Efficacy and safety data from Ph1b, dose optimization trial of two doses of TH1902 (sudocetaxel zendusortide), a novel SORT1-targeting peptide drug conjugate (PDC), administered weekly vs q3weekly in patients (pts) with advanced ovarian cancer.

e15113 Background: TH1902 is a novel PDC that targets SORT1 receptor, which is highly expressed in many solid tumors, including ovarian cancer (OVC). Via SORT1 receptor's normal trafficking function, rapid internalization and release of the docetaxel payload is achieved, resulting in higher intracellular concentrations compared to docetaxel alone. This PDC has a unique multimodal MOA, with an improved efficacy and safety profile in heavily pretreated OVC pts. Data from parts 1&2 of this Ph I study (i.e. q21 day administration of TH1902) were previously reported. An amendment to this study was implemented to evaluate if TH1902 weekly administration for 3 weeks q28days could improve both safety and efficacy. PK parameters and other biomarkers were also evaluated. Methods: Primary Ph1 objective was to characterize the safety/tolerability of TH1902. In Part 3, TH1902 was administered weekly in two cohorts: Arm A (1.75 mg/kg) and Arm B (2.50 mg/kg) on D1, D8, D15 q28 days. Doses were chosen based on safety and PK data from Parts1&2 (200-300 mg/m 2 D1 q21 days). A minimum of 6 evaluable pts was recruited in each cohort and consisted of heavily pretreated (≤8 lines of previous therapy), high grade serous OVC pts, including high grade peritoneal/fallopian tube/endometrioid cancer, who were resistant to both platinum and 1 line of taxane. Pts were followed for 12 weeks to evaluate safety, dose limiting toxicities (DLTs), tumor response, and CA125 levels. Results: 7 and 6 pts were recruited to Arm A and Arm B respectively. Neither arm had any observed DLTs. Safety profile of weekly administration was improved compared to q3weekly, with no ≥Gr 3 neuropathy, ocular or neutropenia TRAEs. At the 1.75 mg/kg/wk dose, minimal efficacy was observed with no tumor shrinkage. One pt had a maximum CA125 reduction of -34%. At the 2.50 mg/kg/wk dose, 3/6 pts had tumor shrinkage, with 2 pts achieving a 27% and 25% RECIST 1.1 reduction, and one of these 2 patients having complete resolution of a target lesion in liver. 4/6 pts on Arm B also had reductions in CA125 (15-57%). Arm A mean duration on treatment was 7.6 weeks vs 10.25 weeks on Arm B. All patients in Arm B received 2-4 cycles of TH1902 and were evaluable for efficacy. PK analyses, done at C1D1, C1D15 and C2D1 in both arms, demonstrate dose proportionality and a linear dose relationship. Conclusions: Weekly administration of TH1902 resulted in an improved safety profile, with no DLTs, few ≥Gr 3 TRAEs, and no ≥Gr 3 neuropathy, ocular or neutropenia events. An emerging efficacy signal in the higher dose arm suggests a dose response. Two additional monotherapy doses will be explored in the proposed amendment (i.e. 3.33 and 3.90 mg/kg/wk) to establish MTD and the optimal monotherapy dose for expansion cohorts. Clinical trial information: NCT04706962 .

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