<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/NCT03838042</url>
  </required_header>
  <id_info>
    <org_study_id>Final3, 21-04-2021</org_study_id>
    <secondary_id>2018-000127-14</secondary_id>
    <secondary_id>NCT-2017-0516</secondary_id>
    <nct_id>NCT03838042</nct_id>
  </id_info>
  <brief_title>INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies</brief_title>
  <acronym>INFORM2 NivEnt</acronym>
  <official_title>INFORM2 Exploratory Multinational Phase I/II Combination Study of Nivolumab and Entinostat in Children and Adolescents With Refractory High-risk Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital Heidelberg</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>German Cancer Research Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital Heidelberg</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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of this trial is to determine preliminary activity of the combination treatment with&#xD;
      nivolumab and entinostat in children and adolescents with high risk&#xD;
      refractory/relapsed/progressive tumors harboring a high mutational load, high PD-L1 mRNA&#xD;
      expression or focal MYC(N) amplification and explore activity in biomarker low tumors (low&#xD;
      mutational load, low PD-L1 mRNA expression and non-MYC(N) amplified).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Compared to adult cancers, most pediatric cancers carry a relatively low mutational burden.&#xD;
      However, a small fraction of pediatric tumors in the INFORM registry cohort display a higher&#xD;
      mutational burden. Truly hypermutated tumors, e.g. in the context of rare cancer&#xD;
      predisposition syndromes, are reported to respond well to immune checkpoint inhibition. In&#xD;
      addition to hypermutation, increased PD-L1 expression is associated with clinical responses&#xD;
      to checkpoint inhibition. Increased PD-L1 mRNA expression is observed in a small fraction of&#xD;
      pediatric patients in the INFORM registry cohort independent from mutational load. We&#xD;
      hypothesize that pediatric tumors with a high mutational burden and/or high PD-L1 expression&#xD;
      will respond to checkpoint inhibition.&#xD;
&#xD;
      HDAC inhibition (HDACi) modifies T-cell regulation and can augment response to checkpoint&#xD;
      inhibition by reducing the number of myeloid-derived suppressor cells and creating an&#xD;
      immunogenic tumor microenvironment including induction of MHCI and neo-antigens. In vitro and&#xD;
      in vivo models showed enhanced anti-tumor activity of the combination of checkpoint&#xD;
      inhibition and HDACi compared to either agent alone. This provides a strong rationale to&#xD;
      combine these drug classes.&#xD;
&#xD;
      Furthermore, MYC- or NMYC-driven (referred to as MYC(N)) malignancies like very high-risk&#xD;
      medulloblastomas or very high-risk neuroblastomas still have a dismal outcome. MYC is not&#xD;
      only reported to upregulate PD-L1 and thereby a possible biomarker for checkpoint inhibition&#xD;
      but also very compelling recent preclinical data strongly suggests that HDAC inhibitors are&#xD;
      active against MYC amplified medulloblastoma in vitro and in vivo. In NMYC amplified&#xD;
      neuroblastoma cell lines similar observations were made in vitro. Taken together, our results&#xD;
      suggest that MYC(N)-driven tumors depend on HDAC and we hypothesize that MYC(N) status can&#xD;
      serve as a biomarker for response prediction to a combinatorial treatment of checkpoint&#xD;
      inhibition and HDAC inhibition.&#xD;
&#xD;
      Pediatric patients aged 6-21 years with refractory/relapsed/progressive high-risk&#xD;
      malignancies with a high mutational load (group A), with high PD-L1 mRNA expression (group&#xD;
      B), with MYC(N) amplification (group C) and with a low mutational load, low PD-L1 mRNA&#xD;
      expression and no MYC(N) amplification (Biomarker low group D) are eligible for this trial.&#xD;
      Phase I determines the recommended phase 2 dose (RP2D) for the combination of the HDACi&#xD;
      entinostat and the checkpoint inhibitor nivolumab for the age groups 6-11 and 12-21 years,&#xD;
      respectively. Phase II investigates activity in 4 groups A, B, C, D. The duration of&#xD;
      treatment is 12 cycles (1 cycle = 28 days), preceded by 1 priming week.&#xD;
&#xD;
      In addition, a comprehensive accompanying research program investigates PD biomarkers for&#xD;
      immune checkpoint and HDAC inhibition.&#xD;
&#xD;
      Clinical trials investigating the combination of nivolumab and entinostat in children have&#xD;
      not been reported so far.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">May 26, 2020</start_date>
  <completion_date type="Anticipated">June 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2024</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Phase I:&#xD;
To determine the recommended phase II dose (RP2D) of the combination treatment with nivolumab and entinostat administered to adolescents 12-21 years with progressive, relapsed, refractory high-risk solid tumors and CNS tumors To determine the recommended phase II dose (RP2D) of the combination treatment with nivolumab and entinostat administered to children 6-11 years with progressive, relapsed, refractory high-risk solid tumors and CNS Tumors&#xD;
