NEW YORK – Cardiff Oncology on Monday said it will begin a new Phase II trial of its polo-like kinase 1 (PLK1) inhibitor onvansertib as a first-line therapy in RAS-mutated metastatic colorectal cancer.
In the CRDF-004 trial, investigators will assess safety and preliminary efficacy of two doses of onvansertib to identify an optimal dose. Ninety patients will be randomized to receive 20 mg of onvansertib plus standard chemotherapy, 30 mg of onvansertib plus standard chemotherapy, or standard chemotherapy alone. The San Diego-based firm expects to report interim top-line results from the trial in mid-2024. The trial will be conducted with execution support from Pfizer Ignite, a developmental and clinical service provider for biotech companies. Cardiff will maintain ownership and control of onvansertib under the terms of the partnership.
If the drug performs well in the Phase II trial, Cardiff will proceed to a Phase III registration trial of onvansertib. The US Food and Drug Administration has provided guidance to Cardiff that a "seamless trial" with an objective response rate at interim analysis will be an acceptable endpoint for accelerated approval, while progression-free survival and a trend toward overall survival would be required for full approval.
"Our advance to the first-line [metastatic colorectal cancer] setting is the result of a comprehensive data-driven review coupled with the agreement and support of the FDA," Cardiff CEO Mark Erlander said in a statement.
According to Cardiff, 48,000 new patients in the US are diagnosed with RAS-mutated metastatic colorectal cancer and those patients have had no new treatment options approved in 20 years, nor are there available ongoing clinical trials for them.
In the ONSEMBLE Phase II trial, patients with KRAS-mutated metastatic colorectal cancer in the second-line setting who were treated with chemotherapy, Genentech's Avastin (bevacizumab), and onvansertib improved overall response rates, median durations of response, and median progression-free survival compared to historical controls. Responses were notable in the group of patients who had never been treated with Avastin, in which the overall response rate was 73 percent and median progression-free survival was 15 months, compared to an overall response rate of 25 percent and seven-to-eight-month median progression-free survival for historical controls.
Erlander said that those results revealed a novel mechanism of action in which onvansertib inhibits angiogenesis by turning off a "survival switch" for tumorigenesis, illuminating the drug's interaction with Avastin and supporting the initiation of the new clinical trial in RAS-mutated metastatic colorectal cancer.
At the same time Cardiff is launching the new trial for onvansertib, it is discontinuing enrolment in the ONSEMBLE trial to optimize its use of resources in response to a suggestion from the FDA to focus on first-line RAS-mutated disease. "Based on highly encouraging interactions with the FDA and Pfizer, we are moving into first-line RAS-mutated metastatic colorectal cancer where we believe enrollment should occur more quickly given the significantly larger number of first-line patients versus second-line," Cardiff Chief Medical Officer Fairooz Kabbinavar said in a statement.