Abstract CT124: First-in-human study of SC-004, an antibody-drug conjugate targeting CLDN6/9, in patients with epithelial ovarian cancers
Authors: Hamilton Erika , Fleming Gini F. , Thaker Premal H. , Subbiah Vivek , Chen Chris , Fong Abraham , Brickman Daniel , Moore Kathleen 
Published: September 2020

Abstract
Background: More than 90% of ovarian cancers are epithelial ovarian cancers (EOC), and approximately 70% of EOCs are serous histology. Despite advancements with the development of PARP inhibitors and incorporation of bevacizumab, a clear unmet need remains for patients (pts) with recurrent EOC which is no longer considered appropriate for platinum-based chemotherapy (platinum-resistant). Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, and there are limited options for pts who progress after first and/or second line chemotherapy. Claudins (CLDNs) are four-pass transmembrane proteins with key roles in tight junction formation and function, regulation of paracellular transport, and maintenance of cell polarity. CLDN6 and CLDN9 are expressed on neoplastic cells in a proportion of high-grade EOC and high-grade serous EC with minimal expression in normal tissues. SC-004 is an antibody-drug conjugate (ADC), consisting of an antibody targeting CLDN6/9 linked to a pyrrolobenzodiazepine (PBD) dimer DNA cross-linking agent. In this open-label, phase 1 clinical trial, the safety, tolerability and maximum tolerated dose (MTD) of SC-004 were assessed in pts with platinum-resistant/refractory EOC and EC (NCT03138408). Methods: Enrolled pts were adults with platinum-refractory or resistant high-grade serous EOC or EC, who had previously received at least 1 platinum-based chemotherapeutic regimen. SC-004 was administered intravenously at 0.005-0.3 mg/kg every 3 weeks (0.3 mg/kg was administered every 4 weeks). Treatment emergent adverse events (TEAEs) were defined as any adverse event (AE) that worsened from the first dose of SC-004 through 90 days following discontinuation of treatment. Membranous CLDN6 expression was assessed by immunohistochemistry retrospectively. Results: A total of 24 pts were enrolled (11 with ovarian and 13 with EC). Pts received SC-004 for a median of 2.5 cycles (range:1-25). The most common TEAEs (&gt;20% of pts, N=24) were fatigue (38%), peripheral edema (33%), vomiting (33%), pleural effusion (25%), urinary tract infection (25%), rash maculo-papular (25%), anemia (21%), abdominal pain (21%), diarrhea (21%), and decreased appetite (21%). Twenty-one pts (88%) had at least 1 AE possibly related to SC-004. Eight pts (33%) had at least 1 grade 3 or higher AE with a possibility of being related to SC-004, the most common being pericardial effusion in 2 pts (8%). Eight pts (33%) had at least 1 SAE, including pericardial effusion, pleural effusion, renal failure, respiratory failure, abdominal pain, and failure to thrive, each occurring in 2 pts (8%) each. Eight pts (33%) had at least 1 AE leading to SC-004 dose interruption. Three pts (13%) had a fatal AE considered unrelated to SC-004. Thirteen pts (54%) died during the trial, mainly due to disease progression. The MTD was 0.2 mg/kg Q3W. Among 19 evaluable pts, best overall response of stable disease occurred in 14 pts (73%), partial response in 1 pt (5%), and progressive disease in 4 pts (21%). 4/19 pts (21%) with evaluable tissue had at least 50% of tumor cells with membranous CLDN6 expression, and one of these pts had the only partial response. Conclusion: SC-004 demonstrated low tolerability with a side effect profile similar to other PBD-conjugated ADCs, along with insufficient evidence of activity to support continued investigation.
Citation Format: Erika Hamilton, Gini F. Fleming, Premal H. Thaker, Vivek Subbiah, Chris Chen, Abraham Fong, Daniel Brickman, Kathleen Moore. First-in-human study of SC-004, an antibody-drug conjugate targeting CLDN6/9, in patients with epithelial ovarian cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT124.