9/12) and universal antiemetic administration (100%, 12/12).\u003c/p\u003e\u003cp\u003eDose cohorts' distribution exhibited uniform baseline traits across the treatment groups and was not significantly different by any demographic variable examined, including age, BMI, FIGO stage, or earlier experience with therapy (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 by Fisher's exact test). This homogeneity across cohorts strengthens the validity of both dose-escalation outcomes and inter-group comparisons, as detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\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\u003eBaseline patient demographics and disease characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e​Characteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 mg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30 mg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e35 mg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e55.0\u0026thinsp;\u0026plusmn;\u0026thinsp;13.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e55.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e51.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e53.8\u0026thinsp;\u0026plusmn;\u0026thinsp;9.46\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI (kg/m\u0026sup2;, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22.40\u0026thinsp;\u0026plusmn;\u0026thinsp;3.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24.32\u0026thinsp;\u0026plusmn;\u0026thinsp;3.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26.80\u0026thinsp;\u0026plusmn;\u0026thinsp;4.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24.67\u0026thinsp;\u0026plusmn;\u0026thinsp;4.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFIGO Stage III/IV (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66.7%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e60.0%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e75.0%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e66.7%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrior Chemotherapy Lines (Median)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eBMI: body mass index, FIGO: Federation of Gynecology and Obstetrics\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eEfficacy Outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe LBP-TAX combination had clinically meaningful antitumor activity in this heavily pretreated platinum-sensitive recurrent ovarian cancer cohort, achieving an ORR of 50% (6/12; 1 complete response [CR], 5 partial responses [PR]) and a 100% DCR across all dose levels (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Notably, the 35 mg/m\u0026sup2; cohort showed a numerically higher ORR (75% vs. 20-66.7% in lower doses), though statistical comparison was limited by small sample sizes. Remarkably, none of the patients developed progressive disease throughout the treatment, demonstrating consistent tumor growth control. The 25 mg/m\u0026sup2; group had the greatest ORR of 66.7% (2/3: 1 CR, 1 PR), while the 30 mg/m\u0026sup2; group had a lower ORR of 20% (1/5 PR) due to potentially smaller tumor size or differential platinum sensitivity in this population. Notably, the 35 mg/m\u0026sup2; cohort achieved a 75% ORR (3/4 PR) reflecting greater antitumor activity at higher doses in the context of dose-limiting toxicities. The answers were immediate, with a median first response time of 1.8 months (range: 1.2\u0026ndash;3.1), and maintained, with median duration of response (DOR) of 8.9 months (95% CI: 5.6\u0026ndash;12.3).\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\u003eEfficacy Summary\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e​Metric\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 mg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30 mg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e35 mg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eORR (CR\u0026thinsp;+\u0026thinsp;PR, %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66.7%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20.0%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e75.0%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e50.0%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDCR (CR\u0026thinsp;+\u0026thinsp;PR\u0026thinsp;+\u0026thinsp;SD, %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e100%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian PFS (months, 95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10.1 (NA\u0026ndash;NA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.3 (4.1\u0026ndash;NA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.0 (NA\u0026ndash;NA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7.0 (5.3\u0026ndash;NA)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian OS (months, 95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNA (23.3\u0026ndash;NA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.4 (4.1\u0026ndash;NA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20.0 (15.9\u0026ndash;NA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e21.7 (7.3\u0026ndash;NA)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eORR: objective response rate, DCR: disease control rate, PFS: progression-free survival, OS: overall survival\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe survival analysis further demonstrated the clinical benefit of the treatment regimen. The median progression-free survival (mPFS) was 7.0 months (95% CI: 5.3\u0026ndash;not reached), and the 6-month and 12-month PFS rates were 71.1% (95% CI: 23.3\u0026ndash;92.3%) and 38.1% (95% CI: 12.1\u0026ndash;64.3%), respectively. The median overall survival (mOS) reached 21.7 months (95% CI: 7.3\u0026ndash;not reached), with corresponding 12-month and 24-month OS rates were 75.0% (95% CI: 40.8\u0026ndash;91.2%) and 38.1% (95% CI: 12.1\u0026ndash;64.3%). Notably, response status significantly impacted survival outcomes. Patients achieving complete or partial responses (CR/PR) showed substantially longer median OS compared to those with stable disease (SD) (28.1 vs 16.5 months; hazard ratio [HR], 0.42; 95% CI, 0.19\u0026ndash;0.93; P\u0026thinsp;=\u0026thinsp;0.03), highlighting the prognostic value of treatment response.\u003c/p\u003e\u003cp\u003ePost hoc exploratory biomarker analysis demonstrated patients with \u0026ge;\u0026thinsp;50% CA-125 reduction in the first two cycles (58.3%, 7/12) were also predictive of improved PFS (9.4 vs. 4.1 months; p\u0026thinsp;=\u0026thinsp;0.02). Tumor response assessment demonstrated consistent antitumor activity, with waterfall plot analysis showing reductions in target lesions ranging from \u0026minus;\u0026thinsp;82% to \u0026minus;\u0026thinsp;14% (median reduction: \u0026minus;43%) across all evaluable patients. Kaplan-Meier analysis showed non-significant trends toward prolonged PFS in higher-dose cohorts (log-rank p\u0026thinsp;=\u0026thinsp;0.21), though limited by small subgroup sizes (n\u0026thinsp;=\u0026thinsp;3\u0026ndash;5).\u003c/p\u003e\u003cp\u003eThese efficacy endpoints demonstrated comparable activity to historical controls. For instance, the ICON4\u003csup\u003e15\u003c/sup\u003e trial showed 66% ORR and 10.2 months mPFS for carboplatin-paclitaxel in PSROC, while the current study's higher dose intensity (35 mg/m\u0026sup2; LBP) achieved comparable activity with various toxicity profiles. The universal disease control rate is especially noteworthy in the recurrent disease setting, where tumor stabilization represents a clinically meaningful endpoint (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eSafety Profile\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe LBP-TAX combination exhibited a predictable and manageable safety profile, primarily hematologic, without treatment-related deaths or irreversible discontinuations due to adverse events (AEs). All patients (12/12, 100%) experienced at least one Treatment-emergent adverse events (TEAEs), of whom 75.0% (9/12) experienced Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 events. Hematologic toxicities were responsible for the spectrum of AEs, as would be expected by the established toxicity profiles of platinum-taxane regimens (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\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\u003eSafety Profile\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e​Adverse Event (SOC)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 mg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30 mg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e35 mg/m\u0026sup2; (n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e​Hematologic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeutropenia (Grade 3\u0026ndash;4)\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\u003e5 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 (100%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThrombocytopenia (Grade 3\u0026ndash;4)\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\u003e2 (40.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (50.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5 (41.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e​Gastrointestinal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNausea/Vomiting (Grade 1\u0026ndash;2)\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\u003e1 (20.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (25.