Ipilimumab + Nivolumab for Colorectal Cancer

Overseen By Nicholas D Klemen, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Autoimmune disorders, Immunodeficiency, 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: 23

Duration: 24 weeks

65 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does exclude participants taking steroids or other immunosuppressive agents that could affect the study drugs. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Ipilimumab and Nivolumab for colorectal cancer?

Research shows that the combination of nivolumab and ipilimumab has been effective in treating certain types of colorectal cancer, specifically those with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) characteristics, as demonstrated in the CheckMate 142 study. ^{1 2 3 4 5}

What safety information is available for the combination of Ipilimumab and Nivolumab?

The combination of Ipilimumab and Nivolumab has been associated with increased risk of immune-related side effects, such as colitis (inflammation of the colon), pneumonitis (lung inflammation), and diarrhea. These side effects can be serious, with some patients experiencing high-grade adverse events, and a small percentage of treatment-related deaths have been reported. Proper management of these side effects is crucial to prevent significant health issues. ^{6 7 8 9 10}

How is the drug combination of Ipilimumab and Nivolumab unique for colorectal cancer?

The combination of Ipilimumab and Nivolumab is unique for treating colorectal cancer with specific genetic features (MSI-H/dMMR) because it targets the immune system to fight cancer cells, offering a new option for patients whose cancer has progressed after standard treatments. ^{1 2 3 5 11}

What is the purpose of this trial?

Background: People with colorectal cancer (CRC) or gastroesophageal cancer (GEC) must often have major surgery to remove tumors from the esophagus, stomach, colon, or rectum. These surgeries can have adverse effects on their quality of life. Researchers want to know if one or two approved drugs (nivolumab with or without ipilimumab) can help people with CRC or GEC delay or avoid surgery. Objective: To test 1 or 2 drugs in people with CRC or GEC. Eligibility: People aged 18 years and older with CRC or GEC. People with GEC must also have changes in a particular gene. Design: Participants will visit the clinic about 15 times over the first 2 years. Each visit will last 4 to 8 hours. Participants will be screened. They will have a physical exam with blood and urine tests. They will have imaging scans. Small samples of tissue will be collected from their upper or lower digestive tract where the tumor is located. Both ipilimumab and nivolumab are administered through a tube attached to a needle inserted into a vein in the arm. Some participants will receive both drugs. Some will receive only nivolumab. Treatment will be given once every 3 weeks for up to 8 cycles up to (24 weeks). Participants will be evaluated every 6 weeks. Those who are responding well will continue with the drug treatments. If their disease progresses, they will go to surgery. After treatment ends, participants will have follow-up visits every 6 months for up to 5 years....

Research Team

Nicholas D Klemen, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for adults with colorectal or gastroesophageal cancer. For gastroesophageal cancer, a specific gene change is required. Participants will undergo numerous clinic visits and tests including blood, urine, imaging scans, and tissue samples from the digestive tract.

Inclusion Criteria

Breastfeeding participants must discontinue breastfeeding during study treatment

Participants must understand and sign a written informed consent document

My medical records show special reasons for my MMR proficient colon cancer treatment.

Exclusion Criteria

I am not on medications that could interfere with the study treatment.

Participants receiving any other investigational agents

I do not have any serious illnesses that would prevent me from having major surgery in my abdomen.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive nivolumab every 3 weeks for up to 8 cycles, with some receiving additional ipilimumab every 6 weeks for up to 4 cycles

24 weeks

8 visits (in-person)

Evaluation

Participants are evaluated every 6 weeks for response to treatment, which dictates further management

24 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up visits every 6 months for up to 5 years

5 years

10 visits (in-person)

Treatment Details

Interventions

• Ipilimumab
• Nivolumab

Trial Overview The study evaluates if nivolumab alone or combined with ipilimumab can delay or avoid surgery in patients. Treatments are given through an IV every 3 weeks for up to 24 weeks. Patients responding well may continue treatment; otherwise, they'll consider surgery.

Participant Groups

Group I: 2: nivolumab Experimental Treatment 1 Intervention

Nivolumab (3 mg/kg) every 3 weeks for up to an initial 4 cycles (an additional 4 cycles may be given depending on response, for a total of 8 cycles).

