Background: ZN-c3 is a novel, selective, and orally bioavailable WEE1 inhibitor that has demonstrated significant antitumor activity in in-vitro and in-vivo models. Combining ZN-c3 with CT may inhibit repair of CT-induced DNA damage and provide therapeutic benefit in patients with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer.

Methods: This Phase 1b, open-label, multicenter study is assessing ZN-c3 plus pegylated liposomal doxorubicin (PLD), carboplatin, paclitaxel, or gemcitabine in adult women with high-grade serous epithelial ovarian, peritoneal, or fallopian tube carcinoma who have received 1-2 prior regimens/lines of therapy in the metastatic setting and are refractory or resistant to platinum-based therapy. The primary objective is to investigate the safety and tolerability of ZN-c3 in combination with chemotherapy including identification of the MTD/RP2D. Secondary endpoints include estimates of clinical activity of ZN-c3 in combination with chemotherapy. Treatment is given in repeated 21- or 28-day cycles with once-daily ZN-c3 until disease progression or unacceptable toxicity.

Results: As of the cutoff date of Oct 28, 2021, based on interim data, a total of 25 subjects (all dose levels, all chemotherapy cohorts) had measurable disease at baseline and at least 1 post-baseline radiological assessment. Of those, 6/25 (24%) had a partial response (1 confirmed and 5 unconfirmed), 14/25 (56%) had stable disease (6 ongoing), and 5/25 (20%) had radiological progressive disease (80% disease control rate defined as complete response, partial response, and stable disease). In the ZN-c3 plus carboplatin cohort (cutoff date Jan 5, 2022), 4/10 (40%) had a partial response (2 confirmed and 2 unconfirmed), 4/10 (40%) had stable disease, and 2/10 (20%) had radiological progressive disease (80% disease control rate). As of the cutoff date of Oct 28, 2021, 41 subjects were evaluable for safety (i.e., received at least 1 dose of ZN-c3). Adverse events (≥20% all Grade in any treatment group) were (all Grade/≥ Grade 3) [n(%)]: nausea 22 (53.7%)/3 (7.3%), neutropenia 21 (51.2%)/14 (34.1%), thrombocytopenia 14 (34.1%)/7 (17.1%), anemia 10 (24.4%)/4 (9.8%), diarrhea 10 (24.4%)/1 (2.4%), fatigue 10 (24.4%)/1 (2.4%), vomiting 10 (24.4%)/4 (9.8%), leukopenia 8 (19.5%)/3 (7.3%), abdominal pain 7 (17.1%)/3 (7.3%), hypoalbuminemia 6 (14.6%)/1 (2.4%), alanine aminotransferase increased 5 (12.2%)/3 (7.3%), and hypomagnesemia 5 (12.2%)/1 (2.4%). The study is ongoing including combination dose-finding (NCT04516447).

Conclusions: ZN-c3, combined with CT, appears to be well-tolerated and is demonstrating clinical activity in patients with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer.

Citation Format: Anes Pasic, Gary Richardson, Zivko Vranjes, Tarek Meniawy, Jennifer Rodriquez, Lukas Makris, Soamnauth Misir, Philippe Pultar, Dimitris Voliotis, Siqing Fu. A phase 1b dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy (CT) in subjects with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT148.