<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/NCT01681368</url>
  </required_header>
  <id_info>
    <org_study_id>120191</org_study_id>
    <secondary_id>12-C-0191</secondary_id>
    <nct_id>NCT01681368</nct_id>
  </id_info>
  <brief_title>Birinapant for Advanced Ovarian, Fallopian Tube, and Peritoneal Cancer</brief_title>
  <official_title>Phase II Open Label Non-Randomized Single Agent Study of the SMAC (Second Mitochondrial-Derived Activator of Caspases)-Mimetic Birinapant (TL32711; NSC 756502) in Relapsed Platinum Resistant or Refractory Epithelial Ovarian Cancer, Primary Peritoneal</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</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>
      Background:&#xD;
&#xD;
      - Birinapant is an experimental cancer treatment drug. It removes certain proteins in cells,&#xD;
      which helps to kill the cells. The drug is more likely to cause the death of cancer cells&#xD;
      than normal cells because cancer cells have more of these proteins. Studies suggest that it&#xD;
      can help treat ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.&#xD;
      Researchers want to see how well Birinapant works against the three types of cancer.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To test the effectiveness of Birinapant for ovarian, primary peritoneal, or fallopian tube&#xD;
      cancer.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Women at least 18 years of age who have ovarian, primary peritoneal, or fallopian tube&#xD;
      cancer that has not responded to standard treatment.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened with a physical exam and medical history. Blood and urine&#xD;
           samples will also be collected. Tumor tissue samples may be collected before treatment.&#xD;
           Imaging studies will also be performed.&#xD;
&#xD;
        -  Participants will have an infusion of Birinapant once per week for 3 weeks in a row,&#xD;
           followed by a break for a week on the fourth week. This 4-week schedule is one cycle of&#xD;
           treatment.&#xD;
&#xD;
        -  Treatment will be monitored with frequent blood tests and imaging studies.&#xD;
&#xD;
        -  Another optional tumor biopsy will be collected 6 weeks after the start of treatment.&#xD;
&#xD;
        -  Treatment will continue as long as the cancer does not grow and the side effects are not&#xD;
           severe.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND:&#xD;
&#xD;
        -  Ovarian cancer is the ninth most common cancer in women (excluding skin cancer). It&#xD;
           ranks fifth as the cause of cancer death in women. In the United States, 21,550 new&#xD;
           cases and 14,600 deaths are estimated annually.&#xD;
&#xD;
        -  Approximately 90% of primary malignant ovarian tumors are epithelial (carcinomas).&#xD;
&#xD;
        -  Although over 70% of women with advanced disease respond to optimal debulking surgery&#xD;
           followed by platinum-taxane based chemotherapy, duration of response is short and&#xD;
           relapse is common. Subsequent responses to salvage therapy regimens tend to be brief&#xD;
           (less than six months) due to the tumors progressive resistance to chemotherapy(1).&#xD;
&#xD;
        -  A family of proteins, known as the Inhibitors of Apoptotic Proteins (or IAPs), plays a&#xD;
           critical role in blocking the apoptotic signals at multiple points. IAPs regulate a&#xD;
           number of pathways including classical or alternative nuclear factor-kappa B (NF-(K)B)&#xD;
           function, and activation of apoptosis through either the extrinsic or intrinsic pathway.&#xD;
           Baculoviral IAP repeat-containing protein 1 (cIAP1) acts as a critical switch to promote&#xD;
           the pro-survival nuclear factor kappa-B (NF-B) pathway and prevent caspase activation.&#xD;
&#xD;
        -  In normal cells that are stimulated to undergo apoptosis by either the extrinsic or&#xD;
           intrinsic pathway, second mitochondrial-derived activation of caspares (SMAC) is&#xD;
           released from the mitochondria, which antagonizes IAP, removes blockade to activated&#xD;
           caspase function, and thereby enables apoptotic cell death. In tumor cells, however,&#xD;
           apoptosis is dysregulated due to insufficient amounts of SMAC or upstream blockades to&#xD;
           apoptotic activation.&#xD;
&#xD;
        -  Classical activation of NF-(K)B is dependent on the presence of cIAP1 and cIAP2 proteins&#xD;
           as part of the TNF receptor-associated factor 2 (TRAF2) complex. SMAC inhibits cIAP1 and&#xD;
           cIAP2, leading to inactivation of tumor necrosis factor alpha (TNFalpha) mediated NF- B&#xD;
           activation. SMAC inhibition of cIAP1 and cIAP2 leads to pathway up-regulation.&#xD;
           Birinapant (TL32711) is a synthetic peptidomimetic antagonist of IAPs (a SMAC-mimetic),&#xD;
           which mimics endogenous SMAC resulting in the rapid and irreversible initiation of&#xD;
           apoptotic cell death. SMAC-mimetics represent a novel targeted therapeutic approach for&#xD;
           cancer therapy. The addition of a SMAC mimetic, can inhibit NF- B activity,&#xD;
           down-regulate cell survival pathways, and overcome blockades to the apoptotic pathway&#xD;
           leading to increased tumor cell death.&#xD;
&#xD;
        -  Our laboratory has demonstrated that serous ovarian cancers have cell-autonomous&#xD;
           activation of NF-B signaling which was shown to correlate with poor prognosis.&#xD;
&#xD;
        -  Therefore, we hypothesize that the SMAC-mimetic activity of birinapant may be&#xD;
           selectively toxic to those ovarian cancers that display high canonical NF-(K)B activity.&#xD;
&#xD;
        -  To summarize, relapsed platinum refractory or resistant ovarian cancer is a disease with&#xD;
           limited therapeutic options and poor prognosis. Birinapant offers the opportunity to&#xD;
           develop an effective and well tolerated therapeutic for the significant unmet need.&#xD;
&#xD;
      OBJECTIVES:&#xD;
&#xD;
        -  The primary objective is to determine the efficacy as defined by Gynecologic Oncology&#xD;
           Group (GOG) criteria2 as either objective response or progession-free survival lasting&#xD;
           greater than 6 months, in patients with relapsed platinum refractory or resistant&#xD;
           ovarian cancer, primary peritoneal cancer, fallopian tube cancer treated with&#xD;
           birinapant.&#xD;
&#xD;
        -  The seconday objectives include overall survival, safety and tolerability of single&#xD;
           agent birinapant in this population.&#xD;
&#xD;
      ELIGIBILITY CRITERIA:&#xD;
&#xD;
