Onvansertib + Chemotherapy for Colorectal Cancer

Not currently recruiting at 41 trial locations

Overseen By Nancy Sherman

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Cardiff Oncology

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: BRAF-V600 mutation, Brain metastasis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Up to approximately 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called onvansertib, combined with standard chemotherapy, for individuals with a specific mutation of metastatic colorectal cancer (cancer that has spread). The goal is to determine the most effective and safe dose of onvansertib. Participants will receive either onvansertib with chemotherapy or just chemotherapy to compare outcomes. Individuals with KRAS or NRAS-mutated colorectal cancer who have not received prior treatment for their metastatic cancer may be suitable candidates. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that onvansertib, when combined with standard chemotherapy treatments like FOLFIRI and bevacizumab, is generally safe. Studies have found that patients with KRAS-mutant colorectal cancer tolerate it well, experiencing no severe side effects. In earlier studies, patients who received onvansertib with standard care reported common chemotherapy side effects, but nothing unusually concerning.

Researchers have tested onvansertib at different doses to identify the lowest effective dose with the fewest side effects. These trials aim to ensure safety while effectively treating cancer. Therefore, for those considering participation, current research indicates that the treatment is relatively safe. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for colorectal cancer?

Researchers are excited about Onvansertib for colorectal cancer because it targets a unique pathway in the cancer cell cycle. Unlike standard treatments like FOLFOX and FOLFIRI, which focus on stopping cancer cell division, Onvansertib inhibits a specific enzyme called PLK1, crucial for cancer cell replication. This novel mechanism of action could make Onvansertib more effective in overcoming resistance to existing therapies and might lead to better outcomes for patients. Additionally, Onvansertib is used in combination with standard chemotherapy regimens, potentially enhancing their effectiveness without significantly increasing side effects.

What evidence suggests that this trial's treatments could be effective for metastatic colorectal cancer?

Research has shown that onvansertib, one of the treatments studied in this trial, shows promise for treating advanced colorectal cancer with specific gene mutations (KRAS or NRAS) when combined with standard chemotherapy. In previous studies, patients taking a 30mg dose of onvansertib had a 49% objective response rate (ORR), meaning nearly half experienced tumor shrinkage. This significantly improved upon the 30% ORR in the group not receiving onvansertib. Additionally, the combination treatment proved safe, with few serious side effects. These findings suggest that onvansertib could enhance current treatment options for this type of cancer. Participants in this trial will receive either onvansertib with standard chemotherapy or standard chemotherapy alone, allowing for a direct comparison of outcomes. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Onvansertib

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.

How Is the Trial Designed?

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.

Onvansertib is already approved in United States, European Union for the following indications:

Approved in United States as Onvansertib for:

• Acute Myeloid Leukemia (AML) - Orphan Drug Designation

Approved in European Union as Onvansertib for:

• Acute Myeloid Leukemia (AML) - Orphan Drug Designation

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

Published Research Related to This Trial

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]

Citations

1. investors.cardiffoncology.com investors.cardiffoncology.com/news-releases/news-release-details/cardiff-oncology-announces-positive-data-ongoing-randomized

Cardiff Oncology Announces Positive Data from Ongoing ... Trial demonstrates 49% confirmed ORR in the 30mg onvansertib dose arm versus 30% confirmed ORR in the control arm in intent-to-treat ...

2. targetedonc.com targetedonc.com/view/onvansertib-shows-promising-early-efficacy-in-first-line-kras-mutated-mcrc

Onvansertib Shows Promising Early Efficacy in First-Line ... “We are highly encouraged by the 19% improvement in confirmed ORR as well as the shorter time to response and deeper tumor regression observed ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38231047/

Onvansertib in Combination with FOLFIRI and ... Onvansertib combined with FOLIFRI/bevacizumab exhibited manageable safety and promising efficacy in second-line treatment of patients with KRAS-mutant ...

4. onclive.com onclive.com/view/first-line-onvansertib-plus-bevacizumab-and-chemo-yields-responses-in-ras-mutated-mcrc

First-Line Onvansertib Plus Bevacizumab and Chemo ... Onvansertib combined with SOC shows a 49% ORR in RAS-mutated mCRC, surpassing the control group's 30% ORR. Early PFS data indicate a favorable ...

5. cancernetwork.com cancernetwork.com/view/onvansertib-combo-shows-significant-efficacy-in-kras-colorectal-cancer

Onvansertib Combo Shows Significant Efficacy in KRAS+ ... The disease control rate was 92.5%, the median duration of response (DOR) was 11.7 months (95% CI, 9.4-not reached), and median progression-free ...

6. investors.cardiffoncology.com investors.cardiffoncology.com/news-releases/news-release-details/cardiff-oncology-announces-positive-initial-data-first-line-ras

Cardiff Oncology Announces Positive Initial Data from First- ... “Our data shows an objective response rate of 64% in patients receiving the 30 mg dose of onvansertib in combination with standard of care, ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03829410

NCT03829410 | Onvansertib in Combination With FOLFIRI ... The purpose of the Phase 1b/2 study is to determine the safety and efficacy of Onvansertib, administered orally, daily on Day 1-5 and Day 15-19 of each 28-day ...

8. ddw-online.com ddw-online.com/promising-data-for-onvansertib-in-combination-with-standard-of-care-28064-202401/

Promising data for onvansertib in combination with ... “Our study showed an improved objective response rate and median progression-free survival compared to historical controls. Encouragingly, the ...