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Phenformin Hydrochloride, Dabrafenib, and Trametinib in Treating Patients with Stage III-IV BRAF V600E / K-Mutated Melanoma

Trial Status: Active

This phase I trial studies the side effects and best dose of phenformin hydrochloride when given together with dabrafenib and trametinib in treating patients with stage III-IV BRAF V600E / K-mutated melanoma. Phenformin hydrochloride may work by shrinking the tumors. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving phenformin hydrochloride, dabrafenib, and trametinib may work better at treating melanoma and might prevent the tumor from becoming resistant to treatment.

Inclusion Criteria

  • American Joint Committee on Cancer (AJCC) (2009) stage IV melanoma, or stage III melanoma not curable by surgery and which is progressing or in patients whom neo-adjuvant treatment is deemed acceptable; patients must have at least 1 target lesion measurable by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
  • The melanoma must harbor an activating BRAF V600 mutation; prior therapy with a BRAF and/or MEK inhibitor is allowed in the dose-escalation phase only; however, patients who discontinued previous RAF inhibitor due to intolerance of the drug rather than due to progression will not be eligible
  • Histologic proof of melanoma reviewed and confirmed by the treating institution; the melanoma must have a documented BRAF V600E or BRAF V600K mutation by genotyping or immunohistochemistry (IHC) performed by a Clinical Laboratory Improvement Act (CLIA) certified laboratory; at Memorial Sloan-Kettering (MSK), the Diagnostic Molecular Pathology laboratory has developed and implemented a targeted capture-based next-generation deoxyribonucleic acid (DNA) sequencing assay, MSK-integrated mutation profiling of actionable cancer targets (IMPACT), to profile all protein-coding exons and selected introns from 410 oncogenes and tumor suppressor genes in formalin-fixed paraffin embedded tissues; MSK-IMPACT has been approved by the New York (NY) State Department of Health to be run as a clinical assay in the CLIA-compliant diagnostic molecular pathology laboratory; MSK-IMPACT is capable of detecting mutations, copy number alterations, and structural variations; BRAF exon15 was captured by the MSK-IMPACT panel and the c.1799T>A (p.V600E) mutation was fully validated as per New York State (NYS) requirements; detailed results of the validation of this mutation were included in the validation package submitted to NY State Department of Health
  • At Massachusetts General Hospital (MGH), samples will be tested using a multiplex polymerase chain reaction (PCR) technology called anchored multiplex PCR (AMP) for single nucleotide variant (SNV) and insertion/deletion (indel) detection in genomic DNA using next generation sequencing (NGS); briefly, genomic DNA was isolated from a formalin-fixed paraffin embedded tumor specimen is sheared with the Covaris M220 instrument, followed by end-repair, adenylation, and ligation with an adapter; a sequencing library targeting hotspots and exons in 39 genes (including BRAF, exons 11 and 15) is generated using two hemi-nested PCR reactions; Illumina MiSeq 2 x 147 base paired-end sequencing results are aligned to the hg19 human genome reference using BWA-MEM; MuTect and a laboratory-developed insertion/deletion analysis algorithm are used for SNV and indel variant detection, respectively; this assay has been validated to detect SNV and indel variants at 5% allelic frequency or higher in target regions with sufficient read coverage; this test was developed, and its performance characteristics were determined by the MGH Center for Integrated Diagnostics
  • Patients must be adequately recovered from surgery, radiation therapy, or any surgical complications prior to enrollment
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • The ability to swallow pills and otherwise follow the protocol
  • Patients with treated central nervous system (CNS) metastases will be eligible if not symptomatic, the CNS disease has been stable for a minimum of 6 weeks and the patient requires less than or equal to the equivalent of 2 mg/day of dexamethasone
  • Absolute neutrophil count >= 1.5 K/mcL
  • Platelets >= 100 K/mcL
  • Hemoglobin >= 9.0 g/dL
  • Total bilirubin =< 1.2 X institutional upper limit of normal (ULN) OR =< 3.0 X institutional ULN if the patient has Gilbert's syndrome
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.2 X institutional upper limit of normal (ULN)
  • Creatinine =< 1.4 mg/dl

Exclusion Criteria

  • Type I or type II diabetes
  • A history of renal failure (unless recovered for at least 6 months), lactic acidosis, recurrent or severe hypoglycemia, or significant chronic obstructive lung disease; patients will not be excluded for reversible episodes of elevated creatinine due to hypovolemia
  • Acute or chronic liver or renal disease
  • Concurrent use of hypoglycemic agents or any systemic therapy for melanoma; palliative limited-field radiation therapy will be allowed
  • Current use of a prohibited medication while on dabrafenib/trametinib
  • Presence of conditions that will interfere significantly with the absorption of drugs
  • A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Pregnant and/or lactating women
  • A prior or concurrent metastatic second malignancy within 3 years, even if it does not require active therapy; for example, patients with concomitant indolent B-cell malignancies will not be eligible; patients with a prior resected in-situ or stage I malignancy felt to be cured will be eligible
  • Other uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; New York Heart Association class >= 2 will be an exclusion criterion
  • Corrected QT (QTc) interval > 500 msec unless a bundle branch block is also present
  • Patients with brain metastases unless they meet the criteria
  • Patients currently receiving other anti-melanoma treatment; toxicities attributable to any prior therapy must have resolved to grade 1 or better prior to enrollment; grade 2 endocrinopathies, except diabetes, that are ongoing from prior immunotherapy will not exclude the patient as long as the patient is on appropriate replacement doses of hormone
  • Patients receiving steroid treatment exceeding replacement dosing
  • In the dose expansion phase of the trial, prior treatment with a BRAF inhibitor will be an exclusion criterion

Massachusetts

Boston
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Keith Thomas Flaherty
Phone: 617-724-4800

New York

New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Paul B. Chapman
Phone: 646-888-4162
West Harrison
Memorial Sloan Kettering Westchester
Status: ACTIVE
Contact: Paul B. Chapman
Phone: 646-888-4162

PRIMARY OBJECTIVE:

I. Determine the maximum-tolerated dose (MTD) of phenformin hydrochloride (phenformin) when given with dabrafenib and trametinib to patients with BRAF-mutated melanoma.

SECONDARY OBJECTIVES:

I. Response proportion.

II. Progression-free survival.

III. Toxicities.

IV. Pharmacodynamics and pharmacokinetic effects of phenformin on tumor (or normal tissue) metabolism.

OUTLINE: This is a dose escalation study of phenformin hydrochloride.

Patients receive dabrafenib orally (PO) twice daily (BID), trametinib PO once daily (QD), and phenformin hydrochloride PO QD or BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients who experience side effects are followed up for at least 28 days. All patients are followed up at 4 weeks and then periodically for 1 year.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Paul B. Chapman

  • Primary ID 15-318
  • Secondary IDs NCI-2017-00104
  • Clinicaltrials.gov ID NCT03026517