Ipilimumab +/- Bevacizumab for Melanoma

Recruiting at 577 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Corticosteroids, NSAIDs, others

Disqualifiers: CNS metastases, Autoimmune disease, Hypertension, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 16

169 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking certain medications, such as systemic steroids, full-dose warfarin, and some non-steroidal anti-inflammatory drugs (NSAIDs), at least 2 weeks before joining. If you are on any of these, you will need to discuss with your doctor about stopping them before participating.

What data supports the effectiveness of the drug combination of Ipilimumab and Bevacizumab for treating melanoma?

Research shows that combining ipilimumab with bevacizumab can lead to changes in tumor size and density, which are linked to better survival outcomes in advanced melanoma patients. Additionally, bevacizumab has been shown to improve survival in other advanced cancers, suggesting potential benefits when used with ipilimumab for melanoma. ^{1 2 3 4 5}

Is the combination of Ipilimumab and Bevacizumab safe for treating melanoma?

Ipilimumab, used for melanoma, can cause side effects, mostly mild to moderate, but some can be severe and life-threatening. It is important to monitor patients closely and manage side effects with medications like corticosteroids. Combining it with other drugs like nivolumab may increase the risk of side effects. ^{6 7 8 9 10}

What makes the drug Ipilimumab unique for treating melanoma?

Ipilimumab is unique because it is a monoclonal antibody that blocks CTLA-4, a molecule that normally dampens the immune response, thereby enhancing the body's ability to attack melanoma cells. This mechanism is different from traditional chemotherapy, and it can lead to durable tumor regression, although it may also cause unique immune-related side effects. ^{1 11 12 13 14}

What is the purpose of this trial?

This randomized phase II trial studies how well ipilimumab with or without bevacizumab works in treating patients with stage III-IV melanoma that cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as ipilimumab and bevacizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Research Team

Frank S Hodi

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for patients with stage III-IV melanoma that can't be surgically removed. Participants must have known BRAF mutation status, normal organ function tests, and no recent history of certain heart conditions or infections like HIV or hepatitis. They should not be pregnant, breastfeeding, or on immunosuppressants and must agree to use contraception.

Inclusion Criteria

I am not pregnant or breastfeeding and have confirmed this with a test.

Your hemoglobin level is 9 grams per deciliter or higher within the last 4 weeks before the study starts.

Your blood bilirubin level should not be higher than 2 times the upper limit of normal, unless you have Gilbert's syndrome, in which case it should be less than 3.0 mg/dL.

Exclusion Criteria

I have not had surgery or a major injury in the last 28 days.

Patients are ineligible if they have a history of any underlying medical or psychiatric conditions or require any medications or treatment that in the opinion of the principal investigator may interfere with compliance, make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea

I have never had cancer spread to my brain or spinal cord.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive ipilimumab with or without bevacizumab every 21 days for 4 cycles

12 weeks

4 visits (in-person)

Maintenance Therapy

Patients receive ipilimumab and/or bevacizumab every 12 weeks starting from cycle 8

Long-term

Every 12 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Bevacizumab
• Ipilimumab

Trial Overview The study is testing the effectiveness of ipilimumab alone versus combined with bevacizumab in treating advanced melanoma. These drugs are types of immunotherapy that may help the immune system fight cancer by stopping tumor growth and spread.

Participant Groups

Group I: Arm B (ipilimumab and bevacizumab) Experimental Treatment 2 Interventions

INDUCTION THERAPY: Patients receive ipilimumab IV over 90 minutes and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive bevacizumab as in Induction Therapy. Beginning cycle 8, patients also receive ipilimumab IV over 90 minutes on day 1. Cycles repeat every 12 weeks in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (ipilimumab) Active Control 1 Intervention

INDUCTION THERAPY: Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Beginning cycle 8, patients receive ipilimumab IV over 90 minutes on day 1. Cycles repeat every 12 weeks in the absence of disease progression or unacceptable toxicity.

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

In a phase 2 trial involving 142 patients with untreated advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 2-year overall survival rate of 63.8%, compared to 53.6% for those receiving ipilimumab alone, suggesting improved survival outcomes with the combination therapy.

However, the combination treatment was associated with a higher incidence of severe side effects, with 54% of patients experiencing grade 3-4 adverse events compared to 20% in the ipilimumab-only group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi, FS., Chesney, J., Pavlick, AC., et al.[2022]

In a study of 21 advanced melanoma patients treated with ipilimumab and bevacizumab, 39% of lesions showed a decrease in tumor density according to Choi criteria, indicating a potential response to treatment.

Larger baseline tumor diameters were significantly linked to shorter progression-free and overall survival, but changes in tumor size or density did not predict survival outcomes, suggesting that further research is needed to clarify the role of density changes in treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response assessment in metastatic melanoma treated with ipilimumab and bevacizumab: CT tumor size and density as markers for response and outcome. Nishino, M., Giobbie-Hurder, A., Ramaiya, NH., et al.[2019]

Nivolumab combined with ipilimumab demonstrated significantly better overall survival compared to BRAF + MEK inhibitors, with hazard ratios indicating a 36% to 44% reduction in the risk of death after 12 months.