Phase II:&#xD;
To evaluate activity and safety of the combination treatment with nivolumab and entinostat in children and adolescents with refractory/relapsed/progressive high-risk solid tumors and CNS tumors with:&#xD;
Group A: a high mutational load (&gt; 100 somatic SNVs/exome) Group B: high PD-L1 mRNA expression (RPKM by RNA-Seq &gt; 3) Group C: Focal MYC(N) amplification Group D: Patients with biomarker low tumors according to the definitions of group A-C.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Phase I: Dose Limiting Toxicity (DLT) of the combination treatment.</measure>
    <time_frame>5 weeks</time_frame>
    <description>A dose limiting toxicity (DLT) is defined as any AE according to the definitions and exceptions listed below that is related to the administration of the combination of investigational agents occurring during the priming week and first cycle of combination treatment (first 5 weeks) in phase I of the trial.&#xD;
A study participant will be considered evaluable for a DLT if at least 2 doses of nivolumab and 4 doses of entinostat were administered during the first 5 weeks (5 weeks normally incorporate the priming week and 1 cycle of planned combination treatment). Participants who discontinue treatment or have treatment delays preventing them from receiving the above defined minimal amount of treatment in the first cycle of combination treatment for reasons unrelated to study drug toxicity, are not evaluable for DLT and will be replaced in enrollment (maximum number of replacement subjects will be 3 per dose level).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase II: Best response (CR or PR)</measure>
    <time_frame>Change in 24 weeks</time_frame>
    <description>Best response (CR or PR) will be based on RANO criteria for all primary CNS tumors and RECIST for non-CNS tumors, defined for each patient as the best response under study combination therapy during the first 6 cycles (assessment every 2 cycles).&#xD;
Calcified or intra-osseous (osteo)sarcoma target lesions which were progressive before initiation of treatment and show SD on response evaluation (confirmation through a subsequent scan at least 4 weeks later) will be considered as a responder.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DOR)</measure>
    <time_frame>Phase II: maximum of 48 weeks</time_frame>
    <description>DOR will be evaluated for all patients who experienced (confirmed) response. Starting time point will be the time when best response was determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate (DCR)</measure>
    <time_frame>Phase II: maximum of 48 weeks</time_frame>
    <description>DCR will be evaluated in addition, also using iRECIST and iRANO.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stable disease (SD)</measure>
    <time_frame>Phase II: maximum of 12 cycles (each cycle is 28 days)</time_frame>
    <description>SD will be evaluated in addition, also using iRECIST and iRANO.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>4 years</time_frame>
    <description>The event-time endpoint PFS will be estimated using the Kaplan-Meier method, considering all the patients who started the treatment, whatever their compliance to treatment, including if the treatment was stopped prematurely for a reason other than disease progression. 95%-Confidence intervals will be provided for the Kaplan-Meier estimates.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Response (TTR)</measure>
    <time_frame>Phase II: maximum of 12 cycles (each cycle is 28 days)</time_frame>
    <description>The event-time endpoint TTR will be estimated using the Kaplan-Meier method, considering all the patients who started the treatment, whatever their compliance to treatment, including if the treatment was stopped prematurely for a reason other than disease progression. 95%-Confidence intervals will be provided for the Kaplan-Meier estimates.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Phase II: maximum of 48 weeks</time_frame>
    <description>The event-time endpoint OS will be estimated using the Kaplan-Meier method, considering all the patients who started the treatment, whatever their compliance to treatment, including if the treatment was stopped prematurely for a reason other than disease progression. 95%-Confidence intervals will be provided for the Kaplan-Meier estimates.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune related Response Rate (RR) measured by iRECIST criteria and iRANO criteria</measure>
    <time_frame>Phase II: maximum of 48 weeks</time_frame>
    <description>As a secondary endpoint for patients who continued treatment beyond progression in case of clinical benefit, response as assessed by iRECIST or iRANO will be performed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Plasma Time (Tmax)</measure>
    <time_frame>one week</time_frame>
    <description>Time to reach the maximum concentration (hr).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Plasma Concentration (Cmax)</measure>
    <time_frame>one week</time_frame>
    <description>The peak plasma concentration of a drug after Administration (ng/mL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Half-life</measure>
    <time_frame>one week</time_frame>