        -  Females greater than or equal to 18 years of age with histologically proven advanced&#xD;
           metastatic or unresectable epithelial ovarian cancer that is relapsed or refractory to&#xD;
           prior platinum-based standard care systemic regimen.&#xD;
&#xD;
        -  Life expectancy greater than 3 months.&#xD;
&#xD;
        -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.&#xD;
&#xD;
        -  Adequate organ functionas defined by liver, kidney, and hematologic laboratory testing.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  This is an open label, non-randomized phase II trial to determine the efficacy of&#xD;
           administration of the SMAC-mimetic birinapant in patients with relapsed platinum&#xD;
           refractory or resistant ovarian cancer, primary peritoneal cancer, fallopian tube&#xD;
           cancer.&#xD;
&#xD;
        -  Birinapant will be given as a single agent until disease progression once weekly for&#xD;
           three weeks of 4 week intervals.&#xD;
&#xD;
        -  The primary endpoint will be efficacy defined according to the GOG guidelines as overall&#xD;
           response rate or progression-free survival lasting at least 6 months. Overall survival,&#xD;
           toxicity and modulation of signal events in tumor are secondary measures.&#xD;
&#xD;
        -  Patients will be evaluated at baseline and prior to each cycle by history and physical&#xD;
           examination and every two cycles by examination and imaging studies (computed tomography&#xD;
           (CT) scan). Laboratory studies will be performed weekly prior to each dose except on&#xD;
           week 4 (rest week).&#xD;
&#xD;
        -  Tumor biopsy will be performed prior to birinapant initiation and an optional tumor&#xD;
           biopsy will be performed 2 to 48 hours after cycle 2 day 15 infusion.&#xD;
&#xD;
        -  Peripheral blood mononuclear cells will also be harvested at the same time points as the&#xD;
           biopsies.&#xD;
&#xD;
        -  Reassessment imaging (computed tomography (CT) scan) to document response will be&#xD;
           performed at the end of 2 cycles and every 2 cycles thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Accrual was terminated for lack of a clinical benefit.&#xD;
  </why_stopped>
  <start_date type="Actual">August 15, 2012</start_date>
  <completion_date type="Actual">April 30, 2014</completion_date>
  <primary_completion_date type="Actual">December 9, 2013</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>Objective Response (Complete Response (CR) or Partial Response (PR) Defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Criteria) or Disease Stabilization for Greater Than 6 Months</measure>
    <time_frame>6 months</time_frame>
    <description>Per the RECIST criteria, CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adverse Events</measure>
    <time_frame>8 months</time_frame>
    <description>Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Plasma Concentration-Time Curve of Birinapant</measure>
    <time_frame>30, 60, 120, 180 minutes after administration of first dose of Birinapant</time_frame>
    <description>Measurement of the plasma concentration of the Birinapant over time. It is used to characterize drug absorption. The single values were analyzed with liquid chromatography/tandem mass spectrometry via a proprietary methodology (TetraLogic Pharma,Malvern, Pa). The values were grouped and averaged for each of the patients to obtain the mean value for each time point.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Birinapant Concentration in Tumor Tissue</measure>
    <time_frame>Prior to treatment and 12 to 22 hours following Cycle 2 Day 15</time_frame>
    <description>Levels of Birinapant were measured in core needle biopsies of tumor that had been frozen at the time of acquisition.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Calculated Volume of Distribution of Birinapant at Steady State (Vss) in Tumor Tissue</measure>
    <time_frame>0-24hr</time_frame>
    <description>Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Calculated Volume of Distribution of Birinapant at Steady State (Vss) in Plasma</measure>
    <time_frame>0-24hr</time_frame>
    <description>Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ratio of Phosphorylated NF-kappaB-p65 Protein to Total NF-kappaBp65 Protein in Tumor Biopsy Samples</measure>
    <time_frame>0-6 weeks</time_frame>
    <description>Proteins were measured using capillary western blot and ratio was calculated between phosphorylated and total NF-kappaB p65. Core 1 tumor samples and peripheral blood mononuclear cells (PBMCs) from each time point were lysed in T-PER buffer (Thermo Scientific) for protein quantification by an automated capillary electrophoresis immunoassay system (Simple Western). The tumor protein lysate (40-60 ng) or PBMC protein lysate (16-77 ng) was analyzed according to the manufacturer's instructions (ProteinSimple, Santa Clara, Calif).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Coexpression of Cleaved Caspase 3 and Gamma-H2AX in Fixed Specimens</measure>
    <time_frame>Pre treatment and post treatment of Birinapant, approximately 0-6 weeks</time_frame>
    <description>Tumor biopsies were measured for cleaved caspase 3 and gamma-H2A.X by immunofluorescence microscopy. Fold change was calculated by comparing the post-treatment measurements to the pre-treatment levels.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total Clearance of Birinapant After Administration</measure>
    <time_frame>0-24hr</time_frame>
    <description>Clearance is a quantitative measure of the rate at which a drug substance is removed from the body.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">11</enrollment>
  <condition>Epithelial Ovarian Cancer</condition>
  <condition>Peritoneal Neoplasms</condition>
  <condition>Fallopian Tube Neoplasms</condition>
  <arm_group>
    <arm_group_label>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>single arm</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Birinapant (TL32711)</intervention_name>
    <description>47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
    <arm_group_label>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
        Study participants will be eligible for study participation if they are/have:&#xD;
&#xD;
          -  Females greater than or equal to 18 years of age. Because no dosing or adverse event&#xD;
             data are currently available on the use of birinapant in patients &lt; 18 years of age,&#xD;
             children are excluded from this study, but will be eligible for future pediatric&#xD;
             trials.&#xD;
&#xD;
          -  Able to understand and voluntarily sign a written informed consent, and are willing&#xD;
