<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/NCT03016871</url>
  </required_header>
  <id_info>
    <org_study_id>16403</org_study_id>
    <secondary_id>NCI-2016-02038</secondary_id>
    <secondary_id>16403</secondary_id>
    <nct_id>NCT03016871</nct_id>
  </id_info>
  <brief_title>Nivolumab, Ifosfamide, Carboplatin, and Etoposide as Second-Line Therapy in Treating Patients With Refractory or Relapsed HL</brief_title>
  <official_title>A Phase II Trial of Response-Adapted Second-Line Therapy for Hodgkin Lymphoma Using Anti-PD-1 Antibody Nivolumab ? ICE Chemotherapy as a Bridge to Autologous Hematopoietic Cell Transplant (NICE Trial)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>City of Hope Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>City of Hope Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies the side effects of nivolumab and to see how well it works when&#xD;
      given together with ifosfamide, carboplatin, and etoposide in treating patients with Hodgkin&#xD;
      lymphoma that has come back (relapsed) and does not respond to treatment (refractory).&#xD;
      Immunotherapy with monoclonal antibodies such as nivolumab, may help the body?s immune system&#xD;
      attack the cancer, and may interfere with the ability of tumor cells to grow and spread.&#xD;
      Drugs used in chemotherapy, such as ifosfamide, carboplatin and etoposide, work in different&#xD;
      ways to stop the growth of cancer cells, either by killing the cells, by stopping them from&#xD;
      dividing, or by stopping them from spreading. Giving nivolumab, ifosfamide, carboplatin and&#xD;
      etoposide may work better in treating patients with Hodgkin lymphoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. Evaluate the anti-tumor activity of nivolumab as single agent and in combination with&#xD;
      ifosfamide, carboplatin, etoposide (ICE) chemotherapy (nivolumab [N]ICE) as assessed by&#xD;
      complete response (CR) rate prior to autologous hematopoietic cell transplantation.&#xD;
&#xD;
      II. To estimate the proportion of patients experiencing unacceptable adverse events. (Cohort&#xD;
      B) III. To assess the safety and tolerability of nivolumab + ICE chemotherapy through&#xD;
      evaluation of toxicities, including type, frequency, severity, attribution, time course, and&#xD;
      duration. (Cohort B) IV. To obtain estimate of overall response rate (ORR), complete response&#xD;
      rate, response duration and survival (overall and event-free). (Cohort B) V. Summarize stem&#xD;
      cell mobilization outcomes (e.g., total CD34+ cell yield, number of apheresis days,&#xD;
      proportion of patients who achieve &gt;= 2 x 10^6 CD34+ cells/kg). (Cohort B) VI. Evaluate&#xD;
      Hodgkin lymphoma biological markers in subjects treated with nivolumab. (Cohort B)&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Assess the safety and tolerability of nivolumab +/- ICE chemotherapy through evaluation of&#xD;
      toxicities, including type, frequency, severity, attribution, time course and duration.&#xD;
&#xD;
      II. Obtain estimates of overall response rate (ORR), response duration and survival (overall&#xD;
      and event-free).&#xD;
&#xD;
      III. Summarize stem cell mobilization outcomes (e.g., total CD34+ cell yield, number of&#xD;
      apheresis days, proportion of patients who achieve &gt;= 2 x 10^6 CD34+ cells/kg).&#xD;
&#xD;
      IV. Evaluate Hodgkin lymphoma biological markers in subjects treated with nivolumab.&#xD;
&#xD;
      V. Among subjects who undergo autologous hematopoietic cell transplantation (AHCT), estimate&#xD;
      the post-AHCT overall/progression free survival (PFS) probability and cumulative incidence of&#xD;
      relapse/progression, non-relapse mortality (NRM) at 100-days, 1-year and 2-years.&#xD;
&#xD;
      VI. Among subjects who undergo autologous hematopoietic cell transplantation (AHCT),&#xD;
      characterize post-AHCT toxicities during the first 30- and 100- days post stem cell infusion&#xD;
      by type, frequency, severity, attribution, time course and duration.&#xD;
&#xD;
      VII. Among subjects who undergo autologous hematopoietic cell transplantation (AHCT),&#xD;
      evaluate short and long-term post-AHCT complications, including: delayed engraftment&#xD;
      (neutrophil and platelet) and infection, graft versus host disease and sinusoidal obstruction&#xD;
      syndrome.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. Collect deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) from lymphoma specimens and&#xD;
      serial plasma samples for future biomarker evaluation.&#xD;
&#xD;
      II. Evaluate potential changes in Hodgkin lymphoma biological markers of patients treated&#xD;
      with nivolumab.&#xD;
&#xD;
      OUTLINE: Patients are sequentially assigned to 1 of 2 cohorts.&#xD;
&#xD;
      COHORT A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles&#xD;
      repeat every 14 days for 6 weeks in the absence of disease progression or unacceptable&#xD;
      toxicity. Patients with CR or partial response (PR) receive nivolumab for an additional 6&#xD;
      weeks. Patients with only stable disease (SD) after 6-week nivolumab treatment receive&#xD;
      nivolumab for an additional 6 weeks or receive nivolumab IV over 30 minutes on day 1,&#xD;
      etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin&#xD;
      IV on day 2 every 21 days for 6 weeks per physician/investigator's discretion. Patients with&#xD;
