<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/NCT03803774</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2019-00175</org_study_id>
    <secondary_id>NCI-2019-00175</secondary_id>
    <secondary_id>19-C-0041</secondary_id>
    <secondary_id>10184</secondary_id>
    <secondary_id>10184</secondary_id>
    <nct_id>NCT03803774</nct_id>
    <nct_alias>NCT03809208</nct_alias>
  </id_info>
  <brief_title>Birinapant and Intensity Modulated Re-Irradiation Therapy in Treating Patients With Locally Recurrent Head and Neck Squamous Cell Carcinoma</brief_title>
  <official_title>Birinapant and Intensity Modulated Re-Irradiation Therapy (IMRRT) for Locoregionally Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and best dose of birinapant when given together&#xD;
      with intensity modulated re-irradiation therapy (IMRRT) in treating patients with head and&#xD;
      neck squamous cell carcinoma that has come back at or near the same place as the original&#xD;
      (primary) tumor (locally recurrent). Birinapant may stop the growth of tumor cells by&#xD;
      blocking IAP, a protein needed for tumor cell survival. IMRRT uses thin beams of radiation of&#xD;
      different intensities that are aimed at the tumor from many angles. This type of&#xD;
      re-irradiation therapy reduces the damage to healthy tissue near the tumor. Giving birinapant&#xD;
      with IMRRT may lower the chance of head and neck squamous cell carcinoma growing or&#xD;
      spreading.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. Determine the toxicities and maximum tolerated dose (MTD) of birinapant concurrent with&#xD;
      intensity modulated re-irradiation therapy (IMRRT).&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Determine the objective response rate of patients with locoregionally recurrent head and&#xD;
      neck squamous cell carcinoma (HNSCC) treated with re-irradiation and birinapant.&#xD;
&#xD;
      II. Determine the local-regional control, progression free survival (PFS), and overall&#xD;
      survival.&#xD;
&#xD;
      III. Determine if FADD and/or BIRC2/3 copy gain in tumor tissue or in the blood are&#xD;
      associated with improved response, locoregional control (LCR), progression-free survival and&#xD;
      overall survival.&#xD;
&#xD;
      IV. Determine the feasibility of detecting effects of birinapant and re-irradiation on pilot&#xD;
      pharmacodynamic markers in tumor tissue, by using microwestern to assess decrease in drug&#xD;
      targets IAP1/2 and increase in apoptosis/necroptosis markers caspase 3 and mixed lineage&#xD;
      kinase domain like pseudokinase gene (MLKL).&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. Explore if mutational load detected with whole exome sequencing of tumor tissue influences&#xD;
      objective response rate.&#xD;
&#xD;
      II. Explore if PD-L1, CD8 T-cell tumor infiltration, TNFalpha, and other immune related&#xD;
      biomarkers in tumor tissue are associated with objective response rate.&#xD;
&#xD;
      III. Explore the pharmacokinetics of birinapant in combination with radiotherapy in blood&#xD;
      samples.&#xD;
&#xD;
      IV. Explore whether specific germline single-nucleotide polymorphisms (SNPs) are associated&#xD;
      with response to birinapant and reirradiation.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of birinapant.&#xD;
&#xD;
      Beginning on day 1, patients undergo IMRRT 5 days a week (Monday-Friday). Patients also&#xD;
      receive birinapant intravenously (IV) over 30 minutes on days 2 and 9 of each cycle.&#xD;
      Treatment repeats every 3 weeks for up to 2 cycles in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 28 days, and at 3, 6, 9, 12,&#xD;
      18, and 24 months until confirmation of disease progression.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 25, 2019</start_date>
  <completion_date type="Anticipated">July 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">July 31, 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>Incidence of dose-limiting toxicities (DLTs) and other toxicities</measure>
    <time_frame>Up to 28 days post-treatment</time_frame>
    <description>Will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Will be evaluated by reporting the DLTs obtained at each dose level, and reporting toxicities noted in tabular form.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum tolerated dose (MTD)</measure>
    <time_frame>Up to 42 days</time_frame>
    <description>Defined as the dose level at which no more than 1 of up to 6 patients experience DLT during 42 days after the start of therapy, and the dose below that at which at least 2 (of =&lt; 6) patients have DLT as a result of the drug. Will be evaluated by reporting the DLTs obtained at each dose level, and reporting toxicities noted in tabular form.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response rate</measure>
    <time_frame>From the start of the treatment until response assessment by positron emission tomography (PET)-computed tomography (CT), assessed at 3 months post-treatment</time_frame>
    <description>Overall response is the best response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Estimates of response rates will be determined at the MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Local-regional control</measure>
    <time_frame>Up to 24 months post-treatment</time_frame>
    <description>Estimates of local control will be determined at the MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>From start of treatment to time of progression or death, whichever occurs first, assessed up to 24 months post-treatment</time_frame>
    <description>Estimates of PFS will be determined at the MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Up to 24 months post-treatment</time_frame>
    <description>Estimates of OS will be determined at the MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FADD copy gain in tumor tissue or in blood</measure>
