<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/NCT01721525</url>
  </required_header>
  <id_info>
    <org_study_id>12-150</org_study_id>
    <nct_id>NCT01721525</nct_id>
  </id_info>
  <brief_title>Induction Chemotherapy With Afatinib, Ribavirin, and Weekly Carboplatin/Paclitaxel for Stage IVA/IVB HPV Associated Oropharynx Squamous Cell Cancer (OPSCC)</brief_title>
  <official_title>Phase I Study of Induction Chemotherapy With Afatinib, Ribavirin, and Weekly Carboplatin/Paclitaxel for Stage IVA/IVB HPV Associated Oropharynx Squamous Cell Cancer (OPSCC)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Memorial Sloan Kettering Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Comprehensive Cancer Network</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Memorial Sloan Kettering Cancer Center</source>
  <brief_summary>
    <textblock>
      This study seeks to develop a new induction chemotherapy regimen which is a combination of&#xD;
      two pill drugs taken by mouth and two drugs given by vein. This is a phase I study, which&#xD;
      means that the primary goal is to establish the recommended dose of an investigational drug&#xD;
      when added to chemotherapy. The researchers wish to evaluate the effects, good and bad, of&#xD;
      the investigational drug.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 2012</start_date>
  <completion_date type="Actual">October 16, 2017</completion_date>
  <primary_completion_date type="Actual">October 16, 2017</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>maximum tolerated dose (For Dose Escalation Portion of the study)</measure>
    <time_frame>1 year</time_frame>
    <description>of daily oral afatinib administered with standard daily weight based ribavirin and intravenous carboplatin and paclitaxel, Up to 2 dose levels of daily afatinib will be studied: 30 mg/day and 40 mg/day. The doses of ribavirin, carboplatin, and paclitaxel are fixed. A standard 3 + 3 phase I dose escalation design will be used.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>expression of PTPN13 (For Expansion Cohort only)</measure>
    <time_frame>1 year</time_frame>
    <description>To determine if a two week run-in with afatinib and ribavirin results in increased expression of PTPN13, as determined by IHC in pre and post treatment biopsies.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>safety and tolerability (toxicity)</measure>
    <time_frame>1 year</time_frame>
    <description>Adverse events (AEs) will be assessed according to NCI common toxicity criteria (CTC) version 4.0. Dose Limiting Toxicity (DLT) include all toxicities of grade 3 or higher felt to be possibly, probably, or definitely related to study drug.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>objective response rate</measure>
    <time_frame>1 year</time_frame>
    <description>Response and progression will be evaluated in this study using modified international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) (51). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>pharmacokinetics</measure>
    <time_frame>1 year</time_frame>
    <description>PK measurements will be collected from patients in the dose excalation cohort during the first cycle of therapy. The area under the curve (AUC0→∞), half-life (t½), and maximum concentration (Cmax) for afatinib will be determined by noncompartmental analysis.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Head and Neck Cancer</condition>
  <condition>Squamous Cell Cancer</condition>
  <arm_group>
    <arm_group_label>afatinib, ribavirin, and weekly carboplatin/paclitaxel</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This will be a single institution phase I study with an expansion cohort. Up to 2 dose levels of daily afatinib will be studied: 30 mg/day and 40 mg/day. The doses of ribavirin, carboplatin, and paclitaxel are fixed. A standard 3 + 3 phase I dose escalation design will be used.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Afatinib, Ribavirin, and weekly carboplatin/paclitaxel</intervention_name>
    <description>Patients will receive oral daily afatinib (days 1 - 21, per dose escalation scheme) plus daily oral ribavirin (days 1- 21) and paclitaxel (80 mg/m2 intravenously, days 1 and 8) + carboplatin (AUC 1.5 intravenously, days 1 and 8) of a 21-day cycle. Ribavirin will be administered according to standard weight-based dosing for this drug (1). Subjects ≤75 kg receive Ribavirin 400 mg PO qAM and 600 mg PO qPM (= 1000 mg/day). Subjects &gt; 75 kg receive Ribavirin 600 mg PO BID (=1200 mg/day). During the Dose Escalation portion of the study (Part 1), research bloodwork for pharmacokinetics is performed on days 1 and 8 of Cycle 1 only.</description>
    <arm_group_label>afatinib, ribavirin, and weekly carboplatin/paclitaxel</arm_group_label>
    <other_name>During the Expansion Cohort (Part 2), there is a two week run in of afatinib +</other_name>
    <other_name>ribavirin. The Expansion Cohort begins with a Run-In period of approximately</other_name>
    <other_name>14 days, in which patients receive only afatinib + ribavirin. On Day -14</other_name>
    <other_name>(Start of the of the Run-In), patients begin afatinib once daily (at 40 mg/daily the dose</other_name>
    <other_name>established in Part 1) and ribavirin twice daily according to standard</other_name>
    <other_name>weight-based dosing. Both afatinib and ribavirin are self-administered each</other_name>
    <other_name>day during the Run-In period.</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Department of Pathology at MSKCC confirmation of diagnosis of oropharynx squamous cell&#xD;
