Abstract CT016: Clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 dose-escalation trial in patients with advanced solid tumors
Authors: Anthony Tolcher, Hirva Mamdani, Pavani Chalasani, Funda Meric-Bernstam, Mihaela Gazdoiu, Lukas Makris, Philippe Pultar, Dimitris Voliotis
Journal: Cancer Research (2021)

Abstract Introduction: ZN-c3 is a selective and orally bioavailable small molecule WEE1 inhibitor. WEE1 is a crucial component of the G2/M cell cycle checkpoint preventing cells from entering mitosis to allow repair of DNA damage before cell cycle progression. ZN-c3 has demonstrated significant growth inhibition in vitro in multiple cell lines from various cancer types and antitumor activity in vivo in human xenograft tumor models. Methods: ZN-c3-001 (NCT04158336) is a dose escalation, open-label, multicenter, Phase 1 clinical trial evaluating the safety, tolerability, and efficacy of ZN-c3 in subjects with advanced or metastatic solid tumors, refractory to standard therapy or for whom no standard therapy is available. ZN-c3 dosing was escalated from 25mg to 450mg administered orally QD. The primary objective of this study is to determine the schedule, Maximum Tolerated Dose (MTD), and Recommended Phase 2 Dose (RP2D) of ZN-c3. Subjects underwent imaging every 9 weeks to assess disease response. Here we report early signal of clinical activity of ZN-c3. Results: As of 30Nov2020 there were 39 subjects treated and of those, 30 experienced treatment related adverse events (TRAEs), the most frequently reported TRAEs were nausea, diarrhea, vomiting, and fatigue. Of the 16 subjects with post-baseline tumor assessments, 5 patients had stable disease (SD) and 2 subjects had partial responses (PR), as per RECIST 1.1. One was a 63-yo Caucasian male with Stage IV colorectal cancer with metastases to the liver, lymph nodes, and pleura who achieved a PR with 42% reduction in overall tumor burden. Carcinoembryonic Antigen tumor marker decreased from 327 ng/mL at baseline to less than 50 ng/mL after 3 weeks on treatment. The second subject was a 72-yo Caucasian female with Stage IV ovarian cancer with metastases to the pleura, peritoneum, and retroperitoneum who achieved a PR with a 56% reduction in overall tumor burden. CA-125 dropped from 610 kU/L at baseline to 125 kU/L within 4 weeks after first dose and normalized 3 weeks later. Based on MTD, as determined by the Bayesian Continual Reassessment model, the overall tolerability and toxicity, and the dose dependent pharmacokinetic profile, the recommended RP2D for ZN-c3 is determined to be 300mg, given orally as continuous once daily dosing. Conclusions: ZN-c3 shows early signal of clinical activity in heavily pretreated advanced solid tumor subjects. It appears safe and tolerable as a single agent at the identified RP2D. An expansion cohort will be included in this Phase 1 study to treat additional subjects. In addition, a Phase 2 clinical study is being planned to enroll additional subjects to further evaluate the efficacy of ZN-c3. Ongoing correlative studies will continue to determine specific mechanisms and biomarkers of response to ZN-c3. Citation Format: Anthony Tolcher, Hirva Mamdani, Pavani Chalasani, Funda Meric-Bernstam, Mihaela Gazdoiu, Lukas Makris, Philippe Pultar, Dimitris Voliotis. Clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 dose-escalation trial in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT016.