Ipilimumab +/- Bevacizumab for Melanoma

Not currently recruiting at 592 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments: ipilimumab (Yervoy) alone and ipilimumab combined with bevacizumab (Avastin), to evaluate their effectiveness against advanced melanoma that cannot be surgically removed. These treatments harness the body's immune system to attack cancer and may help prevent the tumor from growing and spreading. Individuals with stage III or IV melanoma who have undergone one or two previous treatments might be suitable candidates, particularly if their condition affects daily activities. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that combining ipilimumab and bevacizumab has been promising. One study found that 67.4% of patients experienced a temporary halt in disease progression, with a median survival time of 25.1 months. This combination was generally well-tolerated, meaning most patients managed it without severe issues. Another study indicated that bevacizumab, when used with other treatments, was safe for patients with melanoma that had spread to the brain, suggesting it might also be safe when combined with ipilimumab.

For ipilimumab alone, studies have shown it can help patients with melanoma live longer. It has been used for many years and is approved by the FDA for treating melanoma. However, like many cancer treatments, it can have serious side effects, but it is generally considered safe enough for use.

Overall, both treatments have been well-tolerated in previous studies, though some side effects can occur, which is common with cancer treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for melanoma, which typically involves drugs like pembrolizumab or nivolumab, ipilimumab works differently by targeting CTLA-4, a protein that downregulates the immune response, thus enhancing the body's ability to attack cancer cells. Researchers are particularly excited about combining ipilimumab with bevacizumab, an anti-VEGF therapy that inhibits blood vessel growth in tumors, potentially leading to improved outcomes by attacking the cancer on two fronts. This dual approach could offer more robust and comprehensive treatment options for melanoma patients compared to existing therapies.

What evidence suggests that ipilimumab with or without bevacizumab could be effective for melanoma?

This trial will compare the effectiveness of ipilimumab alone versus the combination of ipilimumab and bevacizumab for treating advanced melanoma. Research shows that combining ipilimumab with bevacizumab may help treat advanced melanoma. In one study, this combination controlled the disease in 67% of patients and extended their lives to about 25 months on average. Additionally, 36% of patients experienced tumor shrinkage or halted growth. Ipilimumab alone has been shown to delay melanoma recurrence by about 9 months and improve survival rates in patients with metastatic melanoma. These findings suggest that both treatments are effective against melanoma, and their combination might offer even greater benefits. ^{1 3 6 7 8}

Who Is on the Research Team?

Frank S Hodi

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 (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 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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12080919/

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ... In patients who were progression-free at 3-years, 10-year melanoma-specific survival rates were 96% with nivolumab-plus-ipilimumab, 97% with ...

2. curemelanoma.org curemelanoma.org/patient-eng/melanoma-treatment/options/yervoy-ipilimumab

Ipilimumab, Yervoy - MRA The results showed that ipilimumab extended the amount of time before cancer returned by an average of 9 months.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2210233

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in ... The estimates of 6-month progression-free survival were 34% (90% CI, 25 to 44) in the combination-treatment group and 13% (90% CI, 4 to 27) in ...

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)37101-7/fulltext

Efficacy and safety of ipilimumab in metastatic melanoma ... Conclusions. Ipilimumab results in survival of ≥2 years in one-fifth of pretreated patients with 2 years potential follow-up in a phase III trial.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3549297/

Improved Survival with Ipilimumab in Patients with Metastatic ... Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3462607/

Serious Side Effects and a Hefty Price Tag May Limit Its Use The survival rate for patients with stage IV melanoma is low; from 2001 to 2007, 85% of patients with distant metastases were not expected to survive 5 years.

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa1611299

Prolonged Survival in Stage III Melanoma with Ipilimumab ... At a median follow-up of 2.7 years, adjuvant ipilimumab was associated with significantly prolonged recurrence-free survival, the primary end ...

8. merck.com merck.com/news/ten-year-data-for-mercks-keytruda-pembrolizumab-demonstrates-sustained-overall-survival-benefit-versus-ipilimumab-in-advanced-melanoma/

Ten-Year Data for Merck's KEYTRUDA® (pembrolizumab ... At 10 years, more than one-third (34.0%) of patients with advanced melanoma were alive after treatment with KEYTRUDA, compared to 23.6% of patients treated ...