             cancer, stage IVA/IVB, that is HPV associated.&#xD;
&#xD;
        Evidence of HPV can be p16 immunohistochemistry and/or HPV in situ hybridization positive&#xD;
        test result on tumor tissue, either at MSKCC or other CLIA-approved lab.&#xD;
&#xD;
          -  Age ≥ 18 years of age&#xD;
&#xD;
          -  Karnofsky Performance Status ≥ 80&#xD;
&#xD;
          -  Adequate organ function, as follows:&#xD;
&#xD;
        Adequate bone marrow reserve: absolute neutrophil count (ANC) ≥ 1.5 X 109/L, platelets ≥&#xD;
        160 X 109/L, hemoglobin ≥ 12 g/dL Hepatic: total bilirubin within normal limits (≤ 1.0&#xD;
        mg/dL); alkaline phosphatase (AP), aspartate transaminase (AST) and alanine transaminase&#xD;
        (ALT) ≤ 1.5 X ULN (upper limit of normal) Renal: Serum creatinine ≤ 1.3 mg/dL. Patients&#xD;
        with serum creatinine &gt; 1.3 mg/dL may be eligible if creatinine clearance (CrCl) ≥ 55&#xD;
        mL/min based on the standard Cockroft and Gault formula.&#xD;
&#xD;
          -  Patients of childbearing potential must have a negative serum pregnancy test within 14&#xD;
             days of treatment. Patients must agree to use a reliable method of birth control&#xD;
             during and for 6 months following the last dose of study drug.&#xD;
&#xD;
          -  Ability to swallow oral medication.&#xD;
&#xD;
          -  Expansion Cohort only: At least one unstained slide from pre-treatment diagnostic&#xD;
             biopsy or fine needle aspirate must be available for correlative immunohistochemistry&#xD;
             study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior chemotherapy or radiation for tonsillar or base of tongue squamous cell cancer&#xD;
&#xD;
          -  History of hemolytic anemia or thalassemia&#xD;
&#xD;
          -  Active infection or serious underlying medical condition that would impair the&#xD;
             patient's ability to receive protocol treatment.&#xD;
&#xD;
          -  Current therapeutic anticoagulation with Coumadin (warfarin)&#xD;
&#xD;
          -  Current or prior treatment with ribavirin&#xD;
&#xD;
          -  Known active Hepatitis B or C&#xD;
&#xD;
          -  Any prior documented history of transient ischemic attack (TIA) or cerebrovascular&#xD;
             accident (CVA)&#xD;
&#xD;
          -  New York Heart Association (NYHA) Grade II or greater congestive heart failure&#xD;
&#xD;
          -  Clinically significant peripheral vascular disease&#xD;
&#xD;
          -  Inability to discontinue any of the following potent P-gp inhibitors (cyclosporine,&#xD;
             erythromycin, ketoconazole, itraconazole, quinidine, phenobarbital salt with&#xD;
             quinidine, ritonavir, valspodar, verapamil) or inducers (St John's wort, rifampicin).&#xD;
&#xD;
          -  Known pre-existing interstitial lung disease.&#xD;
&#xD;
          -  Presence of poorly controlled gastrointestinal disorders that could affect the&#xD;
             absorption of the trial drug (e.g. Crohn's disease, ulcerative colitis, malabsorption,&#xD;
             or CTC grade ≥2 diarrhea of any etiology) based on treating physician assessment.&#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>David Pfister, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Memorial Sloan Kettering Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center at Basking Ridge</name>
      <address>
        <city>Basking Ridge</city>
        <state>New Jersey</state>
        <zip>07939</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/</url>
    <description>Memorial Sloan Kettering Cancer Center</description>
  </link>
  <verification_date>October 2017</verification_date>
  <study_first_submitted>November 1, 2012</study_first_submitted>
  <study_first_submitted_qc>November 1, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 4, 2012</study_first_posted>
  <last_update_submitted>October 23, 2017</last_update_submitted>
  <last_update_submitted_qc>October 23, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 25, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>BIBW2992 (AFATINIB)</keyword>
  <keyword>CARBOPLATIN</keyword>
  <keyword>RIBAVIRIN-ICN (VIRAZOLE)</keyword>
  <keyword>TAXOL (PACLITAXEL)</keyword>
  <keyword>OROPHARYNX</keyword>
  <keyword>HPV associated</keyword>
  <keyword>12-150</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms, Squamous Cell</mesh_term>
    <mesh_term>Carcinoma, Squamous Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ribavirin</mesh_term>
    <mesh_term>Paclitaxel</mesh_term>
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Afatinib</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/NCT01721525
org study id: 12-150
nct id: NCT01721525
lead sponsor: 
collaborator: 
collaborator: 
This study seeks to develop a new induction chemotherapy regimen which is a combination of
      two pill drugs taken by mouth and two drugs given by vein. This is a phase I study, which
      means that the primary goal is to establish the recommended dose of an investigational drug
      when added to chemotherapy. The researchers wish to evaluate the effects, good and bad, of
      the investigational drug.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: maximum tolerated dose (For Dose Escalation Portion of the study)
time frame: 1 year
description: of daily oral afatinib administered with standard daily weight based ribavirin and intravenous carboplatin and paclitaxel, Up to 2 dose levels of daily afatinib will be studied: 30 mg/day and 40 mg/day. The doses of ribavirin, carboplatin, and paclitaxel are fixed. A standard 3 + 3 phase I dose escalation design will be used.
