Axitinib + Ipilimumab for Advanced Melanoma

Overseen By Neelam Lal

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Strong CYP3A4/5 inhibitors, inducers

Disqualifiers: Severe hepatic impairment, hemorrhage, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether combining two treatments, axitinib (a targeted therapy) and ipilimumab (an immunotherapy), can effectively treat advanced melanoma, a serious skin cancer. Researchers focus on cases where the cancer cannot be surgically removed and has not responded well to previous treatments, such as anti-PD-1 therapies. Suitable participants have advanced melanoma, excluding uveal melanoma (which affects the eye), and have not found success with other treatments. Participants should also have controlled blood pressure and no recent major health issues, such as severe bleeding or heart problems. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you must stop taking your current medications, but you cannot use drugs or foods that strongly affect certain liver enzymes (CYP3A4/5) within 10 days before starting the trial.

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

Research has shown that axitinib and ipilimumab have been used together in other studies to treat advanced melanoma, enhancing understanding of the combination's safety. Axitinib, when combined with treatments like nivolumab, has proven effective for advanced cases, with a focus on safety. Some patients experienced side effects, but these were manageable, indicating that axitinib is generally well-tolerated.

Ipilimumab has also been studied independently for advanced melanoma, showing positive results for survival, with many patients finding its side effects acceptable.

While strong safety information exists for both axitinib and ipilimumab individually, their combination is still under careful study to ensure safety for patients with advanced melanoma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Axitinib and Ipilimumab for advanced melanoma because it offers a unique approach by combining a tyrosine kinase inhibitor with an immune checkpoint inhibitor. While standard treatments often involve other immune checkpoint inhibitors like pembrolizumab or nivolumab, this combination explores a novel synergy. Axitinib inhibits VEGF receptors to reduce tumor blood supply, potentially enhancing Ipilimumab's ability to activate the immune system against the cancer. This dual mechanism could improve treatment efficacy and provide a promising alternative for patients who may not respond to existing therapies.

What evidence suggests that axitinib and ipilimumab could be effective for advanced melanoma?

Research shows that using axitinib and ipilimumab together might be promising for treating advanced melanoma. Earlier studies with similar treatments have shown benefits, with 21.4% to 48% of patients experiencing a reduction or disappearance of their cancer. This suggests that these drugs could help shrink or control melanoma tumors in some patients. Additionally, axitinib has worked well with other cancer treatments, showing positive results in advanced cancer cases. These findings offer hope that axitinib and ipilimumab together might be effective for advanced melanoma. ^{1 2 4 6 7}

Who Is on the Research Team?

Zeynep Eroglu

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced melanoma, excluding uveal melanoma. Participants can have had any number of prior treatments but not ipilimumab. They must be at least 2 weeks out from major surgery and recovered from previous treatment side effects to Grade 2 or baseline. Those with treated brain metastases are eligible unless they're unstable or need steroids. No active autoimmune diseases requiring therapy, except replacement therapy like corticosteroids, are allowed.

Inclusion Criteria

I have melanoma with a BRAF mutation and may have been treated with or intolerant to BRAF/MEK inhibitors.

My side effects from previous treatments are mild or gone.

My blood tests and organ functions are within normal ranges.

Exclusion Criteria

I have not had severe heart problems or heart failure in the last 6 months.

I have not had a stroke or mini-stroke in the last 6 months.

I am not using, nor do I plan to use, strong CYP3A4/5 inhibitors or inducers.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ipilimumab 3 mg/kg IV every 3 weeks for 4 doses and axitinib 5 mg orally twice daily. Each cycle is 3 weeks/21 days.

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Axitinib
• Ipilimumab

Trial Overview The study is testing the effectiveness of combining axitinib with ipilimumab in treating advanced melanoma. It's looking for people who haven't responded well to anti-PD-1/PD-L1 inhibitors or relapsed soon after treatment. Patients will receive both drugs and their response will be measured using specific criteria for tumor size changes over time.

How Is the Trial Designed?

Group I: Ipilimumab + Axtinib Experimental Treatment 2 Interventions

Participants will receive treatment with ipilimumab 3 mg/kg IV q3 weeks x 4 doses and axitinib at 5 mg by mouth twice daily. Each cycle is 3 weeks/21 days

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

Approved in European Union as Inlyta for:

• Renal cell carcinoma

Approved in United States as Inlyta for:

• Advanced renal cell carcinoma

Approved in United Kingdom as Inlyta for:

• Advanced renal cell carcinoma

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Published Research Related to This Trial

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]

Nivolumab is shown to be the most cost-effective treatment option for advanced melanoma patients in England, with incremental cost-effectiveness ratios of £24,483 for BRAF mutation-negative and £17,362 for mutation-positive patients.

The analysis utilized a Markov state-transition model based on patient-level data from clinical trials, indicating that nivolumab provides long-term survival benefits while being economically favorable compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. Meng, Y., Hertel, N., Ellis, J., et al.[2020]

In a phase Ib study involving 31 patients with advanced melanoma, the combination of ipilimumab and peginterferon alfa-2b showed a maximum tolerated dose of ipilimumab at 3 mg/kg and peginterferon at 2 μg/kg/week, with a 40% overall response rate.

The treatment had a manageable safety profile, with 45.2% of patients experiencing grade 3 drug-related adverse events, but no severe (grade 4/5) adverse events, indicating that this combination therapy could be a promising option for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma. Brohl, AS., Khushalani, NI., Eroglu, Z., et al.[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]

The combination of nivolumab and ipilimumab has achieved over 50% 5-year overall survival rates in patients with metastatic melanoma, although this combination is associated with high toxicity.

Current research is exploring new combinations of immune checkpoint inhibitors with other treatments, such as BRAF/MEK inhibitors and oncolytic viruses, aiming to improve long-term survival, especially in patients with poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Therapy of Metastatic Melanoma: On the Road to Cure. Steininger, J., Gellrich, FF., Schulz, A., et al.[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]

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 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]

In a study of 56 patients with metastatic melanoma who had severe immune-related adverse events (AEs) from ipilimumab, 36% experienced at least one immune-related AE after receiving anti-PD-1 therapy, indicating a notable risk of recurrence but also a manageable safety profile.

Despite the risk of AEs, anti-PD-1 therapy showed a 43% overall response rate and a median overall survival of 21 months, suggesting it may offer improved outcomes for patients previously affected by severe toxic effects from ipilimumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Anti-Programmed Cell Death 1 Antibody Treatment With Risk of Recurrence of Toxic Effects After Immune-Related Adverse Events of Ipilimumab in Patients With Metastatic Melanoma. Brunot, A., Grob, JJ., Jeudy, G., 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]

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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04996823?tab=history&a=8

Axitinib + Ipilimumab in Advanced Melanoma The goal of this clinical research study is to find out if taking axitinib with ipilimumab is effective in treating advanced melanoma. Detailed Description.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0959804921004743

Real-world efficacy and safety of axitinib in combination ... Pembrolizumab plus lenvatinib have shown clinical benefit for advanced melanoma in phase I and II trials with ORRs of 21.4–48%, which has led to a phase III ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.9555

Phase 2 study of axitinib + nivolumab in mucosal ... The frontline combination of nivolumab and axitinib was effective in patients with unresectable or advanced outside of China.

4. cancer.gov cancer.gov/clinicaltrials/NCI-2021-08823

Axitinib and Ipilimumab for the Treatment of Advanced ... This phase 2 clinical trial finds if axitinib with ipilimumab is effective at treating melanoma that has spread to other places in the body (advanced).

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9066368/

Toripalimab plus axitinib in patients with metastatic mucosal ... Among 29 chemotherapy-naïve patients with metastatic MM, the median OS was 20.7 months (95% CI 9.7 to 32.7 months); the median progression-free survival (PFS) ...

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

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ... In conclusion, in patients with advanced melanoma, nivolumab-containing therapy has continued to show prolonged clinical benefit compared with ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/20147741/

Efficacy and safety of ipilimumab monotherapy in patients ... Conclusion: Ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population. Publication ...