<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03026517</url>
  </required_header>
  <id_info>
    <org_study_id>15-318</org_study_id>
    <nct_id>NCT03026517</nct_id>
  </id_info>
  <brief_title>Clinical Trial of Phenformin in Combination With BRAF Inhibitor + MEK Inhibitor for Patients With BRAF-mutated Melanoma</brief_title>
  <official_title>Phase I Trial of Phenformin With Patients With Combination BRAF Inhibitor/MEK Inhibitor in Patients With BRAFV600E/K-mutated Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Memorial Sloan Kettering Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Weill Medical College of Cornell University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Memorial Sloan Kettering Cancer Center</source>
  <brief_summary>
    <textblock>
      The purpose of this study is to test whether it is safe to give phenformin with the standard&#xD;
      drug combination of one of 3 FDA-approved combinations of BRAF inhibitor + MEK inhibitor&#xD;
      which are standard treatments for patients with metastatic melanoma whose melanoma has a&#xD;
      mutation in a gene called BRAF.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 2017</start_date>
  <completion_date type="Anticipated">January 2024</completion_date>
  <primary_completion_date type="Anticipated">January 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Disease-free survival</measure>
    <time_frame>2 years</time_frame>
    <description>The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be used to determine treatment response.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Melanoma</condition>
  <arm_group>
    <arm_group_label>Dabrafenib, Trametinib &amp; Phenformin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dabrafenib</intervention_name>
    <arm_group_label>Dabrafenib, Trametinib &amp; Phenformin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trametinib</intervention_name>
    <arm_group_label>Dabrafenib, Trametinib &amp; Phenformin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Phenformin</intervention_name>
    <arm_group_label>Dabrafenib, Trametinib &amp; Phenformin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  AJCC (2009) stage IV melanoma, or stage III melanoma not curable by surgery and which&#xD;
             is progressing or in patients whom neo-adjuvant treatment is deemed acceptable.&#xD;
             Patients must have at least 1 target lesion measurable by RECIST 1.1 criteria.&#xD;
&#xD;
          -  The melanoma must harbor an activating BRAF V600 mutation. Prior therapy with a BRAF&#xD;
             and/or MEK inhibitor is allowed in the dose-escalation phase only. However, patients&#xD;
             who discontinued previous RAF inhibitor due to intolerance of the drug rather than due&#xD;
             to progression will not be eligible.&#xD;
&#xD;
          -  Histologic proof of melanoma reviewed and confirmed by the treating institution. The&#xD;
             melanoma must have a documented BRAFV600E or BRAFV600K mutation by genotyping or IHC12&#xD;
             performed by a CLIA certified laboratory. At MSK, the Diagnostic Molecular Pathology&#xD;
             laboratory has developed and implemented a targeted capture-based next-generation DNA&#xD;
             sequencing assay, MSK-IMPACTTM, to profile all protein-coding exons and selected&#xD;
             introns from 410 oncogenes and tumor suppressor genes in formalin-fixed paraffin&#xD;
             embedded tissues (Cheng, D.T., et al., J Mol Diagn, 2015. 17(3): p. 251-64).&#xD;
             MSK-IMPACTTM has been approved by the NY State Department of Health to be run as a&#xD;
             clinical assay in the CLIA-compliant Diagnostic Molecular Pathology laboratory.&#xD;
             MSK-IMPACTTM is capable of detecting mutations, copy number alterations, and&#xD;
             structural variations. BRAF Exon15 was captured by the MSK-IMPACTTM panel and the&#xD;
             c.1799T&gt;A (p.V600E) mutation was fully validated as per NYS requirements. Detailed&#xD;
             results of the validation of this mutation were included in the validation package&#xD;
             submitted to NY State Department of Health.&#xD;
&#xD;
          -  At MGH, samples will be tested using a multiplex polymerase chain reaction (PCR)&#xD;