measure: expression of PTPN13 (For Expansion Cohort only)
time frame: 1 year
description: To determine if a two week run-in with afatinib and ribavirin results in increased expression of PTPN13, as determined by IHC in pre and post treatment biopsies.
measure: safety and tolerability (toxicity)
time frame: 1 year
description: Adverse events (AEs) will be assessed according to NCI common toxicity criteria (CTC) version 4.0. Dose Limiting Toxicity (DLT) include all toxicities of grade 3 or higher felt to be possibly, probably, or definitely related to study drug.
measure: objective response rate
time frame: 1 year
description: Response and progression will be evaluated in this study using modified international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) (51). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
measure: pharmacokinetics
time frame: 1 year
description: PK measurements will be collected from patients in the dose excalation cohort during the first cycle of therapy. The area under the curve (AUC0→∞), half-life (t½), and maximum concentration (Cmax) for afatinib will be determined by noncompartmental analysis.
arm group label: afatinib, ribavirin, and weekly carboplatin/paclitaxel
arm group type: Experimental
description: This will be a single institution phase I study with an expansion cohort. Up to 2 dose levels of daily afatinib will be studied: 30 mg/day and 40 mg/day. The doses of ribavirin, carboplatin, and paclitaxel are fixed. A standard 3 + 3 phase I dose escalation design will be used.
intervention type: Drug
intervention name: Afatinib, Ribavirin, and weekly carboplatin/paclitaxel
description: Patients will receive oral daily afatinib (days 1 - 21, per dose escalation scheme) plus daily oral ribavirin (days 1- 21) and paclitaxel (80 mg/m2 intravenously, days 1 and 8) + carboplatin (AUC 1.5 intravenously, days 1 and 8) of a 21-day cycle. Ribavirin will be administered according to standard weight-based dosing for this drug (1). Subjects ≤75 kg receive Ribavirin 400 mg PO qAM and 600 mg PO qPM (= 1000 mg/day). Subjects > 75 kg receive Ribavirin 600 mg PO BID (=1200 mg/day). During the Dose Escalation portion of the study (Part 1), research bloodwork for pharmacokinetics is performed on days 1 and 8 of Cycle 1 only.
arm group label: afatinib, ribavirin, and weekly carboplatin/paclitaxel
other name: During the Expansion Cohort (Part 2), there is a two week run in of afatinib +
other name: ribavirin. The Expansion Cohort begins with a Run-In period of approximately
other name: 14 days, in which patients receive only afatinib + ribavirin. On Day -14
other name: (Start of the of the Run-In), patients begin afatinib once daily (at 40 mg/daily the dose
other name: established in Part 1) and ribavirin twice daily according to standard
other name: weight-based dosing. Both afatinib and ribavirin are self-administered each
other name: day during the Run-In period.
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: David Pfister, MD
role: Principal Investigator
affiliation: Memorial Sloan Kettering Cancer Center
facility: 
facility: 
country: United States
url: http://www.mskcc.org/
description: Memorial Sloan Kettering Cancer Center
responsible party type: Sponsor
mesh term: Neoplasms, Squamous Cell
mesh term: Carcinoma, Squamous Cell
mesh term: Ribavirin
mesh term: Paclitaxel
mesh term: Carboplatin
mesh term: Afatinib