<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/NCT02257424</url>
  </required_header>
  <id_info>
    <org_study_id>UPCC 02614</org_study_id>
    <nct_id>NCT02257424</nct_id>
  </id_info>
  <brief_title>Dabrafenib, Trametinib and Hydroxychloroquine in Patients With Advanced BRAF Mutant Melanoma</brief_title>
  <acronym>BAMM</acronym>
  <official_title>BRAF, Autophagy and MEK Inhibition in Metastatic Melanoma: A Phase I/II Open-Label Trial of Dabrafenib, Trametinib and Hydroxychloroquine in Patients With Advanced BRAF Mutant Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Abramson Cancer Center at Penn Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Abramson Cancer Center at Penn Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary purpose of this study is to determine the maximum tolerated dose (MTD) and&#xD;
      preliminary safety of hydroxychloroquine (HCQ) when administered in conjunction with oral&#xD;
      dabrafenib and trametinib (D+T) in patients with advanced BRAF mutant melanoma.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>October 2014</start_date>
  <completion_date type="Actual">October 2021</completion_date>
  <primary_completion_date type="Actual">October 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</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>Phase 1: To determine the maximum tolerated dose</measure>
    <time_frame>5 weeks</time_frame>
    <description>Phase 1: Maximum tolerated dose (MTD) = a) the dose producing Dose Limiting Toxicity (DLT) in 2/6 patients, or b) the dose level below the dose which produced DLT in ≥ 2/3 patients, or in ≥ 3/6 patients</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 2: To assess the clinical efficacy of HCQ+D+T by 1 year PFS rate.</measure>
    <time_frame>1 year</time_frame>
    <description>Phase 2: Progression free survival (PFS) is defined as the duration of time from start of treatment to time of first progression, death due to any cause or last patient contact alive and progression-free</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Advanced BRAF Mutant Melanoma</condition>
  <arm_group>
    <arm_group_label>Phase 1/2</arm_group_label>
    <arm_group_type>Other</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trametinib 2 mg daily</intervention_name>
    <arm_group_label>Phase 1/2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>hydroxychloroquine (HCQ)</intervention_name>
    <description>hydroxychloroquine (HCQ) is 600 mg orally every 12 hours</description>
    <arm_group_label>Phase 1/2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>dabrafenib 150 mg orally twice a day</intervention_name>
    <arm_group_label>Phase 1/2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must be at least 18 years of age.&#xD;
&#xD;
          -  Patients must have histologically confirmed melanoma unresectable Stage III or Stage&#xD;
             IV positive for BRAF V600E, V600K, V600R or V600D by a CLIA approved assay.&#xD;
&#xD;
          -  Patients must have an ECOG performance status of 0 or 1.&#xD;
&#xD;
          -  Patients must have adequate baseline organ function as determined by table 2.&#xD;
&#xD;
        Table 2. Definitions for adequate baseline organ function&#xD;
&#xD;
        Laboratory Values&#xD;
&#xD;
        Hematologic:&#xD;
&#xD;
          -  ANC (absolute neutrophil count) ≥1.2 × 109/L&#xD;
&#xD;
          -  Hemoglobin ≥ 9 g/dL&#xD;
&#xD;
          -  Platelet count ≥100 x 109/L&#xD;
&#xD;
          -  PT/INR and PTT ≤ 1.3 x ULN (PT = prothrombin time; INR = international normalized&#xD;
             ratio; PTT = partial thromboplastin time; ULN = upper limit of normal)&#xD;
&#xD;
        Hepatic&#xD;
&#xD;
          -  Total bilirubin ≤ 1.5 x ULN&#xD;
&#xD;
          -  AST (aspartate aminotransferase) and ALT (alanine transaminase) ≤ 2.5 x ULN&#xD;
&#xD;
        Renal -- Serum creatinine ≤ 1.5 mg/dL&#xD;
&#xD;
        Cardiac&#xD;
&#xD;
        -- Left Ventricular Ejection fraction (LVEF) ≥ LLN (lower limit of normal) by ECHO&#xD;
&#xD;
        Subjects receiving anticoagulation treatment may be allowed to participate with INR&#xD;
        established within the therapeutic range prior to randomization.&#xD;
&#xD;
        If serum creatinine is &gt; 1.5 mg/dL, calculate creatinine clearance using standard&#xD;
        Cockcroft-Gault formula. Creatinine clearance must be ≥ 50 mL/min to be eligible.&#xD;
&#xD;
        Except subjects with known Gilbert's syndrome. ECHO scans must be used throughout the study&#xD;
        when indicated&#xD;
&#xD;
          -  Patients must be able to provide written informed consent.&#xD;
&#xD;
          -  Negative serum pregnancy test within 7 days prior to commencement of dosing in&#xD;
             premenopausal women. Women of non-childbearing potential may be included without serum&#xD;
             pregnancy test if they are either surgically sterile or have been postmenopausal for ≥&#xD;
             1 year. Women must use an effective method of contraception from 14 days prior to&#xD;
             randomization, throughout the treatment period, and for at least 6 months after the&#xD;
