Onvansertib + FOLFIRI + Bevacizumab for Colorectal Cancer

Recruiting at 45 trial locations

Overseen By Nancy Sherman

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Cardiff Oncology

Must not be taking: QT prolonging drugs, CYP3A4 inhibitors

Disqualifiers: BRAF-V600 mutation, Brain metastasis, GI disorders, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: Up to approximately 1 year

23 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called onvansertib combined with standard chemotherapy and bevacizumab for colorectal cancer patients with specific gene mutations who didn't respond to earlier treatment. The new drug aims to block cancer cell growth, making the existing chemotherapy work better. Bevacizumab is used in combination with chemotherapy for treating advanced colorectal cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not use certain medications that affect heart rhythm or specific enzymes. If you're on these, you may need to switch to alternatives before starting the trial.

What data supports the effectiveness of the drug Onvansertib + FOLFIRI + Bevacizumab for colorectal cancer?

Research shows that adding bevacizumab to chemotherapy regimens like FOLFIRI improves survival rates in patients with metastatic colorectal cancer. Additionally, studies have demonstrated that bevacizumab enhances the effectiveness of various chemotherapy combinations, suggesting potential benefits when used with Onvansertib. ^{1 2 3 4 5}

What is the safety profile of the combination treatment Onvansertib + FOLFIRI + Bevacizumab for colorectal cancer?

Bevacizumab, when combined with chemotherapy like FOLFIRI, is generally safe but can cause side effects such as high blood pressure, bleeding, and blood clots, which are usually mild to moderate and manageable. The combination has been studied primarily in metastatic colorectal cancer, showing that while it can increase some adverse events, these are often outweighed by the benefits in survival. ^{5 6 7 8 9}

What makes the drug combination of Onvansertib, FOLFIRI, and Bevacizumab unique for colorectal cancer?

This treatment is unique because it combines Onvansertib, a newer drug that targets specific cancer cell processes, with the established FOLFIRI chemotherapy regimen and Bevacizumab, which helps prevent the growth of blood vessels that feed tumors. This combination aims to enhance the effectiveness of treatment for colorectal cancer by attacking the cancer in multiple ways. ^{1 2 5 10 11}

Eligibility Criteria

Adults with metastatic colorectal cancer that has progressed after oxaliplatin/fluoropyrimidine-based treatment. They must have KRAS or NRAS mutations, measurable disease via CT/MRI, and good organ function. Not eligible if they've had irinotecan before, brain metastasis, GI absorption issues, certain heart conditions or severe allergies to trial drugs.

Inclusion Criteria

I am 18 years old or older.

My doctor agrees FOLFIRI therapy is suitable for me.

My cancer has a KRAS or NRAS mutation as confirmed by a certified lab.

Exclusion Criteria

My cancer has specific genetic mutations (KRAS, NRAS, BRAF-V600) or is MSI-H/dMMR.

I have had more than one chemotherapy treatment for cancer that has spread.

I have not had major surgery in the last 6 weeks.

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 in 28-day cycles

Up to approximately 1 year

Days 1 to 5 and 15 to 19 for Onvansertib; Days 1 and 15 for SOC in each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Bevacizumab
• FOLFIRI
• Onvansertib

Trial Overview The trial is testing two doses of Onvansertib in combination with FOLFIRI (irinotecan, fluorouracil [5-FU], leucovorin) and Bevacizumab against just FOLFIRI and Bevacizumab for those who didn't respond well to first-line therapy for their KRAS/NRAS mutated 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 15 to 19 of a 28-day treatment cycle and SOC (FOLFIRI + bevacizumab) on Days 1 and 15 of each 28-day cycle.

Group II: Onvansertib 20 mg + Standard of Care (SOC) Experimental Treatment 3 Interventions

Participants will receive 20 mg of onvansertib on Days 1 to 5 and 15 to 19 of a 28-day treatment cycle and SOC (FOLFIRI + bevacizumab) on Days 1 and 15 of each 28-day cycle.

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

Participants will receive SOC (FOLFIRI + bevacizumab) on Days 1 and 15 of each 28-day cycle.

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

Cardiff Oncology

Lead Sponsor

Trials

12

Recruited

650+

Findings from Research

In a phase IV trial involving 209 treatment-naïve patients with metastatic colorectal cancer, the combination of bevacizumab and FOLFIRI resulted in a median progression-free survival (PFS) of 11.1 months and a median overall survival (OS) of 22.2 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with most adverse events being mild (grade 1/2), while serious side effects like neutropenia and venous thromboembolic events occurred in over 10% of patients, indicating manageable safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Sobrero, A., Ackland, S., Clarke, S., et al.[2022]

The combination of FOLFOXIRI and bevacizumab demonstrated a promising progression-free survival (PFS) rate of 74% at 10 months in patients with unresectable metastatic colorectal cancer, based on a phase 2 study involving 57 patients.

