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Pediatric Precision Laboratory Advanced Neuroblastoma Therapy (PEDS-PLAN)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02559778
Recruitment Status : Recruiting
First Posted : September 24, 2015
Last Update Posted : November 18, 2020
Sponsor:
Collaborators:
Dell, Inc.
Beat NB Cancer Foundation
KC Pharma
Information provided by (Responsible Party):
Giselle SaulnierSholler, Atrium Health

Tracking Information
First Submitted Date  ICMJE September 22, 2015
First Posted Date  ICMJE September 24, 2015
Last Update Posted Date November 18, 2020
Actual Study Start Date  ICMJE September 2015
Estimated Primary Completion Date September 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 23, 2019)
  • Number of days from start of therapy to date of first relapse [ Time Frame: Up to 8 years ]
    To measure the response of treatments chosen based on: • Event free survival (EFS)
  • Number of subjects that have a targeted agent chosen for treatment. [ Time Frame: 2 years ]
    At completion of the induction therapy, the investigators will determine feasibility of adding molecularly guided targeted therapy to standard of care chemotherapy. Feasibility will be defined as:
    1. Subject has a targeted agent identified
    2. Receives 75% of dosing of medications while on study protocol during cycles 3-6
    3. Subject is not removed from study due to targeted agent drug related toxicity.
  • Number of subjects that receive 75% of dosing of medications while on study protocol during cycles 3-6. [ Time Frame: 2 years ]
    At completion of the induction therapy, the investigators will determine feasibility of adding molecularly guided targeted therapy to standard of care chemotherapy. Feasibility will be defined as:
    1. Subject has a targeted agent identified
    2. Receives 75% of dosing of medications while on study protocol during cycles 3-6
    3. Subject is not removed from study due to targeted agent drug related toxicity.
Original Primary Outcome Measures  ICMJE
 (submitted: September 23, 2015)
  • Number of subjects that have a targeted agent chosen for treatment. [ Time Frame: 2 years ]
    At completion of the induction therapy, the investigators will determine feasibility of adding molecularly guided targeted therapy to standard of care chemotherapy. Feasibility will be defined as:
    1. Subject has a targeted agent identified
    2. Receives 75% of dosing of medications while on study protocol during cycles 3-6
    3. Subject is not removed from study due to targeted agent drug related toxicity.
  • Number of subjects that receive 75% of dosing of medications while on study protocol during cycles 3-6. [ Time Frame: 2 years ]
    At completion of the induction therapy, the investigators will determine feasibility of adding molecularly guided targeted therapy to standard of care chemotherapy. Feasibility will be defined as:
    1. Subject has a targeted agent identified
    2. Receives 75% of dosing of medications while on study protocol during cycles 3-6
    3. Subject is not removed from study due to targeted agent drug related toxicity.
  • Number of subjects required to go off therapy due to treatment-related adverse events as assessed by CTCAE v4.0. [ Time Frame: 1 year ]
    At completion of the induction therapy, the investigators will determine feasibility of adding molecularly guided targeted therapy to standard of care chemotherapy. Feasibility will be defined as:
    1. Subject has a targeted agent identified
    2. Receives 75% of dosing of medications while on study protocol during cycles 3-6
    3. Subject is not removed from study due to targeted agent drug related toxicity.
  • Number of subjects that are able to complete 2 years of DFMO therapy. [ Time Frame: 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 23, 2019)
  • Number of days that subjects remain alive [ Time Frame: 3 years plus 5 years follow up ]
    To measure the response of treatments chosen based on:
    • Overall response rate (ORR) after induction therapy
    • Overall survival (OS)
  • Overall Response Rate (ORR) of Participants by the presence of radiologically assessable disease by cross-sectional CT or MRI imaging and/or by MIBG or PET scans. [ Time Frame: Up to 8 years ]
    To measure the response of treatments chosen based on: • Overall response rate (ORR) after induction therapy
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 3 years ]
    To compare toxicity effects of difluoromethylornithine (DFMO) in combination with Dinutuximab/GM-CSF/IL-2 and isotretinoin versus Dinutuximab/GM-CSF/IL-2 and isotretinoin alone.