      progressive disease (PD) after 6-week nivolumab treatment or patients with PR, SD, or PD&#xD;
      after 12-week nivolumab treatment receive nivolumab IV over 30 minutes on day 1, etoposide IV&#xD;
      on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2.&#xD;
      Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
&#xD;
      COHORT B: Patients receive nivolumab IV over 30 minutes on cycle 1 (cycle 1 is 14 days), day&#xD;
      1 in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2,&#xD;
      patients receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide&#xD;
      IV continuously over 24 hours on day 2, and carboplatin IV on day 2. Treatment repeats every&#xD;
      21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3 months for up to 2&#xD;
      years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 24, 2017</start_date>
  <completion_date type="Anticipated">January 30, 2026</completion_date>
  <primary_completion_date type="Anticipated">January 30, 2025</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Complete response rate autologous stem cell transplantation assessed by Lugano criteria</measure>
    <time_frame>1 year after primary outcome is met</time_frame>
    <description>Response rates will be calculated as the percent of evaluable patients that have confirmed complete response by radiographic response including computed tomography and/or positron emission tomography scans; 95% Clopper Pearson confidence limits will be calculated for this estimate.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Toxicity will be assessed and reported using the Bearman (non-hematologic) and Common Terminology Criteria for Adverse Events version 4.03 scales. Toxicity information recorded will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall response rate</measure>
    <time_frame>From the time measurement criteria are for complete response or partial response (whichever is first recorded) until the first date that relapsed or progressive disease is objectively documented, assessed up to 2 years</time_frame>
    <description>Will be estimated using the product-limit method of Kaplan and Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>From start of treatment to time of death (due to any cause), assessed up to 2 years</time_frame>
    <description>Will be estimated using the product-limit method of Kaplan and Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years</time_frame>
    <description>Will be estimated using the product-limit method of Kaplan and Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival of hematopoietic cell transplantation</measure>
    <time_frame>From start of hematopoietic cell transplantation treatment to time of death (due to any cause), assessed up to 2 years post hematopoietic cell transplantation</time_frame>
    <description>Will be estimated using the product-limit method of Kaplan and Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival of hematopoietic cell transplantation</measure>
    <time_frame>From start of hematopoietic cell transplantation treatment to time of progression or death, whichever occurs first, assessed up to 2 years post hematopoietic cell transplantation</time_frame>
    <description>Will be estimated using the product-limit method of Kaplan and Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse/progression event</measure>
    <time_frame>From start of hematopoietic cell transplantation treatment, assessed up to 2 years post hematopoietic cell transplantation</time_frame>
    <description>The cumulative incidence of relapse/progression will be calculated as competing risks using the method of Gooley et al.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Non-relapse mortality</measure>
    <time_frame>From start of treatment until non-disease related death, or last follow-up, whichever comes first, assessed up to 2 years post hematopoietic cell transplantation</time_frame>
    <description>The cumulative incidence of non-relapse mortality will be calculated as competing risks using the method of Gooley et al.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Role of PDL1/L2, CD68 on lymphoma specimens</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Summarized using standard descriptive methods.</description>
  </other_outcome>
  <other_outcome>
    <measure>Role of T/B/natural killer cell subsets in the peripheral blood</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Summarized using standard descriptive methods.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">78</enrollment>
  <condition>Recurrent Hodgkin Lymphoma</condition>
  <condition>Refractory Hodgkin Lymphoma</condition>
  <arm_group>
    <arm_group_label>Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 14 days for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients with CR or PR receive nivolumab for an additional 6 weeks. Patients with only SD after 6-week nivolumab treatment receive nivolumab for an additional 6 weeks or receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2 every 21 days for 6 weeks per physician/investigator's discretion. Patients with PD after 6-week nivolumab treatment or patients with PR, SD, or PD after 12-week nivolumab treatment receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive nivolumab IV over 30 minutes on cycle 1 (cycle 1 is 14 days), day 1 in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2, patients receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)</arm_group_label>