             and able to comply with the protocol requirements including the requirement for&#xD;
             biopsies for research purposes.&#xD;
&#xD;
          -  Advanced metastatic or unresectable epithelial ovarian cancer, primary peritoneal&#xD;
             cancer or fallopian tube cancer that is relapsed and resistant or refractory to prior&#xD;
             platinum-based standard care systemic regimen. Patients who are unable to receive&#xD;
             further platinum, due to either allergic reaction or other medical reason, are&#xD;
             eligible for the protocol. There is no limitation on the amount of prior therapies&#xD;
             allowed.&#xD;
&#xD;
          -  Patients must be at least 4 weeks from previous therapy (chemotherapy, hormonal&#xD;
             therapy, and radiation therapy, immunotherapy and monoclonal antibodies, alternative&#xD;
             therapy or investigational therapeutic agents). Patients who have had cranial&#xD;
             radiation therapy need to have completed it greater than or equal to 8 weeks prior to&#xD;
             commencing on study. Patients are permitted to receive investigational imaging agents&#xD;
             while on study.&#xD;
&#xD;
          -  Patients who have had major surgery must be fully recovered and require a recovery&#xD;
             period of greater than or equal to 4 weeks prior to enrolling on study.&#xD;
&#xD;
          -  Histopathologic diagnosis must be confirmed in the Laboratory of Pathology (LP),&#xD;
             National Cancer Institute (NCI).&#xD;
&#xD;
        A block of the primary tumor, or access to recut slides is preferred. If this is&#xD;
        unavailable, a recent resection specimen of a metastatic site is required for entry. In&#xD;
        addition, access to archival formalin fixed paraffin embedded (FFPE) tumor blocks will be&#xD;
        requested to perform correlative studies. Study participants with the following histologic&#xD;
        epithelial ovarian cancer cell types are eligible: Serous adenocarcinoma, endometrioid&#xD;
        adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell&#xD;
        adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant&#xD;
        Brenner's Tumor, or adenocarcinoma not otherwise specified (N.O.S).&#xD;
&#xD;
          -  Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors&#xD;
             defined as at least one lesion that can be accurately measured in at least one&#xD;
             dimension (longest diameter to be recorded for non-nodal lesions and short axis for&#xD;
             nodal lesions) as greater than or equal to 20 mm with conventional techniques or as&#xD;
             greater than or equal to 10 mm with spiral computed tomography (CT) scan, magnetic&#xD;
             resonance imaging (MRI), or calipers by clinical exam and a sentinel lesion adequate&#xD;
             for core biopsy through percutaneous biopsy. See Section 13 for the evaluation of&#xD;
             measurable disease.&#xD;
&#xD;
          -  Life expectancy greater than 3 months.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to&#xD;
             less than or equal to 2.&#xD;
&#xD;
          -  Adequate renal function, defined as serum creatinine less than or equal to 1.5 X upper&#xD;
             limit of normal (ULN), or measured creatinine clearance greater than or equal to 60&#xD;
             ml/min/1.73m^2.&#xD;
&#xD;
          -  Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine&#xD;
             aminotransferase (ALT) levels less than or equal to 3 X ULN and total bilirubin &lt; 1.5&#xD;
             X ULN, unless known diagnosis of Gilberts syndrome.&#xD;
&#xD;
          -  Adequate bone marrow function, defined as absolute neutrophil (ANC) greater than or&#xD;
             equal to 1,500/mm^3 (greater than or equal to1.5 X10^6/L), platelet count greater than&#xD;
             or equal to 75,000/mm^3 (greater than or equal to 75 X10^6/L), and hemoglobin greater&#xD;
             than or equal to 10 mg/dL (transfusion to obtain hemoglobin greater than or equal to&#xD;
             10 mg/dL within 24 hours prior to dosing is allowed).&#xD;
&#xD;
          -  Contraception is not a consideration as these patients have all had surgical removal&#xD;
             of their reproductive organs. Pregnant women are excluded from this study because&#xD;
             birinapant may have potential for teratogenic or abortifacient effects. Because there&#xD;
             is an unknown but potential risk for adverse events in nursing infants secondary to&#xD;
             treatment of the mother with birinapant, breastfeeding should be discontinued prior to&#xD;
             enrollment.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          1. Known or suspected diagnosis of human immunodeficiency virus or chronic active&#xD;
             hepatitis B or C. Viral testing is not required. The reason for exclusion is&#xD;
             insufficient evidence demonstrating safety of administration of birinapant in patients&#xD;
             with human immunodeficiency virus (HIV), hepatitis B or C due to theoretical risk of&#xD;
             unmasking or exacerbating these serious viral illnesses since birinapant may impair&#xD;
             immunological function. Data are not currently available on risk of interaction with&#xD;
             antiretroviral drugs. HIV-positive patients on combination antiretroviral therapy are&#xD;
             ineligible because of the potential for pharmacokinetic interactions with birinapant.&#xD;
             The potential immune suppressive effects and T-cell depletion associated with&#xD;
             birinapant pose an additional increased risk to these patients. Appropriate studies&#xD;
             will be undertaken in patients receiving combination antiretroviral therapy when&#xD;
             indicated.&#xD;
&#xD;
          2. Symptomatic or uncontrolled brain metastases requiring current treatment (&lt; 8 weeks&#xD;
             from last cranial radiation or &lt; 4 weeks from last steroids). (Patients with abnormal&#xD;
             clinical exam or history will require a head CT or MRI to rule out or confirm brain&#xD;
             metastases).&#xD;
&#xD;
          3. Impaired cardiac function or clinically significant cardiac disease including the&#xD;
             following:&#xD;
&#xD;
               1. New York Heart Association grade III or IV congestive heart failure.&#xD;
&#xD;
               2. Myocardial infarction within the last 12 months prior to dosing with birinapant.&#xD;
&#xD;
               3. Subjects known to have impaired left ventricular ejection fraction (LVEF)&#xD;
                  according to institutional standards must be excluded.&#xD;
&#xD;
          4. Lack of recovery of prior adverse events to Grade less than or equal to1 severity&#xD;