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (25.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e​Nervous System\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeripheral Neuropathy (Grade 1\u0026ndash;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (20.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (25.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (16.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe LBP-TAX regimen was associated with universal hematologic toxicity, with all 12 patients (100%) developing Grade 3\u0026ndash;4 neutropenia. The median onset was Day 8 (range: 5\u0026ndash;12), and the median duration was 6 days (range: 4\u0026ndash;9 days). Two patients in the 35 mg/m\u0026sup2; cohort experienced dose-limiting toxicities (DLTs) due to Grade 4 neutropenia lasting more than 7 days despite granulocyte colony-stimulating factor (G-CSF) support. Febrile neutropenia occurred in 2 patients (16.7%), both in the 35 mg/m\u0026sup2; group. Grade 3\u0026ndash;4 thrombocytopenia occurred in 41.7% of patients (5/12), demonstrating a clear dose-dependent relationship. While only 1 of 5 patients (20%) in the 30 mg/m\u0026sup2; cohort developed severe thrombocytopenia, all 4 patients (100%) in the 35 mg/m\u0026sup2; cohort were affected. Notably, one patient receiving 35 mg/m\u0026sup2; experienced Grade 4 thrombocytopenia (platelet count: 25\u0026times;10⁹/L) that required platelet transfusion but resolved completely within 10 days. These findings highlight the increasing hematologic toxicity risk at higher dose levels while demonstrating the transient and manageable nature of these events. Anemia was reported as Grade 3 in 4 patients (33.3%), and was effectively managed with erythropoietin or transfusion support. No Grade 4 anemia was observed.\u003c/p\u003e\u003cp\u003eThe LBP-TAX regimen was associated with manageable non-hematologic toxicities, primarily affecting the gastrointestinal and nervous systems. Gastrointestinal events occurred in 25.0% of patients (3/12), consisting of Grade 2\u0026ndash;3 nausea and vomiting that typically developed within 24\u0026ndash;48 hours after infusion; these symptoms were effectively controlled with intensified antiemetic prophylaxis combining 5-HT3 antagonists and dexamethasone. Peripheral neuropathy emerged in 16.7% of cases (2/12), presenting as Grade 1\u0026ndash;2 transient paresthesia without apparent dose dependency. Mild hepatic and renal laboratory abnormalities were observed, with asymptomatic Grade 1\u0026ndash;2 ALT/AST elevations and serum creatinine increases each occurring in one patient (8.3%), all of which resolved spontaneously. Notably, one patient (8.3%) in the 30 mg/m\u0026sup2; cohort experienced a Grade 2 paclitaxel-related hypersensitivity reaction characterized by rash and hypotension, which was successfully managed with antihistamine administration and infusion rate adjustment without treatment discontinuation. These findings demonstrate that the non-hematologic toxicity profile of LBP-TAX is consistent with platinum-taxane chemotherapy expectations, with all adverse events being clinically manageable and reversible.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDLT and MTD\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe MTD was established as 30 mg/m\u0026sup2; following two events of DLT (Grade 4 neutropenia) at 35 mg/m\u0026sup2;. No DLTs were observed in cohorts at doses of 25 mg/m\u0026sup2; and 30 mg/m\u0026sup2;. 75.0% (9/12) of patients were prophylactically treated with G-CSF, mostly in higher doses, which forestalled complications of neutropenia.\u003c/p\u003e\u003cp\u003e\u003cb\u003eComparative Safety\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe hematologic toxicity profile is aligned with prior experience of platinum regimens, though LBP was associated with a lower incidence of severe non-hematologic AEs versus cisplatin (e.g., nephrotoxicity: 0% vs. 15\u0026ndash;25% in the historical record). The absence of Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neurotoxicity or alopecia compares favorably to carboplatin-paclitaxel regimens and suggests a differentiated tolerability profile.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSupportive Care and Dose Adjustments\u003c/b\u003e\u003c/p\u003e\u003cp\u003eReductions in dose were required in 33.3% (4/12), all of whom were on the 35 mg/m\u0026sup2; arm. Delayed treatment (median: 7 days) due to cytopenia occurred in 41.7% (5/12). Proactive use of G-CSF and thrombopoietin receptor agonists (e.g., eltrombopag) in high-risk patients lowered morbidity. The LBP-TAX regimen had a safety profile consistent with myelosuppressive platinum agents, and the toxicity was dose-escalated in severity. The 30 mg/m\u0026sup2; MTD of LBP achieves an efficacy-tolerability balance with the support of aggressive supportive care. The findings demonstrate the regimen's feasibility for further development in PSROC.