<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/NCT01711554</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2012-02011</org_study_id>
    <secondary_id>NCI-2012-02011</secondary_id>
    <secondary_id>CDR0000741991</secondary_id>
    <secondary_id>N2011-04</secondary_id>
    <secondary_id>NANT 11-04</secondary_id>
    <secondary_id>NANT N2011-04</secondary_id>
    <secondary_id>NANT N2011-04</secondary_id>
    <secondary_id>P01CA081403</secondary_id>
    <nct_id>NCT01711554</nct_id>
  </id_info>
  <brief_title>Lenalidomide and Dinutuximab With or Without Isotretinoin in Treating Younger Patients With Refractory or Recurrent Neuroblastoma</brief_title>
  <official_title>A Phase I Study of Lenalidomide and Anti-GD2 Mab Ch14.18 +/- Isotretinoin in Patients With Refractory/Recurrent Neuroblastoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and best dose of lenalidomide when given together&#xD;
      with dinutuximab with or without isotretinoin in treating younger patients with neuroblastoma&#xD;
      that does not respond to treatment or that has come back. Drugs used in chemotherapy, such as&#xD;
      lenalidomide and isotretinoin, work in different ways to stop the growth of tumor cells,&#xD;
      either by killing the cells, by stopping them from dividing, or by stopping them from&#xD;
      spreading. Monoclonal antibodies, such as dinutuximab, may interfere with the ability of&#xD;
      tumor cells to grow and spread. Giving more than one drug (combination chemotherapy) together&#xD;
      with dinutuximab therapy may kill more tumor cells.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of&#xD;
      lenalidomide in combination with fixed doses of dinutuximab (ch14.18) and isotretinoin given&#xD;
      to children with refractory or recurrent neuroblastoma.&#xD;
&#xD;
      II. To define the toxicities of lenalidomide administered in combination with ch14.18 and&#xD;
      isotretinoin.&#xD;
&#xD;
      III. To describe the differences in immune function modulation between &quot;low&quot; versus &quot;high&quot;&#xD;
      dose lenalidomide given with ch14.18 and isotretinoin.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the pharmacokinetics of lenalidomide given in this combination regimen.&#xD;
&#xD;
      II. To determine the steady state pharmacokinetics of isotretinoin (day 28, course one) given&#xD;
      in combination with lenalidomide.&#xD;
&#xD;
      III. To measure peak and trough levels of ch14.18 in patients receiving lenalidomide and to&#xD;
      compare to historical controls of patients receiving ch14.18 in combination with interleukin&#xD;
      2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF).&#xD;
&#xD;
      IV. To describe the immunological effects of lenalidomide (T cells, natural killer [NK]&#xD;
      cells, monocytes, cytokines, chemokines) within this three drug regimen.&#xD;
&#xD;
      V. To define the incidence and titers of human anti-chimeric antibody (HACA) on this regimen.&#xD;
&#xD;
      VI. To describe, within the context of a phase I study, the response rate to lenalidomide&#xD;
      combined with ch14.18 and isotretinoin in patients with recurrent/refractory neuroblastoma.&#xD;
&#xD;
      VII. To summarize, within the context of a phase I study, the event-free survival of patients&#xD;
      with recurrent/refractory neuroblastoma or in complete response (CR) after progressing, and&#xD;
      who are treated with lenalidomide combined with ch14.18 and isotretinoin.&#xD;
&#xD;
      VIII. To determine, within the context of a phase I study, if killer-cell immunoglobulin-like&#xD;
      receptor (KIR) receptor-ligand mismatch or specific Fc gamma receptor (Fc gamma R) alleles&#xD;
      are associated with anti-tumor response.&#xD;
&#xD;
      IX. To quantify neuroblastoma tumor cell &quot;load&quot; using a 5-gene TaqMan Low Density Array&#xD;
      (TLDA) assay in peripheral blood at study entry, following, with each disease evaluation and&#xD;
      at end of therapy and bone marrow at study entry, with each response evaluation when bone&#xD;
      marrow is sampled, and at end of therapy.&#xD;
&#xD;
      X. To compare the toxicities of this regimen with the historical toxicity data from the&#xD;
      Children's Oncology Group (COG) ANBL0032 and ANBL0931 studies of ch14.18 with IL-2, GM-CSF&#xD;
      and isotretinoin.&#xD;
&#xD;
      XI. To describe the tolerability and ability to give full doses of ch14.18 and lenalidomide&#xD;
      over extended periods of time, i.e. in courses 6-12.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of lenalidomide.&#xD;
&#xD;
      Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, dinutuximab&#xD;
      intravenously (IV) over 10 hours on days 8-11, and isotretinoin PO twice daily (BID) on days&#xD;
      15-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease&#xD;
      progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up periodically.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 4, 2013</start_date>
