Nivolumab + Ipilimumab for Colorectal Cancer

(CheckMate 8HW Trial)

Recruiting at 339 trial locations

Overseen By BMS Study Connect Contact Center www.BMSStudyConnect.com

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Bristol-Myers Squibb

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: Unknown

1147 Participants Needed

Trial Summary

What is the purpose of this trial?

The main purpose of this study is to compare the clinical benefit, as measured by Progression-Free Survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS), achieved by nivolumab in combination with ipilimumab or by nivolumab monotherapy in participants with Microsatellite Instability High (MSI-H) or Mismatch Repair Deficient (dMMR) metastatic colorectal cancer (mCRC). This study will also compare nivolumab plus ipilimumab combination vs chemotherapy for treatment of MSI-H/dMMR mCRC participants.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more details.

What data supports the idea that the drug Nivolumab + Ipilimumab for Colorectal Cancer is an effective treatment?

The available research does not provide specific data on the effectiveness of Nivolumab + Ipilimumab for Colorectal Cancer. Instead, it focuses on other treatments like combinations of fluorouracil, oxaliplatin, and irinotecan, which have shown improvements in survival and disease management. For example, adding oxaliplatin to certain regimens has improved survival rates, and irinotecan has been effective in patients resistant to other treatments. However, there is no direct comparison or data for Nivolumab + Ipilimumab in the provided information. ^{1 2 3 4 5}

What safety data exists for Nivolumab and Ipilimumab in treating colorectal cancer?

Nivolumab and Ipilimumab, both immune checkpoint inhibitors, have been associated with immune-related adverse drug reactions (irADRs) and adverse events (AEs). Common gastrointestinal adverse events include diarrhea, nausea, and colitis, with severe cases often involving colitis and diarrhea. These adverse events can be managed with clinical monitoring and corticosteroids. The combination of Nivolumab and Ipilimumab has shown greater antitumor efficacy but also potential for increased toxicity. Adjusting administration schemes may help minimize these risks. ^{6 7 8 9 10}

Is the drug combination of Fluorouracil, Ipilimumab, Irinotecan, Nivolumab, and Oxaliplatin promising for colorectal cancer?

Yes, this drug combination is promising for colorectal cancer, especially for patients with a specific type of tumor called microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR). Studies show that using Nivolumab and Ipilimumab together can be effective for these patients, and adding Fluorouracil, Irinotecan, and Oxaliplatin can further improve outcomes. ^{5 11 12 13 14}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for adults with a specific type of advanced colorectal cancer that's not suitable for surgery. Participants must have tumors with high microsatellite instability or mismatch repair deficiency, and be in good physical condition (ECOG ≤1). People who've had certain immune diseases, lung conditions, or are HIV positive cannot join.

Inclusion Criteria

I am fully active and can carry on all pre-disease activities without restriction.

My colorectal cancer has returned or spread, and I haven't had chemotherapy or targeted therapy for it.

My tumor is identified as MSI-H or dMMR.

Exclusion Criteria

You have an autoimmune disease that is currently active, known, or suspected.

Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

There are other requirements that you must meet or not meet to participate in this study, as determined by the study guidelines.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Nivolumab monotherapy, Nivolumab in combination with Ipilimumab, or Investigator's choice chemotherapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• Bevacizumab
• Cetuximab
• Fluorouracil
• Ipilimumab
• Irinotecan
• Nivolumab
• Oxaliplatin

Trial Overview The study tests the effectiveness of Nivolumab alone or combined with Ipilimumab against standard chemotherapy options like Irinotecan and Oxaliplatin. It measures how long patients live without their cancer getting worse, their overall response to treatment, and survival time.

Participant Groups

Group I: Arm B: Nivolumab + Ipilimumab Combination Experimental Treatment 2 Interventions

Specified dose on specified days

Group II: Arm A: Nivolumab Monotherapy Experimental Treatment 1 Intervention

Specified dose on specified days

Group III: Arm C: Investigator's Choice Chemotherapy Active Control 6 Interventions

Participants in Arm C would be allowed to receive Nivolumab + Ipilimumab if they progress

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?

