Immunotherapy + Targeted Therapy for Melanoma

Not currently recruiting at 969 trial locations

Overseen By Alexandra P. Ikeguchi

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP2C8 inducers

Disqualifiers: Active CNS metastases, Autoimmune disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 6

Duration: Up to 14 cycles of 6 weeks each

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests different treatment plans for individuals with stage III-IV melanoma, specifically those with a BRAFV600 mutation that cannot be surgically removed. It compares two approaches: starting with immunotherapy (using drugs to boost the immune system to fight cancer) followed by targeted therapy (using drugs to specifically target cancer cells), and vice versa. The goal is to determine which treatment sequence more effectively stops cancer growth. Suitable candidates for this trial have melanoma with the BRAFV600 mutation that has spread or cannot be surgically removed. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot take other anti-cancer therapies, investigational drugs, or medications that strongly affect certain liver enzymes while participating in the study.

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

Research shows that the combination of nivolumab and ipilimumab is generally well-tolerated by patients with melanoma, a type of skin cancer. In earlier studies, only 2.5% of patients experienced infusion-related reactions, indicating that most did not encounter major issues with the treatment. Similarly, the combination of dabrafenib and trametinib has been safely used in patients with metastatic melanoma, where the cancer spreads to other parts of the body. Studies report that many people have used these drugs with manageable side effects. Both treatments are already approved for certain types of cancer, indicating a strong safety record. Participants in this trial can find encouragement in these findings, although individual experiences may vary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for melanoma because they combine immunotherapy and targeted BRAF inhibitor therapy, offering a promising new approach. Unlike traditional chemotherapy, these treatments specifically target cancer cells with unique mechanisms. The immunotherapy arm, using nivolumab and ipilimumab, boosts the body's immune system to attack cancer, which can lead to long-lasting effects. On the other hand, the BRAF inhibitor therapy, involving dabrafenib mesylate and trametinib dimethyl sulfoxide, directly targets mutations in the BRAF gene common in melanoma, potentially leading to rapid tumor shrinkage. This dual approach is designed to be more effective and personalized than existing treatments alone.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research has shown that using nivolumab and ipilimumab together, which participants may receive in Arm A or Arm D of this trial, effectively treats advanced melanoma. Studies indicate that 59% of patients receiving this combination survive for a long time. In another study, 96% of patients who were free of disease progression after 3 years survived for 10 years.

Another combination, dabrafenib and trametinib, is being tested in Arm B and Arm C of this trial. It has improved survival rates in patients with advanced melanoma, with 19% of patients being free of disease progression after 5 years. This combination works especially well for melanoma with the BRAFV600 mutation, which is the focus of this trial. ^{4 6 7 8 9}

Who Is on the Research Team?

Michael B Atkins

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

Adults with stage III-IV melanoma that can't be surgically removed and have the BRAFV600 mutation. They should not have HIV, other cancers within the last 5 years (except certain skin cancers), serious medical conditions, or be pregnant/breastfeeding. Participants must agree to use effective contraception.

Inclusion Criteria

Patients must agree to use contraception and inform physician if pregnancy occurs

This information is not applicable to my condition.

I agree to use effective birth control or abstain from sex during and after the trial as required.

Exclusion Criteria

I have a history of disorders related to lymphocyte proliferation.

I haven't had any cancer except for skin cancer in the last 5 years.

I do not have any other cancers, except for allowed exceptions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Initial treatment with either ipilimumab and nivolumab or dabrafenib and trametinib, followed by crossover to the alternative treatment upon disease progression

Up to 14 cycles of 6 weeks each

Visits every 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 3 months for 2 years, then every 6 months for 3 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib Mesylate
• Ipilimumab
• Nivolumab
• Trametinib Dimethyl Sulfoxide

Trial Overview The trial is testing two treatment sequences for advanced melanoma: starting with ipilimumab and nivolumab (immunotherapies) followed by dabrafenib and trametinib (targeting BRAFV600 gene), versus starting with dabrafenib and trametinib followed by immunotherapies, to see which is more effective.

How Is the Trial Designed?

Group I: Arm D (immunotherapy) Experimental Treatment 7 Interventions

IMMUNOTHERAPY INDUCTION (CYCLES 1-2): Patients receive nivolumab IV over 30-60 minutes and ipilimumab IV over 30-90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. IMMUNOTHERAPY MAINTENANCE (CYCLES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, ECHO or MUGA, and collection of blood samples throughout the trial.

Group II: Arm C (BRAF inhibitor therapy) Experimental Treatment 7 Interventions

Patients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO daily on days 1-42. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, ECHO or MUGA, and collection of blood samples throughout the trial.

Group III: Arm B (BRAF inhibitor therapy) Experimental Treatment 7 Interventions

Patients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO daily on days 1-42. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression (or before), patients re-register and cross over to Arm D. Patients also undergo CT, ECHO or MUGA, and collection of blood samples throughout the trial.