    <description>The time required for the concentration of the drug to reach half of its original value (hr)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the curve (AUC)</measure>
    <time_frame>one week</time_frame>
    <description>The integral of the concentration-time curve (ng/mL·hr)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>total Clearance (CI/F)</measure>
    <time_frame>one week</time_frame>
    <description>The total body clearance will be equal to the renal clearance + hepatic clearance + lung clearance (L/h/m²)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Exploratory: circulating tumor DNA (ctDNA)</measure>
    <time_frame>At baseline and every odd cycle (Cycle 3 - 12) and every third cycle (Cycle 13 - 24) (each cycle is 28 days).</time_frame>
    <description>Assessment of circulating Tumor DNA in peripheral blood.</description>
  </other_outcome>
  <other_outcome>
    <measure>Exploratory: Response prediction</measure>
    <time_frame>4 years</time_frame>
    <description>Response prediction in a co-clinical PDX model and drug testing program</description>
  </other_outcome>
  <other_outcome>
    <measure>Exploratory: Immune phenotyping (FACS Panel) and Luminex cytokine panel</measure>
    <time_frame>At baseline, after the priming week and after 5 weeks of initiation of therapy</time_frame>
    <description>Immune phenotyping (FACS Panel) and Luminex cytokine panel in peripheral blood.</description>
  </other_outcome>
  <other_outcome>
    <measure>Exploratory: mRNA expression</measure>
    <time_frame>4 years</time_frame>
    <description>Analyze mRNA Expression data for Tumor infiltrating immune cell populations</description>
  </other_outcome>
  <other_outcome>
    <measure>Exploratory: gene signatures</measure>
    <time_frame>4 years</time_frame>
    <description>Analyze gene signature in whole exome data</description>
  </other_outcome>
  <other_outcome>
    <measure>Exploratory: cryptic transcription start sites</measure>
    <time_frame>At baseline, after priming week and after 5 weeks of initiation of therapy</time_frame>
    <description>Test induction of cryptic transcription start sites</description>
  </other_outcome>
  <other_outcome>
    <measure>Exploratory: Single nucleotide variant (SNV) load</measure>
    <time_frame>4 years</time_frame>
    <description>Determination of SNV load by different methods (WES, Panel-Seq)</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">128</enrollment>
  <condition>CNS Tumor</condition>
  <condition>Solid Tumor</condition>
  <arm_group>
    <arm_group_label>Nivolumab and Entinostat</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Combination Study of Nivolumab and Entinostat</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab and Entinostat</intervention_name>
    <description>Patients entering phase I will receive one week entinostat without nivolumab (priming phase) before receiving the combination treatment of nivolumab and entinostat.</description>
    <arm_group_label>Nivolumab and Entinostat</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Children and adolescents with refractory/relapsed/progressive high-risk&#xD;
&#xD;
               -  CNS tumors: medulloblastoma, ependymoma, ATRT, ETMR, pediatric high grade glioma&#xD;
                  (including DIPG) or other pediatric embryonal CNS tumors OR&#xD;
&#xD;
               -  solid tumors: neuroblastoma, nephroblastoma, rhabdoid tumor, embryonal or&#xD;
                  alveolar rhabdomyosarcoma, other embryonal small round blue cell tumors including&#xD;
                  pediatric type (bone) sarcoma or other pediatric type solid tumors OR&#xD;
&#xD;
               -  Children and adolescents with newly diagnosed high grade glioma (HGG) in the&#xD;
                  context of a constitutional mismatch repair deficiency syndrome after maximum&#xD;
                  safe surgical resection with no established standard of care treatment option&#xD;
                  with curative intention available. In addition in France: ineligible to&#xD;
                  radiotherapy&#xD;
&#xD;
          -  No standard of care treatment available&#xD;
&#xD;
          -  Age at registration ≥ 6 to ≤ 21 years&#xD;
&#xD;
          -  Molecular analysis for biomarker identification (SNV load, PDL1 mRNA expression, MYC/N&#xD;
             amplification) in laboratories complying with DIN EN ISO/IEC 17025 or similar via&#xD;
             INFORM molecular diagnostic platform or equivalently valid molecular pipeline&#xD;
&#xD;
          -  Biomarker determined using whole exome sequencing (SNV load), RNA-sequencing (PDL1&#xD;
             mRNA expression), whole genome- or whole exome sequencing (MYC/N amplification)&#xD;
&#xD;
          -  In case molecular analysis was not performed via INFORM Registry molecular pipeline:&#xD;
             transfer of molecular data (whole exome and RNA sequencing)&#xD;
&#xD;
          -  Time between biopsy/puncture/resection of the current refractory/relapsed/progressive&#xD;
             tumor and registration ≤ 24 weeks. In patients receiving therapy not impacting&#xD;
             biomarker stratification, time between biopsy/puncture/resection of the current&#xD;
             refractory/relapsed/progressive tumor and registration of ≤ 36 weeks is allowed&#xD;
&#xD;
          -  Disease that is measurable as defined by RANO criteria or RECIST v1.1 (as&#xD;