             (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]&#xD;
             v 4.03) (except alopecia) due to therapy administered prior to the initiation of study&#xD;
             drug dosing. Stable persistent grade 2 peripheral neuropathy may be allowed as&#xD;
             determined on a case-by-case basis at the discretion of the Investigator as birinapant&#xD;
             has not been shown to cause or exacerbate peripheral neuropathy.&#xD;
&#xD;
          5. Known allergy to any of the formulation components of birinapant including citric acid&#xD;
             monohydrate, sodium citrate dehydrate, and sodium chloride.&#xD;
&#xD;
          6. Any concurrent disease and/or medical condition that in the opinion of the&#xD;
             Investigator would prevent the subjects participation, render the subject at excessive&#xD;
             risk or limit the subjects compliance with the protocols required evaluations.&#xD;
&#xD;
          7. Patients with active infection will not be eligible, but may become eligible once&#xD;
             infection has resolved and they are at least 7 days from completion of antibiotics.&#xD;
&#xD;
          8. Another previous or current malignancy within the last 5 years, with the exception of&#xD;
             non-melanoma skin cancer, cervical carcinoma in situ curatively treated, ductal or&#xD;
             lobular carcinoma in situ curatively treated and without ongoing therapeutic&#xD;
             intervention. Patients with breast cancer (BRCA) 1 or 2 mutation, who have had a&#xD;
             previous diagnosis of breast cancer are eligible if the breast cancer was diagnosed 5&#xD;
             years previously and distant or local recurrence of breast cancer has been outruled.&#xD;
&#xD;
          9. Concomitant chronic (daily or almost daily for greater than or equal to1 month prior)&#xD;
             use of steroids or non-steroidal anti-inflammatory drugs (NSAIDS). Intermittent use of&#xD;
             steroids as pre-medications is allowed. Based on research to date the tumor and tumor&#xD;
             microenvironment production of tumor necrosis factor (TNF) alpha could promote&#xD;
             anti-tumor activity. Theoretically, anti-inflammatories could blunt local production,&#xD;
             limiting this possibly positive cofactor.&#xD;
&#xD;
         10. No concomitant use of complementary or alternative medication or other agents&#xD;
             (investigational therapeutic agents) will be allowed without approval of a principal&#xD;
             investigator (PI) or associate investigator (AI). Every effort will be made to&#xD;
             maximize patient safety and minimize changes in chronic medications.&#xD;
&#xD;
         11. Patients with a recent history (within last 5 years) of autoimmune disease or&#xD;
             inflammatory diseases will be excluded, for example, active rheumatoid&#xD;
             arthritis,active inflammatory bowel disease or any chronic inflammatory conditions&#xD;
             because birinapant synergizes with TNF in vitro.&#xD;
&#xD;
        INCLUSION OF MINORITIES:&#xD;
&#xD;
        Women from all racial/ethnic groups are eligible for this study if they meet the&#xD;
        eligibility criteria.&#xD;
&#xD;
        To date, there is no information that suggests that differences in drug metabolism or&#xD;
        disease response would be expected in one group compared to another. Efforts will be made&#xD;
        to extend accrual to a representative population, but in this preliminary study, a balance&#xD;
        must be struck between patient safety considerations and limitations on the number of&#xD;
        individuals exposed to potentially toxic and/or ineffective treatments on the one hand and&#xD;
        the need to explore ethnic aspects of clinical research on the other hand. If differences&#xD;
        in outcome that correlate to ethnic identity are noted, accrual may be expanded or a&#xD;
        follow-up study may be written to investigate those differences more fully. This study will&#xD;
        be recruited through internal referral, our local physician referral base, and through&#xD;
        Cancer Hotline information.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Christina M Annunziata, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center, 9000 Rockville Pike</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2012-C-0191.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <reference>
    <citation>Kaye SB. Management of platinum-sensitive relapsed ovarian cancer, with particular reference to the International Collaboration in Ovarian Neoplasm-4/Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer-2.2 trial. Int J Gynecol Cancer. 2005 May-Jun;15 Suppl 1:31-5. doi: 10.1111/j.1525-1438.2005.15354.x.</citation>
    <PMID>15839956</PMID>
  </reference>
  <reference>
    <citation>Rose PG, Tian C, Bookman MA. Assessment of tumor response as a surrogate endpoint of survival in recurrent/platinum-resistant ovarian carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2010 May;117(2):324-9. doi: 10.1016/j.ygyno.2010.01.040. Epub 2010 Feb 24.</citation>
    <PMID>20185168</PMID>
  </reference>
  <reference>
    <citation>Gordon AN, Granai CO, Rose PG, Hainsworth J, Lopez A, Weissman C, Rosales R, Sharpington T. Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol. 2000 Sep;18(17):3093-100. doi: 10.1200/JCO.2000.18.17.3093.</citation>
    <PMID>10963637</PMID>
  </reference>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>September 5, 2012</study_first_submitted>
  <study_first_submitted_qc>September 5, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 7, 2012</study_first_posted>
  <results_first_submitted>January 21, 2015</results_first_submitted>
  <results_first_submitted_qc>January 21, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">February 3, 2015</results_first_posted>
  <last_update_submitted>April 24, 2017</last_update_submitted>
  <last_update_submitted_qc>April 24, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">May 30, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>National Institutes of Health Clinical Center (CC)</investigator_affiliation>
    <investigator_full_name>Christina Annunziata, M.D.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>NF-Kappa B Pathway</keyword>
  <keyword>Response Biomarkers</keyword>
  <keyword>Progression-Free Survival</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Pharmacodynamics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Ovarian Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Ovarian Epithelial</mesh_term>
    <mesh_term>Peritoneal Neoplasms</mesh_term>
    <mesh_term>Fallopian Tube Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</title>