    <arm_group_label>Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)</arm_group_label>
    <other_name>Blastocarb</other_name>
    <other_name>Carboplat</other_name>
    <other_name>Carboplatin Hexal</other_name>
    <other_name>Carboplatino</other_name>
    <other_name>Carboplatinum</other_name>
    <other_name>Carbosin</other_name>
    <other_name>Carbosol</other_name>
    <other_name>Carbotec</other_name>
    <other_name>CBDCA</other_name>
    <other_name>Displata</other_name>
    <other_name>Ercar</other_name>
    <other_name>JM-8</other_name>
    <other_name>Nealorin</other_name>
    <other_name>Novoplatinum</other_name>
    <other_name>Paraplatin</other_name>
    <other_name>Paraplatin AQ</other_name>
    <other_name>Paraplatine</other_name>
    <other_name>Platinwas</other_name>
    <other_name>Ribocarbo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Etoposide</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)</arm_group_label>
    <arm_group_label>Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)</arm_group_label>
    <other_name>Demethyl Epipodophyllotoxin Ethylidine Glucoside</other_name>
    <other_name>EPEG</other_name>
    <other_name>Lastet</other_name>
    <other_name>Toposar</other_name>
    <other_name>Vepesid</other_name>
    <other_name>VP 16</other_name>
    <other_name>VP 16-213</other_name>
    <other_name>VP-16</other_name>
    <other_name>VP-16-213</other_name>
    <other_name>VP16</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ifosfamide</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)</arm_group_label>
    <arm_group_label>Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)</arm_group_label>
    <other_name>Asta Z 4942</other_name>
    <other_name>Asta Z-4942</other_name>
    <other_name>Cyfos</other_name>
    <other_name>Holoxan</other_name>
    <other_name>Holoxane</other_name>
    <other_name>Ifex</other_name>
    <other_name>IFO</other_name>
    <other_name>IFO-Cell</other_name>
    <other_name>Ifolem</other_name>
    <other_name>Ifomida</other_name>
    <other_name>Ifomide</other_name>
    <other_name>Ifosfamidum</other_name>
    <other_name>Ifoxan</other_name>
    <other_name>IFX</other_name>
    <other_name>Iphosphamid</other_name>
    <other_name>Iphosphamide</other_name>
    <other_name>Iso-Endoxan</other_name>
    <other_name>Isoendoxan</other_name>
    <other_name>Isophosphamide</other_name>
    <other_name>Mitoxana</other_name>
    <other_name>MJF 9325</other_name>
    <other_name>MJF-9325</other_name>
    <other_name>Naxamide</other_name>
    <other_name>Seromida</other_name>
    <other_name>Tronoxal</other_name>
    <other_name>Z 4942</other_name>
    <other_name>Z-4942</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)</arm_group_label>
    <arm_group_label>Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)</arm_group_label>
    <arm_group_label>Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)</arm_group_label>
    <other_name>BMS-936558</other_name>
    <other_name>MDX-1106</other_name>
    <other_name>NIVO</other_name>
    <other_name>ONO-4538</other_name>
    <other_name>Opdivo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically documented or cytologically confirmed Hodgkin&#xD;
             lymphoma; confirmation must include CD30 expression&#xD;
&#xD;
          -  Patients must be either refractory to or relapsed after only induction therapy;&#xD;
             patients who do not achieve CR after induction therapy are considered primary&#xD;
             refractory and are allowed to enter study&#xD;
&#xD;
          -  &gt; 40 kg&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1500/uL; filgrastim can be given before and during&#xD;
             treatment to achieve target ANC &gt;= 1500 uL&#xD;
&#xD;
          -  Platelet (Plt) &gt;= 75,000/uL&#xD;
&#xD;
          -  Hemoglobin &gt;= 8.5 g/dl&#xD;
&#xD;
          -  Platelet transfusion and packed red blood cell transfusion can also be given prior to&#xD;
             the start of treatment and treatment to achieve a target plt &gt;= 75,000/uL and&#xD;
             hemoglobin of &gt;= 8.5 g/dl, provided that patients have not received growth factors for&#xD;
             at least 14 days prior to entering trial&#xD;
&#xD;
          -  Patients must have measurable disease &gt; 1.5 cm evidenced by computed tomography (CT)&#xD;
             scan of the neck/chest/abdomen/pelvis or CT/positron emission tomography (PET) scans&#xD;
&#xD;
          -  Life expectancy of greater than 3 months&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) of 0-2&#xD;
&#xD;
          -  Documented informed consent/assent of the participant or legally responsible guardian&#xD;
&#xD;
          -  Diffusion capacity of the lung for carbon monoxide (DLCO) &gt;= 60%&#xD;
&#xD;
          -  Total bilirubin with 1.5 x the upper limit of normal (ULN) institutional limits;&#xD;
             patients with elevation of unconjugated bilirubin alone, as in Gilbert's disease, are&#xD;
             eligible&#xD;
&#xD;
          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =&lt; 3.0 x the&#xD;
             institutional upper limit of normal (unless demonstrated Hodgkin lymphoma involvement&#xD;
             of the liver); estimated creatinine clearance &gt;= 30 ml/min (Cockcroft-Gault) and/or 24&#xD;
             urine analysis as needed&#xD;
&#xD;
          -  For patients with Hodgkin lymphoma (HL) involvement of the liver, AST/ALT &lt; 5.0 x&#xD;