    <time_frame>At baseline</time_frame>
    <description>The association between results according to whether or not they have a copy gain will be presented for OS and PFS, by comparing Kaplan-Meier curves with a two-tailed log-rank test. In addition, as exploratory analyses, the association between FADD copy gain and BIRC2 copy gain will be individually evaluated for any association with response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>BIRC2/3 copy gain in tumor tissue or in blood</measure>
    <time_frame>At baseline</time_frame>
    <description>The association between results according to whether or not they have a copy gain will be presented for OS and PFS, by comparing Kaplan-Meier curves with a two-tailed log-rank test. In addition, as exploratory analyses, the association between FADD copy gain and BIRC2 copy gain will be individually evaluated for any association with response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic markers in tumor tissue</measure>
    <time_frame>Up to cycle 1, day 4</time_frame>
    <description>Will determine the feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic markers in tumor tissue, including microwestern for decrease in drug targets IAP1/2.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in caspase 3 levels</measure>
    <time_frame>Baseline up to cycle 1, day 4</time_frame>
    <description>Increase in apoptosis/necroptosis marker caspase 3 will be evaluated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in MLKL levels</measure>
    <time_frame>Baseline up to cycle 1, day 4</time_frame>
    <description>Increase in apoptosis/necroptosis marker MLKL will be evaluated.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">34</enrollment>
  <condition>Locally Recurrent Head and Neck Squamous Cell Carcinoma</condition>
  <condition>Nasopharyngeal Squamous Cell Carcinoma</condition>
  <condition>Sinonasal Squamous Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>Treatment (IMRRT, birinapant)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Beginning on day 1, patients undergo IMRRT 5 days a week (Monday-Friday). Patients also receive birinapant IV over 30 minutes on days 2 and 9 of each cycle. Treatment repeats every 3 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Birinapant</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (IMRRT, birinapant)</arm_group_label>
    <other_name>TL32711</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Intensity-Modulated Radiation Therapy</intervention_name>
    <description>Undergo IMRRT</description>
    <arm_group_label>Treatment (IMRRT, birinapant)</arm_group_label>
    <other_name>IMRT</other_name>
    <other_name>Intensity modulated radiation therapy (procedure)</other_name>
    <other_name>Intensity Modulated RT</other_name>
    <other_name>Intensity-Modulated Radiotherapy</other_name>
    <other_name>Radiation, Intensity-Modulated Radiotherapy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically or cytologically confirmed locally recurrent HNSCC,&#xD;
             including nasopharyngeal or sinonasal cancer for whom re-irradiation for local control&#xD;
             is considered standard of care&#xD;
&#xD;
          -  Patients with human papillomavirus (HPV)-negative or HPV-positive head and neck cancer&#xD;
             are eligible&#xD;
&#xD;
          -  Patients who have had prior treatment with immune therapies are eligible&#xD;
&#xD;
          -  Patients must have received curative-intent platinum- and/or cetuximab-based&#xD;
             chemoradiotherapy or radiotherapy alone&#xD;
&#xD;
          -  Patients must have completed their last treatment dose with chemotherapy or&#xD;
             immunotherapy at least 4 weeks (6 weeks for nitrosoureas or mitomycin C) before&#xD;
             enrolling on study&#xD;
&#xD;
          -  Patients must have completed their last treatment dose with radiotherapy at least 6&#xD;
             months before enrolling on study&#xD;
&#xD;
          -  Patients who have had major surgery must be fully recovered and require a recovery&#xD;
             period of at least 4 weeks prior to enrolling on study&#xD;
&#xD;
          -  Age &gt;= 18 years&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2&#xD;
&#xD;
          -  Hemoglobin &gt;= 9 g/dL (transfusion permitted)&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,500/mcL&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mcL&#xD;
&#xD;
          -  Total bilirubin within 1.5 x the upper limit of normal (ULN) institutional limits&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 2.5 x institutional upper limit of normal&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.5 x upper limit of normal (ULN), OR: Creatinine clearance &gt;= 50&#xD;
             mL/min according to Cockcroft Gault formula or other institutional methods&#xD;
&#xD;
          -  Patients must have a corrected QT interval by Fridericia (QTcF) =&lt; 480 msec&#xD;
&#xD;
          -  International normalized ratio (INR) =&lt; 1.5 and no clinically significant bleeding&#xD;
             event within the past six months&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
          -  Patients must have measurable disease, per Response Evaluation Criteria in Solid&#xD;
             Tumors (RECIST) 1.1&#xD;
&#xD;
          -  The effects of birinapant on the developing human fetus are unknown. For this reason,&#xD;
             women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control; abstinence) beginning at study entry and&#xD;
             for the duration of study participation. Male study participants should use an&#xD;
             additional barrier method of contraception for 30 days following the last dose of&#xD;
             birinapant. Should a woman become pregnant or suspect she is pregnant while she or her&#xD;
             partner is participating in this study, she should inform her treating physician&#xD;