          <description>single arm&#xD;
Birinapant (TL32711): 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Refused further treatment</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Refused further follow up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</title>
          <description>single arm&#xD;
Birinapant (TL32711): 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="11"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="58.87" spread="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Eastern Cooperative Oncology Group (ECOG)</title>
          <description>ECOG: 0 (Normal activity. Fully active, able to carry on all pre-disease performance without restriction.), 1 (Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work), and 2 (In bed &lt;50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hour.).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>0</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Histologic subtype, No.</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Serous</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Endometrioid</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Clear cell</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Classified</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>No. of Prior Therapies</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>≤3</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>4-6</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>≥7</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Type of Prior Therapy, No.</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Chemotherapy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Biologic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hormonal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Vaccine</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Objective Response (Complete Response (CR) or Partial Response (PR) Defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Criteria) or Disease Stabilization for Greater Than 6 Months</title>
        <description>Per the RECIST criteria, CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</title>
            <description>single arm&#xD;
Birinapant (TL32711): 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response (Complete Response (CR) or Partial Response (PR) Defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Criteria) or Disease Stabilization for Greater Than 6 Months</title>
          <description>Per the RECIST criteria, CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Complete Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Partial Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Adverse Events</title>
        <description>Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.</description>
        <time_frame>8 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</title>
            <description>single arm&#xD;
Birinapant (TL32711): 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events</title>
          <description>Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Plasma Concentration-Time Curve of Birinapant</title>
        <description>Measurement of the plasma concentration of the Birinapant over time. It is used to characterize drug absorption. The single values were analyzed with liquid chromatography/tandem mass spectrometry via a proprietary methodology (TetraLogic Pharma,Malvern, Pa). The values were grouped and averaged for each of the patients to obtain the mean value for each time point.</description>
        <time_frame>30, 60, 120, 180 minutes after administration of first dose of Birinapant</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</title>
            <description>single arm&#xD;
Birinapant (TL32711): 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Plasma Concentration-Time Curve of Birinapant</title>
          <description>Measurement of the plasma concentration of the Birinapant over time. It is used to characterize drug absorption. The single values were analyzed with liquid chromatography/tandem mass spectrometry via a proprietary methodology (TetraLogic Pharma,Malvern, Pa). The values were grouped and averaged for each of the patients to obtain the mean value for each time point.</description>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Predose</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>30 minutes post end of infusion (EOI)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="699" spread="157"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>60 minutes post end of infusion (EOI)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="415" spread="84"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>120 minutes post end of infusion (EOI)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="202" spread="43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>240 minutes post end of infusion (EOI)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="85" spread="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Birinapant Concentration in Tumor Tissue</title>
        <description>Levels of Birinapant were measured in core needle biopsies of tumor that had been frozen at the time of acquisition.</description>
        <time_frame>Prior to treatment and 12 to 22 hours following Cycle 2 Day 15</time_frame>
        <population>4 patients did not have the second paired biopsy due to patient refusal.</population>
        <group_list>
          <group group_id="O1">
            <title>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</title>
            <description>single arm&#xD;
Birinapant (TL32711): 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Birinapant Concentration in Tumor Tissue</title>
          <description>Levels of Birinapant were measured in core needle biopsies of tumor that had been frozen at the time of acquisition.</description>
          <population>4 patients did not have the second paired biopsy due to patient refusal.</population>
          <units>ng/g</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="952" lower_limit="185" upper_limit="1830"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Calculated Volume of Distribution of Birinapant at Steady State (Vss) in Tumor Tissue</title>
        <description>Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.</description>
        <time_frame>0-24hr</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</title>
            <description>single arm&#xD;
Birinapant (TL32711): 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Calculated Volume of Distribution of Birinapant at Steady State (Vss) in Tumor Tissue</title>
          <description>Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.</description>
