Onvansertib + FOLFIRI + Bevacizumab for Colorectal Cancer

No longer recruiting at 46 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for individuals with advanced colorectal cancer, specifically targeting those with a KRAS or NRAS genetic mutation whose cancer has worsened after initial treatments. Researchers aim to determine the effectiveness of two different doses of a new drug, onvansertib, in combination with standard chemotherapy (FOLFIRI) and bevacizumab, which helps prevent new blood vessels from forming in tumors. Suitable candidates have colorectal cancer that cannot be surgically removed and have not succeeded with certain chemotherapy drugs. Participants should not have received treatment with irinotecan before joining this study. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that onvansertib, when combined with the standard chemotherapy treatment FOLFIRI and the drug bevacizumab, is generally well-tolerated. In these studies, patients did not experience any major or unexpected harmful effects. The treatment was manageable, with side effects not severe enough to halt the treatment. This suggests that onvansertib may be a safe option for patients with certain types of colorectal cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Onvansertib for colorectal cancer because it offers a fresh approach to treatment by targeting a specific enzyme called PLK1, which is crucial for cancer cell division. This is different from the standard of care, which typically involves chemotherapy combinations like FOLFIRI and the biologic agent bevacizumab. Onvansertib's ability to selectively inhibit PLK1 could potentially enhance the effectiveness of existing treatments and improve patient outcomes by directly interfering with cancer cell replication. Additionally, Onvansertib is being tested in two different dosage regimens, which may help identify the optimal balance between efficacy and safety.

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

Research shows that onvansertib, when combined with standard chemotherapy and bevacizumab, may help treat metastatic colorectal cancer with certain gene mutations. In this trial, participants will receive either a 20 mg or 30 mg dose of onvansertib alongside the standard of care (SOC), which includes FOLFIRI and bevacizumab. One study found that a 30 mg dose of onvansertib led to a 49% overall response rate (ORR), meaning nearly half of the patients experienced tumor shrinkage. This is better than the 30% ORR observed in patients who did not receive onvansertib. Additionally, patients experienced faster and more significant tumor shrinkage. These results suggest that onvansertib could be a valuable addition to the current treatment plan for this type of cancer. ^{2 3 4 5 6}

Are You a Good Fit for This Trial?

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

My doctor agrees FOLFIRI therapy is suitable for me.

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

My cancer has worsened despite treatment with specific chemotherapy drugs.

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 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 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

What Are the Treatments Tested in This Trial?

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.

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 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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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/39475591/

A Single-Arm, Phase II Trial Results: Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not ...

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. 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 ...

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

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