             institutional ULN; total bilirubin within 3.0 x institutional ULN; (although patients&#xD;
             with HL involvement of the liver are frequently excluded from trials, their liver&#xD;
             function tests often improve after treatment; the studies that led to nivolumab&#xD;
             approval did not reveal any increased signals of liver toxicities attributed to&#xD;
             nivolumab)&#xD;
&#xD;
          -  Prothrombin time (PT)/international normalized ration (INR) &lt; 1.5 x ULN and partial&#xD;
             thromboplastin time (PTT) (activated [a]PTT) &lt; 1.5 x ULN&#xD;
&#xD;
          -  Female subject is either post-menopausal, surgically sterilized, or willing to use and&#xD;
             acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine&#xD;
             device, diaphragm with spermicide, condom with spermicide, or abstinence) for the&#xD;
             duration of the study; women of childbearing potential (WOCBP) must have a negative&#xD;
             serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG)&#xD;
             within 24 hours prior to the start of nivolumab&#xD;
&#xD;
          -  Men who are sexually active with WOCBP must use any contraceptive method with a&#xD;
             failure rate of less than 1% per year; men receiving nivolumab and who are sexually&#xD;
             active with WOCBP will be instructed to adhere to contraception for a period of 31&#xD;
             weeks after the last dose of investigational product; women who are not of&#xD;
             childbearing potential (i.e., who are postmenopausal or surgically sterile) as well as&#xD;
             azoospermic men do not require contraception&#xD;
&#xD;
          -  All participants will undergo standard written informed consent procedures as dictated&#xD;
             by the City of Hope Human Research Protections Office prior to performing any&#xD;
             screening procedures that are not part of standard-of-care; informed consent will be&#xD;
             obtained by the principal investigator, collaborating investigators, or other&#xD;
             Institutional Review Board (IRB) designated personnel who will meet the training&#xD;
             requirements established by the IRB; with the support of research personnel, he/she&#xD;
             will explain the nature, duration, purpose of the study, potential risks, alternatives&#xD;
             and potential benefits, and all other information contained in the informed consent&#xD;
             document; in addition, they will review the experimental subject's bill of rights and&#xD;
             the Health Insurance Portability and Accountability Act (HIPAA) research authorization&#xD;
             form; prospective research participants will be informed that they may withdraw from&#xD;
             the study at any time and for any reason without prejudice; prospective research&#xD;
             participants will be afforded sufficient time to consider whether or not to&#xD;
             participate in the research&#xD;
&#xD;
          -  Patient must be either refractory to or relapsed after 1 line of therapy; prior&#xD;
             radiation therapy is allowed&#xD;
&#xD;
          -  INCLUSION CRITERIA FOR COHORT B:&#xD;
&#xD;
          -  B symptoms at relapse&#xD;
&#xD;
          -  Extranodal disease at relapse&#xD;
&#xD;
          -  Primary refractory disease&#xD;
&#xD;
          -  Relapsed &lt; 1 year after completion of frontline therapy&#xD;
&#xD;
          -  Have received brentuximab vedotin as initial therapy&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior exposure to PD-1 or PD-L1 inhibitors is not allowed&#xD;
&#xD;
          -  Must not have had second line chemotherapy for Hodgkin lymphoma&#xD;
&#xD;
          -  Active autoimmune diseases requiring systemic treatments&#xD;
&#xD;
          -  Vaccinated with live, attenuated vaccine within 4 weeks of first dose of study drug&#xD;
&#xD;
          -  Any life-threatening illness, medical condition, or organ system dysfunction that, in&#xD;
             the investigator's opinion, could compromise the subject's safety or put the study&#xD;
             outcomes at undue risk&#xD;
&#xD;
          -  Unwilling or unable to participate in all required study evaluations and procedures&#xD;
&#xD;
          -  Unable to understand the purpose and risks of the study and to provide a signed and&#xD;
             dated informed consent for (ICF) and authorization to use protected health information&#xD;
             (in accordance with national and local subject privacy regulations)&#xD;
&#xD;
          -  Patients should not have any uncontrolled illness including ongoing or active&#xD;
             infection&#xD;
&#xD;
          -  Patients may not be receiving any other investigational agents, or concurrent&#xD;
             biological therapy, chemotherapy, or radiation therapy&#xD;
&#xD;
          -  Patients must not have received prior chemotherapy or radiation for =&lt; 3 weeks before&#xD;
             study enrollment, or those who have not recovered from the adverse events due to&#xD;
             agents administered more than 3 weeks earlier are excluded&#xD;
&#xD;
          -  Myocardial infarction within 6 months prior to enrollment or New York Heart&#xD;
             Association (NYHA) class III or IV heart failure, uncontrolled angina, severe&#xD;
             uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute&#xD;
             ischemia or active conduction system abnormalities; prior study entry, any&#xD;