             appropriate).&#xD;
&#xD;
          -  Life expectancy &gt; 3 months, sufficient general condition score (Lansky ≥ 70 or&#xD;
             Karnofsky ≥ 70). Transient states like infections can be accepted, and also stable&#xD;
             disabilities resulting from disease/surgery (hemiparesis, amputations etc.) can be&#xD;
             accepted and will not be considered for Lansky/Karnofsky assessments.&#xD;
&#xD;
          -  Laboratory requirements:&#xD;
&#xD;
               -  Hematology:&#xD;
&#xD;
                    -  absolute granulocytes ≥ 1.0 × 109/l (unsupported)&#xD;
&#xD;
                    -  platelets ≥ 100 × 109/l &amp; stable&#xD;
&#xD;
                    -  hemoglobin ≥ 8 g/dl or ≥ 4.96 mmol/L&#xD;
&#xD;
               -  Biochemistry:&#xD;
&#xD;
                    -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN)&#xD;
&#xD;
                    -  AST(SGOT) ≤ 3.0 x ULN&#xD;
&#xD;
                    -  ALT(SGPT) ≤ 3.0 x ULN&#xD;
&#xD;
                    -  serum creatinine ≤ 1.5 x ULN for age&#xD;
&#xD;
          -  ECG: normal QTc interval according to Bazett formula &lt; 440ms&#xD;
&#xD;
          -  Patient is able to swallow oral study medication&#xD;
&#xD;
          -  Ability of patient and/or legal representative(s) to understand the character and&#xD;
             individual consequences of clinical trial&#xD;
&#xD;
          -  Females of childbearing potential must have a negative serum or urine pregnancy test&#xD;
             within 7 days prior to initiation of treatment. Sexually active women of childbearing&#xD;
             potential must agree to use acceptable and appropriate contraception during the study&#xD;
             and for at least 6 months after the last study treatment administration. Sexually&#xD;
             active male patients must agree to use a condom during the study and for at least 3&#xD;
             months after the last study treatment administration.&#xD;
&#xD;
          -  Absence of any psychological, familial, sociological or geographical condition&#xD;
             potentially hampering compliance with the study protocol and follow-up schedule; those&#xD;
             conditions should be discussed with the patient before registration in the trial&#xD;
&#xD;
          -  Before patient screening and registration, written informed consent, also concerning&#xD;
             data and blood transfer, must be given according to ICH/GCP, and national/local&#xD;
             regulations.&#xD;
&#xD;
          -  No prior therapy with the combination of immune checkpoint inhibitors and HDACi&#xD;
&#xD;
          -  BSA ≥ 0.9m2&#xD;
&#xD;
          -  Phase I: molecular analysis performed and biomarker status known (mutational load,&#xD;
             PD-L1 mRNA expression AND MYC(N) amplification status).&#xD;
&#xD;
          -  Phase II: molecular analysis performed, biomarker status known (mutational load, PD-L1&#xD;
             mRNA expression AND MYC(N) amplification status) and stratification according to the&#xD;
             following criteria:&#xD;
&#xD;
               -  Group A: high mutational load (defined as &gt; 100 somatic SNVs/exome) based on&#xD;
                  whole exome sequencing OR&#xD;
&#xD;
               -  Group B: high PD-L1 mRNA expression (defined as reads per million total reads per&#xD;
                  kilobase of exon model (RPKM) &gt; 3) based on RNA sequencing OR&#xD;
&#xD;
               -  Group C: Focal MYC(N) amplification based on whole genome sequencing or whole&#xD;
                  exome sequencing OR&#xD;
&#xD;
               -  Group D: Patients with biomarker low tumors according to the definitions of group&#xD;
                  A-C.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with CNS tumors or metastases who are neurologically unstable despite&#xD;
             adequate treatment (e.g. convulsions).&#xD;
&#xD;
          -  Patients with low-grade gliomas or tumors of unknown malignant potential are not&#xD;
             eligible&#xD;
&#xD;
          -  Evidence of &gt; Grade 1 recent CNS hemorrhage on the baseline MRI scan.&#xD;
&#xD;
          -  Participants with bulky CNS tumor on imaging are ineligible; bulky tumor is defined&#xD;
             as:&#xD;
&#xD;
               -  Tumor with any evidence of uncal herniation or severe midline shift&#xD;
&#xD;
               -  Tumor with diameter of &gt; 6 cm in one dimension on contrast-enhanced MRI&#xD;
&#xD;
               -  Tumor that in the opinion of the investigator, shows significant mass effect&#xD;
&#xD;
          -  Previous allogeneic bone marrow, stem cell or organ transplantation&#xD;
&#xD;
          -  Diagnosis of immunodeficiency&#xD;
&#xD;
          -  Diagnosis of prior or active autoimmune disease&#xD;
&#xD;
          -  Evidence of interstitial lung disease&#xD;
&#xD;
          -  Any contraindication to oral agents or significant nausea and vomiting, malabsorption,&#xD;
             or significant small bowel resection that, in the opinion of the investigator, would&#xD;
             preclude adequate absorption.&#xD;
&#xD;
          -  Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Known active&#xD;
             hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g.,&#xD;
             hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis B&#xD;
             virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis&#xD;
             B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA test must be&#xD;
             performed in these patients prior to study treatment. Patients positive for hepatitis&#xD;
             C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for&#xD;
             HCV RNA.&#xD;
&#xD;
          -  Clinically significant, uncontrolled heart disease&#xD;
&#xD;
          -  Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal&#xD;
             shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access&#xD;
             devices are not considered major surgery, but for these procedures, a 48 hour interval&#xD;
             must be maintained before the first dose of the investigational drug is administered.&#xD;
&#xD;
          -  Any anticancer therapy (e.g., chemotherapy, HDACi (including valproic acid), DNA&#xD;
             methyltransferase inhibitors, other immunotherapy, targeted therapy, biological&#xD;
             response modifiers, endocrine anticancer therapy or radiotherapy) within 2 weeks or at&#xD;
             least 5 half- lives (whichever is longer) of study drug administration.&#xD;
&#xD;
          -  Radiologically confirmed radiotherapy induced pseudoprogression in CNS tumors&#xD;
&#xD;
          -  Traditional herbal medicines; these therapies are not fully studied and their use may&#xD;
             result in unanticipated drug-drug interactions that may cause or confound the&#xD;
             assessment of toxicity. As part of the enrollment/informed consent procedures, the&#xD;
             patient will be counseled on the risk of interactions with other agents, and what to&#xD;
             do if new medications need to be prescribed or if the patient is considering a new&#xD;
             over-the- counter medicine or herbal product. For information on CYP substrates and&#xD;
             P-gp inhibitors or inducers see section 5.8.&#xD;
&#xD;
          -  History of hypersensitivity to the investigational medicinal product or to any drug&#xD;
             with similar chemical structure or to any excipient present in the pharmaceutical form&#xD;
             (including benzamide) of the investigational medicinal product&#xD;
&#xD;
          -  Participation in other ongoing clinical trials.&#xD;
&#xD;
          -  Pregnant or lactating females.&#xD;
&#xD;
          -  Presence of underlying medical condition (e.g. gastrointestinal disorders or&#xD;
             electrolyte disturbances) that in the opinion of the Investigator or Sponsor could&#xD;
             adversely affect the ability of the subject to comply with or tolerate study&#xD;
             procedures and/or study therapy, or confound the ability to interpret the tolerability&#xD;
             of combined administration of entinostat and nivolumab in treated subjects&#xD;
&#xD;
          -  Patients receiving systemic steroid therapy or any other form of immunosuppressive&#xD;
             therapy within 7 days prior to the first dose of study treatment. The use of&#xD;
             physiologic doses of corticosteroids (up to 5 mg/m2/day prednisone equivalent) may be&#xD;
             approved after consultation with the Sponsor. No patient will be allowed to enroll in&#xD;
             this trial more than once.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Melanie Heiss</last_name>
    <phone>+496221 56 7255</phone>
    <email>melanie.heiss@kitz-heidelberg.de</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ruth Witt</last_name>
    <email>ruth.witt@kitz-heidelberg.de</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Sydney Children's Hospital</name>
      <address>
        <city>Randwick</city>
        <state>New South Wales</state>
        <zip>2031</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>David Ziegler</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Children's Hospital at Westmead</name>
      <address>
        <city>Westmead</city>
        <state>New South Wales</state>
        <zip>2145</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Dinisha Govender</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal Children's Hospital</name>
      <address>
        <city>Parkville</city>
        <state>Victoria</state>
        <zip>3052</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Dong Anh Khuong Quang</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Perth Children's Hospital</name>
      <address>
        <city>Nedlands</city>
        <state>Western Australia</state>
        <zip>6009</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Nick Gottardo</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>St. Anna Children's Hospital</name>
      <address>
        <city>Vienna</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Caroline Hutter</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Institut Curie</name>
      <address>
        <city>Paris</city>
        <zip>75005</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Gudrun Schleiermacher</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Augsburg University Hospital</name>
      <address>
        <city>Augsburg</city>
        <zip>86156</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Michael Frühwald, Prof. Dr. Dr.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Charité University Medicine Berlin</name>
