Nivolumab + Ipilimumab for Rectal Cancer

Not currently recruiting at 241 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Autoimmune disease, Interstitial lung disease, 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: 5

Duration: 16-20 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two immunotherapy drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), along with radiation therapy, to evaluate their effectiveness in treating rectal cancer that has spread to nearby tissues or lymph nodes. The goal is to enhance the body's immune response to attack and shrink the cancer. Individuals diagnosed with stage II or III locally advanced rectal cancer who have not received prior treatment such as chemotherapy or radiation may be suitable candidates for this trial. As a Phase 2 trial, this 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. However, you cannot take certain medications like high-dose corticosteroids or immunosuppressive drugs within 14 days before starting the trial. It's best to discuss your specific medications with the trial team.

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

Research has shown that combining nivolumab and ipilimumab is generally safe and well-tolerated, with no unexpected severe side effects. In earlier studies, patients receiving this treatment had a 38% lower risk of disease progression or death compared to those who received only nivolumab.

While these results are encouraging, individual responses to treatments can vary. Side effects may differ, and this combination might not suit everyone. Always consult healthcare professionals about potential risks and benefits before deciding to join a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of nivolumab and ipilimumab for rectal cancer because it targets the immune system in a novel way. Unlike traditional chemotherapy, which directly attacks cancer cells, this treatment uses nivolumab and ipilimumab to boost the body's own immune response to fight the cancer. Nivolumab blocks the PD-1 pathway, allowing T cells to recognize and attack cancer cells, while ipilimumab works by blocking CTLA-4, another checkpoint that can inhibit immune response. This dual action has the potential to improve outcomes by enhancing the immune system's ability to target and destroy cancer cells more effectively.

What evidence suggests that nivolumab and ipilimumab might be an effective treatment for rectal cancer?

Research has shown that using nivolumab and ipilimumab together can help treat certain cancers. In studies, patients who took both drugs had a 38% lower chance of their cancer worsening or causing death compared to those who only took nivolumab. More patients also experienced a decrease in tumor size with the combination. Another study found that this treatment helped patients live longer without their cancer worsening compared to using nivolumab alone. These results suggest that combining nivolumab and ipilimumab, as done in this trial, may help the immune system fight cancer more effectively. ^{1 3 4 5 6}

Who Is on the Research Team?

Kristen K Ciombor

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for adults with locally advanced rectal cancer that hasn't spread far and can be measured by MRI or CT scans. Participants must have a certain level of white blood cells, liver and kidney function, not be pregnant or planning to become pregnant, use contraception, and not have had major surgery or pelvic radiation before. They should also not have active autoimmune diseases or need immune-suppressing steroids.

Inclusion Criteria

Patients of childbearing potential and sexually active patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for at least one month (female patients) or one week (male patients) prior to the start of study drug and continue for 5 months after the last dose of study drug (for female patients). Investigators must counsel patients on the importance of pregnancy prevention and the implications of an unexpected pregnancy

Leukocytes >= 3,000/mcL (must be obtained =< 14 days prior to protocol registration)

Absolute neutrophil count (ANC) >= 1,500/mcL (must be obtained =< 14 days prior to protocol registration)

Exclusion Criteria

Patient must not have had major surgery performed within 28 days prior to registration

Patient must not have previously received chemotherapy or immunotherapy for rectal cancer

You have not received radiation therapy to your pelvis before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab and ipilimumab intravenously every 28 days for 2 cycles, followed by short-course radiation therapy for 1 week, and then continue with nivolumab and ipilimumab for another 2 cycles

16-20 weeks

4 visits (in-person) for drug administration, 5 visits (in-person) for radiation therapy

Surgery

Participants undergo total mesorectal excision (TME) 8-12 weeks after completion of the 4th cycle of nivolumab and ipilimumab

1 week

1 visit (in-person) for surgery

Follow-up

Participants are monitored for safety and effectiveness after treatment, including MRI, CT, and sigmoidoscopy

5 years

Regular follow-up visits (in-person) as per protocol

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Radiation Therapy

Trial Overview

The study tests combining two immunotherapy drugs (Nivolumab and Ipilimumab) with short-course radiation therapy to see if they help the body fight rectal cancer better. The goal is to determine whether this combination can more effectively kill cancer cells in patients whose tumors haven't spread widely but are locally advanced.

How Is the Trial Designed?

Group I: Treatment (nivolumab, ipilimumab, radiation therapy, TME) Experimental Treatment 7 Interventions

Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 28 days for 2 cycles. Starting at least 2 weeks but no longer than 6 weeks after completion of cycle 2 of nivolumab and ipilimumab, patients undergo short-course radiation therapy of 5 fractions daily for 1 week. Patients then continue to receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. 8-12 weeks after completion of 4th cycle of nivolumab and ipilimumab, patients undergo TME. Patients also undergo MRI and CT prior to TME and during follow up, and undergo sigmoidoscopy prior to TME.

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+

Published Research Related to This Trial

A meta-analysis of 21 trials involving 11,454 patients found that immune checkpoint inhibitors (ICIs) significantly increase the risk of various immune-related adverse events (irAEs), including colitis, liver enzyme elevation, rash, hypothyroidism, and pneumonitis compared to non-ICI treatments.

