<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/NCT01711632</url>
  </required_header>
  <id_info>
    <org_study_id>12-200</org_study_id>
    <nct_id>NCT01711632</nct_id>
  </id_info>
  <brief_title>BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia</brief_title>
  <official_title>A Phase II Study of the BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Memorial Sloan Kettering Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Northwestern University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ohio State University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Dana-Farber Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Scripps Clinic</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Northwell Health</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 find out what effects, good and/or bad, treatment with&#xD;
      vemurafenib (also known as Zelboraf™) has on the patient and on leukemia. Specifically, the&#xD;
      researchers want to know how well vemurafenib eliminates leukemia from the blood.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 2012</start_date>
  <completion_date type="Anticipated">October 2025</completion_date>
  <primary_completion_date type="Anticipated">October 2025</primary_completion_date>
  <phase>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>efficacy of vemurafenib</measure>
    <time_frame>3 months</time_frame>
    <description>as assessed by overall response rates after three months of treatment in patients with relapsed or refractory HCL.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Toxicity (safety and tolerability)</measure>
    <time_frame>2 years</time_frame>
    <description>Toxicity will be graded and recorded using the NCI Common Toxicology Criteria version 4.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess the pharmacodynamics</measure>
    <time_frame>2 years</time_frame>
    <description>Peripheral blood and/or bone marrow aspirate samples from pretreatment and post-treatment at specified time points will be assessed by Western Blot or by phospho-flow for the downstream targets of BRAF (MEK, pMEK, ERK, pERK) to assess the ontarget effect of the Vemurafenib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>evaluate biomarkers</measure>
    <time_frame>2 years</time_frame>
    <description>Reactivation of MAPK pathways: Increased expression of the other RAF isoforms CRAF and ARAF), and MAPK (MAPK8 or COT) will be analyzed by Western Blot and/or real-time PCR39,40. Secondary BRAF mutations (all 18 BRAF exons) and RAS mutations40 will be analyzed by bidirectional Sanger sequencing and by Raindance multiplex PCR and Illumina next generation sequencing, respectively. Activation of RTKs (i.e. PDGFRβ and IGF-IR) will be assessed by Western Blot. Cell Biosciences NanoPro 1000 technology will be used to examine quantitative signaling on the entire MAPK, PI3K and JAK-STAT pathways41.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">36</enrollment>
  <condition>Hairy Cell Leukemia</condition>
  <arm_group>
    <arm_group_label>Vemurafenib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Eligible patients will receive vemurafenib at a dose of 960mg orally twice daily (b.i.d.) continuously in cycles of 4 weeks (28 days).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vemurafenib</intervention_name>
    <description>Patients will receive vemurafenib at a dose of 960mg orally b.i.d. continuously in cycles of 4 weeks (28 days) as outpatient. A bone marrow aspirate and/or biopsy will be performed after the first cycle for research purposes only. After the completion of the third cycle, a repeat bone marrow aspirate and/or biopsy will be performed for assessment of response and evaluation of MRD. Following the third cycle assessments, patients who achieve complete response (CR) with detectable MRD or partial response (PR) may continue with vemurafenib for up to 3 additional cycles at the treating physician's discretion (Cycles 4-6). Patients who achieve CR without MRD will be observed as part of post-treatment followup, and may be re-treated with vemurafenib after relapse (as per below). Patients who achieve no response (NR) after the initial 3 cycles of vemurafenib will be removed from the study. They will be followed every 3 months as part of posttreatment followup for a total of 12 months.</description>
    <arm_group_label>Vemurafenib</arm_group_label>
    <other_name>Zelboraf™</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ≥ 18 years of age&#xD;
&#xD;
          -  Histologically confirmed classical HCL with one of the following:&#xD;
&#xD;
          -  Intolerance to purine analogs or considered to be poor candidates for purine&#xD;
             analog-based therapy&#xD;
&#xD;
          -  Failure to achieve any response (CR or PR) to the initial purine analog-based therapy&#xD;
&#xD;
          -  Relapse ≤ 2 years of purine analog-based therapy&#xD;
&#xD;
          -  ≥ 2 relapses Histologic confirmation of diagnosis will be performed at MSKCC or a&#xD;
             participating site.&#xD;
&#xD;
          -  Patients who meet the standard treatment initiation criteria, as defined by ANC ≤1.0,&#xD;
             Hgb ≤ 10.0 or PLT ≤100K&#xD;
&#xD;
          -  ECOG performance status of 0-2&#xD;
&#xD;
          -  Acceptable pre-study organ function during screening as defined as: Total bilirubin ≤&#xD;
             1.5 times the upper limit of normal (ULN), aspartate aminotransferase (AST) and&#xD;
             alanine aminotransferase (ALT) ≤ 2.5x ULN, and serum creatinine ≤ 1.5x ULN&#xD;
&#xD;
          -  Electrocardiogram (ECG) without evidence of clinically significant ventricular&#xD;
             arrhythmias or ischemia as determined by the investigator and a rate-corrected QT&#xD;
             interval (QTc, Bazett's formula) of &lt; 480 msec.&#xD;
&#xD;
          -  For women of childbearing potential, agreement to the use of two acceptable methods of&#xD;
             contraception, including one barrier method, during the study and for 6 months after&#xD;
             discontinuation of vemurafenib&#xD;
&#xD;
          -  For men with female partners of childbearing potential, agreement to use a latex&#xD;
             condom and to advise their female partner to use an additional method of contraception&#xD;
             during the study and for 6 months after discontinuation of vemurafenib&#xD;
&#xD;
          -  Negative serum pregnancy test within 7 days of commencement of treatment in&#xD;
             premenopausal women.&#xD;
&#xD;
          -  Agreement not to donate blood or blood products during the study and for at least 6&#xD;