Group IV: Arm A (immunotherapy) Experimental Treatment 7 Interventions

IMMUNOTHERAPY INDUCTION (CYCLES 1-2): Patients receive nivolumab IV over 30-60 minutes and ipilimumab IV over 30-90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. IMMUNOTHERAPY MAINTENANCE (CYCLES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Upon disease progression (or before), patients re-register and cross over to Arm C. Patients also undergo CT, ECHO or MUGA, and collection of blood samples throughout the trial.

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 phase II trial involving 21 patients with unresectable locally advanced melanoma, neoadjuvant treatment with dabrafenib and trametinib enabled radical surgical resection in 86% of participants, with 81% achieving complete (R0) resection.

The median recurrence-free survival for patients who underwent surgery was 9.9 months, indicating that this combination therapy is a promising option for patients with previously inoperable melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Cytoreductive Treatment With BRAF/MEK Inhibition of Prior Unresectable Regionally Advanced Melanoma to Allow Complete Surgical Resection, REDUCTOR: A Prospective, Single-arm, Open-label Phase II Trial. Blankenstein, SA., Rohaan, MW., Klop, WMC., et al.[2021]

In a real-world study of 20 patients with resected stage III BRAF-mutant melanoma, 90% experienced treatment-related toxicities requiring at least one interruption, highlighting the need for careful monitoring during therapy.

The most common adverse events included recurrent fever and chills (85%) and liver abnormalities (50%), with 65% of patients permanently discontinuing treatment due to these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment related toxicities with combination BRAF and MEK inhibitor therapy in resected stage III melanoma. Homan, M., Warrier, G., Lao, CD., et al.[2022]

Dabrafenib and trametinib, both targeting the MAPK pathway, have shown significant efficacy in treating BRAF-mutant metastatic melanoma, with dabrafenib achieving a 59% objective response rate and improved progression-free survival compared to traditional chemotherapy.

The combination of dabrafenib and trametinib resulted in higher response rates and longer median progression-free survival than dabrafenib alone, while also presenting less cutaneous toxicity, making it a promising treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. Menzies, AM., Long, GV.[2022]

In a study involving 112 Japanese patients with unresectable and metastatic melanoma, the combination therapy of dabrafenib and trametinib showed a significant objective response rate of 55.45%, indicating its efficacy in treating BRAF V600 mutation-positive melanoma.

The safety profile of the combination therapy was consistent with previous trials, with 75% of patients experiencing adverse drug reactions, the most common being pyrexia and hepatic function abnormalities, but no new safety concerns were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim analysis for post-marketing surveillance of dabrafenib and trametinib combination therapy in Japanese patients with unresectable and metastatic melanoma with BRAF V600 mutation. Teshima, Y., Kizaki, M., Kurihara, R., et al.[2022]

Combination therapy with dabrafenib and trametinib for BRAF-mutated metastatic melanoma showed a high overall response rate, with 64.6% of patients achieving a partial response and 6.2% achieving a complete response, indicating its efficacy in treating this condition.

The treatment was found to be relatively safe, with only 8.3% of patients experiencing severe adverse events, and 62.5% of patients remained on treatment, suggesting good tolerability in a real-life clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined therapy with dabrafenib and trametinib in BRAF-mutated metastatic melanoma in a real-life setting: the INT Milan experience. Cavalieri, S., Di Guardo, L., Cimminiello, C., et al.[2017]

In a study of 66 patients with metastatic BRAF-mutated melanoma treated with dabrafenib and trametinib, 15 patients achieved a complete response (CR), indicating a significant survival benefit from this treatment.

The likelihood of achieving a complete response was higher in patients with smaller lesions (39.3% CR rate) compared to those with larger lesions (10.5% CR rate), suggesting that lesion size and the number of metastatic sites are important factors in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAFi/MEKi in patients with metastatic melanoma: predictive factors of complete response. Ribero, S., Malavenda, O., Fava, P., et al.[2019]

The combination of dabrafenib and trametinib significantly improves progression-free survival and overall survival in patients with unresectable or metastatic melanoma with a BRAF (V600E/K) mutation, compared to monotherapy with dabrafenib or vemurafenib, based on results from two large phase III studies.

This combination therapy is well-tolerated, showing no increase in overall toxicity compared to monotherapy, and results in fewer skin-related adverse events, likely due to reduced activation of the MAPK pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. Dhillon, S.[2022]

The combination of dabrafenib and trametinib showed promising antitumor activity in Japanese patients with BRAF V600E/K mutant melanoma, with an overall response rate of 83% in both phase 1 and phase 2 of the study involving 12 patients.