While the incidence of fatal irAEs was less than 1%, the study highlights the importance of early recognition and intervention for these adverse events to prevent complications, particularly noting that ipilimumab was linked to a higher risk of certain skin and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients. De Velasco, G., Je, Y., Bossé, D., et al.[2023]

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]

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 1 trial involving 53 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 40% objective response rate, with 65% of patients showing clinical activity, indicating significant effectiveness in tumor reduction.

The concurrent treatment had a manageable safety profile, with 53% of patients experiencing grade 3 or 4 adverse events, which were similar to those seen with monotherapy and generally reversible, suggesting that this combination therapy is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in advanced melanoma. Wolchok, JD., Kluger, H., Callahan, MK., et al.[2022]

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]

In a meta-analysis of clinical trials, PD-1 inhibitors (like nivolumab and pembrolizumab) were found to have a higher incidence of colitis compared to PD-L1 inhibitors (like atezolizumab and durvalumab), with rates of 1.49% for all grade colitis and 0.85% for grade 3-4 colitis.

The analysis indicated that the relative risk of developing colitis with PD-1 inhibitors was significantly higher (1.80 for all grade colitis and 2.52 for grade 3-4 colitis), suggesting that patients receiving PD-1 inhibitors may need closer monitoring for this adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and Risk of Colitis With Programmed Death 1 Versus Programmed Death Ligand 1 Inhibitors for the Treatment of Cancer. Miyashita, H., Mikami, T., Satoi, S., et al.[2021]

A study analyzing 70,330 adverse events reported to the FDA found that immune checkpoint inhibitors (ICIs) significantly increase the risk of gastrointestinal (GI) toxicities, particularly colitis, hepatobiliary disorders, and pancreatitis, with colitis showing the highest reporting odds ratio of 17.2.

The risk of these GI adverse events was notably higher with anti-CTLA-4 treatments compared to anti-PD-1 and anti-PD-L1 therapies, and factors such as female gender and polytherapy were identified as strong risk factors for these complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Common Immune-Related Adverse Events of Immune Checkpoint Inhibitors in the Gastrointestinal System: A Study Based on the US Food and Drug Administration Adverse Event Reporting System. Bai, X., Jiang, S., Zhou, Y., et al.[2021]

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]

Combining ipilimumab with nivolumab can significantly improve treatment outcomes for advanced melanoma patients, but ipilimumab alone is not effective for those resistant to nivolumab.

A case study demonstrated that a nivolumab-resistant patient with multiple in-transit melanomas responded well to a combination of ipilimumab and topical imiquimod, suggesting a potential new treatment strategy for similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Nivolumab-Resistant Multiple In-Transit Melanomas with Ipilimumab and Topical Imiquimod. Fujimura, T., Kambayashi, Y., Sato, Y., et al.[2020]

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 phase I study involving 24 patients with locally advanced squamous cell carcinoma of the head and neck, the combination of nivolumab and ipilimumab showed promising efficacy with a 3-year progression-free survival rate of 74% and overall survival rate of 96%.

However, the treatment was associated with significant safety concerns, as 88% of patients experienced grade 3 or higher treatment-related adverse events, including severe soft tissue ulcerations in some cases, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and ipilimumab in combination with radiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck. Johnson, JM., Vathiotis, IA., Harshyne, LA., et al.[2023]

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]

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]

Citations

1.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.LBA143

First results of nivolumab (NIVO) plus ipilimumab (IPI) vs ...

Objective response rate (ORR) by BICR was significantly higher with NIVO + IPI vs NIVO (71% vs 58%; P = 0.0011; Table); best overall response of ...

2.

news.bms.com

news.bms.com/news/details/2025/Bristol-Myers-Squibb-Presents-Results-from-CheckMate--8HW-Analysis-Evaluating-Opdivo-nivolumab-plus-Yervoy-ipilimumab-Compared-to-Opdivo-Monotherapy/default.aspx

8HW Analysis Evaluating Opdivo® (nivolumab) plus ...

Patients experienced a 38% reduction in the risk of disease progression or death when treated with Opdivo plus Yervoy versus Opdivo monotherapy across all ...

3.

thelancet.com

thelancet.com/journals/lancet/article/PIIS0140-6736(24)02848-4/abstract

Nivolumab plus ipilimumab versus ...

Nivolumab plus ipilimumab treatment showed significant and clinically meaningful improvement in progression-free survival versus nivolumab (hazard ratio 0·62, ...

4.

nejm.org

nejm.org/doi/abs/10.1056/NEJMoa2402141

Nivolumab plus Ipilimumab in Microsatellite-Instability ...

At 24 months, the restricted mean survival time was 10.6 months (95% CI, 8.4 to 12.9) longer with nivolumab plus ipilimumab than with ...

5.

fda.gov

fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancer

FDA approves nivolumab with ipilimumab for unresectable ...

The major efficacy outcome measure was progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1. 1 ...

6.

healio.com

healio.com/news/hematology-oncology/20251030/firstline-nivolumabipilimumab-superior-to-nivolumab-monotherapy-for-colorectal-cancer

First-line nivolumab-ipilimumab betters colorectal cancer ...

First-line treatment with nivolumab-ipilimumab improved PFS and response compared with monotherapy for certain metastatic colorectal cancer.