We are updating the design of this site. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

This study is currently recruiting participants.
Verified December 2017 by Memorial Sloan Kettering Cancer Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT03026517
First Posted: January 20, 2017
Last Update Posted: December 8, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Massachusetts General Hospital
Weill Medical College of Cornell University
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center
  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.

Condition Intervention Phase
Melanoma Drug: Dabrafenib Drug: Trametinib Drug: Phenformin Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of Phenformin With Dabrafenib and Trametinib in Patients With BRAFV600E/K-mutated Melanoma

Resource links provided by NLM:


Further study details as provided by Memorial Sloan Kettering Cancer Center:

Primary Outcome Measures:
  • Disease-free survival [ Time Frame: 2 years ]
    The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be used to determine treatment response.


Estimated Enrollment: 40
Actual Study Start Date: January 2017
Estimated Study Completion Date: January 2019
Estimated Primary Completion Date: January 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dabrafenib, Trametinib & Phenformin
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 dose-expansion cohort will enroll up to 10 patients who are treatment- naïve for BRAF inhibitor.
Drug: Dabrafenib Drug: Trametinib Drug: Phenformin

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
    • Hb- A1c ≤ 5.7%, or 5.8-6.5% with a normal fasting glucose

Exclusion Criteria:

  • Type I or Type II diabetes, or Hgb A1c >6.5%.
  • 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.)
  • 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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03026517


Contacts
Contact: Paul Chapman, MD 646-888-4162
Contact: Michael Postow, MD 646-888-4589

Locations
United States, New York
Memorial Sloan Kettering Westchester Recruiting
Harrison, New York, United States, 10604
Contact: Paul Chapman, MD    646-888-4162      
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Paul Chapman, MD    646-888-4162      
Contact: Michael Postow, MD    646-888-4589      
Principal Investigator: Paul Chapman, MD         
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Massachusetts General Hospital
Weill Medical College of Cornell University
Investigators
Principal Investigator: Paul Chapman, MD Memorial Sloan Kettering Cancer Center
  More Information

Additional Information:
Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT03026517     History of Changes
Other Study ID Numbers: 15-318
First Submitted: January 17, 2017
First Posted: January 20, 2017
Last Update Posted: December 8, 2017
Last Verified: December 2017

Keywords provided by Memorial Sloan Kettering Cancer Center:
Phenformin
Dabrafenib
Trametinib
BRAF
15-318

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Trametinib
Dabrafenib
Phenformin
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs