Abstract CT029: Safety and clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 trial in subjects with recurrent or advanced uterine serous carcinoma (USC)
Authors: Meric-Bernstam Funda , Chalsani Pavani , Mamdani Hirva , Zheng Cheng , Viana Marcus , Lambersky Ruth , Pultar Philippe , Tolcher Anthony W. 
Published: June 2022

Introduction: ZN-c3 is a selective, orally bioavailable small molecule inhibitor of WEE1, a crucial component of the G2/M cell cycle checkpoint, which prevents cells from entering mitosis to allow repair of DNA damage. ZN-c3 has demonstrated significant in vitro antitumor activity in multiple cell lines and xenograft models.

Methods: ZN-c3-001 (NCT04158336) is an open label, multicenter, Phase I dose escalation and expansion study evaluating the safety and clinical activity of ZN-c3 in subjects with advanced or metastatic solid tumors, refractory to standard therapy or for whom no standard therapy is available. Oral, daily ZN-c3 dosing was escalated from 25 mg to 450 mg once daily (QD), with a recommended phase 2 dose of 300 mg QD. Here we report preliminary safety and efficacy results for subjects with USC who received ZN-c3 at doses ≥300 mg QD.

Results: As of October 28, 2021, a total of 78 subjects were enrolled across all tumor types. For USC, there were 12 subjects who received ZN-c3 at doses ≥300 mg QD and were evaluated for safety. Median duration of treatment was 12 weeks (range, 2 - 33 weeks). The safety profile for this subgroup is comparable to the overall patient population with 11 of 12 subjects reporting at least one treatment-related adverse event (TRAE). TRAEs grades 1-4 occurring in ≥3 subjects, by decreasing frequency, included nausea, vomiting, fatigue, diarrhea, decreased appetite, dehydration, and anemia. Grade ≥3 TRAEs occurring in ≥2 subjects included anemia and thrombocytopenia. These hematologic events were limited to 2 subjects each. Nine of the 12 subjects had measurable disease and at least 1 post-baseline tumor assessment; 3 subjects (33.3%) had confirmed partial response and 5 (55.6%) had stable disease as their best overall response. Disease control rate, defined as those with complete response, partial response, and stable disease, was 88.9%. One subject with partial response achieved complete response at subsequent tumor assessment.

Conclusions: ZN-c3 appears to be safe and well-tolerated as a single agent at oral doses ≥300 mg QD and demonstrated clinical activity in subjects with recurrent or advanced USC. Safety results in these subjects were consistent with those of the full study population. The ongoing dose expansion study is enrolling USC patients. The preliminary efficacy signal will be confirmed in a dedicated phase 2 study (ZN-c3-004, NCT04814108) in this patient population.

Citation Format: Funda Meric-Bernstam, Pavani Chalsani, Hirva Mamdani, Cheng Zheng, Marcus Viana, Ruth Lambersky, Philippe Pultar, Anthony W. Tolcher. Safety and clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 trial in subjects with recurrent or advanced uterine serous carcinoma (USC) [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 CT029.