      <address>
        <city>Berlin</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Anne Thorwarth, Dr. med.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Essen University Hospital</name>
      <address>
        <city>Essen</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Uta Dirksen, Prof. Dr. med.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hannover Medical School</name>
      <address>
        <city>Hannover</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Andreas Beilken, Dr. med.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hopp Children's Cancer Center Heidelberg (KiTZ)</name>
      <address>
        <city>Heidelberg</city>
        <zip>69120</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>INFORM2 Team</last_name>
      <email>inform2@kitz-heidelberg.de</email>
    </contact>
    <investigator>
      <last_name>Olaf Witt, Prof. Dr. med.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Prinses Máxima Centrum</name>
      <address>
        <city>Utrecht</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Jasper van der Lugt</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Karolinska Institute</name>
      <address>
        <city>Stockholm</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Anna Nilsson</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Children's Hospital Zurich</name>
      <address>
        <city>Zurich</city>
        <zip>8032</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Nicolas Gerber</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Austria</country>
    <country>France</country>
    <country>Germany</country>
    <country>Netherlands</country>
    <country>Sweden</country>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>February 4, 2019</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <last_update_submitted>November 8, 2022</last_update_submitted>
  <last_update_submitted_qc>November 8, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 9, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital Heidelberg</investigator_affiliation>
    <investigator_full_name>Prof. Dr. Olaf Witt</investigator_full_name>
    <investigator_title>Prof. Dr. Olaf Witt</investigator_title>
  </responsible_party>
  <keyword>high-risk solid tumors</keyword>
  <keyword>high-risk CNS tumors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Central Nervous System Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Entinostat</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The pseudonymized data will be shared for transparency reasons in the context of publications and after publication with other physicians and scientists (national and international academia) to promote and accelerate research on causes and treatment development of oncological diseases.&#xD;
Requests for access to pseudonymized patient data for non-INFORM-related scientific purposes will be reviewed by a Data Access Committee consisting of the INFORM Board, and the participating investigators. A positive statement of the respective ethic committee and a signed data protection commitment are requested. Requests should be addressed to the coordinating investigator Prof. Olaf Witt. Results of scientific research based on the INFORM2 NivEnt data may be used for academic teaching, research and scientific publications or presentations at scientific meetings.</ipd_description>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03838042
org study id: Final3, 21-04-2021
secondary id: 2018-000127-14
secondary id: NCT-2017-0516
nct id: NCT03838042
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The aim of this trial is to determine preliminary activity of the combination treatment with
      nivolumab and entinostat in children and adolescents with high risk
      refractory/relapsed/progressive tumors harboring a high mutational load, high PD-L1 mRNA
      expression or focal MYC(N) amplification and explore activity in biomarker low tumors (low
      mutational load, low PD-L1 mRNA expression and non-MYC(N) amplified).
Compared to adult cancers, most pediatric cancers carry a relatively low mutational burden.
      However, a small fraction of pediatric tumors in the INFORM registry cohort display a higher
      mutational burden. Truly hypermutated tumors, e.g. in the context of rare cancer
      predisposition syndromes, are reported to respond well to immune checkpoint inhibition. In
      addition to hypermutation, increased PD-L1 expression is associated with clinical responses
      to checkpoint inhibition. Increased PD-L1 mRNA expression is observed in a small fraction of
      pediatric patients in the INFORM registry cohort independent from mutational load. We
      hypothesize that pediatric tumors with a high mutational burden and/or high PD-L1 expression
      will respond to checkpoint inhibition.

      HDAC inhibition (HDACi) modifies T-cell regulation and can augment response to checkpoint
      inhibition by reducing the number of myeloid-derived suppressor cells and creating an
      immunogenic tumor microenvironment including induction of MHCI and neo-antigens. In vitro and
      in vivo models showed enhanced anti-tumor activity of the combination of checkpoint
      inhibition and HDACi compared to either agent alone. This provides a strong rationale to
      combine these drug classes.

      Furthermore, MYC- or NMYC-driven (referred to as MYC(N)) malignancies like very high-risk
      medulloblastomas or very high-risk neuroblastomas still have a dismal outcome. MYC is not
      only reported to upregulate PD-L1 and thereby a possible biomarker for checkpoint inhibition
      but also very compelling recent preclinical data strongly suggests that HDAC inhibitors are
      active against MYC amplified medulloblastoma in vitro and in vivo. In NMYC amplified
      neuroblastoma cell lines similar observations were made in vitro. Taken together, our results
      suggest that MYC(N)-driven tumors depend on HDAC and we hypothesize that MYC(N) status can
      serve as a biomarker for response prediction to a combinatorial treatment of checkpoint
      inhibition and HDAC inhibition.

      Pediatric patients aged 6-21 years with refractory/relapsed/progressive high-risk
      malignancies with a high mutational load (group A), with high PD-L1 mRNA expression (group
      B), with MYC(N) amplification (group C) and with a low mutational load, low PD-L1 mRNA
      expression and no MYC(N) amplification (Biomarker low group D) are eligible for this trial.
      Phase I determines the recommended phase 2 dose (RP2D) for the combination of the HDACi
      entinostat and the checkpoint inhibitor nivolumab for the age groups 6-11 and 12-21 years,
      respectively. Phase II investigates activity in 4 groups A, B, C, D. The duration of
      treatment is 12 cycles (1 cycle = 28 days), preceded by 1 priming week.

      In addition, a comprehensive accompanying research program investigates PD biomarkers for
      immune checkpoint and HDAC inhibition.

      Clinical trials investigating the combination of nivolumab and entinostat in children have
      not been reported so far.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Phase I:
To determine the recommended phase II dose (RP2D) of the combination treatment with nivolumab and entinostat administered to adolescents 12-21 years with progressive, relapsed, refractory high-risk solid tumors and CNS tumors To determine the recommended phase II dose (RP2D) of the combination treatment with nivolumab and entinostat administered to children 6-11 years with progressive, relapsed, refractory high-risk solid tumors and CNS Tumors
Phase II:
To evaluate activity and safety of the combination treatment with nivolumab and entinostat in children and adolescents with refractory/relapsed/progressive high-risk solid tumors and CNS tumors with:
Group A: a high mutational load (> 100 somatic SNVs/exome) Group B: high PD-L1 mRNA expression (RPKM by RNA-Seq > 3) Group C: Focal MYC(N) amplification Group D: Patients with biomarker low tumors according to the definitions of group A-C.
primary purpose: Treatment
masking: None (Open Label)
measure: Phase I: Dose Limiting Toxicity (DLT) of the combination treatment.
time frame: 5 weeks
description: A dose limiting toxicity (DLT) is defined as any AE according to the definitions and exceptions listed below that is related to the administration of the combination of investigational agents occurring during the priming week and first cycle of combination treatment (first 5 weeks) in phase I of the trial.
A study participant will be considered evaluable for a DLT if at least 2 doses of nivolumab and 4 doses of entinostat were administered during the first 5 weeks (5 weeks normally incorporate the priming week and 1 cycle of planned combination treatment). Participants who discontinue treatment or have treatment delays preventing them from receiving the above defined minimal amount of treatment in the first cycle of combination treatment for reasons unrelated to study drug toxicity, are not evaluable for DLT and will be replaced in enrollment (maximum number of replacement subjects will be 3 per dose level).
measure: Phase II: Best response (CR or PR)
time frame: Change in 24 weeks
description: Best response (CR or PR) will be based on RANO criteria for all primary CNS tumors and RECIST for non-CNS tumors, defined for each patient as the best response under study combination therapy during the first 6 cycles (assessment every 2 cycles).
Calcified or intra-osseous (osteo)sarcoma target lesions which were progressive before initiation of treatment and show SD on response evaluation (confirmation through a subsequent scan at least 4 weeks later) will be considered as a responder.
measure: Duration of Response (DOR)
time frame: Phase II: maximum of 48 weeks
description: DOR will be evaluated for all patients who experienced (confirmed) response. Starting time point will be the time when best response was determined.
measure: Disease Control Rate (DCR)
time frame: Phase II: maximum of 48 weeks
description: DCR will be evaluated in addition, also using iRECIST and iRANO.
measure: Stable disease (SD)
time frame: Phase II: maximum of 12 cycles (each cycle is 28 days)
description: SD will be evaluated in addition, also using iRECIST and iRANO.
measure: Progression-free survival (PFS)
time frame: 4 years
description: The event-time endpoint PFS will be estimated using the Kaplan-Meier method, considering all the patients who started the treatment, whatever their compliance to treatment, including if the treatment was stopped prematurely for a reason other than disease progression. 95%-Confidence intervals will be provided for the Kaplan-Meier estimates.
