On May 29, 2020 Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage oncology therapeutics company developing drugs to treat cancers with the greatest medical need for new treatment options, including KRAS-mutated colorectal cancer, Zytiga-resistant prostate cancer and leukemia, reported additional positive efficacy and favorable safety data were featured in a virtual oral poster presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) conference (Press release, Cardiff Oncology, MAY 29, 2020, View Source [SID1234558760]).
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The new data from Cardiff Oncology’s 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) continues to demonstrate that primary efficacy endpoint of overall objective response (ORR), as measured by tumor regression, is ten-fold greater than current standard-of-care of 4%. To-date, 89% of evaluable patients in the onvansertib trial have achieved a clinical response and the response appears durable with patients having progression-free survival (PFS) of at least 6 months. Onvansertib has also shown its effectiveness in targeting the most prevalent KRAS mutation subtypes associated with colorectal cancer, which until recently have been considered to be undruggable.
"We are pleased to be participating in this clinical trial and importantly, our patients are not only tolerating the combination of onvansertib plus standard-of-care FOLFIRI and bevacizumab, but we are very encouraged by the efficacy we are seeing," said Dr. Daniel Ahn, lead investigator and medical oncologist, Mayo Clinic Cancer Center, Arizona. "Being able to effectively treat patients with KRAS-mutated mCRC has been a challenge and their prognosis is poor. Onvansertib is showing great potential as a new second-line treatment option, in combination with standard-of-care, for these patients."
"Our trial is achieving critical milestones and gaining momentum," said Dr. Mark Erlander, Chief Executive Officer of Cardiff Oncology. "We continue to see safety and efficacy demonstrated and this, coupled with the FDA granting of Fast Track Designation, is further validation of the potential value of onvansertib to tackle the once undruggable KRAS-mutations that drive aggressive growth of CRC tumors."
Highlights of the ASCO (Free ASCO Whitepaper) Presentation – Onvansertib in KRAS-Mutated mCRC Phase 1b/2 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 cutoff date, clinical response was observed in 8 (89%) of the 9 evaluable patients and post the data cutoff 1 additional patient achieved an objective response:
As of the ASCO (Free ASCO Whitepaper) cutoff date, 4 patients had experienced an objective response, and another 4 patients had stable disease
One patient proceeded to have successful curative surgery; an unprecedented event in this patient population
Progression-free survival (PFS) is >6 months, with 6 patients remaining on treatment
Decreases in plasma KRAS mutation level during the first cycle of treatment are highly predictive of tumor regression and subsequent therapeutic response:
Onvansertib effectively targets all prevalent KRAS mutation subtypes associated with CRC
8 of the 9 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
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. Cardiff Oncology 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. Cardiff Oncology 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.
Cardiff Oncology 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).
Cardiff Oncology 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.