             last dose of study treatment as directed by their physician. Effective methods of&#xD;
             contraception are defined as those which result in a low failure rate (i.e., less than&#xD;
             1% per year) when used consistently and correctly (for example implants, injectables,&#xD;
             or intra-uterine devices). At the discretion of the investigator, acceptable methods&#xD;
             of contraception may include total abstinence in cases where the lifestyle of the&#xD;
             patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation,&#xD;
             symptothermal, postovulation methods] and withdrawal are not acceptable methods of&#xD;
             contraception.) Hormonal-based methods (e.g., oral contraceptives) are NOT permitted&#xD;
             as contraception due to potential drug-drug interactions with dabrafenib.&#xD;
&#xD;
          -  Patients with brain metastases treated with whole brain radiation that have been&#xD;
             stable for 2 months are eligible; patients with brain metastases treated with gamma&#xD;
             knife or surgery are allowed to participate after 2 weeks have elapsed since their&#xD;
             procedure. Subjects are excluded if they have leptomeningeal or metastases causing&#xD;
             spinal cord compression that are symptomatic or untreated or not stable for ≥3 months&#xD;
             (must be documented by imaging) or requiring corticosteroids. Subjects on a stable&#xD;
             dose of corticosteroids &gt;1 month or who have been off of corticosteroids for at least&#xD;
             1 week can be enrolled with approval of the medical monitor&#xD;
&#xD;
          -  Any number and type of prior anticancer therapies are allowed except BRAF or MEK&#xD;
             inhibitors .&#xD;
&#xD;
          -  Patients must have discontinued active immunotherapy (IL-2, interferon, CTLA-4, etc.)&#xD;
             or chemotherapy at least 4 weeks prior to entering the study and oral targeted therapy&#xD;
             at least 2 weeks prior to entering the study. Patients must not receive any other&#xD;
             investigational anticancer therapy during the period on study or the four weeks prior&#xD;
             to entry.&#xD;
&#xD;
          -  All prior anti-cancer treatment-related toxicities (except alopecia and laboratory&#xD;
             values as listed in Eligibility Criteria #4) must be Grade 1 according to the Common&#xD;
             Terminology Criteria for Adverse Events version 4 (CTCAE version 4.03, 2009) at the&#xD;
             time of starting treatment. Patients that are asymptomatic on low dose maintenance&#xD;
             hormone replacement delivered at a stable dose for prior toxicities are eligible.&#xD;
&#xD;
          -  Patient much have measurable disease as defined by RECIST 1.1.&#xD;
&#xD;
          -  Patients must be able to swallow and retain oral medication and must not have any&#xD;
             clinically significant gastrointestinal abnormalities that may alter absorption such&#xD;
             as malabsorption syndrome or major resection of the stomach or bowels.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with known serious concurrent infection or medical illness, including&#xD;
             psychiatric disorders, which would jeopardize the ability of the patient to receive&#xD;
             the treatment outlined in this protocol with reasonable safety.&#xD;
&#xD;
          -  Patients who are pregnant or breast-feeding.&#xD;
&#xD;
          -  Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or&#xD;
             investigational agents).&#xD;
&#xD;
          -  Patients who are known to be experiencing an objective partial response to&#xD;
             immunotherapy at the time of study enrollment&#xD;
&#xD;
          -  History of malignancy other than disease under study within 3 years of study&#xD;
             enrollment with exceptions below:&#xD;
&#xD;
        Exception: Subjects with a history of completely resected non-melanoma skin cancer, or&#xD;
        subjects with indolent second malignancies are eligible&#xD;
&#xD;
          -  History of malignancy with confirmed activating RAS mutation at any time. Note:&#xD;
             Prospective RAS testing is not required. However, if the results of previous RAS&#xD;
             testing are known, they must be used in assessing eligibility.&#xD;
&#xD;
          -  History of interstitial lung disease or chronic pneumonitis&#xD;
&#xD;
          -  Due to risk of disease exacerbation patients with porphyria or psoriasis are&#xD;
             ineligible unless the disease is well controlled and they are under the care of a&#xD;
             specialist for the disorder who agrees to monitor the patient for exacerbations.&#xD;
&#xD;
          -  Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs&#xD;
             chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).&#xD;
&#xD;
          -  Patients receiving cytochrome P450 enzyme-inducing anticonvulsant drugs (EIADs) (i.e.&#xD;
             phenytoin, carbamazepine, Phenobarbital, primidone or oxcarbazepine) within 4 weeks of&#xD;