Bristol-Myers Squibb

Lead Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Ono Pharmaceutical Co. Ltd

Industry Sponsor

Trials

182

Recruited

97,100+

Shinji Takai

Ono Pharmaceutical Co. Ltd

Chief Medical Officer since 2023

MD from an unspecified institution

Gyo Sagara

Ono Pharmaceutical Co. Ltd

Chief Executive Officer since 2024

PhD in Pharmaceutical Sciences from Kyoto University

Findings from Research

Adjuvant therapy using 5-fluorouracil/leucovorin (5-FU/LV) regimens and capecitabine has significantly improved 3-year disease-free survival rates in stage III colorectal cancer patients, indicating its efficacy in early disease stages.

The addition of oxaliplatin to 5-FU-based regimens has been confirmed to enhance disease-free survival, establishing it as a standard treatment alongside other chemotherapy options for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid evolution in colorectal cancer: therapy now and over the next five years. de Gramont, A.[2007]

In a study of 62 advanced colorectal cancer patients resistant to fluorouracil, the oxaliplatin/irinotecan (OC) combination showed promising safety and efficacy, with median overall survival of 12.3 months.

The tritherapy regimen (5-FU/folinic acid combined with irinotecan and oxaliplatin) resulted in lower activity, possibly due to reduced dose intensities of the drugs, despite both regimens being generally safe with no treatment-related deaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients. Bécouarn, Y., Gamelin, E., Coudert, B., et al.[2018]

In a study of 16 patients with 5-fluorouracil-resistant metastatic colorectal cancer, irinotecan (CPT-11) demonstrated a partial response rate of 6.3% and a high rate of stable disease (43.7%), indicating its efficacy in this challenging patient population.

The median survival time for patients treated with CPT-11 was 69.6 weeks, with no toxic deaths reported, suggesting that CPT-11 is a safe and beneficial treatment option for patients resistant to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical activity and benefit of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma pre-treated with fluorouracil-based chemotherapy. Ratanatharathorn, V., Sirachainan, E., Jirajarus, M., et al.[2018]

Irinotecan (CPT-11) is significantly more effective than continuous-infusion 5-FU for patients with colorectal cancer who have not responded to previous treatments, improving survival and quality of life despite some treatment-related side effects.

Oxaliplatin, another new agent, shows significant activity against colorectal cancer and can be combined with irinotecan or 5-FU, potentially enhancing treatment effectiveness due to their different toxicity profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer. Khayat, D., Gil-Delgado, M., Antoine, EC., et al.[2018]

In a study of 25 patients with metastatic colorectal cancer treated with the triplet chemotherapy regimen OCX (oxaliplatin, irinotecan, capecitabine), the treatment showed a promising partial remission rate of 61% and a median overall survival of 32.9 months.

The OCX regimen was well tolerated, with no severe hematological side effects, although 24% of patients experienced grade 3 diarrhea, indicating manageable toxicity levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of triplet combination chemotherapy with oxaliplatin, irinotecan and capecitabine (OCX) in metastatic colorectal cancer in relation to RAS/RAF mutation status: results of a retrospective analysis. Brunner, S., von Moos, R., Mey, U., et al.[2018]

A meta-analysis of gastrointestinal adverse events in patients treated for malignant tumors with nivolumab and ipilimumab found that diarrhea was the most common side effect, along with nausea and decreased appetite.

Severe gastrointestinal issues, particularly colitis and diarrhea, were identified as significant risks, suggesting that adjusting the administration scheme of the treatment could help reduce these adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-related gastrointestinal adverse events of nivolumab plus ipilimumab in randomized clinical trials: a systematic review and meta-analysis. Liu, K., Wang, YH., Luo, N., et al.[2023]

Nivolumab and ipilimumab, two FDA-approved immunotherapeutic agents targeting PD-1 and CTLA-4, are effective in treating various cancers but can cause significant immune-related adverse effects (irAEs).

In a case study of a 66-year-old female patient, steroid-resistant colitis induced by these checkpoint inhibitors was successfully treated with infliximab, highlighting a potential management strategy for severe irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. Tidwell, C., Gutnik, S.[2020]

Ipilimumab has shown a positive impact on overall survival in patients with stage IV melanoma, with long-term follow-up indicating its effectiveness compared to conventional treatments.

While 84.8% of patients experience drug-related adverse events, most are mild to moderate; however, severe reactions can occur, necessitating careful monitoring and management, especially when combined with other therapies like vemurafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Camacho, LH.[2022]

In a study analyzing 2,088 individual case safety reports (ICSRs) related to immune checkpoint inhibitors (ICIs) in Italy, 801 reports documented serious immune-related adverse drug reactions (irADRs), primarily affecting male patients with gastrointestinal and skin toxicities.