Group II: 1: nivolumab and ipilimumab Experimental Treatment 2 Interventions

Nivolumab (3 mg/kg) every 3 weeks for up to an initial 4 cycles (an additional 4 cycles may be given depending on response, for a total of 8 cycles); low-dose ipilimumab at 1 mg/kg every other cycle (every 6 weeks) for up to an initial 2 doses (an additional 2 doses may be given depending on response, for a maximum of 4 doses).

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

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more effective therapeutic strategy.

This combination therapy may enhance the immune response against cancer, but specific details on the number of subjects or study duration are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

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]

In a pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

Nivolumab combined with ipilimumab significantly improves overall survival in adult patients with intermediate/poor-risk advanced renal cell carcinoma compared to sunitinib, with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death.

In the study involving 1096 patients, the median overall survival was not reached for the nivolumab + ipilimumab group, while it was 25.95 months for the sunitinib group, highlighting the potential of this combination therapy for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. Ali, S., Camarero, J., Hennik, P., et al.[2021]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

A systematic review of 14 randomized controlled trials found that combining nivolumab (NIVO) with ipilimumab (IPI) significantly increases the risk of treatment-related adverse events (TRAEs) compared to NIVO alone, with an overall risk ratio of 1.11 for any grade TRAEs and 1.95 for severe (grade 3 or 4) TRAEs.

Specific adverse events were notably higher with the combination therapy, including colitis (RR = 4.52), pneumonitis (RR = 3.06), and diarrhea (RR = 1.68), indicating that while the combination may be effective, it comes with increased safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. Kamat, S., Patel, J., Brown, BR., et al.[2022]

The combination of nivolumab and ipilimumab resulted in an overall objective response rate (ORR) of 34.5% among 2,114 patients, indicating its efficacy in treating advanced malignancies.

Patients receiving nivolumab at 3 mg/kg with ipilimumab at 1 mg/kg experienced significantly fewer high-grade adverse events (39.9% incidence) compared to those receiving nivolumab at 1 mg/kg with ipilimumab at 3 mg/kg (55.9% incidence), suggesting a safer dosing strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Activity and Treatment-Related Toxicity Associated With Nivolumab Plus Ipilimumab in Advanced Malignancies: A Systematic Review and Meta-Analysis. Xu, H., Tan, P., Ai, J., et al.[2023]

In a study of 274 elderly patients with advanced melanoma, the risk of developing colitis was similar for those treated with anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab or pembrolizumab) therapies.

However, when considering patients across all stages of melanoma, anti-PD1 treatment was associated with a significantly lower risk of colitis compared to anti-CTLA4, suggesting a safer profile for anti-PD1 in this broader patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. Almutairi, AR., Slack, M., Erstad, BL., et al.[2022]

In a review of 129 oncology patients treated with immune checkpoint inhibitors, 51.9% experienced at least one immune-related adverse event (irAE), highlighting the common occurrence of these side effects.

Nearly half of the irAEs were managed according to established guidelines, but there was significant variability in documentation and management practices, indicating a need for improved adherence as immunotherapy use increases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. Teimouri, A., Minard, LV., Scott, SN., et al.[2022]

In a meta-analysis of 8 studies involving 1727 patients with advanced cancers (excluding melanoma), the combination of nivolumab and ipilimumab did not significantly improve overall survival compared to nivolumab alone, with some studies even showing lower median survival with the combination.

While there was a statistically significant but clinically marginal improvement in progression-free survival with the combination therapy, it was associated with a substantially higher risk of severe treatment-related adverse events and discontinuations, indicating a need for careful consideration of the risks versus benefits in nonmelanoma cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Ipilimumab vs Nivolumab Alone in Advanced Cancers Other Than Melanoma: A Meta-Analysis. Serritella, AV., Shenoy, NK.[2023]

References

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

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. [2021]

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

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

3. 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]

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

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. [2023]

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

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. [2021]

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

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. [2022]

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

Antitumor Activity and Treatment-Related Toxicity Associated With Nivolumab Plus Ipilimumab in Advanced Malignancies: A Systematic Review and Meta-Analysis. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. [2022]

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

Nivolumab Plus Ipilimumab vs Nivolumab Alone in Advanced Cancers Other Than Melanoma: A Meta-Analysis. [2023]