  <primary_completion_date type="Actual">September 14, 2018</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum tolerated dose defined as the highest dose level tested at which 0/6 or 1/6 patients experience dose-limiting toxicity (DLT) graded using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) criteria, version 4.0</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>All toxicities observed will be summarized in terms of type (organ affected or laboratory determination), severity (by NCI CTCAE), and attribution. Tables will be created to summarize these toxicities and side effects by dose level and by course as well as with Kaplan-Meier plots (i.e. time to first delay or dose reduction) in order to assess the tolerability of the regime over multiple courses.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Recommended phase II dose</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>Determination of the recommended phase II dose of lenalidomide will include consideration of obtaining median peak plasma lenalidomide levels of 5-10 uM (based on laboratory modeling of this regimen in neuroblastoma), acceptable clinical toxicity, and laboratory evidence of an augmentation in immune function.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>From start of lenalidomide until death for any reason or date that patient was last known to be alive if the patient is still alive, assessed up to 3 years</time_frame>
    <description>Will be summarized with Kaplan-Meier plots.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event-free survival</measure>
    <time_frame>From the start of treatment with lenalidomide until progression, clinical deterioration mandating that the patient terminate treatment or death due to any cause, whichever occurs first, assessed up to 3 years</time_frame>
    <description>Will be summarized with Kaplan-Meier plots.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the levels of T cells, natural killer (NK) cells, monocytes, cytokines, and chemokines</measure>
    <time_frame>Baseline to up to 28 days</time_frame>
    <description>These levels and the changes relative to baseline will be summarized by dose level by simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatterplots will be used to explore possible associations between the dose and day and toxicity experienced (as reflected in the maximum grade of toxicity experienced, infections or platelet recovery).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in levels of HACA (or other genotype) and tumor response</measure>
    <time_frame>Baseline to up to 3 years</time_frame>
    <description>These levels and the changes relative to baseline will be summarized by dose level by simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatterplots will be used to explore possible associations between the dose and day and toxicity experienced (as reflected in the maximum grade of toxicity experienced, infections or platelet recovery).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic determinations of lenalidomide</measure>
    <time_frame>Baseline, at 60 and 90 minutes, at 2, 6, 24 hours and days 7 and 22 after last dose of lenalidomide in course 1</time_frame>
    <description>These will be summarized by dose level with simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatterplots will be used to explore possible associations between the dose and estimates of the pharmacokinetic parameters, and between the pharmacokinetic determinations and toxicity experienced (as reflected in the maximum grade of toxicity experienced or in clinical measurements).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in TaqMan low density array (TLDA) scores</measure>
    <time_frame>Baseline to up to 3 years</time_frame>
    <description>Standard descriptive summaries as well as scatterplots will be used. The association between the changes in TLDA scores and overall tumor response will also be summarized graphically and quantitatively. Changes (from baseline) in the TLDA scores over the course of treatment will be plotted and summarized by dose level and course.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall response</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>The association between the changes in TLDA scores and overall tumor response will be summarized graphically and quantitatively.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">27</enrollment>
  <condition>Recurrent Neuroblastoma</condition>
  <condition>Refractory Neuroblastoma</condition>
  <arm_group>
    <arm_group_label>Treatment (lenalidomide, dinutuximab, isotretinoin)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive lenalidomide PO QD on days 1-21, dinutuximab IV over 10 hours on days 8-11, and isotretinoin PO BID on days 15-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Dinutuximab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (lenalidomide, dinutuximab, isotretinoin)</arm_group_label>
    <other_name>Ch 14.18UTC</other_name>
    <other_name>Ch14.18</other_name>
    <other_name>Dinutuximab Beta</other_name>
    <other_name>MOAB Ch14.18</other_name>
    <other_name>monoclonal antibody Ch14.18</other_name>
    <other_name>Qarziba</other_name>
    <other_name>Unituxin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isotretinoin</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (lenalidomide, dinutuximab, isotretinoin)</arm_group_label>
