Background: CYC065 is a potent and selective inhibitor of CDK2 and CDK9. CDK2 drives cell cycle transition and activates major DNA double‐strand break repair pathways; CDK9 regulates transcription of genes through phosphorylation of RNAP II. This first-in-human phase 1 study evaluates CYC065 administered by 4-hour infusion every 3 weeks in patients with advanced cancers.

Methods: Dose escalation was 100% initially. Upon the occurrence of the first grade 2 drug-related toxicity, dose escalation decreased to 50% and then to 25% upon the occurrence of the first dose-limiting toxicity (DLT). Recommended phase 2 dose (RP2D) was MTD defined as highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Blood samples were taken in at pre-dose and up to 24 hours after the first dose of cycle 1 to assess pharmacokinetic (PK) and pharmacodynamic (PD) effects. Biomarkers related to CYC065 target inhibition, e.g. phosphorylation of Ser2 RNA polymerase II - a direct substrate of CDK9, and protein levels of downstream targets, such as Mcl-1, were determined in patient's PBMCs.

Results: 26 patients were treated. The MTD was 192 mg/m2. DLTs are reversible neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, hypomagnesemia, white blood cell lysis syndrome and its associated electrolyte abnormalities and liver enzyme elevations. The most frequent adverse events (all cycles, regardless of causality) included constipation, diarrhea, decreased appetite, dehydration, fatigue, nausea, and vomiting, the majority mild to moderate in intensity. All patients participated in the PK/PD samplings. Exposure to CYC065 increased with dose. Average half-life ranged from 1.64 h to 3.9 h. Mcl-1 suppression, lasting at least 24 hours after a single dose, was observed in 11 out of 13 evaluable patients at the RP2D (192 mg/m2). Stable disease ≥ 6 cycles was observed in 6 patients, 5 of which treated at the RP2D: larynx neuroendocrine carcinoma (n=1), ovarian adenocarcinoma (n=2); uterine carcinosarcoma (1), parotid gland actinic cell carcinoma (n=1) and submandibular gland adenoid cystic carcinoma (n=1). Two patients with uterine and ovarian cancer are continuing on treatment having received 9 and 17 cycles respectively.

Conclusion: CYC065 administered by 4-hour infusion is safe and demonstrated durable MCL-1 suppression at the RP2D. Durable stable diseases were observed. Additional dosing schedules to intensify dose density will be evaluated.

Citation Format: Khanh T. Do, Nicole Chau, Andrew Wolanski, Brian Beardslee, Faith Hassinger, Ketki Bhushan, Solida Pruitt-Thompson, Amber Scotton, Sheelagh Frame, Daniella I. Zheleva, David Blake, Judy Chiao, Geoffrey I. Shapiro. Phase I safety, pharmacokinetic and pharmacodynamic study of CYC065, a cyclin dependent kinase inhibitor, in patients with advanced cancers (NCT02552953) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT037.