Nilotinib + Dabrafenib/Trametinib for Melanoma

Recruiting at 2 trial locations

Overseen By Yvonne Taul, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Ruta Arays

Must be taking: BRAF/MEK inhibitors

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Chronic hypokalemia, Long QT syndrome, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 1 dose-escalation study of nilotinib in combination with fixed-dose dabrafenib and trametinib regimen for patients with metastatic or unresectable melanoma carrying a BRAF V600 mutation and have relapsed on a BRAF/MEK inhibitor therapy. The goal is to assess the toxicity and tolerability and determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of the combination of nilotinib with dabrafenib and trametinib or with encorafenib and binimetinib. Additionally, this study will assess pharmacokinetic parameters of dabrafenib and nilotinib when used in combination.

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications that are strong CYP3A or CYP2C8 inhibitors, as well as proton pump inhibitors and drugs that prolong the QT interval. You should discuss your current medications with the trial team to ensure they don't interact with the study drugs.

What data supports the effectiveness of the drug combination of Nilotinib, Dabrafenib, and Trametinib for melanoma?

Research shows that the combination of dabrafenib and trametinib is effective in treating advanced melanoma with a specific BRAF mutation, improving survival rates and reducing tumor size. This combination is well-tolerated and offers a significant treatment option for patients with this type of melanoma. ^{1 2 3 4 5}

Is the combination of Nilotinib, Dabrafenib, and Trametinib safe for humans?

The combination of Dabrafenib and Trametinib has been shown to be generally safe in humans, with most side effects being mild to moderate and manageable. Common side effects include fever, fatigue, and nausea, but these can often be controlled with dose adjustments. ^{1 3 6 7 8}

What makes the drug combination of Nilotinib, Dabrafenib, and Trametinib unique for treating melanoma?

This drug combination is unique because it combines Nilotinib, a drug not typically used for melanoma, with Dabrafenib and Trametinib, which target specific mutations in the BRAF gene and the MAPK pathway, potentially offering a novel approach for patients with BRAF-mutant melanoma who may not respond to standard treatments. ^{1 3 9 10 11}

Research Team

Ruta Arays, MD

Principal Investigator

University of Kentucky

Eligibility Criteria

Adults with metastatic or unresectable melanoma and a BRAF V600 mutation who have not responded to previous BRAFi/MEKi therapy can join. They must be HIV, HBV, and HCV undetectable if applicable, have treated brain metastases without progression, good organ function, no severe heart issues, and agree to use contraception.

Inclusion Criteria

My hepatitis B virus load is undetectable with treatment.

My melanoma cannot be removed by surgery and has spread.

My cancer has a BRAF V600 mutation.

Exclusion Criteria

I am not taking any strong medication that affects enzyme activity in my body.

I am allergic to medications similar to nilotinib, dabrafenib, or trametinib.

Patients with uncontrolled intercurrent illness

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Treatment

Participants receive dabrafenib and trametinib or encorafenib and binimetinib for the first week to achieve steady-state levels

1 week

Weekly visits for pharmacokinetic sampling

Dose-Escalation Treatment

Nilotinib is added to the treatment regimen, and all three drugs are dosed concurrently. Pharmacokinetic samples and biopsies are collected.

3 weeks

Weekly visits for pharmacokinetic sampling and biopsies

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Dabrafenib
• Nilotinib
• Trametinib

Trial Overview This phase 1 trial tests different doses of Nilotinib combined with fixed-dose Dabrafenib and Trametinib in patients whose melanoma has spread. It aims to find the safest dose that's also effective while checking how these drugs affect each other in the body.

Participant Groups

Group I: Level 4 Experimental Treatment 5 Interventions

Patients in this group will receive 400mg Nilotinib PO BID.

Group II: Level 3 Experimental Treatment 5 Interventions

Patients in this group will receive 300mg Nilotinib PO BID.

Group III: Level 2 Experimental Treatment 5 Interventions

Patients in this group will receive 200mg Nilotinib PO BID.

Group IV: Level 1 Experimental Treatment 5 Interventions

Patients in this group will receive 100mg Nilotinib PO BID.

Dabrafenib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation
• Adjuvant treatment of melanoma with a BRAF V600 mutation

Approved in United States as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600E mutation
• Adjuvant treatment of melanoma with a BRAF V600E or V600K mutation
• Metastatic non-small cell lung cancer with a BRAF V600E mutation

Approved in Canada as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation
• Adjuvant treatment of melanoma with a BRAF V600 mutation

Approved in Japan as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Who Is Running the Clinical Trial?

Ruta Arays

Lead Sponsor

Trials

1

Recruited

30+

Peng Wang, MD PhD

Lead Sponsor

Trials

4

Recruited

80+

Jill M Kolesar

Lead Sponsor

Trials

4

Recruited

540+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

In a phase 3 trial involving 870 patients with resected stage III melanoma and BRAF V600 mutations, the combination of dabrafenib and trametinib significantly improved relapse-free survival, with a 3-year rate of 58% compared to 39% for the placebo group.

The combination therapy also showed a higher overall survival rate of 86% versus 77% in the placebo group, indicating its efficacy without introducing new safety concerns, as the safety profile was consistent with previous studies in metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. Long, GV., Hauschild, A., Santinami, M., et al.[2023]

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 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 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 BRAF inhibitor dabrafenib and MEK inhibitor trametinib significantly improves outcomes for metastatic melanoma patients compared to single-agent therapies, with a manageable safety profile.

While 98% of patients experience at least one adverse event during combination therapy, these events are mostly mild to moderate and can be effectively managed, highlighting the importance of addressing even minor side effects to maintain patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. Knispel, S., Zimmer, L., Kanaki, T., et al.[2017]

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]

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 demonstrated significant clinical activity in patients with BRAF(V600E/K) mutation-positive metastatic melanoma, with a 59% overall response rate in the BRAF(V600E) group and a median overall survival of 13.1 months.

The treatment was generally well tolerated, with common side effects including arthralgia and hyperkeratosis, and baseline circulating cell-free DNA (cfDNA) levels were found to predict treatment response and progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. Ascierto, PA., Minor, D., Ribas, A., et al.[2022]

In a study of 14 patients treated with dabrafenib and trametinib for an average of 24 weeks, all patients experienced at least one skin-related side effect, with papillomas being the most common.

The combination therapy can lead to serious skin issues, including the development of squamous cell carcinoma, highlighting the need for careful monitoring and management of these adverse effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective Case Series of Cutaneous Adverse Effects Associated With Dabrafenib and Trametinib. Lacroix, JP., Wang, B.[2017]

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]

References

1. France pubmed.ncbi.nlm.nih.gov

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

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

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. [2023]

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

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

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

Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. [2022]

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

BRAFi/MEKi in patients with metastatic melanoma: predictive factors of complete response. [2019]

6. England pubmed.ncbi.nlm.nih.gov

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. [2017]

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

Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib. [2020]

8. England 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. [2018]

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

Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. [2022]

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

Prospective Case Series of Cutaneous Adverse Effects Associated With Dabrafenib and Trametinib. [2017]

11. France pubmed.ncbi.nlm.nih.gov

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