    <other_name>13-cis retinoic acid</other_name>
    <other_name>13-cis-Retinoate</other_name>
    <other_name>13-cis-Retinoic Acid</other_name>
    <other_name>13-cis-Vitamin A Acid</other_name>
    <other_name>13-cRA</other_name>
    <other_name>Absorica</other_name>
    <other_name>Accure</other_name>
    <other_name>Accutane</other_name>
    <other_name>Amnesteem</other_name>
    <other_name>cis-Retinoic Acid</other_name>
    <other_name>Cistane</other_name>
    <other_name>Claravis</other_name>
    <other_name>Isotretinoinum</other_name>
    <other_name>Isotrex</other_name>
    <other_name>Isotrexin</other_name>
    <other_name>Myorisan</other_name>
    <other_name>Neovitamin A</other_name>
    <other_name>Neovitamin A Acid</other_name>
    <other_name>Oratane</other_name>
    <other_name>Retinoicacid-13-cis</other_name>
    <other_name>Ro 4-3780</other_name>
    <other_name>Ro-4-3780</other_name>
    <other_name>Roaccutan</other_name>
    <other_name>Roaccutane</other_name>
    <other_name>Roacutan</other_name>
    <other_name>Sotret</other_name>
    <other_name>ZENATANE</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (lenalidomide, dinutuximab, isotretinoin)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenalidomide</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (lenalidomide, dinutuximab, isotretinoin)</arm_group_label>
    <other_name>CC-5013</other_name>
    <other_name>CC5013</other_name>
    <other_name>CDC 501</other_name>
    <other_name>Revlimid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Pharmacological Study</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (lenalidomide, dinutuximab, isotretinoin)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have a diagnosis of neuroblastoma either by histologic verification of&#xD;
             neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased&#xD;
             urinary catecholamines&#xD;
&#xD;
          -  Patients must have high-risk neuroblastoma&#xD;
&#xD;
          -  Patients must have at least ONE of the following:&#xD;
&#xD;
               -  Recurrent/progressive disease at any time prior to enrollment - regardless of&#xD;
                  response to frontline therapy&#xD;
&#xD;
               -  Refractory disease: persistent sites of disease (after less than a partial&#xD;
                  response to frontline therapy, following a minimum of 4 cycles of induction&#xD;
                  therapy) AND patient has never had a relapse/progression&#xD;
&#xD;
               -  Persistent disease: persistent disease after achieving at least a partial&#xD;
                  response to frontline therapy after a minimum of 4 cycles of induction therapy&#xD;
                  and patient has never had a relapse/progression&#xD;
&#xD;
          -  Patients must have at least ONE of the following (lesions may have received prior&#xD;
             radiation therapy as long as they meet the other criteria listed below):&#xD;
&#xD;
               -  Bone disease&#xD;
&#xD;
                    -  At least one metaiodobenzylguanidine (MIBG) avid bone site or diffuse MIBG&#xD;
                       uptake&#xD;
&#xD;
                         -  For recurrent/progressive or refractory disease a biopsy is not&#xD;
                            required regardless of number of MIBG avid lesions&#xD;
&#xD;
                         -  For persistent disease, if patient has only 1 or 2 MIBG avid lesions OR&#xD;
                            a Curie score of 1-2, then biopsy confirmation of neuroblastoma and/or&#xD;
                            ganglioneuroblastoma in at least one site present at the time of&#xD;
                            enrollment (bone marrow, bone, or soft tissue) is required to be&#xD;
                            obtained at any time point prior to enrollment and two weeks subsequent&#xD;
                            to most recent prior therapy; if a patient has 3 or more MIBG avid&#xD;
                            lesions OR a Curie score of &gt;= 3 then no biopsy is required for&#xD;
                            eligibility&#xD;
&#xD;
                    -  If a tumor is known to be MIBG non-avid, then a patient must have at least&#xD;
                       one fludeoxyglucose (FDG)-positron emission tomography (PET) avid bone site&#xD;
                       present at the time of enrollment with biopsy confirmation of neuroblastoma&#xD;
                       and/or ganglioneuroblastoma obtained at any time prior to enrollment and two&#xD;
                       weeks subsequent to most recent prior therapy&#xD;
&#xD;
               -  Any amount of neuroblastoma tumor cells in the bone marrow based on routine&#xD;
                  morphology (with or without immunocytochemistry) in at least one sample from&#xD;
                  bilateral aspirates and biopsies&#xD;
&#xD;
               -  At least one soft tissue lesion that meets the criteria for a TARGET lesion as&#xD;
                  defined by:&#xD;
&#xD;
                    -  SIZE: Lesion can be accurately measured in at least one dimension with a&#xD;