          <units>L</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="119" lower_limit="80" upper_limit="183"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Calculated Volume of Distribution of Birinapant at Steady State (Vss) in Plasma</title>
        <description>Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.</description>
        <time_frame>0-24hr</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</title>
            <description>single arm&#xD;
Birinapant (TL32711): 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Calculated Volume of Distribution of Birinapant at Steady State (Vss) in Plasma</title>
          <description>Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.</description>
          <units>L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="132" spread="33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Ratio of Phosphorylated NF-kappaB-p65 Protein to Total NF-kappaBp65 Protein in Tumor Biopsy Samples</title>
        <description>Proteins were measured using capillary western blot and ratio was calculated between phosphorylated and total NF-kappaB p65. Core 1 tumor samples and peripheral blood mononuclear cells (PBMCs) from each time point were lysed in T-PER buffer (Thermo Scientific) for protein quantification by an automated capillary electrophoresis immunoassay system (Simple Western). The tumor protein lysate (40-60 ng) or PBMC protein lysate (16-77 ng) was analyzed according to the manufacturer's instructions (ProteinSimple, Santa Clara, Calif).</description>
        <time_frame>0-6 weeks</time_frame>
        <population>4 patients refused second biopsy.</population>
        <group_list>
          <group group_id="O1">
            <title>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</title>
            <description>single arm&#xD;
Birinapant (TL32711): 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Ratio of Phosphorylated NF-kappaB-p65 Protein to Total NF-kappaBp65 Protein in Tumor Biopsy Samples</title>
          <description>Proteins were measured using capillary western blot and ratio was calculated between phosphorylated and total NF-kappaB p65. Core 1 tumor samples and peripheral blood mononuclear cells (PBMCs) from each time point were lysed in T-PER buffer (Thermo Scientific) for protein quantification by an automated capillary electrophoresis immunoassay system (Simple Western). The tumor protein lysate (40-60 ng) or PBMC protein lysate (16-77 ng) was analyzed according to the manufacturer's instructions (ProteinSimple, Santa Clara, Calif).</description>
          <population>4 patients refused second biopsy.</population>
          <units>pixel intensity per ng protein</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.2" lower_limit="0" upper_limit="0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Coexpression of Cleaved Caspase 3 and Gamma-H2AX in Fixed Specimens</title>
        <description>Tumor biopsies were measured for cleaved caspase 3 and gamma-H2A.X by immunofluorescence microscopy. Fold change was calculated by comparing the post-treatment measurements to the pre-treatment levels.</description>
        <time_frame>Pre treatment and post treatment of Birinapant, approximately 0-6 weeks</time_frame>
        <population>Only 2 pairs of adequate pre- and post-treatment biopsy samples were available for analysis. The remaining paired samples were inadequate for immunohistochemistry because of necrotic debris in the post-treatment biopsy sample (1 specimen) or contamination with blood (4 specimens).</population>
        <group_list>
          <group group_id="O1">
            <title>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</title>
            <description>single arm&#xD;
Birinapant (TL32711): 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Coexpression of Cleaved Caspase 3 and Gamma-H2AX in Fixed Specimens</title>
          <description>Tumor biopsies were measured for cleaved caspase 3 and gamma-H2A.X by immunofluorescence microscopy. Fold change was calculated by comparing the post-treatment measurements to the pre-treatment levels.</description>
          <population>Only 2 pairs of adequate pre- and post-treatment biopsy samples were available for analysis. The remaining paired samples were inadequate for immunohistochemistry because of necrotic debris in the post-treatment biopsy sample (1 specimen) or contamination with blood (4 specimens).</population>
          <units>Fold over baseline</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3" lower_limit="2" upper_limit="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Total Clearance of Birinapant After Administration</title>
        <description>Clearance is a quantitative measure of the rate at which a drug substance is removed from the body.</description>
        <time_frame>0-24hr</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</title>
            <description>single arm&#xD;
Birinapant (TL32711): 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Total Clearance of Birinapant After Administration</title>
          <description>Clearance is a quantitative measure of the rate at which a drug substance is removed from the body.</description>
          <units>L/hr</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="67.93091577" lower_limit="45.1843727" upper_limit="105.7101965"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>8 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Birinapant for Advanced Ovarian,Fallopian Tube &amp; Peritoneal Ca</title>
          <description>single arm&#xD;
Birinapant (TL32711): 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="5" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye disorders - Other, specify (diplopia)</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Colonic obstruction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Small intestinal obstruction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="10" subjects_affected="6" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Facial nerve disorder</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pain of skin</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Edema trunk</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic reaction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="7" subjects_affected="4" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Metabolism and nutrition disorders - Other, specify (low protein)</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Vaginal hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Christina Annunziata</name_or_title>
      <organization>National Cancer Institute</organization>
      <phone>301-402-7189</phone>
      <email>annunzic@mail.nih.gov</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01681368
org study id: 120191
secondary id: 12-C-0191
nct id: NCT01681368
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Background:

