Nivolumab +/- Ipilimumab for Anal Cancer

Recruiting at 59 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: HAART

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, Active infection, 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: Unknown

Duration: Up to 2 years

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase II trial studies how well nivolumab with or without ipilimumab works in treating patients with anal canal cancer that has not responded to previous treatment (refractory) and that has spread from where it first started (primary site) to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

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, you must wait at least 28 days after completing chemotherapy or radiotherapy before starting the trial treatment. It's best to discuss your specific medications with the trial team.

What is known about the safety of nivolumab and ipilimumab in humans?

Nivolumab and ipilimumab, used in cancer treatment, can cause immune-related side effects like diarrhea, colitis (inflammation of the colon), and skin rashes. These side effects are generally manageable, but in some cases, they can be severe and require stopping the treatment or using medications like steroids to control them. Fatal side effects are rare, occurring in less than 1% of cases. ^{1 2 3 4 5}

How is the drug combination of nivolumab and ipilimumab unique for treating anal cancer?

The combination of nivolumab and ipilimumab is unique for treating anal cancer because it uses the body's immune system to fight cancer cells, which is different from the standard chemotherapy treatments like cisplatin and 5-fluorouracil. This approach is particularly promising for anal cancer, which is often linked to viral infections, making immunotherapy a novel and potentially effective option. ^{6 7 8 9 10}

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

Research shows that immunotherapy, including drugs like Nivolumab and Ipilimumab, has been promising in treating cancers linked to viruses like HPV, which is often associated with anal cancer. Additionally, the combination of these drugs has shown long-term effectiveness in other cancers, such as lung cancer, suggesting potential benefits for anal cancer as well. ^{7 8 11 12 13}

Who Is on the Research Team?

Cathy Eng

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with metastatic anal canal cancer that hasn't improved after treatment. Participants must have adequate organ function, agree to contraception, and be willing to undergo HIV/hepatitis testing. Exclusions include recent chemotherapy, other investigational drugs, allergies to similar compounds, uncontrolled illnesses, certain prior cancers unless in remission for three years or more.

Inclusion Criteria

My cancer can be measured by scans and was checked within the last 28 days.

I am fully active or have some restrictions but can still care for myself.

I have had at least one treatment for advanced anal cancer that cannot be cured.

Exclusion Criteria

History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab and/or ipilimumab

I haven't taken high-dose steroids or immunosuppressants in the last 14 days.

I have previously been treated with specific immunotherapy drugs.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive nivolumab with or without ipilimumab intravenously, with regular imaging and blood sample collection to monitor response and toxicity

Up to 2 years

Bi-weekly to monthly visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

100 days post-treatment, then every 3 months for 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab

Trial Overview The study examines the effectiveness of nivolumab alone or combined with ipilimumab in treating refractory metastatic anal canal cancer. These are immunotherapy drugs designed to help the immune system fight cancer by blocking tumor growth and spread.

How Is the Trial Designed?

Group I: Part B Arm II (nivolumab, ipilimumab) Experimental Treatment 5 Interventions

Patients receive nivolumab as in Arm I. Patients also receive ipilimumab IV over 30 minutes once every 8 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.

Group II: Part B Arm I (nivolumab) Experimental Treatment 4 Interventions

Patients receive nivolumab IV over 30 minutes once every 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.

Group III: Part A (nivolumab) Experimental Treatment 4 Interventions

Patients receive nivolumab IV over 60 minutes once every two weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood sample collection throughout the study.

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

In a study of 1266 anal cancer patients treated according to Nordic guidelines, the 3-year recurrence-free survival rate was between 63% and 76%, indicating effective treatment outcomes.

Factors such as older age, male gender, and larger tumors were linked to worse outcomes, and the study suggests that inguinal prophylactic irradiation should be considered even for small tumors to reduce recurrence rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anal carcinoma - Survival and recurrence in a large cohort of patients treated according to Nordic guidelines. Leon, O., Guren, M., Hagberg, O., et al.[2022]

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 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]

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]

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]

Ipilimumab, an anti-CTLA-4 monoclonal antibody, is a significant advancement in cancer immunotherapy, effectively targeting T-cell inhibitory checkpoints to enhance the immune response against tumors.

In a review of 44 prostate cancer patients treated with ipilimumab, it was found that while the therapy is effective, it is also associated with immune-related adverse events (irAEs) that require careful management with immunosuppressive agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of immune-related adverse events in prostate cancer patients treated with ipilimumab: MD Anderson experience. Gao, J., He, Q., Subudhi, S., et al.[2022]

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]

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]

Nivolumab, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

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]

Citations

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

Role of Immunotherapy in the Treatment of Squamous Cell Carcinoma of the Anal Canal. [2020]

2. Ireland pubmed.ncbi.nlm.nih.gov

Anal carcinoma - Survival and recurrence in a large cohort of patients treated according to Nordic guidelines. [2022]

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

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

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

Dramatic response to modified docetaxel, cisplatin, and fluorouracil chemotherapy after immunotherapy in a patient with refractory metastatic anal cancer. [2023]

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

Immunotherapy in Anal Cancer. [2023]

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

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

7. 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]

8. United States 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. [2023]

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

Review of immune-related adverse events in prostate cancer patients treated with ipilimumab: MD Anderson experience. [2022]

10. 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]

11. 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]

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

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. [2023]

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

Nivolumab plus ipilimumab in advanced melanoma. [2022]