                       longest diameter &gt;= 10 mm, or for lymph nodes &gt;= 15 mm on short axis;&#xD;
                       lesions meeting size criteria will be considered measurable&#xD;
&#xD;
                    -  In addition to size, a lesion needs to meet ONE of the following criteria:&#xD;
&#xD;
                         -  MIBG avid; for patients with persistent disease only: if a patient has&#xD;
                            only 1 or 2 MIBG avid lesions OR a Curie score of 1-2, then biopsy&#xD;
                            confirmation of neuroblastoma and/or ganglioneuroblastoma in at least&#xD;
                            one site present at time of enrollment (either bone marrow, bone and/or&#xD;
                            soft tissue) is required to be obtained at any time point prior to&#xD;
                            enrollment and at least two weeks subsequent to most recent prior&#xD;
                            therapy; if a patient has 3 or more MIBG avid lesions OR a Curie score&#xD;
                            of &gt;= 3 then no biopsy is required for eligibility&#xD;
&#xD;
                         -  FDG-PET avid (only if tumor is known to be MIBG non-avid); these&#xD;
                            patients must have had a biopsy confirming neuroblastoma and/or&#xD;
                            ganglioneuroblastoma in at least one FDG-PET avid site present at the&#xD;
                            time of enrollment done prior to enrollment and at least two weeks&#xD;
                            subsequent to the most recent prior therapy&#xD;
&#xD;
                         -  Non-avid lesion (both MIBG and FDG-PET non-avid); these patients must&#xD;
                            have had a biopsy confirming neuroblastoma and/or ganglioneuroblastoma&#xD;
                            in at least one non-avid lesion present at the time of enrollment done&#xD;
                            prior to enrollment and at least two weeks subsequent to the most&#xD;
                            recent prior therapy&#xD;
&#xD;
          -  Patients with prior progressive disease who do not meet criteria above, are eligible&#xD;
             as long as they have not been off treatment for &gt; 3 months prior to enrollment on NANT&#xD;
             2011-04&#xD;
&#xD;
          -  Patients must have a life expectancy of at least 6 weeks&#xD;
&#xD;
          -  Lansky (=&lt; 16 years) or Karnofsky (&gt; 16 years) score of at least 50&#xD;
&#xD;
          -  Patients must have fully recovered from the acute toxic effects of all prior&#xD;
             chemotherapy, immunotherapy, or radiotherapy prior to study enrollment&#xD;
&#xD;
          -  Patients must not have received the therapies indicated below for the specified time&#xD;
             period prior to the first day of administration of protocol therapy on this study&#xD;
&#xD;
               -  Myelosuppressive chemotherapy: must have received last dose at least 2 weeks&#xD;
                  prior to protocol therapy; this includes cytotoxic agents given on a low dose&#xD;
                  metronomic regimen&#xD;
&#xD;
               -  Biologic (anti-neoplastic agent) (includes retinoids): must have received last&#xD;
                  dose at least 7 days prior to protocol therapy&#xD;
&#xD;
               -  Monoclonal antibodies: must have received last dose at least 7 days or 3&#xD;
                  half-lives, whichever is longer, prior to protocol therapy&#xD;
&#xD;
          -  Radiation:&#xD;
&#xD;
               -  Patients must not have received radiation (small port) for a minimum of two weeks&#xD;
                  prior to protocol therapy&#xD;
&#xD;
               -  Except for patients with a history of progressive disease, patients whose only&#xD;
                  site(s) of disease have been radiated are eligible if at least one lesion meets&#xD;
                  at least one of the criteria listed in sites of disease above&#xD;
&#xD;
               -  A minimum of 12 weeks prior to start of protocol therapy is required following&#xD;
                  large field radiation therapy (i.e. total body irradiation, craniospinal, whole&#xD;
                  abdominal, total lung, &gt; 50% marrow space)&#xD;
&#xD;
               -  A minimum of 6 weeks must have elapsed prior to start of protocol therapy for&#xD;
                  other substantial bone marrow radiation&#xD;
&#xD;
          -  Stem Cell Transplant (SCT):&#xD;
&#xD;
               -  Patients are eligible 6 weeks after date of autologous stem cell infusion&#xD;
                  following myeloablative therapy (timed from first day of protocol therapy)&#xD;
&#xD;
               -  Patients are not eligible post allogeneic stem cell transplant&#xD;
&#xD;
               -  Patients who have received an autologous stem cell infusion to support&#xD;
                  non-myeloablative therapy (such as 131 iodine [I]-MIBG) are eligible at any time&#xD;
                  as long as they meet the other criteria for eligibility&#xD;
&#xD;
          -  A minimum of 6 weeks must have elapsed after 131I-MIBG therapy prior to start of&#xD;
             protocol therapy&#xD;