measure: Time to Response (TTR)
time frame: Phase II: maximum of 12 cycles (each cycle is 28 days)
description: The event-time endpoint TTR will be estimated using the Kaplan-Meier method, considering all the patients who started the treatment, whatever their compliance to treatment, including if the treatment was stopped prematurely for a reason other than disease progression. 95%-Confidence intervals will be provided for the Kaplan-Meier estimates.
measure: Overall Survival (OS)
time frame: Phase II: maximum of 48 weeks
description: The event-time endpoint OS will be estimated using the Kaplan-Meier method, considering all the patients who started the treatment, whatever their compliance to treatment, including if the treatment was stopped prematurely for a reason other than disease progression. 95%-Confidence intervals will be provided for the Kaplan-Meier estimates.
measure: Immune related Response Rate (RR) measured by iRECIST criteria and iRANO criteria
time frame: Phase II: maximum of 48 weeks
description: As a secondary endpoint for patients who continued treatment beyond progression in case of clinical benefit, response as assessed by iRECIST or iRANO will be performed.
measure: Maximum Plasma Time (Tmax)
time frame: one week
description: Time to reach the maximum concentration (hr).
measure: Maximum Plasma Concentration (Cmax)
time frame: one week
description: The peak plasma concentration of a drug after Administration (ng/mL)
measure: Half-life
time frame: one week
description: The time required for the concentration of the drug to reach half of its original value (hr)
measure: Area under the curve (AUC)
time frame: one week
description: The integral of the concentration-time curve (ng/mL·hr)
measure: total Clearance (CI/F)
time frame: one week
description: The total body clearance will be equal to the renal clearance + hepatic clearance + lung clearance (L/h/m²)
measure: Exploratory: circulating tumor DNA (ctDNA)
time frame: At baseline and every odd cycle (Cycle 3 - 12) and every third cycle (Cycle 13 - 24) (each cycle is 28 days).
description: Assessment of circulating Tumor DNA in peripheral blood.
measure: Exploratory: Response prediction
time frame: 4 years
description: Response prediction in a co-clinical PDX model and drug testing program
measure: Exploratory: Immune phenotyping (FACS Panel) and Luminex cytokine panel
time frame: At baseline, after the priming week and after 5 weeks of initiation of therapy
description: Immune phenotyping (FACS Panel) and Luminex cytokine panel in peripheral blood.
measure: Exploratory: mRNA expression
time frame: 4 years
description: Analyze mRNA Expression data for Tumor infiltrating immune cell populations
measure: Exploratory: gene signatures
time frame: 4 years
description: Analyze gene signature in whole exome data
measure: Exploratory: cryptic transcription start sites
time frame: At baseline, after priming week and after 5 weeks of initiation of therapy
description: Test induction of cryptic transcription start sites
measure: Exploratory: Single nucleotide variant (SNV) load
time frame: 4 years
description: Determination of SNV load by different methods (WES, Panel-Seq)
arm group label: Nivolumab and Entinostat
arm group type: Experimental
description: Combination Study of Nivolumab and Entinostat
intervention type: Drug
intervention name: Nivolumab and Entinostat
description: Patients entering phase I will receive one week entinostat without nivolumab (priming phase) before receiving the combination treatment of nivolumab and entinostat.
arm group label: Nivolumab and Entinostat
criteria: 
gender: All
minimum age: 6 Years
maximum age: 21 Years
healthy volunteers: No
last name: Melanie Heiss
phone: +496221 56 7255
email: melanie.heiss@kitz-heidelberg.de
last name: Ruth Witt
email: ruth.witt@kitz-heidelberg.de
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
country: Australia
country: Austria
country: France
country: Germany
country: Netherlands
country: Sweden
country: Switzerland
responsible party type: Principal Investigator
investigator affiliation: University Hospital Heidelberg
investigator full name: Prof. Dr. Olaf Witt
investigator title: Prof. Dr. Olaf Witt
mesh term: Neoplasms
mesh term: Central Nervous System Neoplasms
mesh term: Nivolumab
mesh term: Entinostat
sharing ipd: Yes
ipd description: The pseudonymized data will be shared for transparency reasons in the context of publications and after publication with other physicians and scientists (national and international academia) to promote and accelerate research on causes and treatment development of oncological diseases.
Requests for access to pseudonymized patient data for non-INFORM-related scientific purposes will be reviewed by a Data Access Committee consisting of the INFORM Board, and the participating investigators. A positive statement of the respective ethic committee and a signed data protection commitment are requested. Requests should be addressed to the coordinating investigator Prof. Olaf Witt. Results of scientific research based on the INFORM2 NivEnt data may be used for academic teaching, research and scientific publications or presentations at scientific meetings.
ipd info type: Clinical Study Report (CSR)