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

Trial Conditions

  • Neuroblastoma
  • Cancer

Trial Interventions

DrugSynonymsArms
CeritinibLDK378Group 1- ALK
TrametinibMEKINISTGroup 2-RAS-MAPK
HDM201Group 3- p53
RibociclibLEE011Group 1- ALK

Trial 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.

Detailed Description

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. Participants will receive the same dose of ceritinib, but 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 participants start at a lower dose of ribociclib, participants may take a higher dose once that dose has been deemed safe.
      • Ceritinib
                                  • Ribociclib
    Group 2-RAS-MAPKExperimentalQualified participants whose tumors show certain mutations in the rat sarcoma - mitogen activated protein kinase (RAS-MAPK) pathway (based on genetic sequencing results) will receive trametinib as a single agent, to be administered orally in 28-day cycles.
        • Trametinib
      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 once every 21 days. 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:

        - Age <1 year old

        - 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)

        - Corticosteroids initiated for tumor therapy within 7 days prior to study enrollment

        - Other anti-cancer agents

        - Other investigational drugs

        - 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:Both
        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:Yes
        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:No
        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.

        Trial Keywords

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