The treatment was found to be safe, with no unexpected adverse events reported, although common serious side effects included neutropenia and hypertension, indicating that while effective, careful monitoring for these side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Masi, G., Loupakis, F., Salvatore, L., et al.[2022]

In a meta-analysis of 11 randomized controlled trials involving 3178 patients, the combination of bevacizumab (BEV) with the FOLFOX regimen significantly improved the objective response rate and cancer control rate compared to FOLFOX alone.

However, this combination treatment was associated with a higher incidence of gastrointestinal adverse reactions, indicating a trade-off between increased efficacy and potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of bevacizumab combined with FOLFOX regimen in the treatment of advanced colorectal cancer: A systematic review and meta-analysis. Zhang, H., You, J., Liu, W., et al.[2023]

In a study of 69 Asian patients with metastatic colorectal cancer, the combination of FOLFOXIRI and bevacizumab resulted in a high progression-free survival (PFS) rate of 75.2% at 10 months, indicating its effectiveness as a first-line treatment.

However, this regimen was associated with significant adverse events, particularly high rates of neutropenia (72.5%) and hypertension (34.8%), highlighting the need for careful monitoring, especially in patients with specific UGT1A1 genetic polymorphisms that increase the risk of severe neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multicenter Clinical Phase II Study of FOLFOXIRI Plus Bevacizumab as First-line Therapy in Patients With Metastatic Colorectal Cancer: QUATTRO Study. Oki, E., Kato, T., Bando, H., et al.[2022]

Bevacizumab (Avastin) effectively targets VEGF to inhibit tumor angiogenesis, showing a safety profile that includes mostly mild to moderate side effects such as hypertension and proteinuria, which are manageable in clinical settings.

The side effects associated with bevacizumab, including rare but serious events like gastrointestinal perforation and arterial thrombosis, do not typically exacerbate the toxicity of standard chemotherapy, making it a suitable adjunct treatment for metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing patients treated with bevacizumab combination therapy. Gordon, MS., Cunningham, D.[2015]

The combination of FOLFIRI and aflibercept was found to be active and tolerable in treating metastatic colorectal cancer (mCRC), with an objective response rate of 46.6% among 73 patients, indicating potential effectiveness in this patient population.

Despite its activity, the regimen did not surpass historical benchmarks for efficacy in chemotherapy-naive patients, with a 12-month progression-free survival rate of only 21.9% and a median overall survival of 20.9 months, suggesting that while it may help some patients, it may not be a significant improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AMALTHEA: Prospective, Single-Arm Study of the Hellenic Cooperative Oncology Group (HeCOG) Evaluating Efficacy and Safety of First-Line FOLFIRI + Aflibercept for 6 Months Followed by Aflibercept Maintenance in Patients With Metastatic Colorectal Cancer. Pentheroudakis, G., Kotoula, V., Koliou, GA., et al.[2019]

In a meta-analysis of 6 randomized controlled trials involving 2165 participants, the addition of bevacizumab to chemotherapy regimens (FOLFIRI or IFL) significantly improved the partial and objective response rates in patients with metastatic colorectal cancer (mCRC).

While bevacizumab reduced the risk of mortality and improved progression-free survival (PFS) and overall survival (OS), it also increased the risk of adverse events, indicating a trade-off between efficacy and safety in its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of addition of bevacizumab to FOLFIRI or irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer: A meta-analysis. Chen, K., Gong, Y., Zhang, Q., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. [2022]

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

Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. [2022]

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

The efficacy and safety of bevacizumab combined with FOLFOX regimen in the treatment of advanced colorectal cancer: A systematic review and meta-analysis. [2023]

4. England pubmed.ncbi.nlm.nih.gov

FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. [2022]

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

A Multicenter Clinical Phase II Study of FOLFOXIRI Plus Bevacizumab as First-line Therapy in Patients With Metastatic Colorectal Cancer: QUATTRO Study. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Managing patients treated with bevacizumab combination therapy. [2015]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Targeted therapies in the management of colorectal carcinoma: role of bevacizumab. [2021]

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

AMALTHEA: Prospective, Single-Arm Study of the Hellenic Cooperative Oncology Group (HeCOG) Evaluating Efficacy and Safety of First-Line FOLFIRI + Aflibercept for 6 Months Followed by Aflibercept Maintenance in Patients With Metastatic Colorectal Cancer. [2019]

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

Efficacy and safety of addition of bevacizumab to FOLFIRI or irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer: A meta-analysis. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of bevacizumab-based combination regimens in patients with previously untreated metastatic colorectal cancer: final results from a randomised phase II study of bevacizumab plus 5-fluorouracil, leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC ACCORD 13/0503 study). [2018]

11. England pubmed.ncbi.nlm.nih.gov

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study. [2022]