Onvansertib Receives FDA Fast Track Designation in KRAS+ mCRC

The FDA has granted a Fast Track Designation to onvansertib for the second-line treatment of patients with KRAS-mutant metastatic colorectal cancer (mCRC) in combination with FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) and bevacizumab (Avastin), according to a press release from Cardiff Oncology, Inc.

"We are very pleased with the FDA's decision to grant Fast Track designation for development of onvansertib to treat patients with KRAS-mutated mCRC," said Mark Erlander, PhD, CEO of Cardiff Oncology, in a statement. "This designation is a significant validation of not only our onvansertib clinical program, which is now eligible for priority review and accelerated approval, but it also signifies recognition of the medical need for new effective treatment options.”

This regimen is currently under evaluation in an ongoing open-label phase 1b/2 clinical trial (NCT03829410), which is evaluating the safety and efficacy of the onvansertib combination as a second-line treatment for patients with KRAS-mutant mCRC. The trial is expected to enroll 44 patients who harbor a KRAS mutation and have histologically confirmed metastatic or unresectable disease.

To be eligible for the study, patients must have failed prior FOLFOX (fluoropyrimidine and oxaliplatin) therapy or become intolerant to the regimen, with or without the addition of bevacizumab. They must also have an ECOG performance status of 0 or 1 and cannot be receiving any other cancer therapy. If patients have concomitant KRAS and BRAF V600 mutations or microsatellite instability–high or mismatch repair deficient disease, they are ineligible for the study. They are also ineligible if they have had more than 1 prior chemotherapy regimen in the metastatic setting or had a major surgery within 6 weeks prior to randomization, among other criteria.

In the phase 1b portion of the study, patients receive a starting dose of oral onvansertib of 12 mg/m2 for days 1 through 5 every 14 days over 1 cycle in combination with standard FOLFIRI and bevacizumab. For the phase 2 portion, patients will receive the recommended phase 2 dose of onvansertib on days 1 through 4 every 14 days over 1 cycle in combination with FOLFIRI and bevacizumab with treatment modifications or delays based on unresolved toxicity from a previous cycle.

The study is being conducted at the University of Southern California Norris Comprehensive Cancer Center and The Mayo Clinic in Arizona.

Onvansertib is a first-in-class, third-generation adenosine triphosphate (ATP) inhibitor of the serine/threonine polo-like-kinase 1 (PLK1) enzyme, which is overexpressed in many cancers, such as leukemias, lymphomas, and solid tumors. The agent targets the PLK1 isoform alone and has a 24-hour half-life. Only mild to moderate adverse effects have been reported with the agent to date.

The company believes that by targeting only PLK1 as opposed to PLK1/2/3 and because this agent has a favorable safety profile and tolerability, onvansertib should significantly improve the outcomes of patients compared with pan-PLK inhibition.

The agent is under evaluation in 2 more clinical trials, which include a phase 2 study of onvansertib plus abiraterone acetate (Zytiga) plus prednisone in patients with metastatic castration-resistant prostate cancer who have early signs of progressive disease on abiraterone acetate alone and a phase 2 study of the agent with decitabine in patients with relapsed or refractory acute myeloid leukemia.

“The efficacy of current second-line therapy in terms of response and survival prolongation remains very limited, particularly in the KRAS-mutated population, and we are confident that onvansertib, in combination with FOLFIRI/bevacizumab, represents a promising new treatment option,” stated Erlander.

_Reference

_{Cardiff Oncology Announces Fast Track Designation Granted by the FDA to Onvansertib for Second-Line Treatment of KRAS-Mutated Colorectal Cancer [news release]. San Diego, CA: Cardiff Oncology; May 28, 2020. https://bit.ly/2XBAd57. Accessed May 28, 2020.}