Chemotherapy + Bevacizumab + Atezolizumab for Colorectal Cancer

Recruiting at 508 trial locations

Overseen By Amjad Jalil

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Antibiotics

Disqualifiers: Hypertension, Heart failure, Autoimmune, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 8

Duration: 96 weeks

120 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase III trial studies how well combination chemotherapy, bevacizumab, and/or atezolizumab work in treating patients with deficient deoxyribonucleic acid (DNA) mismatch repair colorectal cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Chemotherapy drugs, such as fluorouracil, oxaliplatin, and leucovorin calcium, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab may stop or slow colorectal cancer by blocking the growth of new blood vessels necessary for tumor growth. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy, bevacizumab, and atezolizumab may work better in treating patients with colorectal cancer.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on systemic immunosuppressive medications, you may need to stop them 14 days before joining the trial, unless they are low-dose or inhaled corticosteroids.

What data supports the effectiveness of the drug combination of Chemotherapy, Bevacizumab, and Atezolizumab for Colorectal Cancer?

Research shows that adding Bevacizumab to chemotherapy regimens like 5-fluorouracil (5-FU) and leucovorin significantly improves survival and delays cancer progression in colorectal cancer patients. Bevacizumab, when combined with other drugs, has shown to enhance treatment outcomes, making it a promising part of colorectal cancer therapy. ^{1 2 3 4 5}

Is the combination of chemotherapy, bevacizumab, and atezolizumab generally safe for humans?

Bevacizumab, when combined with chemotherapy, has been shown to have manageable side effects like high blood pressure, minor bleeding, and protein in the urine, with more serious issues like wound healing problems and gastrointestinal perforations being less common. The combination of bevacizumab with chemotherapy is generally considered safe, but it can increase the risk of certain side effects. ^{4 6 7 8 9}

What makes the drug combination of Atezolizumab, Bevacizumab, Fluorouracil, Leucovorin, and Oxaliplatin unique for colorectal cancer?

This drug combination is unique because it includes Atezolizumab, an immunotherapy that helps the immune system attack cancer cells, alongside Bevacizumab, which inhibits blood vessel growth in tumors, and a chemotherapy regimen that has shown improved outcomes in colorectal cancer. This combination leverages both targeted therapy and immunotherapy, which is a novel approach compared to traditional chemotherapy alone. ^{1 10 11 12 13}

Research Team

Caio Max S Rocha Lima

Principal Investigator

NRG Oncology

Eligibility Criteria

This trial is for adults with metastatic colorectal cancer that hasn't been treated systemically. They must have a certain type of tumor (dMMR or MSI-H), adequate organ function, and no recent heart issues or severe infections. Participants need to agree to use effective contraception and not be pregnant.

Inclusion Criteria

Urine sample tested for proteinuria by specified methods

My scans show measurable cancer spread.

My tumor is identified as mismatch-repair deficient or has high microsatellite instability.

Exclusion Criteria

I have not taken certain medications recently.

I have not received a live vaccine in the last 28 days.

I am HIV positive, on treatment, and my viral load has been undetectable for the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive either combination chemotherapy with bevacizumab and atezolizumab or single agent atezolizumab. Treatment cycles repeat every 2 weeks for up to 48 cycles.

96 weeks

Bi-weekly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up includes imaging and optional blood sample collection.

5 years

Every 8 weeks for 18 months, then every 12 weeks

Treatment Details

Interventions

• Atezolizumab
• Bevacizumab
• Fluorouracil
• Leucovorin
• Oxaliplatin

Trial Overview The study tests how well a combination of chemotherapy drugs (fluorouracil, oxaliplatin, leucovorin) works with Bevacizumab and/or Atezolizumab in treating metastatic colorectal cancer. It looks at the effects on tumors that don't repair DNA mistakes well.

Participant Groups

Group I: Arm III (atezolizumab, bevacizumab, mFOLFOX6) Experimental Treatment 11 Interventions

Patients receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeats every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive bevacizumab IV over 30-90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 cycles 1-10, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on day 1. Treatment with oxaliplatin repeats every 2 weeks for up to 10 cycles in the absence of disease progression or unacceptable toxicity. Treatment of bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT with or without PET or MRI throughout the trial. Patients may also undergo collection of optional blood samples throughout the trial.