\u003c/p\u003e\u003cp\u003e\u003cb\u003ePK Analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePK profile of LBP administered in combination with paclitaxel was dose-proportional exposure and clearance was rapid, and no drug accumulation was seen between cycles. Blood samples were drawn at the planned time points (pre-dose, 1 h, 4 h, and 24 h after LBP infusion) during Cycle 1 and analyzed by high-performance liquid chromatography\u0026ndash;tandem mass spectrometry (HPLC-MS/MS). PK parameters of interest were derived from non-compartmental analysis.\u003c/p\u003e\u003cp\u003eLBP at the MTD of 30 mg/m\u0026sup2; had an average plasma clearance (CL) of 12.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 L/h/m\u0026sup2; and a steady-state volume of distribution (Vss) of 25.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7 L/m\u0026sup2;, indicating extensive tissue penetration. Pharmacokinetic analysis revealed rapid absorption (median Tmax\u0026thinsp;=\u0026thinsp;1.2 hours post-infusion) with a peak plasma concentration (Cmax) of 1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31 \u0026micro;g/mL and an AUC0-24h of 8.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 mg\u0026middot;h/L. Dose-proportional pharmacokinetics were confirmed across the 25\u0026ndash;35 mg/m\u0026sup2; dose range, as evidenced by a slope of 1.02 (95% CI: 0.94\u0026ndash;1.10) for the log(AUC)-log(dose) relationship, with the 90% confidence interval fully contained within the predefined proportionality boundaries (0.9\u0026ndash;1.1). These pharmacokinetic properties support the observed clinical activity profile while maintaining a manageable safety window at the MTD.\u003c/p\u003e\u003cp\u003eThe terminal half-life of elimination (t1/2) of LBP was 6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3 h, less than the previously reported ones for carboplatin (t1/2\u0026thinsp;~\u0026thinsp;12 h) but comparable to cisplatin (t1/2\u0026thinsp;~\u0026thinsp;5\u0026ndash;8 h). Renal excretion appeared to be the main route, with 68.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2% of the dose given recovered unaltered in urine within 24 h, in line with LBP's low plasma protein binding (25.1\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4%). No PK parameter differences between cycles were observed, confirming the absence of time-dependent accumulation.\u003c/p\u003e\u003cp\u003eInterpatient variations of exposure parameters were moderate, i.e., 18\u0026ndash;24% for CV% of AUC0\u0026ndash;24h and Cmax. Subgroup analysis revealed no clinically significant impact of age, renal function (baseline creatinine clearance\u0026thinsp;\u0026ge;\u0026thinsp;55 mL/min), or hepatic status on PK parameters. Notably, no influence of paclitaxel coadministration on LBP's disposition was detected, with similar CL and Vss values compared to historical controls from LBP monotherapy.\u003c/p\u003e\u003cp\u003eExposure-response relationships were explored post hoc. Partial or complete responders (n\u0026thinsp;=\u0026thinsp;6) had a trend towards higher AUC0\u0026ndash;24h (9.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8 vs. 7.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3 mg\u0026middot;h/L, p\u0026thinsp;=\u0026thinsp;0.08) and lower CL (11.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9 vs. 13.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3 L/h/m\u0026sup2;, p\u0026thinsp;=\u0026thinsp;0.06) than non-responders and thus may reflect an exposure-efficacy relationship. Grade 4 neutropenia was related to higher Cmax (1.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28 vs. 1.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25 \u0026micro;g/mL, p\u0026thinsp;=\u0026thinsp;0.04) and supports myelosuppression as a toxicity of exposure relationship (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePK Parameters\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e​PK Parameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 mg/m\u0026sup2;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30 mg/m\u0026sup2;\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e35 mg/m\u0026sup2;\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAUC₀\u0026ndash;24h (mg\u0026middot;h/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e6.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e8.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e10.