Phase I, two-part, multicenter, first-in-human (FIH) study of DS-6000a in subjects with advanced renal cell carcinoma (RCC) and ovarian tumors (OVC).

3002 Background: Cadherin 6 (CDH6) is part of the cadherin family, which is involved with cell-cell adhesion, organ development, and epithelial-mesenchymal transition. CDH6 is found to be overexpressed in various cancers, particularly RCC and OVC. DS-6000a is an antibody-drug conjugate, comprised of an humanized anti-CDH6 IgG1 monoclonal antibody attached to a topoisomerase I (TOP1) inhibitor payload via a cleavable linker. DS-6000a specifically binds to CDH6 on the surface of tumor cells and is internalized upon binding. The payload is then released, resulting in target cell apoptosis. In preclinical studies, DS-6000a inhibited tumor growth and induced tumor regression in CDH6-expressing RCC and OVC. Here, we report initial results from a phase I trial of DS-6000a in patients (pts) with advanced RCC and OVC (NCT04707248). Methods: This dose-escalation (Part A) and expansion (Part B) study will recruit pts with advanced RCC and OVC. DS-6000a is administered IV as monotherapy on Day 1 of 21-day cycles. Part A assesses safety, tolerability, and maximum tolerated dose or recommended dose for expansion (RDE) using Bayesian optimal interval design; additional pts are enrolled to examine safety and efficacy. The starting dose of DS-6000a is 1.6 mg/kg followed by 3.2, 4.8, 6.4, 8, and 9.6 mg/kg. Part B will assess safety, tolerability and efficacy at the RDE. Results: Part A interim results are presented. At data cutoff (19 NOV 2021), 22 pts had enrolled (7 RCC, 15 OVC). All RCC pts had received an immune checkpoint inhibitor and the majority of OVC had platinum resistant (Pt-R) disease; median age was 63.5 years (range, 41-78); median of 4 (range, 1-12) prior lines of therapy were administered; and median treatment duration was 8.0 wks (range, 3-33.14). Fifteen pts (68.2%) were ongoing at the cutoff date. Treatment-emergent adverse events (TEAEs) occurred in 19 pts (86.4%). Related TEAEs occurred in 17 pts (77.3%). The most common related TEAEs (>20%) were fatigue and nausea (45.5% each), and vomiting (27.3%). Grade ≥3 related TEAEs occurred in 4 pts (18.2%); the most common was neutropenia (13.6%). One patient (4.5%) had a Grade 3 febrile neutropenia. One dose-limiting toxicity of Grade 4 thrombocytopenia (9.6 mg/kg) occurred. There was no study drug discontinuation due to a TEAE. Among 15 evaluable pts, 2 partial responses (PRs; 1 confirmed in RCC and 1 unconfirmed PR in Pt-R OVC) were observed; 9 pts had stable disease. Moreover, 5 out of 11 OVC evaluable pts showed CA-125 responses using GCIG criteria and all CA-125 responders had Pt-R disease. Conclusions: The interim data from dose-escalation of this FIH study showed acceptable tolerability with early signals of efficacy in heavily pretreated pts with advanced RCC and Pt-R OVC, which support further clinical evaluation of DS-6000a in the planned dose-expansion cohorts in advanced RCC and OVC. Clinical trial information: NCT04707248.