Group II: Arm II (atezolizumab) Experimental Treatment 7 Interventions

Patients receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeats every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT with or without PET or MRI throughout the trial. Patients may also undergo collection of optional blood samples throughout the trial.

Group III: Arm I (bevacizumab, mFOLFOX6) Active Control 10 Interventions

Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 of cycles 1-10, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1 and 2. Treatment with oxaliplatin repeats every 2 weeks for up to 10 cycles in the absence of disease progression or unacceptable toxicity. Treatment of bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT with or without PET or MRI throughout the trial. Patients may also undergo collection of optional blood samples throughout the trial. (CLOSED TO ACCRUAL)

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

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Findings from Research

The evolution of chemotherapy for colorectal cancer has shifted from the single-agent use of 5-fluorouracil (5-FU) to more effective combination regimens that include irinotecan, oxaliplatin, and targeted agents like bevacizumab, significantly improving patient survival rates.

Combination therapies utilizing 5-FU as a base have been shown to enhance treatment outcomes, highlighting the importance of integrating newer drugs into established regimens for better management of colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current approaches to first-line treatment of advanced colorectal cancer. Goldberg, RM.[2019]

Bevacizumab (Avastin) significantly improves overall and progression-free survival in patients with metastatic colorectal cancer when combined with standard chemotherapy regimens like IFL or 5-FU/LV, based on clinical data from various trials.

The drug shows potential for use in both first-line and second-line treatments, as well as in the adjuvant setting, by inhibiting vascular endothelial growth factor to prevent tumor angiogenesis, with ongoing Phase III trials exploring its efficacy in combination with oxaliplatin-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The future development of bevacizumab in colorectal cancer. Díaz-Rubio, E., Schmoll, HJ.[2015]

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]

Bevacizumab, a monoclonal antibody that targets VEGF, significantly improves response rates, time to tumor progression, and overall survival in patients with advanced colorectal cancer when added to fluorouracil-based chemotherapy regimens, based on two clinical trials.

While bevacizumab shows efficacy in treating advanced colorectal cancer, it is associated with serious safety concerns, including thromboembolic events, hypertension, hemorrhage, and gastrointestinal perforation, highlighting the need for careful monitoring and further studies comparing its effectiveness with other chemotherapy options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab for advanced colorectal cancer. Hadj Tahar, A.[2013]

In Stage II/III colorectal cancer (CRC), adding oxaliplatin to the standard treatment of 5-fluorouracil (5-FU)/leucovorin significantly reduces relapse and mortality rates, especially in Stage III patients, suggesting it should be included in treatment plans for Stage III CRC.

For metastatic CRC, the addition of bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, has been shown to extend both progression-free and overall survival, indicating it may soon become a standard part of treatment for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Which drug combination for colorectal cancer? Doggrell, SA.[2019]

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 study of 570 patients with stage III colorectal cancer, three different administration types of 5-fluorouracil (5-FU) in FOLFOX treatment showed similar disease-free survival (DFS) and overall survival (OS) rates, indicating comparable efficacy.

While all treatment regimens were manageable in terms of toxicity, the modified FOLFOX-6 group experienced more grade 1-2 adverse events like thrombocytopenia and neuropathy, suggesting that while efficacy is similar, side effects may vary among the different regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The comparison of FOLFOX regimens with different doses of 5-FU for the adjuvant treatment of colorectal cancer: a multicenter study. Akdeniz, N., Kaplan, MA., Uncu, D., et al.[2021]

In a study of 26 frail patients with unresectable or metastatic colorectal cancer, first-line chemotherapy combining bevacizumab with fluoropyrimidine achieved a 50% response rate and a 100% disease control rate, indicating effective treatment outcomes.

The safety profile was acceptable, with 31% of patients experiencing all grades of neutropenia and hypertension, but serious adverse events were rare, suggesting that this treatment regimen is a viable option for frail patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective study as first-line chemotherapy combined anti-VEGF antibody with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer. Yoshida, M., Goto, M., Kii, T., et al.[2015]

In a study of 66 patients with chemotherapy-refractory metastatic colorectal cancer, the combination of cetuximab with bevacizumab and mFOLFOX6 showed manageable safety, but significant toxicity led to a high discontinuation rate, with 56% of patients stopping treatment before disease progression.

