Combining CDK2/9 Inhibitor CYC065 with Venetoclax, a BCL2 Inhibitor, to Treat Patients with Relapsed or Refractory AML or MDS
Authors: Borthakur Gautam M. , Kadia Tapan M. , Al Azzawi Hind , Zheleva Daniella , Blake David , Chiao Judy H 
Published: November 2019

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 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's 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).

Acute myeloid leukemia (AML) frequently relapses after initial treatment by intensive or low-intensive therapy. Drug resistance has been attributed to dysregulation in apoptotic pathways. AML cells often upregulate pro-survival members of the BCL2 family, such as BCL2 and MCL1, to avoid apoptosis (Grundy M et al, Oncotarget, 2018). Suppression of MCL1 triggered rapid apoptosis in AML, and cured AML-afflicted mice (Glaser SP et al, Genes Dev. 2012). Preclinically, CYC065 has demonstrated potent anti-tumor effect in various AML cell lines, including those with MLL rearrangements, and xenograft models (Frame S et al, AACR, 2010 Abs 3886; Frame S et al, SOHO, 2014 Abs 209). Venetoclax has modest single agent activity in AML. MCL1 dependence appeared to correlate with resistance to venetoclax (Konopleva M et al, Cancer Discovery, 2016). Preclinical study confirmed synergy of CYC065 and venetoclax, suggesting that the suppression of both BCL2 and MCL1 may be more beneficial than inhibiting either one alone (MacKay C et al. AACR-NCI-EORTC 2015 Abs B182).

Based on the above rationale, a clinical study (NCT04017546) has been initiated to evaluate a combination of CYC065 with venetoclax in relapsed/refractory AML and MDS. CYC065 will be administered intravenously via 4-hour infusion on Day 1 and Day 15 in combination with daily venetoclax every 4 weeks. 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 previously treated AML or MDS and ≥10% blasts in bone marrow or peripheral blood; 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 the 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 bone marrow aspirate/biopsy will be performed to assess response according to standard criteria.

Disclosures

Borthakur: AbbVie: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; GSK: Research Funding; Polaris: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Incyte: Research Funding; Cyclacel: Research Funding; Janssen: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Oncoceutics, Inc.: Research Funding; Strategia Therapeutics: Research Funding; PTC Therapeutics: Consultancy; BMS: Research Funding; Oncoceutics: Research Funding; Eisai: Research Funding; NKarta: Consultancy; Xbiotech USA: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; Agensys: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Arvinas: Research Funding. Kadia:BMS: Research Funding; Bioline RX: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Al Azzawi:Cyclacel LTD: Research Funding. Zheleva:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Blake:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Chiao:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties.