Phenformin + BRAF/MEK Inhibitors for Melanoma

No longer recruiting at 2 trial locations

Overseen By Michael A. Postow

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Hypoglycemics, Vemurafenib, Encorafenib, Dabrafenib

Disqualifiers: Diabetes, Renal failure, Liver disease, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safety of adding phenformin to the usual treatment for individuals with metastatic melanoma and a specific BRAF gene mutation. The treatment involves a combination of drugs targeting the BRAF and MEK genes, commonly used for this melanoma type. The trial seeks participants with stage IV melanoma, a BRAF V600 mutation, and at least one measurable tumor. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants an opportunity to contribute to groundbreaking research.

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

The trial requires that you do not use any hypoglycemic agents or systemic therapy for melanoma. Additionally, you should avoid certain medications that interact with the trial drugs, such as those affecting CYP3A4 and CYP2CA8 enzymes. It's best to discuss your current medications with the trial team to see if any need to be stopped or adjusted.

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

Research shows that combining phenformin with the standard drugs dabrafenib and trametinib holds promise for treating melanoma with a BRAF mutation. Previous studies have assessed the safety of this combination and found that adding phenformin to dabrafenib and trametinib was generally well-tolerated by patients.

The FDA already approves dabrafenib and trametinib together for certain melanoma cases, indicating thorough safety testing in similar conditions. Trials reported manageable side effects, such as fatigue and nausea.

Researchers are studying phenformin to determine the best dose that patients can handle without severe side effects. Initial findings suggest that doses up to 100 mg twice daily were tolerable.

While no treatment is without risks, these results offer a hopeful outlook on safety for those considering joining a trial with this combination. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of Dabrafenib, Trametinib, and Phenformin for treating metastatic BRAFV600E/K mutated melanoma because it introduces a new twist to the existing treatment approach. While current treatments often involve BRAF and MEK inhibitors like Dabrafenib and Trametinib, adding Phenformin could enhance effectiveness by targeting cancer cell metabolism differently. Phenformin, often used for diabetes, is being repurposed here to potentially boost the cancer-fighting effects of the other drugs. This novel combination could lead to better outcomes for patients by tackling the cancer from multiple angles, offering hope for improved responses and potentially longer-lasting results.

What evidence suggests that this treatment might be an effective treatment for metastatic melanoma?

Research shows that combining phenformin with dabrafenib and trametinib may help treat advanced melanoma with a BRAF V600 mutation. This trial will administer this combination to participants to evaluate its effectiveness. Previous studies have found that dabrafenib and trametinib together can help patients with this mutation live longer. Researchers are testing phenformin, a drug usually used for diabetes, to see if it can enhance the effectiveness of these cancer drugs. Early trials suggest that adding phenformin might increase the ability of dabrafenib and trametinib to fight cancer. This combination works by interfering with the cancer cells' energy use and growth signals. ^{1 2 3 4 6}

Who Is on the Research Team?

Michael Postow, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced melanoma that has a specific BRAF V600 mutation. Participants must be in good physical condition, have measurable cancer growth, and their major organs need to function well. They can't join if they're pregnant, on certain medications like other BRAF inhibitors or steroids beyond replacement doses, have diabetes or severe lung disease, or any other serious health issues.

Inclusion Criteria

My melanoma is at an advanced stage and cannot be removed by surgery.

I can swallow pills and follow treatment instructions.

My melanoma diagnosis has been confirmed by my treatment center.

Exclusion Criteria

I have liver or kidney disease.

I have a known G6PD deficiency.

Your heart's electrical activity (QTc interval) is longer than 500 milliseconds, unless you have a specific heart condition called bundle branch block.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Cohorts of patients are treated with standard dose Dabrafenib plus Trametinib and increasing doses of Phenformin to determine the maximally tolerated dose.

8-12 weeks

Dose Expansion

Up to 10 treatment-naïve patients are treated with the maximally tolerated dose of Phenformin in combination with any of the 3 FDA-approved BRAFi/MEKi combinations.

12-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment using RECIST v1.1 criteria.

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib
• Phenformin
• Trametinib

Trial Overview The study tests the safety of combining Phenformin with standard FDA-approved treatments (Trametinib and Dabrafenib) for metastatic melanoma with a BRAF mutation. It aims to see how well patients tolerate this combination and what effects it has on their cancer.

How Is the Trial Designed?

Group I: Dabrafenib, Trametinib & Phenformin Experimental Treatment 3 Interventions

This is a multi-institution single-arm phase I trial with an expansion cohort at the MTD of Phenformin, in patients with metastatic BRAFV600E/K mutated melanoma. In the dose escalation phase, cohorts of patients will be treated with standard dose Dabrafenib (150 mg PO BID) plus Trametinib (2 mg PO QD) and increasing doses of Phenformin. In the dose-escalation phase of the trial, both patients who have already been treated with a BRAF and/or MEK inhibitor, and treatment-naïve patients will be eligible. The maximally tolerated Phenformin dose was determined to be 100 mg BID. The dose-expansion cohort will enroll up to 10 patients who are treatment- naïve for BRAF inhibitor. In this cohort, patients may be treated with any of the 3 FDA-approved BRAFi/MEKi combinations: dabrafenib/trametinib, vemurafenib/cobimetinib, or encorafenib/binimetinib.

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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Weill Medical College of Cornell University

Collaborator

Trials

1,103

Recruited

1,157,000+

Massachusetts General Hospital

Collaborator

Trials

3,066

Recruited

13,430,000+

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10695100/

Phase Ib Trial of Phenformin in Patients with V600-mutated ... We conducted a phase Ib dose-escalation trial of phenformin with standard dose dabrafenib/trametinib in patients with metastatic BRAF V600-mutated melanoma.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03026517

Study Details | NCT03026517 | Clinical Trial of Phenformin ... The purpose of this study is to test whether it is safe to give phenformin with the standard drug combination of one of 3 FDA-approved combinations of BRAF ...

3. gsk.com gsk.com/en-gb/media/press-releases/trametinib-mekinist-and-dabrafenib-tafinlar-combination-demonstrated-overall-survival-benefit-compared-to-vemurafenib/

Trametinib (Mekinist™) and dabrafenib (Tafinlar ... Trametinib (Mekinist™) and dabrafenib (Tafinlar™) combination demonstrated overall survival benefit compared to vemurafenib; phase III BRAF V600-mutant ...

4. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid

FDA grants accelerated approval to dabrafenib in ... FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.9536

Targeting AMP kinase in melanoma: A phase I trial of ... For these reasons, we designed a phase I trial combining phen with dabrafenib/trametinib (dab/tram) in patients (pts) with metastatic BRAF V600- ...

6. gsk.com gsk.com/en-gb/media/press-releases/two-new-gsk-oral-oncology-treatments-braf-inhibitor-tafinlar-dabrafenib-capsules-and-the-first-mek-inhibitor-mekinist-trametinib-tablets-approved-by-fda-as-single-agent-therapies/

Mekinist also approved for BRAF V600K mutation Both approved for unresectable or metastatic melanoma with BRAF V600E mutation; Mekinist also approved for BRAF V600K mutation.