&#xD;
          -  Prior anti-disialoganglioside (GD2) antibody, isotretinoin, or lenalidomide therapy:&#xD;
&#xD;
               -  Patients who have received prior anti-GD2 antibody therapy are eligible if they&#xD;
                  did not have tumor relapse/progression while receiving this therapy&#xD;
&#xD;
               -  Patients who have received either isotretinoin or lenalidomide are eligible, but&#xD;
                  not if they have received the two agents concomitantly&#xD;
&#xD;
          -  All cytokines or hematopoietic growth factors must be discontinued a minimum of 7 days&#xD;
             prior to protocol therapy&#xD;
&#xD;
          -  Patients must not be receiving any other anti-cancer agents or radiotherapy at the&#xD;
             time of study entry or while on study&#xD;
&#xD;
          -  Absolute phagocyte count (APC = neutrophils and monocytes): &gt;= 1000/mm^3&#xD;
&#xD;
          -  Absolute neutrophil count: &gt;= 750/mm^3&#xD;
&#xD;
          -  Platelet count: &gt;= 50,000/mm^3, transfusion independent (no platelet transfusions&#xD;
             within 1 week)&#xD;
&#xD;
          -  Hemoglobin &gt;= 8.0 (may transfuse)&#xD;
&#xD;
          -  Patients with known bone marrow metastatic disease will be eligible for study as long&#xD;
             as they meet hematologic function criteria; patients with marrow disease are not&#xD;
             evaluable for hematologic toxicity&#xD;
&#xD;
          -  Age-adjusted serum creatinine =&lt; 1.5 x normal for age or creatinine clearance or&#xD;
             glomerular filtration rate (GFR) &gt;= 60 cc/min/1.73 m^2&#xD;
&#xD;
               -  Age 1 month to &lt; 6 months: 0.4 mg/dL for males and 0.4 mg/dL for females&#xD;
&#xD;
               -  Age 6 months to &lt; 1 year: 0.5 mg/dL for males and 0.5 mg/dL for females&#xD;
&#xD;
               -  Age 1 to &lt; 2 years: 0.6 mg/dL for males and 0.6 mg/dL for females&#xD;
&#xD;
               -  Age 2 to &lt; 6 years: 0.8 mg/dL for males and 0.8 mg/dL for females&#xD;
&#xD;
               -  Age 6 to &lt; 10 years: 1.0 mg/dL for males and 1.0 mg/dL for females&#xD;
&#xD;
               -  Age 10 to &lt; 13 years: 1.2 mg/dL for males and 1.2 mg/dL for females&#xD;
&#xD;
               -  Age 13 to &lt; 16 years: 1.5 mg/dL for males and 1.4 mg/dL for females&#xD;
&#xD;
               -  Age &gt;= 16 years: 1.7 mg/dL for males and 1.4 mg/dL for females&#xD;
&#xD;
          -  =&lt; grade 2 hematuria (criteria applicable only for dose levels that include&#xD;
             isotretinoin) and =&lt; grade 2 proteinuria&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x upper limit of normal for age&#xD;
&#xD;
          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =&lt; 135&#xD;
             and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])&#xD;
             =&lt; 3 x upper limit of normal (note that for ALT, the upper limit of normal is defined&#xD;
             as 45 U/L)&#xD;
&#xD;
          -  Sinusoidal obstruction syndrome (SOS) if present, must be stable or improving&#xD;
             clinically&#xD;
&#xD;
          -  Cardiac function:&#xD;
&#xD;
               -  Normal ejection fraction (&gt;= 55%) documented by either echocardiogram or&#xD;
                  radionuclide multi gated acquisition scan (MUGA) evaluation; OR&#xD;
&#xD;
               -  Normal fractional shortening (&gt;= 27%) documented by echocardiogram&#xD;
&#xD;
          -  No dyspnea at rest&#xD;
&#xD;
          -  Serum triglyceride =&lt; 300 mg/dL (applicable only for dose levels that include&#xD;
             isotretinoin) (note that a non-fasting triglyceride value could be obtained, if this&#xD;
             is &gt; 300 mg/dL then a fasting triglyceride should be obtained and patient will be&#xD;
             eligible if the fasting level is =&lt; 300 mg/dL)&#xD;
&#xD;
          -  =&lt; grade 2 hypercalcemia (applicable only for dose levels that include cis retinoic&#xD;
             acid [RA])&#xD;
&#xD;
          -  Skin toxicity =&lt; grade 1&#xD;
&#xD;
          -  All post-menarchal females must have a negative beta-human chorionic gonadotropin&#xD;
             (HCG); males and females of reproductive age and childbearing potential must use&#xD;
             effective contraception for the duration of their participation; females of&#xD;
             childbearing potential (FCBP) must have a negative serum or urine pregnancy test with&#xD;
             a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24 hours prior&#xD;
             to prescribing lenalidomide for cycle 1 and must either commit to continued abstinence&#xD;
             from heterosexual intercourse or begin TWO acceptable methods of birth control, one&#xD;
             highly effective method and one additional effective method AT THE SAME TIME, at least&#xD;
             28 days before she starts taking lenalidomide; FCBP must also agree to ongoing&#xD;
             pregnancy testing; men must agree to use a latex condom during sexual contact with a&#xD;
             FCBP even if they have had a successful vasectomy&#xD;
&#xD;
          -  Patients with other ongoing serious medical issues must be approved by the study chair&#xD;