             technology called Anchored Multiplex PCR (AMP) for single nucleotide variant (SNV) and&#xD;
             insertion/deletion (indel) detection in genomic DNA using next generation sequencing&#xD;
             (NGS). Briefly, genomic DNA was isolated from a formalin-fixed paraffin embedded tumor&#xD;
             specimen is sheared with the Covaris M220 instrument, followed by end-repair,&#xD;
             adenylation, and ligation with an adapter. A sequencing library targeting hotspots and&#xD;
             exons in 39 genes (including BRAF, exons 11 and 15) is generated using two hemi-nested&#xD;
             PCR reactions. Illumina MiSeq 2 x 147 base paired-end sequencing results are aligned&#xD;
             to the hg19 human genome reference using BWA-MEM (Li H and Durbin R. Bioinformatics&#xD;
             2009;25(14):1754-60). MuTect (Cibulskis K, et al. Nat Biotechnol 2013;31(3):213-9) and&#xD;
             a laboratory-developed insertion/deletion analysis algorithm are used for SNV and&#xD;
             indel variant detection, respectively. This assay has been validated to detect SNV and&#xD;
             indel variants at 5% allelic frequency or higher in target regions with sufficient&#xD;
             read coverage. This test was developed, and its performance characteristics were&#xD;
             determined by the MGH Center for Integrated Diagnostics.&#xD;
&#xD;
          -  Patients must be adequately recovered from surgery, radiation therapy, or any surgical&#xD;
             complications prior to enrollment.&#xD;
&#xD;
          -  Age ≥ 18 years old.&#xD;
&#xD;
          -  ECOG performance status of 0-2.&#xD;
&#xD;
          -  The ability to swallow pills and otherwise follow the protocol.&#xD;
&#xD;
          -  Patients with treated CNS metastases will be eligible if not symptomatic the CNS&#xD;
             disease has been stable for a minium of 6 weeks and the patient requires less than or&#xD;
             equal to the equivalent of 2 mg/day of dexamethasone.&#xD;
&#xD;
          -  Patients must have adequate organ and marrow function as defined below:&#xD;
&#xD;
               -  Absolute Neutrophil Count ≥1.5 K/mcL&#xD;
&#xD;
               -  Platelets ≥100 K/mcL&#xD;
&#xD;
               -  Hemoglobin ≥ 9.0 g/dL&#xD;
&#xD;
               -  Total Bilirubin ≤ 1.2 X institutional upper limit of normal (ULN) or ≤ 3.0 X&#xD;
                  institutional ULN if the patient has Gilbert's Syndrome&#xD;
&#xD;
               -  AST (SGOT) and ALT (SGPT) ≤ 1.2 X institutional upper limit of normal (ULN)&#xD;
&#xD;
               -  Creatinine ≤ 1.4 mg/dl&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Type I or Type II diabetes&#xD;
&#xD;
          -  A history of renal failure (unless recovered for at least 6 months), lactic acidosis,&#xD;
             recurrent or severe hypoglycemia, or significant chronic obstructive lung disease.&#xD;
             Patients will not be excluded for reversible episodes of elevated creatinine due to&#xD;
             hypovolemia.&#xD;
&#xD;
          -  Acute or chronic liver or renal disease.&#xD;
&#xD;
          -  Concurrent use of hypoglycemic agents or any systemic therapy for melanoma. Palliative&#xD;
             limited-field radiation therapy will be allowed&#xD;
&#xD;
          -  Current use of a prohibited medication.&#xD;
&#xD;
          -  Vemurafenib&#xD;
&#xD;
               -  Avoid inducers and inhibitors of CYP3A4&#xD;
&#xD;
               -  Careful with drugs metabolized by CTP1A2 (Clozapam, olanzapine, fluvoxamine,&#xD;
                  haloperidol, theophylline, caffeine).&#xD;
&#xD;
          -  Encorafenib&#xD;
&#xD;
               -  Avoid inducers and inhibitors of CYP3A4&#xD;
&#xD;
               -  Avoid drugs that increase QTc interval&#xD;
&#xD;
          -  Dabrafenib&#xD;
&#xD;
               -  Avoid inducers and inhibitors of CYP3A4 or CYP2CA8 (Refer to Appendix C for&#xD;
                  specific drugs).&#xD;
&#xD;
          -  Presence of conditions that will interfere significantly with the absorption of drugs.&#xD;
&#xD;
          -  A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.&#xD;
&#xD;
          -  Pregnant and/or lactating women&#xD;
&#xD;
          -  A prior or concurrent metastatic second malignancy within 3 years, even if it does not&#xD;
