Clinical Trials /

Next Generation Personalized Neuroblastoma Therapy

NCT02780128

Description:

The purpose of this research study is to match genomic aberrations in tumor cells at time of relapse to rationally designed combinations of molecularly targeted agents. This study will be done in two parts: Part I: Tumor will be accessed at study entry via a biopsy and subjected to deep sequencing to identify protocol-specified biomarkers for therapy assignment. Part II: If the tumor contains a genetic change defined by the study as being actionable, and other criteria are met, participants will be assigned to therapy based upon the genetic changes identified in the tumor biopsy.

Related Conditions:
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Next Generation Personalized Neuroblastoma Therapy
  • Official Title: Next Generation Personalized Neuroblastoma Therapy (The NEPENTHE Trial)

Clinical Trial IDs

  • ORG STUDY ID: 14-011071
  • NCT ID: NCT02780128

Conditions

  • Neuroblastoma
  • Cancer

Interventions

DrugSynonymsArms
CeritinibLDK378Group 1: ALK
TrametinibMEKINISTGroup 2B: RAS-MAPK or CDK4/6
HDM201Group 3: p53
RibociclibLEE011Group 1: ALK

Purpose

The purpose of this research study is to match genomic aberrations in tumor cells at time of relapse to rationally designed combinations of molecularly targeted agents. This study will be done in two parts: Part I: Tumor will be accessed at study entry via a biopsy and subjected to deep sequencing to identify protocol-specified biomarkers for therapy assignment. Part II: If the tumor contains a genetic change defined by the study as being actionable, and other criteria are met, participants will be assigned to therapy based upon the genetic changes identified in the tumor biopsy.

Trial Arms

NameTypeDescriptionInterventions
Molecular AnalysisOtherAll participants with relapsed or refractory neuroblastoma will have a tumor biopsy to identify genetic mutations. There is no drug given in this arm of the trial.
    Group 1: ALKExperimentalQualified participants whose tumors show certain mutations in the anaplastic lymphoma kinase (ALK) pathway (based on genetic sequencing results) will receive a combination therapy of ceritinib and ribociclib, to be administered orally in 28-day cycles. Two different doses of ceritinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level. It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
    • Ceritinib
    • Ribociclib
    Group 2B: RAS-MAPK or CDK4/6ExperimentalQualified participants whose tumors show certain mutations in the rat sarcoma - mitogen activated protein kinase (RAS-MAPK) or CDK4/6 pathway (based on genetic sequencing results) will receive a combination therapy of trametinib and ribociclib, to be administered orally in 21-day cycles. Two different doses of trametinib and three different doses of ribociclib will be evaluated. Once the investigators have identified the highest safe dose of both drugs that can be given at the same time, additional participants will be enrolled in the study at this dose level. It is possible that if starting at a lower dose, participants may take a higher dose once that dose has been deemed safe.
    • Trametinib
    • Ribociclib
    Group 3: p53ExperimentalQualified participants that do not match Groups 1 or 2, and whose tumors show wild-type p53 (based on genetic sequencing results) will receive HDM201 as a single agent, to be administered orally on Day 1 and Day 8 in 28-day cycles. The investigators will perform a dose-escalation of HDM201. Once the investigators have identified the highest safe dose of HDM201, additional participants will be enrolled in the study at this dose level.
    • HDM201

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Aged ≥1 years to ≤ 21 years
    
              -  Relapsed or refractory neuroblastoma
    
              -  A sufficient interval between the last dose of prior anti-cancer therapy (including
                 cytotoxic and biological therapies) and enrollment in this study, to allow recovery
                 from the acute toxic effects of all prior anti-cancer therapy. Please contact site for
                 specific details
    
              -  Adequate bone marrow function (bone marrow may be involved with tumor. Contact site
                 for specific details)
    
              -  Adequate renal function, defined as Creatinine clearance or radioisotope glomerular
                 filtration rate (GFR) ≥ 70 mL/min/1.73 m2 OR serum creatinine based on age/gender
                 normal (contact site for details)
    
              -  Adequate liver function, defined as total serum bilirubin ≤ 1.5 times the upper limit
                 of normal AND alanine transaminase (ALT) ≤ 110 U/L.
    
              -  Adequate cardiac function, defined as corrected QT interval (QTc) ≤ 480 msec AND
                 shortening fraction > 27%
    
              -  Males and females who are sexually active must agree to use effective contraception
                 during and for 3 months after treatment
    
            Exclusion Criteria:
    
              -  Subjects taking certain drugs or herbal medications that impact drug metabolism and/or
                 cardiac function that cannot be discontinued (contact site for details).
    
              -  Subjects with concurrent severe and/or uncontrolled concurrent medical conditions that
                 could compromise participation in the study (contact site for details)
    
              -  Other concomitant therapies:
    
              -  Corticosteroids initiated for tumor therapy within 7 days prior to study enrollment
    
              -  Other anti-cancer agents
    
              -  Other investigational drugs
    
              -  Hematological growth factors
    
              -  Radiation therapy
    
              -  Subjects < 0.5m2
    
              -  Pregnant or lactating females
    
              -  Sexually active males unless they use a condom during intercourse while taking study
                 drug/s and for 3 months after study drug discontinuation and thus do not attempt to
                 father a child in this period.
          
    Maximum Eligible Age:21 Years
    Minimum Eligible Age:1 Year
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Incidence of dose limiting toxicities when combining ceritinib combined with ribociclib
    Time Frame:28-day cycle one of therapy
    Safety Issue:
    Description:The primary variable is the incidence of dose limiting toxicities (DLTs) during the first 28 days of therapy.

    Secondary Outcome Measures

    Measure:Cataloguing of genomic alterations identified from biopsies performed at time of relapse in patients with relapsed or refractory neuroblastoma
    Time Frame:3 years
    Safety Issue:
    Description:Neuroblastomas undergo substantial mutational evolution during therapy, and relapsed disease is more likely to be driven by a targetable oncogenic pathway. Genomic alterations measured by next-generation sequencing at time of disease progression will be characterized and reported in a descriptive manner.

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Yael P Mosse

    Trial Keywords

    • neuroblastoma
    • cancer
    • genetic profiling
    • ceritinib
    • ribociclib
    • trametinib
    • HDM201

    Last Updated

    July 18, 2019