The treatment was generally well-tolerated, with common adverse events including fever (75%) and increased liver enzymes (67%), indicating that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma. Yamazaki, N., Tsutsumida, A., Takahashi, A., et al.[2018]

Dabrafenib plus trametinib has been approved for treating non-small cell lung cancer (NSCLC) with the BRAF V600E mutation, showing a response rate of approximately 65% and a median progression-free survival of 10-11 months based on clinical trials.

While the combination therapy has a manageable safety profile, it presents unique toxicities such as pyrexia, fatigue, and nausea, which may be unfamiliar to oncologists treating lung cancer, but can be effectively managed using strategies developed from experience in melanoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib. Chalmers, A., Cannon, L., Akerley, W.[2020]

Trametinib, when combined with dabrafenib, significantly prolongs median survival by about 8 months compared to vemurafenib alone in patients with metastatic or inoperable melanoma, based on a study of 704 patients.

While trametinib can enhance treatment efficacy, it also carries serious adverse effects, including life-threatening conditions like heart failure and gastrointestinal perforation, making it essential for patients to weigh the benefits against the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib (MEKINIST°) Metastatic or inoperable BRAF V600-positive melanoma: a few extra months of life. [2019]

In a study of 27 metastatic BRAFV600mut melanoma patients, higher plasma concentrations of dabrafenib were linked to a greater likelihood of adverse events (AEs) that required dose reductions, with a significant threshold identified at 48 ng/ml.

While dabrafenib showed a strong correlation with AEs, trametinib concentrations did not differ significantly between patients who experienced AEs and those who did not, suggesting that dabrafenib's plasma levels are more critical for managing treatment safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trough dabrafenib plasma concentrations can predict occurrence of adverse events requiring dose reduction in metastatic melanoma. Rousset, M., Dutriaux, C., Bosco-Lévy, P., et al.[2018]

In a study of 78 BRAF inhibitor-naive patients with BRAF V600 mutation-positive metastatic melanoma treated with dabrafenib and trametinib, the median overall survival was over 2 years, with 72% of patients alive at 1 year and 47% at 3 years.

Approximately 20% of patients were progression-free at 3 years, with better outcomes associated with having fewer than three organ metastases and lower baseline lactate dehydrogenase levels, suggesting these factors may help predict durable responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. Long, GV., Weber, JS., Infante, JR., et al.[2022]

In a phase III study involving patients with BRAF V600 mutation-positive melanoma, trametinib significantly improved quality of life (QOL) compared to chemotherapy, with patients reporting better global health status and less functional impairment.

Patients treated with trametinib experienced improvements in symptoms like pain and insomnia, while chemotherapy led to worsening symptoms and a decline in overall health, highlighting trametinib's potential as a more tolerable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study. Schadendorf, D., Amonkar, MM., Milhem, M., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31166680/

Five-Year Outcomes with Dabrafenib plus Trametinib in ... The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02224781

Study Details | NCT02224781 | Dabrafenib and Trametinib ... This phase III trial studies how well initial treatment with ipilimumab and nivolumab followed by dabrafenib and trametinib works and compares it to initial ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9856246/

Melanoma Treatments and Mortality Rate Trends in the US, ... In the COMBI-v study, the reported 3-year follow-up overall survival was 45% with combination therapy vs 32% with vemurafenib monotherapy.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01682083

Study Details | NCT01682083 | Dabrafenib With Trametinib ... This was a two-arm, randomized, double-blind Phase III study of dabrafenib in combination with trametinib versus two placebos in the adjuvant treatment of ...

5. curemelanoma.org curemelanoma.org/patient-eng/melanoma-treatment/options/dabrafenib-tafinlar-trametinib-mekinist

Dabrafenib (Tafinlar) + Trametinib (Mekinist) Through clinical trials, cancer researchers have found that combining dabrafenib and trametinib can treat advanced melanoma more effectively than either ...

6. pro.novartis.com pro.novartis.com/uk-en/medicines/oncology/tafinlar-mekinist/melanoma/safety/combi-v-and-combi-d

Pooled COMBI-v and COMBI-d safety data TAFINLAR® (dabrafenib) and MEKINIST® (trametinib). Pooled safety data from the COMBI-v and COMBI-d trials. For UK healthcare professionals only.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2019/202806Orig1s002.pdf

Approval Package - accessdata.fda.gov TAFINLAR in combination with trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31876308/

Real-world efficacy and safety data for dabrafenib ... Real-world efficacy and safety data for dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced melanoma.

9. clinicaltrials.eu clinicaltrials.eu/trial/long-term-safety-study-of-dabrafenib-mesylate-and-trametinib-dimethyl-sulfoxide-for-patients-benefiting-from-previous-treatment-in-multiple-indications/

Long-Term Safety Study of Dabrafenib Mesylate and ... This study assesses the long-term safety of Dabrafenib Mesylate and Trametinib Dimethyl Sulfoxide in treating various types of cancer, ...