             require active therapy. For example, patients with concomitant indolent B-cell&#xD;
             malignancies will not be eligible. Patients with a prior resected in-situ or stage I&#xD;
             malignancy felt to be cured will be eligible.&#xD;
&#xD;
          -  Other uncontrolled intercurrent illness including, but not limited to, ongoing or&#xD;
             active infection, symptomatic congestive heart failure, unstable angina pectoris,&#xD;
             cardiac arrhythmia, or psychiatric illness/social situations that would limit&#xD;
             compliance with study requirements. New York Heart Association class ≥2 will be an&#xD;
             exclusion criterion.&#xD;
&#xD;
          -  QTc interval &gt; 500 msec unless a bundle branch block is also present.&#xD;
&#xD;
          -  Patients with brain metastases unless they meet the criteria of section 6.1.8.&#xD;
&#xD;
          -  Patients currently receiving other anti-melanoma treatment. Toxicities attributable to&#xD;
             any prior therapy must have resolved to grade 1 or better prior to enrollment. Grade 2&#xD;
             endocrinopathies, except diabetes, that are ongoing from prior immunotherapy will not&#xD;
             exclude the patient as long as the patient is on appropriate replacement doses of&#xD;
             hormone.&#xD;
&#xD;
          -  Patients receiving steroid treatment exceeding replacement dosing&#xD;
&#xD;
          -  In the dose expansion phase of the trial, prior treatment with a BRAF inhibitor will&#xD;
             be an exclusion criterion. This includes prior adjuvant dabrafenib/trametinib.&#xD;
&#xD;
        Inclusion of Women and Minorities:&#xD;
&#xD;
          -  Both men and women, and members of all races and ethnic groups are eligible for this&#xD;
             trial.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paul Chapman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Memorial Sloan Kettering Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Westchester</name>
      <address>
        <city>Harrison</city>
        <state>New York</state>
        <zip>10604</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mskcc.org/mskcc/html/44.cfm</url>
    <description>Memorial Sloan Kettering Cancer Center</description>
  </link>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 17, 2017</study_first_submitted>
  <study_first_submitted_qc>January 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 20, 2017</study_first_posted>
  <last_update_submitted>June 14, 2023</last_update_submitted>
  <last_update_submitted_qc>June 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Phenformin</keyword>
  <keyword>Dabrafenib</keyword>
  <keyword>Trametinib</keyword>
  <keyword>BRAF/MEKi</keyword>
  <keyword>15-318</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Phenformin</mesh_term>
    <mesh_term>Trametinib</mesh_term>
    <mesh_term>Dabrafenib</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03026517
org study id: 15-318
nct id: NCT03026517
lead sponsor: 
collaborator: 
collaborator: 
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 inhibitor + MEK inhibitor
      which are standard treatments for patients with metastatic melanoma whose melanoma has a
      mutation in a gene called BRAF.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Disease-free survival
time frame: 2 years
description: The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be used to determine treatment response.
arm group label: Dabrafenib, Trametinib & Phenformin
arm group type: Experimental
description: 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.
intervention type: Drug
intervention name: Dabrafenib
arm group label: Dabrafenib, Trametinib & Phenformin
intervention type: Drug
intervention name: Trametinib
arm group label: Dabrafenib, Trametinib & Phenformin
intervention type: Drug
intervention name: Phenformin
arm group label: Dabrafenib, Trametinib & Phenformin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Paul Chapman, MD
role: Principal Investigator
affiliation: Memorial Sloan Kettering Cancer Center
facility: 
facility: 
facility: 
country: United States
url: http://www.mskcc.org/mskcc/html/44.cfm
description: Memorial Sloan Kettering Cancer Center
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Phenformin
mesh term: Trametinib
mesh term: Dabrafenib