Dual kinase inhibitor shows promise in multiple cancer types in phase I trial

CYC065, an inhibitor of CDK2 and CDK9, produces stable disease in some patients with advanced cancers.

A highly potent drug that inhibits two distinct gene pathways has been shown to be safe at the dose tested in a phase I clinical trial and kept tumors under control in some patients with advanced cancer, Dana-Farber Cancer Institute researchers will report the findings on April 15^th at the 2018 American Association of Cancer Research (AACR) Annual Meeting in Chicago.

The study represents the first time the drug compound, CYC065, has been tested in humans. An inhibitor of cyclin-dependent kinases (proteins often involved in regulating the cell cycle), CYC065 targets two such kinases: CDK2 and CDK9. CDK2 helps drive the cell cycle and activates the repair of double-stranded DNA breaks. CDK9 regulates gene transcription.

The study enrolled 26 patients, who as a group had a variety of advanced cancers – including ovarian, head and neck, pancreatic, and colon – that had become resistant to treatment.  The drug was administered by infusion every three weeks.

After six or more treatment cycles, six patients had stable disease, showing neither growth nor shrinkage of their tumors. One of these patients, who had received several previous treatments for ovarian cancer, continues to have stable disease a year after entering the trial, says study lead author Khanh Do, MD, of Dana-Farber, who will present the findings at the AACR meeting. The drug produced the best results in patients with laryngeal tumors, and patients with abnormalities in gene pathways involving CDK2 and CDK9 generally had the strongest responses.

The most frequent side effects of the drug involved the gastrointestinal system: constipation, diarrhea, decreased appetite, dehydration, nausea and vomiting, most of which were mild to moderate in intensity, investigators found.

If the benefits of CYC065 are borne out in subsequent trials, the drug could be particularly valuable for patients whose tumors don't respond to drugs that target two other cyclin-dependent kinases, CDK4 and CDK6, investigators say. One of the ways that cancer cells circumvent CDK4/6 inhibitors is by activating CDK2, which is inhibited by CYC065.

Investigators are planning a follow-up study to optimize the schedule for administering CYC065 so patients receive more intensified doses of the drug.

The senior author of the study is Geoffrey Shapiro, MD, PhD, of Dana-Farber. Co-authors are Nicole Chau, MD, Andrew Wolanski, DNP, Brian Beardslee, RN, MSN, Faith Hassinger, RN, BSN, Ketki Bhushan, MPH, Solida Pruitt-Thompson, and Amber Scotton, of Dana-Farber; and Sheelagh Frame, Daniella I. Zheleva, David Blake, Judy Chiao of Cyclacel Ltd., Dundee, United Kingdom.