Clinical Trials /

Clinical Trial of Phenformin in Combination With Dabrafenib and Trametinib for Patients With BRAF-mutated Melanoma

NCT03026517

Description:

The purpose of this study is to test whether it is safe to give phenformin with the standard drug combination of dabrafenib + trametinib. The combination of dabrafenib plus trametinib is a standard treatment for patients with metastatic melanoma whose melanoma has a mutation in a gene called BRAF.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Clinical Trial of Phenformin in Combination With Dabrafenib and Trametinib for Patients With BRAF-mutated Melanoma
  • Official Title: Phase I Trial of Phenformin With Dabrafenib and Trametinib in Patients With BRAFV600E/K-mutated Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 15-318
  • NCT ID: NCT03026517

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
DabrafenibDabrafenib, Trametinib & Phenformin
TrametinibDabrafenib, Trametinib & Phenformin
PhenforminDabrafenib, Trametinib & Phenformin

Purpose

The purpose of this study is to test whether it is safe to give phenformin with the standard drug combination of dabrafenib + trametinib. The combination of dabrafenib plus trametinib is a standard treatment for patients with metastatic melanoma whose melanoma has a mutation in a gene called BRAF.

Trial Arms

NameTypeDescriptionInterventions
Dabrafenib, Trametinib & PhenforminExperimentalThis 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 dose-expansion cohort will enroll up to 10 patients who are treatment- naïve for BRAF inhibitor.
  • Dabrafenib
  • Trametinib
  • Phenformin

Eligibility Criteria

        Inclusion Criteria:

          -  AJCC (2009) stage IV melanoma, or stage III melanoma not curable by surgery and which
             is progressing. Patients must have at least 1 target lesion measurable by 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 BRAFV600E or BRAFV600K mutation by genotyping or IHC12
             performed by a CLIA certified laboratory. At MSK, the Diagnostic Molecular Pathology
             laboratory has developed and implemented a targeted capture-based next-generation DNA
             sequencing assay, MSK-IMPACTTM, to profile all protein-coding exons and selected
             introns from 410 oncogenes and tumor suppressor genes in formalin-fixed paraffin
             embedded tissues (Cheng, D.T., et al., J Mol Diagn, 2015. 17(3): p. 251-64).
             MSK-IMPACTTM has been approved by the NY State Department of Health to be run as a
             clinical assay in the CLIA-compliant Diagnostic Molecular Pathology laboratory.
             MSK-IMPACTTM is capable of detecting mutations, copy number alterations, and
             structural variations. BRAF Exon15 was captured by the MSK-IMPACTTM panel and the
             c.1799T>A (p.V600E) mutation was fully validated as per NYS requirements. Detailed
             results of the validation of this mutation were included in the validation package
             submitted to NY State Department of Health.

          -  At 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 (Li H and Durbin R. Bioinformatics
             2009;25(14):1754-60). MuTect (Cibulskis K, et al. Nat Biotechnol 2013;31(3):213-9) 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.

          -  Age ≥ 18 years old.

          -  ECOG performance status of 0-2.

          -  The ability to swallow pills and otherwise follow the protocol.

          -  Patients with treated CNS metastases will be eligible if not symptomatic the CNS
             disease has been stable for a minium of 6 weeks and the patient requires less than or
             equal to the equivalent of 2 mg/day of dexamethasone.

          -  Patients must have adequate organ and marrow function as defined below:

               -  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

               -  AST (SGOT) and ALT (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.

          -  QTc interval > 500 msec unless a bundle branch block is also present.

          -  Patients with brain metastases unless they meet the criteria of section 6.1.8.

          -  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.

        Inclusion of Women and Minorities:

          -  Both men and women, and members of all races and ethnic groups are eligible for this
             trial.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease-free survival
Time Frame:2 years
Safety Issue:
Description:The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be used to determine treatment response.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Phenformin
  • Dabrafenib
  • Trametinib
  • BRAF
  • 15-318

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