             immediately&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Eligibility for curative-intent surgery, unless the patient is considered a poor&#xD;
             surgical candidate related to resectability, functional outcome, or prefers&#xD;
             non-surgical therapy&#xD;
&#xD;
          -  More than 2 lines of palliative systemic therapy (platinum-, taxane- or&#xD;
             cetuximab-based chemotherapy or immunotherapy)&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents&#xD;
&#xD;
          -  Patients with known brain metastases should be excluded from this clinical trial&#xD;
             because of their poor prognosis and because they often develop progressive neurologic&#xD;
             dysfunction that would confound the evaluation of neurologic and other adverse events&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to birinapant&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Pregnant women are excluded from this study because birinapant may have potential for&#xD;
             teratogenic or abortifacient effects. Because there is an unknown but potential risk&#xD;
             for adverse events in nursing infants secondary to treatment of the mother with&#xD;
             birinapant, breastfeeding should be discontinued prior to enrollment. A negative&#xD;
             pregnancy test is required for women of childbearing potential. Women who are&#xD;
             postmenopausal (age-related amenorrhea &gt;= 12 consecutive months, or who had undergone&#xD;
             hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If&#xD;
             necessary, to confirm postmenopausal status, a follicle stimulating hormone (FSH)&#xD;
             level may be included at screening&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV) positive patients on combination antiretroviral&#xD;
             therapy are ineligible because of the potential for pharmacokinetic interactions with&#xD;
             birinapant&#xD;
&#xD;
          -  Patients requiring the use of anti-tumor necrosis factor (anti TNF) therapies, such as&#xD;
             infliximab, or patients who have received treatment with anti-TNF therapies within 5&#xD;
             half-lives of the drug (48 days for infliximab, 55 days for golimumab, 70 days for&#xD;
             certolizumab and adalimumab, and 16 days for etanercept)&#xD;
&#xD;
          -  Patients with previous exposure to birinapant&#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>Vassiliki Saloura</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute LAO</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama at Birmingham Cancer Center</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Los Angeles County-USC Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>USC / Norris Comprehensive Cancer Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>UC Irvine Health/Chao Family Comprehensive Cancer Center</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>UM Sylvester Comprehensive Cancer Center at Coral Gables</name>
      <address>
        <city>Coral Gables</city>
        <state>Florida</state>
        <zip>33146</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Suspended</status>
  </location>
  <location>
    <facility>
      <name>UM Sylvester Comprehensive Cancer Center at Deerfield Beach</name>
      <address>
        <city>Deerfield Beach</city>
        <state>Florida</state>
        <zip>33442</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Suspended</status>
  </location>
  <location>
    <facility>
      <name>University of Miami Miller School of Medicine-Sylvester Cancer Center</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Suspended</status>
  </location>
  <location>
    <facility>
      <name>UM Sylvester Comprehensive Cancer Center at Plantation</name>
      <address>
        <city>Plantation</city>
        <state>Florida</state>
        <zip>33324</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Suspended</status>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center-International Plaza</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33607</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Suspended</status>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center - McKinley Campus</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Suspended</status>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-679-0775</phone>
      <email>ClinicalTrials@moffitt.org</email>
    </contact>
    <investigator>
      <last_name>Christine H. Chung</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Kansas Clinical Research Center</name>
      <address>
        <city>Fairway</city>
        <state>Kansas</state>
        <zip>66205</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>913-588-3671</phone>
      <email>KUCC_Navigation@kumc.edu</email>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>HaysMed University of Kansas Health System</name>
      <address>
        <city>Hays</city>
        <state>Kansas</state>
        <zip>67601</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>785-623-5774</phone>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>913-588-3671</phone>
      <email>KUCC_Navigation@kumc.edu</email>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Lawrence Memorial Hospital</name>
      <address>
        <city>Lawrence</city>
        <state>Kansas</state>
        <zip>66044</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>785-505-2800</phone>
      <email>Stephanie.Norris@LMH.ORG</email>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Olathe Health Cancer Center</name>
      <address>
        <city>Olathe</city>
        <state>Kansas</state>
        <zip>66061</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>913-355-8000</phone>
      <email>Jeni.wakefield@olathehealth.org</email>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center-Overland Park</name>