Despite not causing excessive life-threatening toxicity, the addition of cetuximab resulted in a notable number of patients experiencing severe side effects, prompting the conclusion that this combination therapy should not be used together for treating metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab is associated with excessive toxicity when combined with bevacizumab Plus mFOLFOX6 in metastatic colorectal carcinoma. Ocean, AJ., Polite, B., Christos, P., et al.[2021]

In a study of 138 patients with untreated metastatic colorectal cancer, the FOLFOXIRI-Bev treatment resulted in a longer progression-free survival of 13.5 months compared to 10.4 months for XELOXIRI-Bev, indicating better efficacy for FOLFOXIRI-Bev.

While FOLFOXIRI-Bev showed a higher objective response rate (71% vs. 52.2%), it also led to significantly more severe side effects, such as neurotoxicity and neutropenia, highlighting a trade-off between effectiveness and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of FOLFOXIRI versus XELOXIRI plus bevacizumab in the treatment of metastatic colorectal cancer. Cheng, Y., Song, W.[2022]

In a study involving 508 patients with untreated metastatic colorectal cancer, the combination of FOLFOXIRI and bevacizumab significantly improved progression-free survival (12.1 months) compared to FOLFIRI and bevacizumab (9.7 months), indicating enhanced treatment efficacy.

While FOLFOXIRI plus bevacizumab showed better outcomes, it also resulted in higher rates of severe side effects, such as neurotoxicity and diarrhea, highlighting the need to balance treatment benefits with potential risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. Loupakis, F., Cremolini, C., Masi, G., et al.[2022]

The combination of oxaliplatin with oral fluoropyrimidines like capecitabine (XELOX) has shown over 50% response rates in first-line treatment for advanced colorectal cancer, indicating its efficacy.

Ongoing studies are exploring various combinations of oxaliplatin with biological therapies, such as cetuximab and bevacizumab, which target different cancer pathways, potentially leading to improved treatment outcomes for patients with advanced disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New oxaliplatin-based combinations in the treatment of colorectal cancer. Cassidy, J., Hochster, H.[2019]

Oral fluoropyrimidines, such as capecitabine and UFT/LV, offer a more convenient and less toxic alternative to traditional intravenous 5-fluorouracil (5-FU) for treating advanced colorectal cancer (CRC).

Oxaliplatin, with a different mechanism of action than 5-FU, significantly improves response rates and time to disease progression when used in combination with 5-FU and leucovorin in first-line treatment, and is effective even in patients whose cancer has progressed after 5-FU treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel chemotherapy agents for colorectal cancer: oral fluoropyrimidines, oxaliplatin, and raltitrexed. Royce, ME., Hoff, PM., Padzur, R.[2019]

References

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

Current approaches to first-line treatment of advanced colorectal cancer. [2019]

2. Switzerland pubmed.ncbi.nlm.nih.gov

The future development of bevacizumab in colorectal cancer. [2015]

3. 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]

4. Canada pubmed.ncbi.nlm.nih.gov

Bevacizumab for advanced colorectal cancer. [2013]

5. England pubmed.ncbi.nlm.nih.gov

Which drug combination for colorectal cancer? [2019]

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

Managing patients treated with bevacizumab combination therapy. [2015]

7. Germany pubmed.ncbi.nlm.nih.gov

The comparison of FOLFOX regimens with different doses of 5-FU for the adjuvant treatment of colorectal cancer: a multicenter study. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective study as first-line chemotherapy combined anti-VEGF antibody with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer. [2015]

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

Cetuximab is associated with excessive toxicity when combined with bevacizumab Plus mFOLFOX6 in metastatic colorectal carcinoma. [2021]

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

Efficacy of FOLFOXIRI versus XELOXIRI plus bevacizumab in the treatment of metastatic colorectal cancer. [2022]

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

Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. [2022]

12. England pubmed.ncbi.nlm.nih.gov

New oxaliplatin-based combinations in the treatment of colorectal cancer. [2019]

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

Novel chemotherapy agents for colorectal cancer: oral fluoropyrimidines, oxaliplatin, and raltitrexed. [2019]