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCmax (\u0026micro;g/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e1.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e1.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003et₁/₂ (h)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e6.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e7.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrinary Excretion (24h, %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e65.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e68.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e70.1\u0026thinsp;\u0026plusmn;\u0026thinsp;10.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003ePK: Pharmacokinetic, AUC: area under the curve\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eComparison PK Insights\u003c/b\u003e\u003c/p\u003e\u003cp\u003eLBP's elimination with a short t1/2 and renal-dominant excretion differ from carboplatin's extended elimination (solely glomerular filtration) and hepatic metabolism of cisplatin. These characteristics could account for LBP's lesser non-hematologic toxicity, including nephrotoxicity (0% Grade\u0026thinsp;\u0026ge;\u0026thinsp;2 events versus 15\u0026ndash;30% with cisplatin). The brief t1/2 also allows for weekly dose fractionation regimens to reduce toxicity, a hypothesis deserving further investigation.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study establishes 30 mg/m\u0026sup2; as the MTD of LBP with TAX in PSROC where efficacy and safety are balanced. The emergence of Grade 4 neutropenia lasting\u0026thinsp;\u0026gt;\u0026thinsp;7 days as a DLT at the 35 mg/m\u0026sup2; dose level underscores LBP's distinct hematologic profile compared to conventional carboplatin-paclitaxel regimens, while carboplatin-based combinations rarely encounter dose-limiting myelosuppression\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. This partitioning is very likely due to LBP's bifunctional DNA crosslinking activity, which induces greater stem cell inhibition than the monofunctional adducts of carboplatin\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Surprisingly, the MTD attained a 100% DCR, which shows synergy between LBP and TAX based on enhanced platinum incorporation due to tubulin-mediated endocytosis, as illustrated in preclinical models\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. However, the observed dose-response relationships should be interpreted with caution given the limited sample size (n\u0026thinsp;=\u0026thinsp;12), which reduces statistical power to detect subtle but clinically meaningful differences between dose levels. LBP's linear PK and rapid clearance suggest a predictable exposure profile, potentially reducing the need for therapeutic drug monitoring compared to carboplatin. These properties can reduce cumulative toxicity, which is a valuable property in recurrent disease with the need for prolonged therapy.\u003c/p\u003e\u003cp\u003eThe regimen achieved its target ORR of 50% and mPFS of 7.0 months, comparable to carboplatin-paclitaxel comparators (ICON4 ORR: 66%; mPFS: 10.2 months)\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. However, the median DOR of 8.9 months exceeds historical controls (CALYPSO: 7.4 months)\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, and this is perhaps due to LBP's stable DNA adducts being refractory to excision repair\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. A numerically higher ORR was observed in the 35 mg/m\u0026sup2; cohort (75% vs. 20-66.7% in lower doses), ​though the small subgroup sizes (n\u0026thinsp;=\u0026thinsp;3\u0026ndash;5 per cohort) and lack of statistical power preclude definitive conclusions about dose-dependent efficacy. Preclinical models suggest that lobaplatin could overcome PARPi resistance via PARP-independent mechanisms\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, but the clinical relevance of this hypothesis remains to be tested in BRCA-stratified cohorts. While our study was not powered to detect biomarker-defined subgroups, future trials should prioritize integrating HRD/BRCA testing to explore predictive biomarkers for LBP-TAX.