Vemurafenib + Metformin for Melanoma

Overseen by Jason Chesney, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: University of Louisville

Disqualifiers: Prior Vemurafenib, Metformin hypersensitivity, others

No Placebo Group

Breakthrough Therapy

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

The main purpose of this study is to evaluate the safety of Vemurafenib in combination with Metformin in melanoma patients. The phase II part of the study will also evaluate the clinical activity of the combined regiment. Based on pre-clinical studies and a phase I trial, the investigators hypothesize that the combination of an FDA-approved non-toxic dose of oral Metformin with Vemurafenib will yield little toxicity and improve clinical outcomes in terms of objective response rates and survival in metastatic melanoma patients.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the drug Vemurafenib + Metformin for melanoma?

Vemurafenib has been shown to improve survival rates in patients with melanoma that have a specific genetic mutation (BRAF V600E), with studies showing a significant reduction in the risk of death and disease progression. Metformin, while primarily used for diabetes, has shown potential anticancer effects when combined with other treatments in laboratory studies. ^{1 2 3 4 5}

Is the combination of Vemurafenib and Metformin safe for humans?

Vemurafenib, used for treating melanoma with a specific mutation, has been shown to improve survival rates but can have side effects, including secondary skin tumors. Metformin, commonly used for diabetes, is generally considered safe, but specific safety data for the combination of Vemurafenib and Metformin is not provided in the available research. ^{1 2 4 5 6}

What makes the drug Vemurafenib unique for treating melanoma?

Vemurafenib is unique because it specifically targets the BRAF V600E mutation in melanoma, improving survival rates compared to traditional chemotherapy. It was the first selective BRAF inhibitor approved for this purpose, offering a targeted approach with a favorable safety profile. ^{1 4 5 6 7}

Research Team

Jason Chesney, MD

Principal Investigator

James Graham Brown Cancer Center-U of Louisville

Eligibility Criteria

This trial is for adults with BRAFV600E melanoma (Stage IIIC or IV) who can perform daily activities (ECOG PS 0-2) and have a life expectancy of at least 3 months. Participants must be able to use contraception, not be pregnant, and have adequate organ function. They cannot have had prior Vemurafenib treatment or known Metformin hypersensitivity.

Inclusion Criteria

My melanoma is BRAFV600E positive and is at stage IIIC or IV.

My blood, kidney, and liver tests meet the required levels.

I am 18 years old or older.

Exclusion Criteria

I do not have any uncontrolled infections or conditions that could affect the study.

I have not had radiotherapy for non-brain issues in the last 2 weeks or I have recovered from its side effects.

You are allergic to metformin or any of the ingredients in it.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Evaluation of the safety of Vemurafenib in combination with Metformin in patients with unresectable Stage IIIC and Stage IV melanoma

Approximately 6 months

Regular monitoring visits

Phase II Treatment

Evaluation of the clinical activity of the combined Vemurafenib/Metformin regimen

28-day cycles until progression or unacceptable toxicity

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Every 12 weeks (+/- 7 days) after last drug dose

Treatment Details

Interventions

• Metformin (Other)
• Vemurafenib (Kinase Inhibitor)

Trial Overview The study tests the safety and effectiveness of combining Vemurafenib with Metformin in treating melanoma. It aims to see if this combination improves response rates and survival with little toxicity based on earlier studies.

Participant Groups

Group I: Vemurafenib and Metformin Experimental Treatment 2 Interventions

Vemurafenib is already approved in Canada for the following indications:

Approved in Canada as Zelboraf for:

• Unresectable or metastatic melanoma with BRAF V600E mutation

Who Is Running the Clinical Trial?

University of Louisville

Lead Sponsor

Trials

353

Recruited

76,400+

James Graham Brown Cancer Center

Collaborator

Trials

44

Recruited

9,200+

Findings from Research

In a phase 3 trial involving 675 patients with metastatic melanoma and the BRAF V600E mutation, vemurafenib significantly improved overall survival rates (84% at 6 months) compared to dacarbazine (64%).