While nivolumab + ipilimumab had improved survival outcomes, it also resulted in a higher rate of grade 3/4 adverse events (54.1%) compared to dabrafenib + trametinib (31.6%) and similar rates to vemurafenib + cobimetinib (59.5%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy of combination immunotherapy and targeted therapy in the treatment of BRAF-mutant advanced melanoma: a matching-adjusted indirect comparison. Atkins, MB., Tarhini, A., Rael, M., et al.[2020]

In a phase 3 trial with patients suffering from advanced melanoma, the combination of nivolumab and ipilimumab resulted in significantly longer overall survival rates (58% at 3 years) compared to ipilimumab alone (34%).

The safety profile of the combination therapy was consistent with previous reports, showing that 59% of patients experienced severe treatment-related adverse events, indicating that while effective, the combination therapy has a higher risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. Wolchok, JD., Chiarion-Sileni, V., Gonzalez, R., et al.[2023]

In a study of 1343 melanoma patients at high risk of recurrence, adjuvant bevacizumab improved the disease-free interval (DFI) with 51% of patients disease-free at 5 years compared to 45% in the observation group, indicating its efficacy in delaying recurrence.

However, there was no significant difference in overall survival (OS) between the bevacizumab and observation groups, with both showing a 5-year OS rate of 64%, suggesting that while bevacizumab may help prevent recurrence, it does not extend overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial. Corrie, PG., Marshall, A., Nathan, PD., et al.[2022]

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]

Ipilimumab, an anti-CTLA-4 antibody, has been shown to improve survival in patients with unresectable or metastatic melanoma, with a standard dosing of 3 mg/kg every 3 weeks for a total of 4 doses.

While ipilimumab can cause immune-related adverse events in 15% of patients, most are mild and manageable; however, high-grade events can be serious and require careful monitoring and treatment with corticosteroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab for advanced melanoma: a pharmacologic perspective. Trinh, VA., Hagen, B.[2021]

Ipilimumab showed a best overall response rate (BORR) of 5.8% and a disease control rate (DCR) of 27% in patients with advanced melanoma, indicating some level of efficacy in this challenging population.

The treatment resulted in promising long-term survival rates, with 1- and 2-year survival rates of 47.2% and 32.8%, respectively, and a median overall survival of 10.2 months, while adverse events were primarily immune-related but manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. O'Day, SJ., Maio, M., Chiarion-Sileni, V., et al.[2022]

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]

Ipilimumab (Yervoy®) is an approved monoclonal antibody for treating malignant melanoma by blocking the CTLA-4 protein, which enhances T-cell responses against tumor cells, showing its efficacy in cancer immunotherapy.

Currently, ipilimumab is also being tested in phase III trials for prostate cancer and phase II trials for non-small cell lung cancer, indicating its potential for broader applications in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab: first global approval. Cameron, F., Whiteside, G., Perry, C.[2021]

Ipilimumab, a monoclonal antibody used to enhance anti-tumor T-cell responses, can cause significant side effects, including ipilimumab-induced hypophysitis (IH), which affects hormone levels and requires hormone replacement therapy in most cases.

In a review of 10 patients with IH, early detection and management guidelines were developed, highlighting the importance of monitoring hormone levels and recognizing imaging abnormalities, which often resolve without high-dose glucocorticoid therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. Lam, T., Chan, MM., Sweeting, AN., et al.[2022]

Ipilimumab significantly improves overall survival in patients with advanced melanoma compared to the gp100 peptide vaccine, reducing the risk of death by 34% with monotherapy and 32% when combined with the vaccine.

The treatment can cause unique immune-related side effects, particularly affecting the skin and gastrointestinal system, which require careful monitoring and management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab: a guide to its use in advanced melanoma. Lyseng-Williamson, KA., Sanford, M.[2017]

Ipilimumab (Yervoy) is the first new therapy approved for melanoma in over a decade, functioning as an antibody that blocks CTLA-4, which enhances the immune response against tumors, leading to durable tumor regression and improved overall survival in patients with advanced melanoma.

The clinical development of ipilimumab revealed its unique side effects profile and the long-lasting nature of its therapeutic responses, paving the way for future combination therapies with other checkpoint inhibitors currently being tested.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory therapy for melanoma: ipilimumab and beyond. Callahan, MK., Postow, MA., Wolchok, JD.[2021]

References

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

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Response assessment in metastatic melanoma treated with ipilimumab and bevacizumab: CT tumor size and density as markers for response and outcome. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Comparative efficacy of combination immunotherapy and targeted therapy in the treatment of BRAF-mutant advanced melanoma: a matching-adjusted indirect comparison. [2020]

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

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. [2023]

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

Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial. [2022]

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

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

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

Ipilimumab for advanced melanoma: a pharmacologic perspective. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. [2022]

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

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

10. Germany pubmed.ncbi.nlm.nih.gov

Phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma. [2022]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Ipilimumab: first global approval. [2021]

12. Australia pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. [2022]

13. New Zealand pubmed.ncbi.nlm.nih.gov

Ipilimumab: a guide to its use in advanced melanoma. [2017]

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

Immunomodulatory therapy for melanoma: ipilimumab and beyond. [2021]