             the start of the study treatment&#xD;
&#xD;
          -  Current use of a prohibited medication as described in Section 6.3.8 of the protocol&#xD;
             for Potential for Drug-Drug Interaction: apply moisturizing creams frequently, topical&#xD;
             keratolytics (e.g. urea 20-40 % cream, salicylic acid 6%, tazarotene 0.1% cream,&#xD;
             fluorouracil 5% cream), clobetasol propionate 0.05% ointment for erythematous areas,&#xD;
             topical lidocaine 2%, and / or systemic pain medication such as nonsteroidal&#xD;
             anti-inflammatory drugs, codeine, and pregabalin for pain.&#xD;
&#xD;
          -  Known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with&#xD;
             laboratory evidence of cleared HBV and/or HCV will be permitted&#xD;
&#xD;
          -  Patients with a previously documented retinal vein occlusion.&#xD;
&#xD;
          -  History or evidence of increased cardiovascular risk including any of the following&#xD;
&#xD;
          -  Left ventricular ejection fraction (LVEF) &lt; institutional lower limit of normal.&#xD;
&#xD;
          -  A QT interval corrected for heart rate using the Bazett's formula ≥ 480 msec;&#xD;
&#xD;
          -  Current clinically significant uncontrolled arrhythmias. Exception: Subjects with&#xD;
             controlled atrial fibrillation for &gt;30 days prior to randomization are eligible.&#xD;
&#xD;
          -  History of acute coronary syndromes (including myocardial infarction and unstable&#xD;
             angina), coronary angioplasty, or stenting within 6 months prior to randomization.&#xD;
&#xD;
          -  Current ≥ Class II congestive heart failure as defined by New York Heart Association&#xD;
&#xD;
          -  Patients with intra-cardiac defibrillators&#xD;
&#xD;
          -  Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram (subjects&#xD;
             with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on&#xD;
             study). Subjects with moderate valvular thickening should not be entered on study.&#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>Ravi Amaravadi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Abramson Cancer Center at Penn Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Robert H. Lurie Comprehensive Cancer Center</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rutgers Cancer Institute of New Jersey</name>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <zip>08903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Abramson Cancer Center of the University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2022</verification_date>
  <study_first_submitted>October 2, 2014</study_first_submitted>
  <study_first_submitted_qc>October 2, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 6, 2014</study_first_posted>
  <last_update_submitted>January 18, 2022</last_update_submitted>
  <last_update_submitted_qc>January 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">January 20, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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>Hydroxychloroquine</mesh_term>
    <mesh_term>Trametinib</mesh_term>
    <mesh_term>Dabrafenib</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>January 19, 2023</submitted>
    <returned>February 14, 2023</returned>
  </pending_results>
  <!-- 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/NCT02257424
org study id: UPCC 02614
nct id: NCT02257424
lead sponsor: 
has dmc: Yes
The primary purpose of this study is to determine the maximum tolerated dose (MTD) and
      preliminary safety of hydroxychloroquine (HCQ) when administered in conjunction with oral
      dabrafenib and trametinib (D+T) in patients with advanced BRAF mutant melanoma.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Phase 1: To determine the maximum tolerated dose
time frame: 5 weeks
description: Phase 1: Maximum tolerated dose (MTD) = a) the dose producing Dose Limiting Toxicity (DLT) in 2/6 patients, or b) the dose level below the dose which produced DLT in ≥ 2/3 patients, or in ≥ 3/6 patients
measure: Phase 2: To assess the clinical efficacy of HCQ+D+T by 1 year PFS rate.
time frame: 1 year
description: Phase 2: Progression free survival (PFS) is defined as the duration of time from start of treatment to time of first progression, death due to any cause or last patient contact alive and progression-free
arm group label: Phase 1/2
arm group type: Other
intervention type: Drug
intervention name: Trametinib 2 mg daily
arm group label: Phase 1/2
intervention type: Drug
intervention name: hydroxychloroquine (HCQ)
description: hydroxychloroquine (HCQ) is 600 mg orally every 12 hours
arm group label: Phase 1/2
intervention type: Drug
intervention name: dabrafenib 150 mg orally twice a day
arm group label: Phase 1/2
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ravi Amaravadi, MD
role: Principal Investigator
affiliation: Abramson Cancer Center at Penn Medicine
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Hydroxychloroquine
mesh term: Trametinib
mesh term: Dabrafenib
submitted: January 19, 2023
returned: February 14, 2023