             prior to registration&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Quantitative serum b-HCG must be negative in girls who are post-menarchal; males or&#xD;
             females of reproductive potential may not participate unless they have agreed to use&#xD;
             an effective contraceptive method; pregnant or breast-feeding women will not be&#xD;
             entered on this study&#xD;
&#xD;
          -  Breast feeding women are not eligible&#xD;
&#xD;
          -  Patients who have an active or uncontrolled infection are excluded&#xD;
&#xD;
          -  Patients with a paraben allergy cannot take isotretinoin preparations containing this&#xD;
             compound (i.e. Accutane, Sotret) but are eligible if they can take an alternate&#xD;
             preparation without paraben; (applicable only for entry onto dose levels receiving&#xD;
             isotretinoin)&#xD;
&#xD;
          -  Patients with a history of venous or arterial thrombosis personally before the age of&#xD;
             40 years unless associated with a central line&#xD;
&#xD;
          -  Patients with a history of prior central nervous system (CNS) metastases or skull&#xD;
             lesions with intracranial extension will be required to have a head computed&#xD;
             tomography (CT) or magnetic resonance imaging (MRI) at study entry demonstrating no&#xD;
             active CNS metastases; patients with skull metastases with associated intracranial&#xD;
             soft tissue masses will remain eligible&#xD;
&#xD;
          -  Inability to swallow lenalidomide capsules whole; capsules of 13-isotretinoin may be&#xD;
             opened&#xD;
&#xD;
          -  Patient declines participation in NANT 2004-05; unless the institution has been&#xD;
             granted special exemption from mandatory enrollment on NANT 2004-05 by the NANT&#xD;
             Operations Center&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Araz Marachelian</last_name>
    <role>Principal Investigator</role>
    <affiliation>New Approaches to Neuroblastoma Treatment (NANT)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children's Hospital Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lucile Packard Children's Hospital Stanford University</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCSF Medical Center-Parnassus</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Healthcare of Atlanta - Egleston</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Chicago Comer Children's Hospital</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Boston Children's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>C S Mott Children's Hospital</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UNC Lineberger Comprehensive Cancer Center</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cook Children's Medical Center</name>
      <address>
        <city>Fort Worth</city>
        <state>Texas</state>
        <zip>76104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Children's Hospital</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital for Sick Children</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 1X8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>October 18, 2012</study_first_submitted>
  <study_first_submitted_qc>October 18, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 22, 2012</study_first_posted>
  <last_update_submitted>March 24, 2023</last_update_submitted>
  <last_update_submitted_qc>March 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 27, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuroblastoma</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin A</mesh_term>
    <mesh_term>Lenalidomide</mesh_term>
    <mesh_term>Tretinoin</mesh_term>
    <mesh_term>Dinutuximab</mesh_term>
    <mesh_term>Isotretinoin</mesh_term>
    <mesh_term>Antibodies, Monoclonal</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/NCT01711554
org study id: NCI-2012-02011
secondary id: NCI-2012-02011
secondary id: CDR0000741991
secondary id: N2011-04
secondary id: NANT 11-04
secondary id: NANT N2011-04
secondary id: NANT N2011-04
secondary id: P01CA081403
nct id: NCT01711554
lead sponsor: 
has dmc: No
This phase I trial studies the side effects and best dose of lenalidomide when given together
      with dinutuximab with or without isotretinoin in treating younger patients with neuroblastoma
      that does not respond to treatment or that has come back. Drugs used in chemotherapy, such as
      lenalidomide and isotretinoin, work in different ways to stop the growth of tumor cells,
      either by killing the cells, by stopping them from dividing, or by stopping them from
      spreading. Monoclonal antibodies, such as dinutuximab, may interfere with the ability of
      tumor cells to grow and spread. Giving more than one drug (combination chemotherapy) together
      with dinutuximab therapy may kill more tumor cells.
PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of
      lenalidomide in combination with fixed doses of dinutuximab (ch14.18) and isotretinoin given
      to children with refractory or recurrent neuroblastoma.