             months after discontinuation of vemurafenib; for male partners, agreement not to&#xD;
             donate sperm during the study and for at least 6 months after discontinuation of&#xD;
             vemurafenib&#xD;
&#xD;
          -  Ability to understand and willingness to sign a written informed consent document.&#xD;
&#xD;
          -  Willingness and ability to comply with scheduled visits, treatment plans, laboratory&#xD;
             tests, and other study procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or breast-feeding&#xD;
&#xD;
          -  Have had chemotherapy (including purine analogs, rituximab, and other investigational&#xD;
             agents) within six weeks prior to entering the study&#xD;
&#xD;
          -  Major surgery within 4 weeks prior to entering the study&#xD;
&#xD;
          -  Invasive malignancy within the past 2 years prior to first study drug administration,&#xD;
             except for adequately treated (with curative intent) basal or squamous cell carcinoma,&#xD;
             melanoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the&#xD;
             breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from&#xD;
             which the patient has been disease-free for at least 2 years&#xD;
&#xD;
          -  Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of&#xD;
             any type of gastrointestinal surgery that would preclude adequate absorption of study&#xD;
             drug&#xD;
&#xD;
          -  Prior treatment with MEK or BRAF inhibitors&#xD;
&#xD;
          -  Active HIV, hepatitis B and hepatitis C&#xD;
&#xD;
          -  Patients with HCL variant (as defined by absence of expression of CD25 or absence of&#xD;
             BRAF V600E mutation)&#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>Jae H. Park, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Memorial Sloan Kettering Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Scripps Clinic</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92037</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwestern University</name>
      <address>
        <city>Evanston</city>
        <state>Illinois</state>
        <zip>60208</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</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>
    <facility>
      <name>Ohio State University</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mskcc.org/</url>
    <description>Memorial Sloan Kettering Cancer Center</description>
  </link>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>October 17, 2012</study_first_submitted>
  <study_first_submitted_qc>October 18, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 22, 2012</study_first_posted>
  <last_update_submitted>July 28, 2023</last_update_submitted>
  <last_update_submitted_qc>July 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>VEMURAFENIB</keyword>
  <keyword>BRAF Inhibitor</keyword>
  <keyword>12-200</keyword>
  <keyword>Zelboraf™</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Hairy Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vemurafenib</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/NCT01711632
org study id: 12-200
nct id: NCT01711632
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
The purpose of this study is to find out what effects, good and/or bad, treatment with
      vemurafenib (also known as Zelboraf™) has on the patient and on leukemia. Specifically, the
      researchers want to know how well vemurafenib eliminates leukemia from the blood.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: efficacy of vemurafenib
time frame: 3 months
description: as assessed by overall response rates after three months of treatment in patients with relapsed or refractory HCL.
measure: Toxicity (safety and tolerability)
time frame: 2 years
description: Toxicity will be graded and recorded using the NCI Common Toxicology Criteria version 4.0.
measure: To assess the pharmacodynamics
time frame: 2 years
description: Peripheral blood and/or bone marrow aspirate samples from pretreatment and post-treatment at specified time points will be assessed by Western Blot or by phospho-flow for the downstream targets of BRAF (MEK, pMEK, ERK, pERK) to assess the ontarget effect of the Vemurafenib.
measure: evaluate biomarkers
time frame: 2 years
description: Reactivation of MAPK pathways: Increased expression of the other RAF isoforms CRAF and ARAF), and MAPK (MAPK8 or COT) will be analyzed by Western Blot and/or real-time PCR39,40. Secondary BRAF mutations (all 18 BRAF exons) and RAS mutations40 will be analyzed by bidirectional Sanger sequencing and by Raindance multiplex PCR and Illumina next generation sequencing, respectively. Activation of RTKs (i.e. PDGFRβ and IGF-IR) will be assessed by Western Blot. Cell Biosciences NanoPro 1000 technology will be used to examine quantitative signaling on the entire MAPK, PI3K and JAK-STAT pathways41.
arm group label: Vemurafenib
arm group type: Experimental
description: Eligible patients will receive vemurafenib at a dose of 960mg orally twice daily (b.i.d.) continuously in cycles of 4 weeks (28 days).
intervention type: Drug
intervention name: Vemurafenib
description: Patients will receive vemurafenib at a dose of 960mg orally b.i.d. continuously in cycles of 4 weeks (28 days) as outpatient. A bone marrow aspirate and/or biopsy will be performed after the first cycle for research purposes only. After the completion of the third cycle, a repeat bone marrow aspirate and/or biopsy will be performed for assessment of response and evaluation of MRD. Following the third cycle assessments, patients who achieve complete response (CR) with detectable MRD or partial response (PR) may continue with vemurafenib for up to 3 additional cycles at the treating physician's discretion (Cycles 4-6). Patients who achieve CR without MRD will be observed as part of post-treatment followup, and may be re-treated with vemurafenib after relapse (as per below). Patients who achieve no response (NR) after the initial 3 cycles of vemurafenib will be removed from the study. They will be followed every 3 months as part of posttreatment followup for a total of 12 months.
arm group label: Vemurafenib
other name: Zelboraf™
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jae H. Park, MD
role: Principal Investigator
affiliation: Memorial Sloan Kettering Cancer Center
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
url: http://www.mskcc.org/
description: Memorial Sloan Kettering Cancer Center
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Hairy Cell
mesh term: Vemurafenib