\u003c/p\u003e\u003cp\u003eIn this exploratory analysis, we observed an association between early CA-125 reduction (\u0026ge;\u0026thinsp;50% within two cycles) and prolonged PFS (9.4 vs.4.1 months; p\u0026thinsp;=\u0026thinsp;0.02). ​However, this finding should be interpreted as hypothesis-generating due to the small sample size (n\u0026thinsp;=\u0026thinsp;7 patients with CA-125 response), which increases the risk of type I error. Prospective validation in larger cohorts is required before clinical application. aligning with prior studies suggesting CA-125 kinetics as a surrogate for treatment response in ovarian cancer\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. While promising, these findings require validation in larger cohorts to confirm their utility as predictive biomarkers. Future trials could integrate CA-125-driven adaptive dosing strategies, potentially enabling early escalation or de-escalation based on molecular response. Furthermore, the observed trend between higher LBP exposure (AUC) and clinical response (p\u0026thinsp;=\u0026thinsp;0.08) warrants pharmacokinetic-pharmacodynamic modeling in expanded studies to optimize dose individualization.\u003c/p\u003e\u003cp\u003eOne of the major findings is the low incidence of peripheral neuropathy (16.7% Grade 1\u0026ndash;2 as opposed to 68% in carboplatin-paclitaxel regimens)\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. This is because of LBP's polar nature and rapid clearance, preventing dorsal root ganglion accumulation\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. In this small cohort, the absence of Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 neuropathy (0%) and manageable hematologic toxicity allowed 83.3% of patients to complete\u0026thinsp;\u0026ge;\u0026thinsp;4 cycles, contrasting with historical carboplatin-paclitaxel regimens where Grade\u0026thinsp;\u0026ge;\u0026thinsp;2 neuropathy occurred in 68% of patients and often limited treatment duration\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Additionally, the lack of nephrotoxicity (0% Grade\u0026thinsp;\u0026ge;\u0026thinsp;2 events) may broaden applicability to patients with preexisting renal impairment. Furthermore, the lack of nephrotoxicity (0% Grade\u0026thinsp;\u0026ge;\u0026thinsp;2 events vs 15\u0026ndash;30% with cisplatin) enhances the likelihood of candidacy in frail or elderly patients. ​However, direct comparative inferences are limited by the restricted sample size and single-arm study design.\u003c/p\u003e\u003cp\u003eAlthough such initial results have been encouraging for clinical activity, some limitations exist. Most important among them is that the cohort is of small size (n\u0026thinsp;=\u0026thinsp;12), which restricts statistical power to detect clinically relevant differences and makes subgroup analyses inaccurate. This constraint manifests itself in three general features: first, the reported dose-response tendencies (e.g., higher ORR at 35 mg/m\u003csup\u003e2\u003c/sup\u003e) can result from stochastic fluctuation and not true pharmacodynamic effects; second, our exploratory biomarker analysis of CA-125 reduction as an indicator of PFS extension (9.4 vs. 4.1 months; p\u0026thinsp;=\u0026thinsp;0.02) requires verification in larger populations because of the small number of responders (n\u0026thinsp;=\u0026thinsp;7); third, the borderline pharmacokinetic-pharmacodynamic associations (e.g., AUC-response trend with p\u0026thinsp;=\u0026thinsp;0.08) should be read as hypothesis-generating and not confirmatory, particularly without adjustment for multiplicity for multiple testing.\u003c/p\u003e\u003cp\u003eSingle-arm design introduces additional uncertainty because historical controls rather than concurrent comparators were used in efficacy benchmarking. Maturation of survival data is still ongoing (median OS 21.7 months; 95% CI 7.3-NA), and longer follow-up is needed to confirm durability of response. Furthermore, exclusion of patients with a history of PARPis exposure limits generalizability to contemporary treatment settings.\u003c/p\u003e\u003cp\u003eFuture validation would have three highest priorities: 1) confirmation of the MTD in big phase Ib expansion cohorts (n\u0026thinsp;\u0026ge;\u0026thinsp;30) with PK follow-up; 2) establishment of CA-125 kinetic thresholds by pre-specified adaptive biomarker designs; 3) mechanistic evaluation of LBP's claimed neuroprotective activity compared to conventional platinum analogs in randomized settings. Parallel translational studies investigating homologous recombination repair status and inflammatory microenvironment signatures can also contribute to further refining patient selection criteria.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis trial positions LBP-TAX as a potentially useful regimen for PSROC with unique benefits in terms of response durability, neuroprotection, and renal safety. The established MTD and exposure-response correlations offer a platform for biomarker-guided confirmatory trials.