      II. To define the toxicities of lenalidomide administered in combination with ch14.18 and
      isotretinoin.

      III. To describe the differences in immune function modulation between "low" versus "high"
      dose lenalidomide given with ch14.18 and isotretinoin.

      SECONDARY OBJECTIVES:

      I. To determine the pharmacokinetics of lenalidomide given in this combination regimen.

      II. To determine the steady state pharmacokinetics of isotretinoin (day 28, course one) given
      in combination with lenalidomide.

      III. To measure peak and trough levels of ch14.18 in patients receiving lenalidomide and to
      compare to historical controls of patients receiving ch14.18 in combination with interleukin
      2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF).

      IV. To describe the immunological effects of lenalidomide (T cells, natural killer [NK]
      cells, monocytes, cytokines, chemokines) within this three drug regimen.

      V. To define the incidence and titers of human anti-chimeric antibody (HACA) on this regimen.

      VI. To describe, within the context of a phase I study, the response rate to lenalidomide
      combined with ch14.18 and isotretinoin in patients with recurrent/refractory neuroblastoma.

      VII. To summarize, within the context of a phase I study, the event-free survival of patients
      with recurrent/refractory neuroblastoma or in complete response (CR) after progressing, and
      who are treated with lenalidomide combined with ch14.18 and isotretinoin.

      VIII. To determine, within the context of a phase I study, if killer-cell immunoglobulin-like
      receptor (KIR) receptor-ligand mismatch or specific Fc gamma receptor (Fc gamma R) alleles
      are associated with anti-tumor response.

      IX. To quantify neuroblastoma tumor cell "load" using a 5-gene TaqMan Low Density Array
      (TLDA) assay in peripheral blood at study entry, following, with each disease evaluation and
      at end of therapy and bone marrow at study entry, with each response evaluation when bone
      marrow is sampled, and at end of therapy.

      X. To compare the toxicities of this regimen with the historical toxicity data from the
      Children's Oncology Group (COG) ANBL0032 and ANBL0931 studies of ch14.18 with IL-2, GM-CSF
      and isotretinoin.

      XI. To describe the tolerability and ability to give full doses of ch14.18 and lenalidomide
      over extended periods of time, i.e. in courses 6-12.

