A Phase I Study Combining CDK2/9 Inhibitor CYC065 with Venetoclax, a BCL2 Inhibitor, to Treat Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Cyclin dependent kinases (CDKs) are critical for cell cycle regulation and transcriptional elongation. Dysregulated CDKs have been linked to the cancer hallmarks of uncontrolled proliferation and increased survival. CYC065 is a potent and orally‐available inhibitor of CDK2 and CDK9. CDK9 regulates transcription of genes through phosphorylation of RNA polymerase II (RNAP II) C-terminal domain (CTD). Through inhibition of CDK9, CYC065 suppresses CDK9-dependent gene expression and reduces the level of MCL1, a key anti-apoptotic protein.

In the first-in-human study, CYC065 was administered by 4-hour infusion every 3 weeks in patients with advanced solid cancers. Biomarkers related to CYC065 target inhibition, e.g. phosphorylation of RNAP II CTD Ser2, a direct substrate of CDK9, and protein levels of downstream targets, such as MCL1, were determined in patient peripheral blood mononuclear cells (PBMCs). Durable MCL1 suppression was observed after a single dose in 11 out of 13 patients treated at the recommended phase 2 dose (RP2D) of 192 mg/m². Five of these 13 patients achieved stable disease lasting ≥6 cycles (Do, KT et al, AACR Annual Meeting 2018 Abs CT037).

Chronic lymphocytic leukemia (CLL) is a disease that depends upon the overexpression of anti-apoptotic proteins (MCL1, BCL2) for survival. Venetoclax, a BCL2 inhibitor, is one of the most active agents against CLL. However upregulation of MCL1 is associated with resistance to venetoclax (Oppermann S et al., Blood, 2016). Preclinical studies have demonstrated that CYC065 and venetoclax are synergistic in primary CLL cells, inducing apoptosis (Chen R et al, AACR Annual Meeting 2018 Abs 3905). This synergy may arise from targeting parallel anti-apoptotic mechanisms in the intrinsic apoptotic pathway that promote survival in CLL cells.

The above findings support the conduct of an ongoing clinical study (NCT03739554) investigating a combination of CYC065 with venetoclax in CLL. CYC065 will be administered intravenously via 4-hour infusion on Day 1 and Day 15 in combination with daily venetoclax. One cycle is 28 days. Initial dose escalation is 33% and then 25% upon occurrence of the first dose limiting toxicity (DLT). RP2D is the highest dose level at which less than one-third of at least 6 patients experience a DLT during the first treatment cycle.

Eligible patients are ≥18 years with CLL relapsed or refractory to standard treatment(s) including those with Richter transformation; adequate bone marrow, renal and liver functions are required. All patients will be asked to participate in the pharmacokinetic and pharmacodynamic studies. Plasma levels of CYC065 and its metabolites as well as venetoclax will be determined. PBMCs will be collected to assess MCL1 levels and phosphorylation and protein levels of other downstream targets of CDK9 inhibition. Treatment will continue until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment. Laboratory tests and CT scans will be performed regularly to assess response according to standard criteria.