             electrocardiogram (ECG) abnormality at screening has to be documented by the&#xD;
             investigator as not medically relevant&#xD;
&#xD;
          -  Significant screening electrocardiogram (ECG) abnormalities including, but not limited&#xD;
             to, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd&#xD;
             degree block, or corrected QT interval (QTc) &gt;= 470 msec; subjects with a cardiac&#xD;
             pacemaker who have a QTc interval of &gt;= 470 msec may be eligible if these findings are&#xD;
             considered not clinically significant as documented via a cardiology evaluation&#xD;
&#xD;
          -  DLCO &lt; 60%; the clinical studies in support of accelerated approval for nivolumab in&#xD;
             chronic (c)HL after failure of ASCT required DLCO &gt; 60%; certain HL induction regimens&#xD;
             have the potential for pulmonary toxicity, and nivolumab carries the potential of&#xD;
             pneumonitis or other pulmonary toxicities&#xD;
&#xD;
          -  Diagnosed or treated for another malignancy within 3 years of enrollment, with the&#xD;
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of&#xD;
             the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy&#xD;
&#xD;
          -  Patients with active central nervous system (CNS) disease or history of brain&#xD;
             metastases are excluded from study&#xD;
&#xD;
          -  Patients should be excluded if they have a condition requiring systemic treatment with&#xD;
             either corticosteroids (&gt; 10 mg daily prednisone equivalents) or other&#xD;
             immunosuppressive medications within 14 days of study drug administration; inhaled or&#xD;
             topical steroids and adrenal replacement doses &gt; 10 mg daily prednisone equivalents&#xD;
             are permitted in the absence of active autoimmune disease&#xD;
&#xD;
          -  Pregnant women are excluded from this study because of the potential for teratogenic&#xD;
             or abortifacient effects; because there is an unknown but potential risk of adverse&#xD;
             events in nursing infants secondary to treatment of the mother, breastfeeding should&#xD;
             be discontinued&#xD;
&#xD;
          -  Recent infection requiring systemic treatment that was completed =&lt; 14 days before the&#xD;
             first dose of study drug&#xD;
&#xD;
          -  Known history of human immunodeficiency virus (HIV), hepatitis C virus (HCV) or&#xD;
             hepatitis B virus (HBV) infection; subjects who are positive for hepatitis B core&#xD;
             antibody or hepatitis B surface antigen must have a negative polymerase chain reaction&#xD;
             (PCR) result before enrollment, those who are PCR positive will be excluded; subjects&#xD;
             who have an undetectable HIV viral load with CD4 &gt;= 300 and are on highly active&#xD;
             antiretroviral therapy (HAART) medication are allowed; previously treated hepatitis C&#xD;
             patients are also allowed; as there is potential for hepatic toxicity with nivolumab&#xD;
             or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity&#xD;
             should be used with caution in patients treated with nivolumab-containing regimen&#xD;
&#xD;
          -  History of allergy or adverse drug reaction to study components&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alex F Herrera</last_name>
    <role>Principal Investigator</role>
    <affiliation>City of Hope Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>City of Hope Medical Center</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yale University</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fred Hutchinson Cancer Research Center</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>January 6, 2017</study_first_submitted>
  <study_first_submitted_qc>January 9, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 11, 2017</study_first_posted>
  <last_update_submitted>October 24, 2022</last_update_submitted>
  <last_update_submitted_qc>October 24, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 26, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Hodgkin Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Etoposide</mesh_term>
    <mesh_term>Etoposide phosphate</mesh_term>
    <mesh_term>Ifosfamide</mesh_term>
    <mesh_term>Isophosphamide mustard</mesh_term>
    <mesh_term>Podophyllotoxin</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03016871
org study id: 16403
secondary id: NCI-2016-02038
secondary id: 16403
nct id: NCT03016871
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies the side effects of nivolumab and to see how well it works when
      given together with ifosfamide, carboplatin, and etoposide in treating patients with Hodgkin
      lymphoma that has come back (relapsed) and does not respond to treatment (refractory).
      Immunotherapy with monoclonal antibodies such as nivolumab, may help the body?s immune system
      attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
      Drugs used in chemotherapy, such as ifosfamide, carboplatin and etoposide, work in different
      ways to stop the growth of cancer cells, either by killing the cells, by stopping them from
      dividing, or by stopping them from spreading. Giving nivolumab, ifosfamide, carboplatin and
      etoposide may work better in treating patients with Hodgkin lymphoma.
PRIMARY OBJECTIVES:

