Onvansertib + Chemotherapy for Colorectal Cancer

Recruiting at 40 trial locations

Overseen By Nancy Sherman

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Cardiff Oncology

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: BRAF-V600 mutation, Brain metastasis, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

The purpose of this study is to assess 2 different doses of onvansertib to select the lowest dose that is maximally effective, and to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of onvansertib in combination with FOLFIRI + bevacizumab or FOLFOX + bevacizumab in patients with KRAS or NRAS-mutated metastatic colorectal cancer (CRC) in the first-line setting.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot use strong CYP3A4 or CYP2C19 inhibitors or strong CYP3A4 inducers. It's best to discuss your current medications with the trial team.

What makes the drug Onvansertib unique for colorectal cancer treatment?

Onvansertib is unique because it is a targeted therapy that works by inhibiting a specific enzyme called PLK1, which is involved in cancer cell division. This mechanism is different from traditional chemotherapy, which generally targets all rapidly dividing cells. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for adults with metastatic colorectal cancer that has specific mutations (KRAS or NRAS). They should not have had previous systemic therapy for their metastatic condition, must be able to undergo scans to document the disease, and agree to provide tissue samples. Participants need to be relatively active and healthy (ECOG status 0 or 1) and take steps to prevent pregnancy.

Inclusion Criteria

Participants must be willing to submit archival tissue or undergo fresh biopsy

Women of childbearing potential must use contraception or take measures to avoid pregnancy

My colorectal cancer has spread and was confirmed by a lab test.

Exclusion Criteria

I have a known DPD deficiency.

I have been treated with oxaliplatin in the last 12 months.

Known hypersensitivity to fluoropyrimidine or leucovorin, irinotecan, or oxaliplatin

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive onvansertib in combination with FOLFIRI and bevacizumab or FOLFOX and bevacizumab in 28-day cycles

Up to approximately 1 year

Visits on Day 1 and Day 15 of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• Onvansertib (Protein Kinase Inhibitor)

Trial Overview The study is testing two different doses of a drug called Onvansertib in combination with standard chemotherapy regimens FOLFIRI or FOLFOX, both also paired with Bevacizumab. The goal is to find the lowest effective dose of Onvansertib and evaluate its safety and effectiveness against metastatic colorectal cancer.

Participant Groups

Group I: Onvansertib 30 mg + Standard of Care (SOC) Experimental Treatment 3 Interventions

Participants will receive 30 mg of onvansertib + on Days 1 to 5 and Days 15 to 19 of each 28-day treatment cycle + FOLFIRI on Day 1 and Day 15 of each 28-day treatment cycle.

Group II: Onvansertib 30 mg + Standard of Care Experimental Treatment 3 Interventions

Participants will receive 30 mg onvansertib on Days 1 to 5 and Days 15 to 19 of each 28-day treatment cycle + FOLFOX on Day 1 and Day 15 of each 28-day treatment cycle.

Group III: Onvansertib 20mg + Standard of Care Experimental Treatment 3 Interventions

Participants will receive 20 mg of onvansertib on Days 1 to 5 and Days 15 to 19 of each 28-day treatment cycle + FOLFIRI/BEV on Day 1 and Day 15 of each 28-day treatment cycle.

Group IV: Onvansertib 20 mg + Standard of Care Experimental Treatment 3 Interventions

Participants will receive 20 mg of onvansertib on Days 1 to 5 and Days 15 to 19 of each 28-day treatment cycle + FOLFOX on Day 1 and Day 15 of each 28-day treatment cycle.

Group V: Standard of Care Active Control 2 Interventions

Participants will receive FOLFOX/Bev on Day 1 and Day 15 of each 28-day treatment cycle.

Group VI: Standard of Care (SOC) Active Control 2 Interventions

Participants will receive FOLFIRI/Bev on Day 1 and Day 15 of each 28-day treatment cycle.

Who Is Running the Clinical Trial?

Cardiff Oncology

Lead Sponsor

Trials

12

Recruited

650+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Findings from Research

In a phase II trial involving 25 patients with RAS-mutant, microsatellite stable metastatic colorectal cancer, the combination of sintilimab, bevacizumab, oxaliplatin, and capecitabine showed a high objective response rate of 84% and a disease control rate of 100%, indicating promising anti-tumor activity.

The treatment was generally well-tolerated, with manageable adverse events; the most common were anemia and neutropenia, but no grade 5 adverse events occurred, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trial. Fang, X., Zhu, N., Zhong, C., et al.[2023]

In a study involving patients with untreated microsatellite-stable metastatic colorectal cancer, adding the immunotherapy avelumab and a CEA-targeted vaccine to standard treatment (FOLFOX plus bevacizumab) did not improve progression-free survival compared to standard treatment alone, with median PFS of 8.8 months versus 10.1 months, respectively.

Both treatment groups showed a similar objective response rate of 50%, but the combination therapy led to a significant increase in multifunctional CD4+/CD8+ T-cell responses against specific antigens, indicating an immune response despite not translating into improved survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Phase II Trial of mFOLFOX6 + Bevacizumab Alone or with AdCEA Vaccine + Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer. Redman, JM., Tsai, YT., Weinberg, BA., et al.[2022]

In a study of 25 patients with metastatic colorectal cancer, the combination of camrelizumab with XELOX chemotherapy and bevacizumab showed a high objective response rate of 72% and a disease control rate of 96%, indicating strong efficacy as a first-line treatment.

The treatment was generally well-tolerated, with most adverse effects being mild (grade 1 or 2), although 32% of patients experienced grade 3 toxicities, suggesting that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary Efficacy and Safety of Camrelizumab in Combination With XELOX Plus Bevacizumab or Regorafenib in Patients With Metastatic Colorectal Cancer: A Retrospective Study. Zhou, H., Wang, Y., Lin, Y., et al.[2022]

In the Intergroup Trial N9741, combination treatments of 5-fluorouracil (5-FU) with either irinotecan or oxaliplatin led to severe gastrointestinal toxicities, particularly high rates of diarrhea and neutropenia, resulting in a mortality rate of 8.2% in one treatment arm and 8.5% in another within 60 days of treatment.

The study highlights the critical need for immediate supportive care in managing these toxicities and suggests that infusional 5-FU regimens may be safer alternatives for treating advanced colorectal carcinoma, given the high mortality associated with bolus 5-FU combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. Delaunoit, T., Goldberg, RM., Sargent, DJ., et al.[2018]

In a phase 2 clinical trial involving 133 patients with refractory metastatic colorectal cancer, the addition of atezolizumab to capecitabine and bevacizumab therapy resulted in a median progression-free survival (PFS) of 4.4 months compared to 3.6 months for the placebo group, indicating a potential benefit, although not clinically meaningful.

Patients with microsatellite-stable disease and those without liver metastasis showed greater benefits from the combination therapy, suggesting that specific patient characteristics may influence the efficacy of atezolizumab in this treatment context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Capecitabine and Bevacizumab With or Without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer: A Randomized Clinical Trial. Mettu, NB., Ou, FS., Zemla, TJ., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trial. [2023]

2. England pubmed.ncbi.nlm.nih.gov

A Randomized Phase II Trial of mFOLFOX6 + Bevacizumab Alone or with AdCEA Vaccine + Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Preliminary Efficacy and Safety of Camrelizumab in Combination With XELOX Plus Bevacizumab or Regorafenib in Patients With Metastatic Colorectal Cancer: A Retrospective Study. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Assessment of Capecitabine and Bevacizumab With or Without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer: A Randomized Clinical Trial. [2022]