      <address>
        <city>Overland Park</city>
        <state>Kansas</state>
        <zip>66210</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>913-588-3671</phone>
      <email>KUCC_Navigation@kumc.edu</email>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ascension Via Christi - Pittsburg</name>
      <address>
        <city>Pittsburg</city>
        <state>Kansas</state>
        <zip>66762</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>620-235-7900</phone>
      <email>jennifer.jameson@ascension.org</email>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Salina Regional Health Center</name>
      <address>
        <city>Salina</city>
        <state>Kansas</state>
        <zip>67401</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>785-452-7038</phone>
      <email>mleepers@srhc.com</email>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Kansas Health System Saint Francis Campus</name>
      <address>
        <city>Topeka</city>
        <state>Kansas</state>
        <zip>66606</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>785-295-8000</phone>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Kansas Hospital-Westwood Cancer Center</name>
      <address>
        <city>Westwood</city>
        <state>Kansas</state>
        <zip>66205</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>913-588-3671</phone>
      <email>KUCC_Navigation@kumc.edu</email>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Kentucky/Markey Cancer Center</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40536</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>NCI - Center for Cancer Research</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-411-1222</phone>
    </contact>
    <investigator>
      <last_name>Vassiliki Saloura</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Truman Medical Centers</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64108</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Suspended</status>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center - North</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64154</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>913-588-3671</phone>
      <email>KUCC_Navigation@kumc.edu</email>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center - Lee's Summit</name>
      <address>
        <city>Lee's Summit</city>
        <state>Missouri</state>
        <zip>64064</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>913-588-3671</phone>
      <email>KUCC_Navigation@kumc.edu</email>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Kansas Cancer Center at North Kansas City Hospital</name>
      <address>
        <city>North Kansas City</city>
        <state>Missouri</state>
        <zip>64116</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>913-588-3671</phone>
      <email>KUCC_Navigation@kumc.edu</email>
    </contact>
    <investigator>
      <last_name>Prakash C. Neupane</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>NYU Winthrop Hospital</name>
      <address>
        <city>Mineola</city>
        <state>New York</state>
        <zip>11501</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Suspended</status>
  </location>
  <location>
    <facility>
      <name>Laura and Isaac Perlmutter Cancer Center at NYU Langone</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <email>CancerTrials@nyulangone.org</email>
    </contact>
    <investigator>
      <last_name>Zujun Li</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Wake Forest Baptist Health - Wilkes Medical Center</name>
      <address>
        <city>Wilkesboro</city>
        <state>North Carolina</state>
        <zip>28659</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Wake Forest University Health Sciences</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Ohio State University Comprehensive Cancer Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-293-5066</phone>
      <email>Jamesline@osumc.edu</email>
    </contact>
    <investigator>
      <last_name>Dukagjin M. Blakaj</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Huntsman Cancer Institute/University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>January 14, 2019</study_first_submitted>
  <study_first_submitted_qc>January 14, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 15, 2019</study_first_posted>
  <last_update_submitted>August 17, 2023</last_update_submitted>
  <last_update_submitted_qc>August 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 21, 2023</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>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Squamous Cell</mesh_term>
    <mesh_term>Squamous Cell Carcinoma of Head and Neck</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.</ipd_description>
    <ipd_url>https://grants.nih.gov/policy/sharing.htm</ipd_url>
  </patient_data>
  <!-- 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/NCT03803774
org study id: NCI-2019-00175
secondary id: NCI-2019-00175
secondary id: 19-C-0041
secondary id: 10184
secondary id: 10184
nct id: NCT03803774
nct alias: NCT03809208
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies the side effects and best dose of birinapant when given together
      with intensity modulated re-irradiation therapy (IMRRT) in treating patients with head and
      neck squamous cell carcinoma that has come back at or near the same place as the original
      (primary) tumor (locally recurrent). Birinapant may stop the growth of tumor cells by
      blocking IAP, a protein needed for tumor cell survival. IMRRT uses thin beams of radiation of
      different intensities that are aimed at the tumor from many angles. This type of
      re-irradiation therapy reduces the damage to healthy tissue near the tumor. Giving birinapant
      with IMRRT may lower the chance of head and neck squamous cell carcinoma growing or
      spreading.
PRIMARY OBJECTIVE:

      I. Determine the toxicities and maximum tolerated dose (MTD) of birinapant concurrent with
      intensity modulated re-irradiation therapy (IMRRT).

      SECONDARY OBJECTIVES:

      I. Determine the objective response rate of patients with locoregionally recurrent head and
      neck squamous cell carcinoma (HNSCC) treated with re-irradiation and birinapant.

      II. Determine the local-regional control, progression free survival (PFS), and overall
      survival.

      III. Determine if FADD and/or BIRC2/3 copy gain in tumor tissue or in the blood are
      associated with improved response, locoregional control (LCR), progression-free survival and
      overall survival.

      IV. Determine the feasibility of detecting effects of birinapant and re-irradiation on pilot
      pharmacodynamic markers in tumor tissue, by using microwestern to assess decrease in drug
      targets IAP1/2 and increase in apoptosis/necroptosis markers caspase 3 and mixed lineage
      kinase domain like pseudokinase gene (MLKL).

      EXPLORATORY OBJECTIVES:

      I. Explore if mutational load detected with whole exome sequencing of tumor tissue influences
      objective response rate.

      II. Explore if PD-L1, CD8 T-cell tumor infiltration, TNFalpha, and other immune related
      biomarkers in tumor tissue are associated with objective response rate.

      III. Explore the pharmacokinetics of birinapant in combination with radiotherapy in blood
      samples.

      IV. Explore whether specific germline single-nucleotide polymorphisms (SNPs) are associated
      with response to birinapant and reirradiation.

      OUTLINE: This is a dose-escalation study of birinapant.