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

      Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, dinutuximab
      intravenously (IV) over 10 hours on days 8-11, and isotretinoin PO twice daily (BID) on days
      15-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up periodically.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose defined as the highest dose level tested at which 0/6 or 1/6 patients experience dose-limiting toxicity (DLT) graded using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) criteria, version 4.0
time frame: Up to 28 days
description: All toxicities observed will be summarized in terms of type (organ affected or laboratory determination), severity (by NCI CTCAE), and attribution. Tables will be created to summarize these toxicities and side effects by dose level and by course as well as with Kaplan-Meier plots (i.e. time to first delay or dose reduction) in order to assess the tolerability of the regime over multiple courses.
measure: Recommended phase II dose
time frame: Up to 28 days
description: Determination of the recommended phase II dose of lenalidomide will include consideration of obtaining median peak plasma lenalidomide levels of 5-10 uM (based on laboratory modeling of this regimen in neuroblastoma), acceptable clinical toxicity, and laboratory evidence of an augmentation in immune function.
measure: Overall survival
time frame: From start of lenalidomide until death for any reason or date that patient was last known to be alive if the patient is still alive, assessed up to 3 years
description: Will be summarized with Kaplan-Meier plots.
measure: Event-free survival
time frame: From the start of treatment with lenalidomide until progression, clinical deterioration mandating that the patient terminate treatment or death due to any cause, whichever occurs first, assessed up to 3 years
description: Will be summarized with Kaplan-Meier plots.
measure: Changes in the levels of T cells, natural killer (NK) cells, monocytes, cytokines, and chemokines
time frame: Baseline to up to 28 days
description: These levels and the changes relative to baseline will be summarized by dose level by simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatterplots will be used to explore possible associations between the dose and day and toxicity experienced (as reflected in the maximum grade of toxicity experienced, infections or platelet recovery).
measure: Changes in levels of HACA (or other genotype) and tumor response
time frame: Baseline to up to 3 years
description: These levels and the changes relative to baseline will be summarized by dose level by simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatterplots will be used to explore possible associations between the dose and day and toxicity experienced (as reflected in the maximum grade of toxicity experienced, infections or platelet recovery).
measure: Pharmacokinetic determinations of lenalidomide
time frame: Baseline, at 60 and 90 minutes, at 2, 6, 24 hours and days 7 and 22 after last dose of lenalidomide in course 1
description: These will be summarized by dose level with simple summary statistics: means (possibly after transformation) or medians, ranges, and standard deviations (if numbers and distribution permit). Scatterplots will be used to explore possible associations between the dose and estimates of the pharmacokinetic parameters, and between the pharmacokinetic determinations and toxicity experienced (as reflected in the maximum grade of toxicity experienced or in clinical measurements).
measure: Changes in TaqMan low density array (TLDA) scores
time frame: Baseline to up to 3 years
description: Standard descriptive summaries as well as scatterplots will be used. The association between the changes in TLDA scores and overall tumor response will also be summarized graphically and quantitatively. Changes (from baseline) in the TLDA scores over the course of treatment will be plotted and summarized by dose level and course.
measure: Overall response
time frame: Up to 3 years
description: The association between the changes in TLDA scores and overall tumor response will be summarized graphically and quantitatively.
arm group label: Treatment (lenalidomide, dinutuximab, isotretinoin)
arm group type: Experimental
description: Patients receive lenalidomide PO QD on days 1-21, dinutuximab IV over 10 hours on days 8-11, and isotretinoin PO BID on days 15-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
intervention type: Biological
intervention name: Dinutuximab
description: Given IV
arm group label: Treatment (lenalidomide, dinutuximab, isotretinoin)
other name: Ch 14.18UTC
other name: Ch14.18
other name: Dinutuximab Beta
other name: MOAB Ch14.18
other name: monoclonal antibody Ch14.18
other name: Qarziba
other name: Unituxin
intervention type: Drug
intervention name: Isotretinoin
description: Given PO
arm group label: Treatment (lenalidomide, dinutuximab, isotretinoin)
other name: 13-cis retinoic acid
other name: 13-cis-Retinoate
other name: 13-cis-Retinoic Acid
other name: 13-cis-Vitamin A Acid
other name: 13-cRA
other name: Absorica
other name: Accure
other name: Accutane
other name: Amnesteem
other name: cis-Retinoic Acid
other name: Cistane
other name: Claravis
other name: Isotretinoinum
other name: Isotrex
other name: Isotrexin
other name: Myorisan
other name: Neovitamin A
other name: Neovitamin A Acid
other name: Oratane
other name: Retinoicacid-13-cis
other name: Ro 4-3780
other name: Ro-4-3780
other name: Roaccutan
other name: Roaccutane
other name: Roacutan
other name: Sotret
other name: ZENATANE
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (lenalidomide, dinutuximab, isotretinoin)
intervention type: Drug
intervention name: Lenalidomide
description: Given PO
arm group label: Treatment (lenalidomide, dinutuximab, isotretinoin)
other name: CC-5013
other name: CC5013
other name: CDC 501
other name: Revlimid
intervention type: Other
intervention name: Pharmacological Study
description: Correlative studies
arm group label: Treatment (lenalidomide, dinutuximab, isotretinoin)
criteria: 
gender: All
minimum age: N/A
maximum age: 21 Years
healthy volunteers: No
last name: Araz Marachelian
role: Principal Investigator
affiliation: New Approaches to Neuroblastoma Treatment (NANT)
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Canada
country: United States
responsible party type: Sponsor
mesh term: Neuroblastoma
mesh term: Recurrence
mesh term: Vitamin A
mesh term: Lenalidomide
mesh term: Tretinoin
mesh term: Dinutuximab
mesh term: Isotretinoin
mesh term: Antibodies, Monoclonal