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAEs: adverse events\u003c/p\u003e\n\u003cp\u003eAUC: area under the curve\u003c/p\u003e\n\u003cp\u003eBMI: body mass index\u003c/p\u003e\n\u003cp\u003eCR/PR: complete or partial responses\u003c/p\u003e\n\u003cp\u003eCTCAE: Common Terminology Criteria for Adverse Events\u003c/p\u003e\n\u003cp\u003eDCR: disease control rate\u003c/p\u003e\n\u003cp\u003eDOR: duration of response\u003c/p\u003e\n\u003cp\u003eDLTs: dose-limiting toxicities\u003c/p\u003e\n\u003cp\u003eECOG: Eastern Cooperative Oncology Group\u003c/p\u003e\n\u003cp\u003eFIGO: Federation of Gynecology and Obstetrics\u003c/p\u003e\n\u003cp\u003eG-CSF: granulocyte colony-stimulating factor\u003c/p\u003e\n\u003cp\u003eHPLC-MS/MS: high-performance liquid chromatography-tandem mass spectrometry\u003c/p\u003e\n\u003cp\u003eHR: hazard ratio\u003c/p\u003e\n\u003cp\u003eHRD: homologous recombination deficiency\u003c/p\u003e\n\u003cp\u003eICD: immunogenic cell death\u003c/p\u003e\n\u003cp\u003eIV: intravenously\u003c/p\u003e\n\u003cp\u003eLBP: Lobaplatin\u003c/p\u003e\n\u003cp\u003eMTD: maximum tolerated dose\u003c/p\u003e\n\u003cp\u003eNK: natural killer\u003c/p\u003e\n\u003cp\u003eORR: objective response rate\u003c/p\u003e\n\u003cp\u003eOS: overall survival\u003c/p\u003e\n\u003cp\u003ePARPis: Poly(ADP-ribose) polymerase (PARP) inhibitors\u003c/p\u003e\n\u003cp\u003ePFS: progression-free survival\u003c/p\u003e\n\u003cp\u003ePK: pharmacokinetic\u003c/p\u003e\n\u003cp\u003ePIPN: paclitaxel peripheral neuropathy\u003c/p\u003e\n\u003cp\u003ePSROC: Platinum-Sensitive Recurrent Ovarian Epithelial Carcinoma\u003c/p\u003e\n\u003cp\u003eQSPR: quantitative structure-property relationship\u003c/p\u003e\n\u003cp\u003eRECIST v1.1: Response Evaluation Criteria in Solid Tumors version 1.1\u003c/p\u003e\n\u003cp\u003eSD: stable disease\u003c/p\u003e\n\u003cp\u003eTAX: paclitaxel\u003c/p\u003e\n\u003cp\u003eTEAEs: treatment-emergent adverse events\u003c/p\u003e\n\u003cp\u003eTME: tumor microenvironment\u003c/p\u003e\n\u003cp\u003eTNF: tumor necrosis factor\u003c/p\u003e\n\u003cp\u003eVss: volume of distribution\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eDongling Zou and Yi Gong wrote the main manuscript text. Yingjie Yang and Lifang Ma prepared tables. Li Yuan, Jiaying Bai and Qi Zhou revised the manuscript.All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKonstantinopoulos PA, Matulonis UA. Clinical and translational advances in ovarian cancer therapy. \u003cem\u003eNat Cancer\u003c/em\u003e. 2023; 4: 1239-1257.\u003c/li\u003e\n\u003cli\u003eO'Malley DM, Krivak TC, Kabil N, Munley J, Moore KN. PARP Inhibitors in Ovarian Cancer: A Review. \u003cem\u003eTarget Oncol\u003c/em\u003e. 2023; 18: 471-503.\u003c/li\u003e\n\u003cli\u003eLi H, Liu ZY, Wu N, Chen YC, Cheng Q, Wang J. PARP inhibitor resistance: the underlying mechanisms and clinical implications. \u003cem\u003eMol Cancer\u003c/em\u003e. 2020; 19: 107.\u003c/li\u003e\n\u003cli\u003eChen K, Pan Q, Gao Y, et al. 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Characterizing tumor biology and immune microenvironment in high-grade serous ovarian cancer via single-cell RNA sequencing: insights for targeted and personalized immunotherapy strategies. \u003cem\u003eFront Immunol\u003c/em\u003e. 2024; 15: 1500153.\u003c/li\u003e\n\u003cli\u003eMulthoff G, Molls M, Radons J. Chronic inflammation in cancer development. \u003cem\u003eFront Immunol\u003c/em\u003e. 2011; 2: 98.\u003c/li\u003e\n\u003cli\u003eSeery T, Sender L, Jafari O, et al. Case report: PD-L1-targeted high-affinity natural killer cells and IL-15 superagonist N-803-based therapy extend overall survival of advanced metastatic pancreatic cancer patients. \u003cem\u003eFront Oncol\u003c/em\u003e. 2025; 15: 1472714.\u003c/li\u003e\n\u003cli\u003eZhao L, Chen X, Wu H, He Q, Ding L, Yang B. Strategies to synergize PD-1/PD-L1 targeted cancer immunotherapies to enhance antitumor responses in ovarian cancer. \u003cem\u003eBiochem Pharmacol\u003c/em\u003e. 2023; 215: 115724.\u003c/li\u003e\n\u003cli\u003eStecklein SR, Sharma P. Tumor homologous recombination deficiency assays: another step closer to clinical application? \u003cem\u003eBreast Cancer Res\u003c/em\u003e. 2014; 16: 409.\u003c/li\u003e\n\u003cli\u003eXu J, Huang P, Bie B, et al. Complement Receptor C3aR1 Contributes to Paclitaxel-Induced Peripheral Neuropathic Pain in Mice and Rats. \u003cem\u003eJ Immunol\u003c/em\u003e. 2023; 211: 1736-1746.\u003c/li\u003e\n\u003cli\u003eArockiaraj M, Jeni Godlin JJ, Radha S, Aziz T, Al-Harbi M. Comparative study of degree, neighborhood and reverse degree based indices for drugs used in lung cancer treatment through QSPR analysis. \u003cem\u003eSci Rep\u003c/em\u003e. 2025; 15: 3639.\u003c/li\u003e\n\u003cli\u003eParmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. \u003cem\u003eLancet\u003c/em\u003e. 2003; 361: 2099-2106.\u003c/li\u003e\n\u003cli\u003eMcKeage MJ. Lobaplatin: a new antitumour platinum drug. \u003cem\u003eExpert Opin Investig Drugs\u003c/em\u003e. 2001; 10: 119-128.