Chemotherapy +/− Bevacizumab for Stage II Colon Cancer

Recruiting at 1016 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Disqualifiers: Inflammatory bowel disease, Hypertension, Heart failure, 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

Compensation: Varies

Number of Visits: 27

Duration: 24 weeks

2432 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase III trial studies oxaliplatin, leucovorin calcium, fluorouracil, and bevacizumab to see how well they work compared to oxaliplatin, leucovorin calcium, and fluorouracil in treating patients who have undergone surgery for stage II colon cancer. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, 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. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving combination chemotherapy together with bevacizumab is more effective than combination chemotherapy alone in treating colon cancer.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug combination including Bevacizumab, 5-FU, Leucovorin, and Oxaliplatin for treating colon cancer?

Research shows that combining 5-FU and Leucovorin with Oxaliplatin improves response rates and delays disease progression in colorectal cancer compared to 5-FU and Leucovorin alone. Additionally, Bevacizumab has been studied in combination with these drugs for metastatic colorectal cancer, suggesting potential benefits in treatment. ^{1 2 3 4 5}

Is the combination of chemotherapy drugs, including 5-FU, leucovorin, and oxaliplatin, safe for humans?

The combination of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin has been shown to be generally safe for humans, with common severe side effects including diarrhea, mouth sores, nausea, vomiting, and abdominal pain. These treatments are well tolerated and have been used effectively in patients with colorectal cancer. ^{6 7 8 9 10}

What makes the chemotherapy with or without bevacizumab unique for stage II colon cancer?

This treatment is unique because it combines chemotherapy drugs with bevacizumab, which targets and inhibits the formation of new blood vessels that tumors need to grow. While bevacizumab is commonly used for advanced colorectal cancer, its use in stage II colon cancer is less common, potentially offering a novel approach for this earlier stage. ^{11 12 13 14 15}

Research Team

Al B Benson

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for patients who've had surgery for stage II colon cancer. They should have stable blood pressure, no severe neuropathy, and no history of inflammatory bowel disease or significant bleeding unrelated to their tumor. Participants must not have started any other treatments for this cancer, be in good physical condition (ECOG 0-2), and agree to use contraception if applicable. Those with certain heart conditions or a history of serious blood clots can't join.

Inclusion Criteria

I have a tumor sample available for specific genetic testing.

Patients must have >= 8 lymph nodes evaluated and reported

Low-risk patients will be registered to Arm C for observation

Exclusion Criteria

I have had a condition where my lymphocytes multiply unusually.

I haven't had any cancer except for skin cancer in the last 5 years.

I have not had a heart attack or unstable angina in the last year.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive oxaliplatin, leucovorin calcium, and fluorouracil with or without bevacizumab every 2 weeks for 12 courses

24 weeks

12 visits (in-person)

Bevacizumab Extension

Patients in Arm B receive bevacizumab alone for 12 additional courses

24 weeks

12 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Every 3 months for 2 years, every 6 months for 3 years, then annually for 10 years

Treatment Details

Interventions

• Bevacizumab
• Fluorouracil
• Laboratory Biomarker Analysis
• Leucovorin Calcium
• Oxaliplatin

Trial Overview The study compares two treatment methods after surgery: one group receives chemotherapy drugs oxaliplatin, leucovorin calcium, fluorouracil alone; the other gets these drugs plus bevacizumab, an antibody that may block tumor growth. The goal is to find out which combination is more effective against colon cancer.

Participant Groups

Group I: Arm B (combination chemotherapy, bevacizumab) Experimental Treatment 5 Interventions

Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in Arm A and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab alone for 12 additional courses in the absence of disease progression or unacceptable toxicity.

Group II: Arm C (observation) Active Control 1 Intervention

Patients undergo observation.

Group III: Arm A (oxaliplatin, leucovorin calcium, fluorouracil) Active Control 4 Interventions

Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Skin cancer

Approved in European Union as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in Canada as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Postoperative adjuvant chemotherapy with fluorouracil (5-FU) and leucovorin significantly improves disease-free and overall survival in patients with node-positive (stage III) colorectal cancer, based on clinical trials involving over 5,000 cases.

Current clinical trials are exploring the effectiveness of combining 5-FU/leucovorin with other agents like irinotecan and oxaliplatin, which have shown superior results compared to 5-FU/leucovorin alone in advanced colorectal cancer, aiming to refine the standard of care for resected cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant therapy of colon cancer. Macdonald, JS., Astrow, AB.[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]

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 retrospective analysis of patients with metastatic colorectal cancer, bevacizumab significantly improved progression-free survival (PFS) and overall survival (OS) in patients aged 65 and older, showing similar benefits to younger patients.

While older patients experienced an increase in thromboembolic events when treated with bevacizumab, no other significant age-related increases in severe adverse events were noted, indicating a manageable safety profile for this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies. Cassidy, J., Saltz, LB., Giantonio, BJ., et al.[2022]

In a study of 107 patients with metastatic colorectal cancer, the combination of irinotecan plus bevacizumab showed similar efficacy to FOLFIRI plus bevacizumab, with median progression-free survival of 6.4 months versus 5.8 months, and overall survival of 16.6 months versus 16.5 months, respectively.

Omitting fluorouracil from the FOLFIRI regimen resulted in fewer adverse events, such as nausea and neutropenia, suggesting that irinotecan plus bevacizumab may be a safer second-line treatment option for patients who are refractory to fluoropyrimidines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of omitting fluorouracil from FOLFIRI plus bevacizumab as second-line chemotherapy for patients with metastatic colorectal cancer. Matsubara, Y., Masuishi, T., Ogata, T., et al.[2023]

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]

References

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

Adjuvant therapy of colon cancer. [2019]

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

Fluorodeoxyuridine with continuous leucovorin infusion. A phase II clinical trial in patients with metastatic colorectal cancer. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

Randomized trial of the efficacy of adjuvant chemotherapy for colon cancer with combination therapy incorporating the oral pyrimidine 1-hexylcarbamoyl-5-fluorouracil. [2021]

4. Japan pubmed.ncbi.nlm.nih.gov

Phase II trial of an alternating regimen consisting of first-line mFOLFOX6 plus bevacizumab and FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: FIREFOX plus bevacizumab trial (KSCC0801). [2018]

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

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

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

UFT plus calcium folinate vs 5-FU plus calcium folinate in colon cancer. [2013]

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. Germany pubmed.ncbi.nlm.nih.gov

Phase I trial of a 5-day infusion of L-leucovorin plus daily bolus 5-fluorouracil in patients with advanced gastrointestinal malignancies. [2019]

9. Netherlands pubmed.ncbi.nlm.nih.gov

FOLFOX3 in heavily pretreated patients with metastatic colorectal cancer. [2018]

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

The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. [2022]

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]

12. Germany pubmed.ncbi.nlm.nih.gov

Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies. [2022]

13. Germany pubmed.ncbi.nlm.nih.gov

Impact of omitting fluorouracil from FOLFIRI plus bevacizumab as second-line chemotherapy for patients with metastatic colorectal cancer. [2023]

14. Canada pubmed.ncbi.nlm.nih.gov

Bevacizumab for advanced colorectal cancer. [2013]

15. England pubmed.ncbi.nlm.nih.gov

Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. [2022]