      - Birinapant is an experimental cancer treatment drug. It removes certain proteins in cells,
      which helps to kill the cells. The drug is more likely to cause the death of cancer cells
      than normal cells because cancer cells have more of these proteins. Studies suggest that it
      can help treat ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.
      Researchers want to see how well Birinapant works against the three types of cancer.

      Objectives:

      - To test the effectiveness of Birinapant for ovarian, primary peritoneal, or fallopian tube
      cancer.

      Eligibility:

      - Women at least 18 years of age who have ovarian, primary peritoneal, or fallopian tube
      cancer that has not responded to standard treatment.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will also be collected. Tumor tissue samples may be collected before treatment.
           Imaging studies will also be performed.

        -  Participants will have an infusion of Birinapant once per week for 3 weeks in a row,
           followed by a break for a week on the fourth week. This 4-week schedule is one cycle of
           treatment.

        -  Treatment will be monitored with frequent blood tests and imaging studies.

        -  Another optional tumor biopsy will be collected 6 weeks after the start of treatment.

        -  Treatment will continue as long as the cancer does not grow and the side effects are not
           severe.
BACKGROUND:

        -  Ovarian cancer is the ninth most common cancer in women (excluding skin cancer). It
           ranks fifth as the cause of cancer death in women. In the United States, 21,550 new
           cases and 14,600 deaths are estimated annually.

        -  Approximately 90% of primary malignant ovarian tumors are epithelial (carcinomas).

        -  Although over 70% of women with advanced disease respond to optimal debulking surgery
           followed by platinum-taxane based chemotherapy, duration of response is short and
           relapse is common. Subsequent responses to salvage therapy regimens tend to be brief
           (less than six months) due to the tumors progressive resistance to chemotherapy(1).

        -  A family of proteins, known as the Inhibitors of Apoptotic Proteins (or IAPs), plays a
           critical role in blocking the apoptotic signals at multiple points. IAPs regulate a
           number of pathways including classical or alternative nuclear factor-kappa B (NF-(K)B)
           function, and activation of apoptosis through either the extrinsic or intrinsic pathway.
           Baculoviral IAP repeat-containing protein 1 (cIAP1) acts as a critical switch to promote
           the pro-survival nuclear factor kappa-B (NF-B) pathway and prevent caspase activation.

        -  In normal cells that are stimulated to undergo apoptosis by either the extrinsic or
           intrinsic pathway, second mitochondrial-derived activation of caspares (SMAC) is
           released from the mitochondria, which antagonizes IAP, removes blockade to activated
           caspase function, and thereby enables apoptotic cell death. In tumor cells, however,
           apoptosis is dysregulated due to insufficient amounts of SMAC or upstream blockades to
           apoptotic activation.

        -  Classical activation of NF-(K)B is dependent on the presence of cIAP1 and cIAP2 proteins
           as part of the TNF receptor-associated factor 2 (TRAF2) complex. SMAC inhibits cIAP1 and
           cIAP2, leading to inactivation of tumor necrosis factor alpha (TNFalpha) mediated NF- B
           activation. SMAC inhibition of cIAP1 and cIAP2 leads to pathway up-regulation.
           Birinapant (TL32711) is a synthetic peptidomimetic antagonist of IAPs (a SMAC-mimetic),
           which mimics endogenous SMAC resulting in the rapid and irreversible initiation of
           apoptotic cell death. SMAC-mimetics represent a novel targeted therapeutic approach for
           cancer therapy. The addition of a SMAC mimetic, can inhibit NF- B activity,
           down-regulate cell survival pathways, and overcome blockades to the apoptotic pathway
           leading to increased tumor cell death.

        -  Our laboratory has demonstrated that serous ovarian cancers have cell-autonomous
           activation of NF-B signaling which was shown to correlate with poor prognosis.

        -  Therefore, we hypothesize that the SMAC-mimetic activity of birinapant may be
           selectively toxic to those ovarian cancers that display high canonical NF-(K)B activity.

        -  To summarize, relapsed platinum refractory or resistant ovarian cancer is a disease with
           limited therapeutic options and poor prognosis. Birinapant offers the opportunity to
           develop an effective and well tolerated therapeutic for the significant unmet need.

      OBJECTIVES:

        -  The primary objective is to determine the efficacy as defined by Gynecologic Oncology
           Group (GOG) criteria2 as either objective response or progession-free survival lasting
           greater than 6 months, in patients with relapsed platinum refractory or resistant
           ovarian cancer, primary peritoneal cancer, fallopian tube cancer treated with
           birinapant.

        -  The seconday objectives include overall survival, safety and tolerability of single
           agent birinapant in this population.

      ELIGIBILITY CRITERIA:

        -  Females greater than or equal to 18 years of age with histologically proven advanced
           metastatic or unresectable epithelial ovarian cancer that is relapsed or refractory to
           prior platinum-based standard care systemic regimen.

        -  Life expectancy greater than 3 months.

        -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.

        -  Adequate organ functionas defined by liver, kidney, and hematologic laboratory testing.

      Design:

        -  This is an open label, non-randomized phase II trial to determine the efficacy of
           administration of the SMAC-mimetic birinapant in patients with relapsed platinum
           refractory or resistant ovarian cancer, primary peritoneal cancer, fallopian tube
           cancer.