\u003c/li\u003e\n\u003cli\u003eZhang J, Liu D, Li Y, Sun J, Wang L, Zang A. Status of non-classical mononuclear platinum anticancer drug development. \u003cem\u003eMini Rev Med Chem\u003c/em\u003e. 2009; 9: 1357-1366.\u003c/li\u003e\n\u003cli\u003eTsvetkova D, Ivanova S. Application of Approved Cisplatin Derivatives in Combination Therapy against Different Cancer Diseases. \u003cem\u003eMolecules\u003c/em\u003e. 2022; 27.\u003c/li\u003e\n\u003cli\u003eGladieff L, Ferrero A, De Rauglaudre G, et al. Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in partially platinum-sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase III trial. \u003cem\u003eAnn Oncol\u003c/em\u003e. 2012; 23: 1185-1189.\u003c/li\u003e\n\u003cli\u003eJiang S, Pan AW, Lin TY, et al. Paclitaxel Enhances Carboplatin-DNA Adduct Formation and Cytotoxicity. \u003cem\u003eChem Res Toxicol\u003c/em\u003e. 2015; 28: 2250-2252.\u003c/li\u003e\n\u003cli\u003eSun X, Lou LG, Sui DH, Wu XH. Preclinical activity of lobaplatin as a single agent and in combination with taxanes for ovarian carcinoma cells. \u003cem\u003eAsian Pac J Cancer Prev\u003c/em\u003e. 2014; 15: 9939-9943.\u003c/li\u003e\n\u003cli\u003eYou B, Robelin P, Tod M, et al. CA-125 ELIMination Rate Constant K (KELIM) Is a Marker of Chemosensitivity in Patients with Ovarian Cancer: Results from the Phase II CHIVA Trial. \u003cem\u003eClin Cancer Res\u003c/em\u003e. 2020; 26: 4625-4632.\u003c/li\u003e\n\u003cli\u003eLee CK, Gurney H, Brown C, et al. Carboplatin-paclitaxel-induced leukopenia and neuropathy predict progression-free survival in recurrent ovarian cancer. \u003cem\u003eBr J Cancer\u003c/em\u003e. 2011; 105: 360-365.\u003c/li\u003e\n\u003cli\u003eElfarnawany A, Dehghani F. Palmitoylethanolamide Mitigates Paclitaxel Toxicity in Primary Dorsal Root Ganglion Neurons. \u003cem\u003eBiomolecules\u003c/em\u003e. 2022; 12.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Platinum-sensitive ovarian cancer, Lobaplatin, Paclitaxel, Phase I clinical trial","lastPublishedDoi":"10.21203/rs.3.rs-7127907/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7127907/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Platinum-Sensitive Recurrent Ovarian Epithelial Carcinoma (PSROC) is challenging to treat due to cumulative toxicity and resistance to platinum rechallenge. Lobaplatin (LBP), a third-generation platinum agent, offers advantages such as lower nephrotoxicity and lack of cross-resistance with carboplatin.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Twelve patients were entered to three LBP dose cohorts (25, 30, 35 mg/m²) and TAX fixed to 175 mg/m². MTD was established by the 3+3 escalation design based on the occurrence of dose-limiting toxicities (DLTs) within Cycle 1. Safety evaluation was performed with CTCAE v5.0 criteria while pharmacokinetic (PK) analysis employed HPLC-MS/MS. Efficacy endpoints measured were objective response rate (ORR) in accordance with RECIST v1.1, progression-free survival (PFS), and overall survival (OS).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: MTD was established at 30 mg/m² after two DLTs of Grade 4 neutropenia \u0026gt;7 days at 35 mg/m². The regimen had 50% ORR (1 CR, 5 PR) and 100% disease control rate. Median PFS was 7.0 months (95% CI:5.3-NA) with median OS of 21.7 months (95% CI:7.3-NA). Grade 3-4 hematologic toxicities were neutropenia (100%), thrombocytopenia (41.7%), and anemia (33.3%) that were manageable with supportive care. Non-hematologic toxicities were primarily Grade 1-2 (nausea/vomiting 25%, neuropathy 16.7%). PK analysis revealed dose-proportional exposure (AUC slope 1.02) and rapid renal clearance (68.5% of the dose excreted in urine in 24h).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: The LBP-TAX regimen shows promising efficacy and manageable toxicity in PSROC. The established MTD of 30 mg/m² supports future trials against standard platinum therapies.\u003c/p\u003e","manuscriptTitle":"A Phase I Dose-Escalation Study of Lobaplatin Combined with Paclitaxel in Platinum-Sensitive Recurrent Ovarian Epithelial Carcinoma: Safety, Tolerability, and Preliminary Efficacy Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 10:29:33","doi":"10.21203/rs.3.rs-7127907/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b382c9e2-4959-4329-89ce-cd649d0b6f93","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-25T14:38:41+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-18 10:29:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7127907","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7127907","identity":"rs-7127907","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}