On April 28, 2020 Trovagene, Inc. (Nasdaq: TROV), a clinical-stage, oncology therapeutics company developing drugs to treat cancers with the greatest medical need for new treatment options, including colorectal cancer, prostate cancer and leukemia, reported new positive results from its ongoing Phase 1b/2 clinical trial of onvansertib in combination with FOLFIRI and Avastin (bevacizumab) for second-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC) (Press release, Trovagene, APR 28, 2020, View Source [SID1234556684]). The data were featured in a virtual oral presentation, delivered by Dr. Afsaneh Barzi, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) conference on Monday, April 27th, 2020.

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There is a significant, unmet medical need to develop a safe and effective second-line treatment option for patients with KRAS-mutated mCRC. Currently available treatments have limited efficacy with only a 4% response rate and a median of 5.5 months PFS. Other compounds currently in clinical development that target KRAS-mutated cancers have shown minimal activity in mCRC.
"We are encouraged by the level of activity that we are observing with the combination of onvansertib and standard-of-care FOLFIRI and bevacizumab in our patients with KRAS-mutated colorectal cancer," said Dr. Afsaneh Barzi, principal investigator, who led the trial as an associate professor of clinical medicine at Keck School of Medicine of USC and medical oncologist at USC Norris Comprehensive Cancer Center. "So far we are observing what we had hoped for in this trial – lack of toxicity and positive signs of efficacy. We remain optimistic because we are observing anti-tumor effects of onvansertib, which could present the opportunity for a new treatment designed to attack KRAS-mutant tumors and act synergistically with standard-of-care chemotherapy."

Highlights of AACR (Free AACR Whitepaper) Presentation – Onvansertib in KRAS-Mutated mCRC Trial

In the Phase 1b dose escalation, the 1st two dose levels (onvansertib 12 mg/m2 and 15 mg/m2) have been cleared for safety; the 3rd dose level (onvansertib 18 mg/m2) is enrolling; the maximum tolerated dose has not been reached to-date

As of the data cut-off date, clinical response was observed in 7 (88%) of the 8 evaluable patients:

3 patients had partial response (PR), 4 patients had stable disease (SD)

1 patient proceeded to have successful curative surgery

Progression-free survival (PFS) is 6.5 months to date, with 6 patients remaining on treatment

Decreases in plasma KRAS mutation level has been demonstrated to be an early marker for therapeutic response:

Onvansertib effectively targets predominant KRAS mutants associated with CRC

7 of the 8 patients had a KRAS mutation detected by ctDNA analysis at baseline (ddPCR and NGS)

Changes in KRAS mutant during cycle 1 of treatment were highly predictive of tumor regression:

5 patients had a decrease in KRAS mutant to non-detectable level in cycle 1 (28 days) and subsequent tumor regression at 8 weeks

2 patients had detectable KRAS mutant at end of cycle 1 and showed tumor growth at 8 weeks

The Phase 2 continuation trial will further assess the safety and efficacy of onvansertib at the recommended Phase 2 dose (RP2D) in combination with FOLFIRI + bevacizumab, as well as the value of KRAS liquid biopsy to predict treatment response
About the Phase 1b/2 Clinical Trial of Onvansertib in KRAS-Mutated mCRC
The ongoing 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 (NCT03829410) is evaluating 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 or are 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 Cancer Center.
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 2 clinical trial of onvansertib in combination with decitabine in patients with relapsed or refractory AML (NCT03303339).
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.