On October 1, 2019 Trovagene, Inc. (Nasdaq: TROV), a clinical-stage, Precision Cancer Medicine oncology therapeutics company developing drugs that target cell division (mitosis) for the treatment of various cancers including prostate, colorectal and leukemia, reported the presentation of its Phase 1b/2 trial evaluating onvansertib in combination with FOLFIRI and Avastin (bevacizumab) in patients with KRAS-mutated metastatic Colorectal Cancer (mCRC) (Press release, Trovagene, OCT 1, 2019, View Source [SID1234539987]).
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The trial overview, featured in a poster presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress showed the supportive preclinical data underlying the scientific rationale for the trial, as well as the trial design and primary safety and efficacy endpoints. In addition, early biomarker data demonstrates proof-of-concept that patient response can be monitored by a non-invasive blood test to quantitate the KRAS mutation burden within one week following initial dosing with onvansertib.
"Although early in the trial, the potential to bring a much-needed new treatment option to patients with KRAS-mutated mCRC with the combination of these drugs is promising," said Heinz-Josef Lenz, MD, FACP, Professor of Medicine, J. Terrence Lanni Chair in Gastrointestinal Cancer Research, Co-Director, USC Center for Molecular Pathway and Drug Discovery. "As of September 1, 2019, four patients have been treated and one has successfully completed their first cycle of treatment. We believe onvansertib may provide clinical benefit for patients who are faced with a poor prognosis and for whom therapeutic options are limited."
Colorectal cancer (CRC) is the second leading cause of cancer mortality in the U.S. Despite significant progress in the treatment of mCRC, the majority of patients with metastatic disease succumb to the disease. Therefore, improving the effectiveness of treatments is critical in changing the outcomes for this patient population. Approximately 50% of mCRC has the KRAS mutation. The efficacy of second-line therapy in terms of survival prolongation and response remains very limited, especially in this population, where there is only a 5% response rate.
Presentation Highlights
Metastatic Colorectal Cancer:
Tumor biomarkers drive therapy decisions for 1st and 2nd line mCRC therapy
~50% of mCRC is KRAS-mutated
Standard second-line therapy in KRAS mutated patients is chemotherapy (FOLFOX/FOLFIRI) + Bevacizumab
Second-line therapies have only a ~5% response rate in mCRC
Primary Endpoints:
Phase 1b: Assess the safety and preliminary efficacy of onvansertib in combination with FOLFIRI and bevacizumab and identify the recommended Phase 2 dose (RP2D)
Phase 2: Evaluate the efficacy of onvansertib in combination with FOLFIRI and bevacizumab based on objective response rate (ORR) in patients who receive at least 1 cycle (2 courses) of treatment
About the Phase 1b/2 Clinical Trial of Onvansertib in mCRC
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 evaluate the safety and efficacy of onvansertib in combination with standard-of-care FOLFIRI and Avastin (bevacizumab). Up to 44 patients, with a confirmed KRAS mutation, metastatic and unresectable disease, who have failed/intolerant of treatment with FOLFOX (fluoropyrimidine and oxaliplatin) with or without Avastin (bevacizumab), will be enrolled. The trial is being conducted at two prestigious cancer centers: USC Norris Comprehensive Cancer Center and The Mayo Clinic Arizona.
About Onvansertib
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 (PLK1) 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 and triple-negative breast cancer (TNBC), as well as other types of cancer.
Trovagene has three ongoing clinical trials of onvansertib: A Phase 2 trial of onvansertib in combination with Zytiga (abiraterone acetate)/prednisone in patients with mCRPC who are showing signs of early progressive disease (rise in PSA but minimally symptomatic or asymptomatic) while currently receiving Zytiga (NCT03414034); a Phase 1b/2 Study of onvansertib in combination with FOLFIRI and Avastin for second-line treatment in patients with mCRC with a KRAS mutation (NCT03829410); and a Phase 1b/2 clinical trial of onvansertib in combination with low-dose cytarabine or decitabine in patients with relapsed or refractory AML (NCT03303339). Onvansertib has been granted orphan drug designation by the FDA in the U.S. and by the EC in the European Union for the treatment of patients with AML.
Trovagene licensed onvansertib (also known as NMS-1286937 and PCM-075) from Nerviano Medical Sciences (NMS), the largest oncology-focused research and development company in Italy, and a leader in protein kinase drug development. NMS has an excellent track record of licensing innovative drugs to pharma/biotech companies, including Array (recently acquired by Pfizer), Ignyta (acquired by Roche) and Genentech.