      I. Evaluate the anti-tumor activity of nivolumab as single agent and in combination with
      ifosfamide, carboplatin, etoposide (ICE) chemotherapy (nivolumab [N]ICE) as assessed by
      complete response (CR) rate prior to autologous hematopoietic cell transplantation.

      II. To estimate the proportion of patients experiencing unacceptable adverse events. (Cohort
      B) III. To assess the safety and tolerability of nivolumab + ICE chemotherapy through
      evaluation of toxicities, including type, frequency, severity, attribution, time course, and
      duration. (Cohort B) IV. To obtain estimate of overall response rate (ORR), complete response
      rate, response duration and survival (overall and event-free). (Cohort B) V. Summarize stem
      cell mobilization outcomes (e.g., total CD34+ cell yield, number of apheresis days,
      proportion of patients who achieve >= 2 x 10^6 CD34+ cells/kg). (Cohort B) VI. Evaluate
      Hodgkin lymphoma biological markers in subjects treated with nivolumab. (Cohort B)

      SECONDARY OBJECTIVES:

      I. Assess the safety and tolerability of nivolumab +/- ICE chemotherapy through evaluation of
      toxicities, including type, frequency, severity, attribution, time course and duration.

      II. Obtain estimates of overall response rate (ORR), response duration and survival (overall
      and event-free).

      III. Summarize stem cell mobilization outcomes (e.g., total CD34+ cell yield, number of
      apheresis days, proportion of patients who achieve >= 2 x 10^6 CD34+ cells/kg).