        -  Birinapant will be given as a single agent until disease progression once weekly for
           three weeks of 4 week intervals.

        -  The primary endpoint will be efficacy defined according to the GOG guidelines as overall
           response rate or progression-free survival lasting at least 6 months. Overall survival,
           toxicity and modulation of signal events in tumor are secondary measures.

        -  Patients will be evaluated at baseline and prior to each cycle by history and physical
           examination and every two cycles by examination and imaging studies (computed tomography
           (CT) scan). Laboratory studies will be performed weekly prior to each dose except on
           week 4 (rest week).

        -  Tumor biopsy will be performed prior to birinapant initiation and an optional tumor
           biopsy will be performed 2 to 48 hours after cycle 2 day 15 infusion.

        -  Peripheral blood mononuclear cells will also be harvested at the same time points as the
           biopsies.

        -  Reassessment imaging (computed tomography (CT) scan) to document response will be
           performed at the end of 2 cycles and every 2 cycles thereafter.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective Response (Complete Response (CR) or Partial Response (PR) Defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Criteria) or Disease Stabilization for Greater Than 6 Months
time frame: 6 months
description: Per the RECIST criteria, CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
measure: Number of Participants With Adverse Events
time frame: 8 months
description: Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
measure: Mean Plasma Concentration-Time Curve of Birinapant
time frame: 30, 60, 120, 180 minutes after administration of first dose of Birinapant
description: Measurement of the plasma concentration of the Birinapant over time. It is used to characterize drug absorption. The single values were analyzed with liquid chromatography/tandem mass spectrometry via a proprietary methodology (TetraLogic Pharma,Malvern, Pa). The values were grouped and averaged for each of the patients to obtain the mean value for each time point.
measure: Birinapant Concentration in Tumor Tissue
time frame: Prior to treatment and 12 to 22 hours following Cycle 2 Day 15
description: Levels of Birinapant were measured in core needle biopsies of tumor that had been frozen at the time of acquisition.
measure: Calculated Volume of Distribution of Birinapant at Steady State (Vss) in Tumor Tissue
time frame: 0-24hr
description: Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
measure: Calculated Volume of Distribution of Birinapant at Steady State (Vss) in Plasma
time frame: 0-24hr
description: Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
measure: Ratio of Phosphorylated NF-kappaB-p65 Protein to Total NF-kappaBp65 Protein in Tumor Biopsy Samples
time frame: 0-6 weeks
description: Proteins were measured using capillary western blot and ratio was calculated between phosphorylated and total NF-kappaB p65. Core 1 tumor samples and peripheral blood mononuclear cells (PBMCs) from each time point were lysed in T-PER buffer (Thermo Scientific) for protein quantification by an automated capillary electrophoresis immunoassay system (Simple Western). The tumor protein lysate (40-60 ng) or PBMC protein lysate (16-77 ng) was analyzed according to the manufacturer's instructions (ProteinSimple, Santa Clara, Calif).
measure: Coexpression of Cleaved Caspase 3 and Gamma-H2AX in Fixed Specimens
time frame: Pre treatment and post treatment of Birinapant, approximately 0-6 weeks
description: Tumor biopsies were measured for cleaved caspase 3 and gamma-H2A.X by immunofluorescence microscopy. Fold change was calculated by comparing the post-treatment measurements to the pre-treatment levels.
measure: Total Clearance of Birinapant After Administration
time frame: 0-24hr
description: Clearance is a quantitative measure of the rate at which a drug substance is removed from the body.
arm group label: Birinapant for Advanced Ovarian,Fallopian Tube & Peritoneal Ca
arm group type: Experimental
description: single arm
intervention type: Drug
intervention name: Birinapant (TL32711)
description: 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle
arm group label: Birinapant for Advanced Ovarian,Fallopian Tube & Peritoneal Ca
criteria: 
gender: All
gender based: Yes
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Christina M Annunziata, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
url: http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2012-C-0191.html
description: NIH Clinical Center Detailed Web Page
citation: Kaye SB. Management of platinum-sensitive relapsed ovarian cancer, with particular reference to the International Collaboration in Ovarian Neoplasm-4/Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer-2.2 trial. Int J Gynecol Cancer. 2005 May-Jun;15 Suppl 1:31-5. doi: 10.1111/j.1525-1438.2005.15354.x.
PMID: 15839956
citation: Rose PG, Tian C, Bookman MA. Assessment of tumor response as a surrogate endpoint of survival in recurrent/platinum-resistant ovarian carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2010 May;117(2):324-9. doi: 10.1016/j.ygyno.2010.01.040. Epub 2010 Feb 24.
PMID: 20185168
citation: Gordon AN, Granai CO, Rose PG, Hainsworth J, Lopez A, Weissman C, Rosales R, Sharpington T. Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol. 2000 Sep;18(17):3093-100. doi: 10.1200/JCO.2000.18.17.3093.
PMID: 10963637
responsible party type: Principal Investigator
investigator affiliation: National Institutes of Health Clinical Center (CC)
investigator full name: Christina Annunziata, M.D.
investigator title: Principal Investigator
mesh term: Neoplasms
mesh term: Ovarian Neoplasms
mesh term: Carcinoma, Ovarian Epithelial
mesh term: Peritoneal Neoplasms
mesh term: Fallopian Tube Neoplasms
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 