      Beginning on day 1, patients undergo IMRRT 5 days a week (Monday-Friday). Patients also
      receive birinapant intravenously (IV) over 30 minutes on days 2 and 9 of each cycle.
      Treatment repeats every 3 weeks for up to 2 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 28 days, and at 3, 6, 9, 12,
      18, and 24 months until confirmation of disease progression.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of dose-limiting toxicities (DLTs) and other toxicities
time frame: Up to 28 days post-treatment
description: Will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Will be evaluated by reporting the DLTs obtained at each dose level, and reporting toxicities noted in tabular form.
measure: Maximum tolerated dose (MTD)
time frame: Up to 42 days
description: Defined as the dose level at which no more than 1 of up to 6 patients experience DLT during 42 days after the start of therapy, and the dose below that at which at least 2 (of =< 6) patients have DLT as a result of the drug. Will be evaluated by reporting the DLTs obtained at each dose level, and reporting toxicities noted in tabular form.
measure: Response rate
time frame: From the start of the treatment until response assessment by positron emission tomography (PET)-computed tomography (CT), assessed at 3 months post-treatment
description: Overall response is the best response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Estimates of response rates will be determined at the MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval.
measure: Local-regional control
time frame: Up to 24 months post-treatment
description: Estimates of local control will be determined at the MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval.
measure: Progression-free survival (PFS)
time frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 24 months post-treatment
description: Estimates of PFS will be determined at the MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval.
measure: Overall survival (OS)
time frame: Up to 24 months post-treatment
description: Estimates of OS will be determined at the MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval.
measure: FADD copy gain in tumor tissue or in blood
time frame: At baseline
description: The association between results according to whether or not they have a copy gain will be presented for OS and PFS, by comparing Kaplan-Meier curves with a two-tailed log-rank test. In addition, as exploratory analyses, the association between FADD copy gain and BIRC2 copy gain will be individually evaluated for any association with response.
measure: BIRC2/3 copy gain in tumor tissue or in blood
time frame: At baseline
description: The association between results according to whether or not they have a copy gain will be presented for OS and PFS, by comparing Kaplan-Meier curves with a two-tailed log-rank test. In addition, as exploratory analyses, the association between FADD copy gain and BIRC2 copy gain will be individually evaluated for any association with response.
measure: Feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic markers in tumor tissue
time frame: Up to cycle 1, day 4
description: Will determine the feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic markers in tumor tissue, including microwestern for decrease in drug targets IAP1/2.
measure: Change in caspase 3 levels
time frame: Baseline up to cycle 1, day 4
description: Increase in apoptosis/necroptosis marker caspase 3 will be evaluated.
measure: Change in MLKL levels
time frame: Baseline up to cycle 1, day 4
description: Increase in apoptosis/necroptosis marker MLKL will be evaluated.
arm group label: Treatment (IMRRT, birinapant)
arm group type: Experimental
description: Beginning on day 1, patients undergo IMRRT 5 days a week (Monday-Friday). Patients also receive birinapant IV over 30 minutes on days 2 and 9 of each cycle. Treatment repeats every 3 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Birinapant
description: Given IV
arm group label: Treatment (IMRRT, birinapant)
other name: TL32711
intervention type: Radiation
intervention name: Intensity-Modulated Radiation Therapy
description: Undergo IMRRT
arm group label: Treatment (IMRRT, birinapant)
other name: IMRT
other name: Intensity modulated radiation therapy (procedure)
other name: Intensity Modulated RT
other name: Intensity-Modulated Radiotherapy
other name: Radiation, Intensity-Modulated Radiotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Vassiliki Saloura
role: Principal Investigator
affiliation: National Cancer Institute LAO
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Suspended
facility: 
status: Suspended
facility: 
status: Suspended
facility: 
status: Suspended
facility: 
status: Suspended
facility: 
status: Suspended
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
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status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Suspended
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Suspended
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Active, not recruiting
country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Squamous Cell
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Recurrence
sharing ipd: Yes
ipd description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
ipd url: https://grants.nih.gov/policy/sharing.htm