      IV. Evaluate Hodgkin lymphoma biological markers in subjects treated with nivolumab.

      V. Among subjects who undergo autologous hematopoietic cell transplantation (AHCT), estimate
      the post-AHCT overall/progression free survival (PFS) probability and cumulative incidence of
      relapse/progression, non-relapse mortality (NRM) at 100-days, 1-year and 2-years.

      VI. Among subjects who undergo autologous hematopoietic cell transplantation (AHCT),
      characterize post-AHCT toxicities during the first 30- and 100- days post stem cell infusion
      by type, frequency, severity, attribution, time course and duration.

      VII. Among subjects who undergo autologous hematopoietic cell transplantation (AHCT),
      evaluate short and long-term post-AHCT complications, including: delayed engraftment
      (neutrophil and platelet) and infection, graft versus host disease and sinusoidal obstruction
      syndrome.

      EXPLORATORY OBJECTIVES:

      I. Collect deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) from lymphoma specimens and
      serial plasma samples for future biomarker evaluation.

      II. Evaluate potential changes in Hodgkin lymphoma biological markers of patients treated
      with nivolumab.

      OUTLINE: Patients are sequentially assigned to 1 of 2 cohorts.

      COHORT A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles
      repeat every 14 days for 6 weeks in the absence of disease progression or unacceptable
      toxicity. Patients with CR or partial response (PR) receive nivolumab for an additional 6
      weeks. Patients with only stable disease (SD) after 6-week nivolumab treatment receive
      nivolumab for an additional 6 weeks or receive nivolumab IV over 30 minutes on day 1,
      etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin
      IV on day 2 every 21 days for 6 weeks per physician/investigator's discretion. Patients with
      progressive disease (PD) after 6-week nivolumab treatment or patients with PR, SD, or PD
      after 12-week nivolumab treatment receive nivolumab IV over 30 minutes on day 1, etoposide IV
      on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2.
      Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or
      unacceptable toxicity.