Among the ICIs, nivolumab and pembrolizumab were most frequently associated with irADRs, with significant risks identified for pembrolizumab and ipilimumab, highlighting the need for oncologists to recognize and manage these serious side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database. Ruggiero, R., Fraenza, F., Scavone, C., et al.[2022]

In a study of 373 patients from 11 phase I clinical trials, ipilimumab-related grade 3/4 adverse events were more common in patients who responded to treatment, indicating a potential link between therapeutic response and toxicity.

The likelihood of experiencing severe adverse events increased with the number of additional agents used alongside ipilimumab, while longer treatment duration was associated with more low-grade toxicities but not high-grade ones.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic and predictive factors associated with ipilimumab-related adverse events: a retrospective analysis of 11 NCI-sponsored phase I clinical trials. Chauhan, A., Kabir, T., Wu, J., et al.[2023]

In a study of 20 patients with advanced colorectal cancer who were rechallenged with the FOX chemotherapy regimen, there was a modest response rate of 18%, with 47% of patients experiencing stable disease.

The median progression-free survival was 3.7 months and median overall survival was 7.8 months, suggesting that while the radiologic response is uncommon, there may still be some benefit in terms of survival for selected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rechallenge with oxaliplatin and fluoropyrimidine for metastatic colorectal carcinoma after prior therapy. Townsend, AR., Bishnoi, S., Broadbridge, V., et al.[2022]

In a phase II study involving 45 patients with MSI-H/dMMR metastatic colorectal cancer, the combination of nivolumab and low-dose ipilimumab showed a high objective response rate of 69% and a disease control rate of 84%, indicating strong efficacy as a first-line treatment.

The treatment was well tolerated, with only 22% of patients experiencing grade 3-4 treatment-related adverse events, and 74% of responders maintained their response at the time of data cutoff, suggesting durability of the treatment effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. Lenz, HJ., Van Cutsem, E., Luisa Limon, M., et al.[2022]

Nivolumab, a PD-1 inhibitor, is approved for treating various cancers, including metastatic colorectal cancer with specific genetic markers (deficient mismatch repair or microsatellite-instability high).

The FDA granted accelerated approval for nivolumab in July 2017 for patients with this type of colorectal cancer who have not responded to standard chemotherapy, highlighting its potential efficacy in a challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer. Mehrvarz Sarshekeh, A., Overman, MJ., Kopetz, S.[2022]

In a study of 30 patients aged over 80 with metastatic colorectal cancer, combination chemotherapy with a targeted agent (TA) showed a median progression-free survival of 7.4 months and overall survival of 15.4 months, compared to 4.4 months and 15.6 months for those without TA, although these differences were not statistically significant.

The study found that while combination chemotherapy with TA is feasible for elderly patients, careful monitoring is necessary due to potential hematologic toxicities, and salvage chemotherapy significantly improved overall survival after disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes of targeted therapies in elderly patients aged ≥ 80 years with metastatic colorectal cancer. Jang, HR., Lee, HY., Song, SY., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Rapid evolution in colorectal cancer: therapy now and over the next five years. [2007]

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

Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients. [2018]

3. Thailand pubmed.ncbi.nlm.nih.gov

Clinical activity and benefit of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma pre-treated with fluorouracil-based chemotherapy. [2018]

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

The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer. [2018]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy of triplet combination chemotherapy with oxaliplatin, irinotecan and capecitabine (OCX) in metastatic colorectal cancer in relation to RAS/RAF mutation status: results of a retrospective analysis. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Treatment-related gastrointestinal adverse events of nivolumab plus ipilimumab in randomized clinical trials: a systematic review and meta-analysis. [2023]

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

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. [2020]

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

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database. [2022]

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

Prognostic and predictive factors associated with ipilimumab-related adverse events: a retrospective analysis of 11 NCI-sponsored phase I clinical trials. [2023]

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

Rechallenge with oxaliplatin and fluoropyrimidine for metastatic colorectal carcinoma after prior therapy. [2022]

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

First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer. [2022]

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

Clinical outcomes of targeted therapies in elderly patients aged ≥ 80 years with metastatic colorectal cancer. [2022]