Vemurafenib also demonstrated a 63% reduction in the risk of death and a 74% reduction in the risk of disease progression compared to dacarbazine, although it was associated with common adverse effects that led to dose modifications in 38% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved survival with vemurafenib in melanoma with BRAF V600E mutation. Chapman, PB., Hauschild, A., Robert, C., et al.[2022]

The combination of metformin with trametinib and paclitaxel demonstrated varying effects on melanoma cell growth, showing synergistic effects in some cell lines while being antagonistic in others, indicating that the effectiveness of this combination may depend on the specific cellular context.

Metformin appears to enhance the efficacy of trametinib and paclitaxel by suppressing factors involved in epithelial-mesenchymal transition (EMT) and reducing melanoma cell motility, suggesting its potential as an adjuvant treatment to combat melanoma progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Metformin in Combination With Trametinib and Paclitaxel on Cell Survival and Metastasis in Melanoma Cells. Lee, Y., Park, D.[2021]

Vemurafenib (Zelboraf) is an FDA-approved medication specifically for treating unresectable or metastatic melanoma in patients with the BRAF(V600E) mutation.

This drug works by inhibiting BRAF kinase, which is a key player in the growth and spread of melanoma cells with this specific mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib. Flaherty, KT., Yasothan, U., Kirkpatrick, P.[2021]

Vemurafenib significantly improves overall and progression-free survival in patients with advanced melanoma harboring the BRAF V600E mutation, showing a 63% reduction in the risk of death compared to dacarbazine and a 74% reduction in the risk of death or disease progression.

The drug demonstrated a high objective response rate of 48% in patients treated with vemurafenib, compared to only 5% in those receiving dacarbazine, although it is associated with unique side effects, including the development of secondary skin tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Vemurafenib (Zelboraf) in the therapy of melanoma]. Liszkay, G.[2018]

Vemurafenib is the first selective BRAF inhibitor approved for treating advanced melanoma with the BRAF V600 mutation, demonstrating strong efficacy and a favorable safety profile.

The article reviews various studies comparing vemurafenib's effectiveness and toxicity with other treatments like dabrafenib and ipilimumab, highlighting its potential role in future melanoma therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib for the treatment of BRAF mutant metastatic melanoma. Martin-Liberal, J., Larkin, J.[2022]

A new liquid chromatography-tandem mass spectrometry method was developed to accurately quantify vemurafenib levels in human plasma, demonstrating a lower limit of quantification of 0.1 mcg/mL and a linear range from 1.0 to 100.0 mcg/mL.

Vemurafenib showed stability in human plasma for up to one month at various temperatures, which is important for ensuring reliable pharmacokinetic studies in patients with advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and validation of a rapid and simple LC-MS/MS method for quantification of vemurafenib in human plasma: application to a human pharmacokinetic study. Bihan, K., Sauzay, C., Goldwirt, L., et al.[2019]

References

1. Poland pubmed.ncbi.nlm.nih.gov

The outcomes of Polish patients with advanced BRAF-positive melanoma treated with vemurafenib in a safety clinical trial. [2020]

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

Improved survival with vemurafenib in melanoma with BRAF V600E mutation. [2022]

3. Greece pubmed.ncbi.nlm.nih.gov

Effect of Metformin in Combination With Trametinib and Paclitaxel on Cell Survival and Metastasis in Melanoma Cells. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Vemurafenib. [2021]

5. Hungary pubmed.ncbi.nlm.nih.gov

[Vemurafenib (Zelboraf) in the therapy of melanoma]. [2018]

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

Vemurafenib for the treatment of BRAF mutant metastatic melanoma. [2022]

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

Development and validation of a rapid and simple LC-MS/MS method for quantification of vemurafenib in human plasma: application to a human pharmacokinetic study. [2019]