      COHORT B: Patients receive nivolumab IV over 30 minutes on cycle 1 (cycle 1 is 14 days), day
      1 in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2,
      patients receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide
      IV continuously over 24 hours on day 2, and carboplatin IV on day 2. Treatment repeats every
      21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for up to 2
      years.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Complete response rate autologous stem cell transplantation assessed by Lugano criteria
time frame: 1 year after primary outcome is met
description: Response rates will be calculated as the percent of evaluable patients that have confirmed complete response by radiographic response including computed tomography and/or positron emission tomography scans; 95% Clopper Pearson confidence limits will be calculated for this estimate.
measure: Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03
time frame: Up to 2 years
description: Toxicity will be assessed and reported using the Bearman (non-hematologic) and Common Terminology Criteria for Adverse Events version 4.03 scales. Toxicity information recorded will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity.
measure: Overall response rate
time frame: From the time measurement criteria are for complete response or partial response (whichever is first recorded) until the first date that relapsed or progressive disease is objectively documented, assessed up to 2 years
description: Will be estimated using the product-limit method of Kaplan and Meier.
measure: Overall survival
time frame: From start of treatment to time of death (due to any cause), assessed up to 2 years
description: Will be estimated using the product-limit method of Kaplan and Meier.
measure: Progression free survival
time frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years
description: Will be estimated using the product-limit method of Kaplan and Meier.
measure: Overall survival of hematopoietic cell transplantation
time frame: From start of hematopoietic cell transplantation treatment to time of death (due to any cause), assessed up to 2 years post hematopoietic cell transplantation
description: Will be estimated using the product-limit method of Kaplan and Meier.
measure: Progression free survival of hematopoietic cell transplantation
time frame: From start of hematopoietic cell transplantation treatment to time of progression or death, whichever occurs first, assessed up to 2 years post hematopoietic cell transplantation
description: Will be estimated using the product-limit method of Kaplan and Meier.
measure: Relapse/progression event
time frame: From start of hematopoietic cell transplantation treatment, assessed up to 2 years post hematopoietic cell transplantation
description: The cumulative incidence of relapse/progression will be calculated as competing risks using the method of Gooley et al.
measure: Non-relapse mortality
time frame: From start of treatment until non-disease related death, or last follow-up, whichever comes first, assessed up to 2 years post hematopoietic cell transplantation
description: The cumulative incidence of non-relapse mortality will be calculated as competing risks using the method of Gooley et al.
measure: Role of PDL1/L2, CD68 on lymphoma specimens
time frame: Up to 2 years
description: Summarized using standard descriptive methods.
measure: Role of T/B/natural killer cell subsets in the peripheral blood
time frame: Up to 2 years
description: Summarized using standard descriptive methods.
arm group label: Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)
arm group type: Experimental
description: Patients receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 14 days for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients with CR or PR receive nivolumab for an additional 6 weeks. Patients with only SD after 6-week nivolumab treatment receive nivolumab for an additional 6 weeks or receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2 every 21 days for 6 weeks per physician/investigator's discretion. Patients with PD after 6-week nivolumab treatment or patients with PR, SD, or PD after 12-week nivolumab treatment receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.
arm group label: Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)
arm group type: Experimental
description: Patients receive nivolumab IV over 30 minutes on cycle 1 (cycle 1 is 14 days), day 1 in the absence of disease progression or unacceptable toxicity. Beginning in cycle 2, patients receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1-3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Carboplatin
description: Given IV
arm group label: Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)
arm group label: Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)
other name: Blastocarb
other name: Carboplat
other name: Carboplatin Hexal
other name: Carboplatino
other name: Carboplatinum
other name: Carbosin
other name: Carbosol
other name: Carbotec
other name: CBDCA
other name: Displata
other name: Ercar
other name: JM-8
other name: Nealorin
other name: Novoplatinum
other name: Paraplatin
other name: Paraplatin AQ
other name: Paraplatine
other name: Platinwas
other name: Ribocarbo
intervention type: Drug
intervention name: Etoposide
description: Given IV
arm group label: Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)
arm group label: Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)
other name: Demethyl Epipodophyllotoxin Ethylidine Glucoside
other name: EPEG
other name: Lastet
other name: Toposar
other name: Vepesid
other name: VP 16
other name: VP 16-213
other name: VP-16
other name: VP-16-213
other name: VP16
intervention type: Drug
intervention name: Ifosfamide
description: Given IV
arm group label: Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)
arm group label: Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)
other name: Asta Z 4942
other name: Asta Z-4942
other name: Cyfos
other name: Holoxan
other name: Holoxane
other name: Ifex
other name: IFO
other name: IFO-Cell
other name: Ifolem
other name: Ifomida
other name: Ifomide
other name: Ifosfamidum
other name: Ifoxan
other name: IFX
other name: Iphosphamid
other name: Iphosphamide
other name: Iso-Endoxan
other name: Isoendoxan
other name: Isophosphamide
other name: Mitoxana
other name: MJF 9325
other name: MJF-9325
other name: Naxamide
other name: Seromida
other name: Tronoxal
other name: Z 4942
other name: Z-4942
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)
arm group label: Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)
intervention type: Biological
intervention name: Nivolumab
description: Given IV
arm group label: Cohort A (nivolumab, etoposide, ifosfamide, carboplatin)
arm group label: Cohort B (nivolumab, etoposide, ifosfamide, carboplatin)
other name: BMS-936558
other name: MDX-1106
other name: NIVO
other name: ONO-4538
other name: Opdivo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alex F Herrera
role: Principal Investigator
affiliation: City of Hope Medical Center
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Hodgkin Disease
mesh term: Carboplatin
mesh term: Nivolumab
mesh term: Etoposide
mesh term: Etoposide phosphate
mesh term: Ifosfamide
mesh term: Isophosphamide mustard
mesh term: Podophyllotoxin