Trovagene Initiates Enrollment for KRAS-Mutated Colorectal Cancer Trial

Trovagene announced the initiation of patient enrollment of its Phase 1b/2 study of onvansertib in combination with FOLFIRI and Avastin® (bevacizumab) for second-line treatment of patients with metastatic colorectal cancer (mCRC) with a KRAS mutation (NCT03829410). Trovagene is developing onvansertib, a first-in-class, third-generation, oral and highly-selective Polo-like Kinase 1 (PLK1) inhibitor that targets the key master regulator of tumor cell division, for the treatment of leukemias, lymphomas and solid tumor cancers. The trial is being conducted at USC Norris Comprehensive Cancer Center, Hoag Cancer Center and The Mayo Clinic, under the leadership of recognized colorectal cancer key opinion leaders, Heinz-Josef Lenz, MD, FACP, Section Head of GI Oncology and Co-Director of the Colorectal Center at USC Norris, and Afsaneh Barzi, MD, PhD, oncologist at USC Norris and principal investigator of the trial.

"It is well-recognized that there is a significant medical need for better treatment options for KRAS-mutated gastrointestinal cancers," said Dr. Lenz, who is also a professor of medicine at Keck School of Medicine of USC. "We are targeting these patients in this trial because in onvansertib preclinical studies, tumor cells that harbor KRAS mutations, when treated with onvansertib, have what we call 'synthetic lethality,' or in other words, have a greater susceptibility to tumor cell death."

"We look forward to this trial and the opportunity to examine a potential therapy for a patient population in need of options," said Dr. Barzi, who is also an associate professor of clinical medicine at the Keck School. "Use of genomic profiling to understand the molecular underpinnings of mCRC is critical to our precision medicine approach and treating our patients. In addition, KRAS profiling in this trial, by a simple blood test, is anticipated to enable us to get a very early indication of response to treatment. This is key not only for this trial, but for how we can quickly assess response and, in real-time, integrate this approach as part of future patient management."

Colorectal cancer (CRC) is the second leading cause of cancer mortality in the U.S. Despite progress in the treatment of mCRC, the majority of patients with metastatic disease succumb to the disease. Therefore, improving the treatment options and effectiveness is critical in changing the outcomes for this patient population. KRAS is a common mutation in the CRC population and approximately 50% of patients with CRC carry RAS mutations. In the U.S., FOLFOX (5-flourouracil, leucovorin, oxaliplatin) and FOLFIRI (fluorouracil, leucovorin, irinotecan) are standard-of-care options for patients with metastatic CRC in the first-line setting, irrespective of the KRAS mutation status. The majority of CRC patients respond to first-line therapy with a response rate of > 50%. The efficacy of second-line therapy in terms of survival prolongation and response remains very limited, particularly in the KRAS-mutated population, where treatment options are more restricted. FOLFIRI (a chemotherapy regimen of irinotecan, fluorouracil [5-FU], and leucovorin) + Avastin® (bevacizumab) in the second-line setting is the standard treatment in US. The response rate in the second-line setting is less than 5% as reported in a large international trial of bevacizumab in the second-line setting.

In this open-label, Phase 1b/2 trial, onvansertib in combination with standard-of-care FOLFIRI and Avastin® is being evaluated for safety and efficacy. The trial, A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination with FOLFIRI and Bevacizumab for Second‑Line Treatment of Metastatic Colorectal Cancer in Patients with a KRAS Mutation, will enroll up to 44 patients with a KRAS mutation and histologically confirmed metastatic and unresectable disease. In addition, patients must have failed treatment or be intolerant of FOLFOX (fluoropyrimidine and oxaliplatin) with or without Avastin® (bevacizumab).

Onvansertib is a first-in-class, third-generation, oral and highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK 1) enzyme, which is over-expressed in multiple cancers, including leukemias, lymphomas and solid tumors. Onvansertib targets the PLK1 isoform only (not PLK2 or PLK3), is orally administered and has a 24-hour half-life with only mild-to-moderate side effects reported. Trovagene believes that targeting only PLK1 and having a favorable safety and tolerability profile, along with an improved dose/scheduling regimen will significantly improve on the outcome observed in previous studies with a former panPLK inhibitor in AML.

Onvansertib has demonstrated synergy in preclinical studies with numerous chemotherapies and targeted therapeutics used to treat leukemias, lymphomas and solid tumor cancers, including irinotecan, FLT3 and HDAC inhibitors, taxanes and cytotoxins. Trovagene believes the combination of onvansertib with other compounds has the potential to improve clinical efficacy in acute myeloid leukemia (AML), metastatic castration-resistant prostate cancer (mCRPC), non-Hodgkin lymphoma (NHL), colorectal cancer, triple-negative breast cancer (TNBC), as well as other types of cancer.

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