  • Amount of pain medicine required by Arm A versus Arm B [ Time Frame: 3 years ]
    To compare level of pain medicine needed during immunotherapy in patients receiving difluoromethylornithine (DFMO) in combination with Dinutuximab/GM-CSF/IL-2 and Isotretinoin versus those receiving Dinutuximab/GM-CSF/IL-2 and isotretinoin alone.
  • Number of subjects required to go off therapy due to treatment-related adverse events as assessed by CTCAE v4.0. [ Time Frame: 1 year ]
    At completion of the induction therapy, the investigators will determine feasibility of adding molecularly guided targeted therapy to standard of care chemotherapy. Feasibility will be defined as:
    1. Subject has a targeted agent identified
    2. Receives 75% of dosing of medications while on study protocol during cycles 3-6
    3. Subject is not removed from study due to targeted agent drug related toxicity.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 23, 2015)
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 3 years ]
  • Overall Response Rate (ORR) of Participants by the presence of radiologically assessable disease by cross-sectional CT or MRI imaging and/or by MIBG or PET scans. [ Time Frame: 3 years ]
    • To measure the response of treatments chosen based on:
    • Overall response rate (ORR) after induction therapy
    • Progression free survival (PFS)
  • Number of days that subjects remain disease free [ Time Frame: 3 years ]
    • To measure the response of treatments chosen based on:
    • Overall response rate (ORR) after induction therapy
    • Progression free survival (PFS)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pediatric Precision Laboratory Advanced Neuroblastoma Therapy
Official Title  ICMJE A Study Using Molecular Guided Therapy With Induction Chemotherapy Followed by a Randomized Controlled Trial of Standard Immunotherapy With or Without DFMO Followed by DFMO Maintenance for Subjects With Newly Diagnosed High-Risk Neuroblastoma
Brief Summary A prospective open label, multicenter study to evaluate the feasibility and acute toxicity of using molecularly guided therapy in combination with standard therapy followed by a Randomized Controlled Trial of standard immunotherapy with or without DFMO followed by DFMO maintenance for Subjects with Newly Diagnosed High-Risk Neuroblastoma.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neuroblastoma
Intervention  ICMJE
  • Drug: Ceritinib
    One of the following drugs will be chosen for each subject based on molecular guided results: Ceritinib, dasatinib, sorafenib or vorinostat. This will be followed by consolidation, immunotherapy +/- DFMO, and then all subjects will receive DFMO for 2 years as maintenance.
    Other Name: Zykadia
  • Drug: dasatinib
    One of the following drugs will be chosen for each subject based on molecular guided results: Ceritinib, dasatinib, sorafenib or vorinostat. This will be followed by consolidation, immunotherapy +/- DFMO, and then all subjects will receive DFMO for 2 years as maintenance.
    Other Name: Sprycel
  • Drug: sorafenib
    One of the following drugs will be chosen for each subject based on molecular guided results: Ceritinib, dasatinib, sorafenib or vorinostat. This will be followed by consolidation, immunotherapy +/- DFMO, and then all subjects will receive DFMO for 2 years as maintenance.
    Other Name: Nexavar
  • Drug: vorinostat
    One of the following drugs will be chosen for each subject based on molecular guided results: Ceritinib, dasatinib, sorafenib or vorinostat. This will be followed by consolidation, immunotherapy +/- DFMO, and then all subjects will receive DFMO for 2 years as maintenance.
    Other Name: ZOLINZA
  • Drug: DFMO
    DFMO will be given to Arm B during immunotherapy and then for 2 years as maintenance to all subjects completing immunotherapy.
    Other Name: Eflornithine, α-difluoromethylornithine
Study Arms  ICMJE
  • Active Comparator: Standard Immunotherapy without DFMO
    One of the following drugs will be chosen for each subject based on molecular guided results: ceritinib, dasatinib, sorafenib or vorinostat. This will be followed standard immunotherapy with Dinutuximab/GM-CSF/IL-2 and isotretinoin. At the end of immunotherapy, DFMO will be given to all subjects BID for 730 days.
    Interventions:
    • Drug: Ceritinib
    • Drug: dasatinib
    • Drug: sorafenib
    • Drug: vorinostat
  • Active Comparator: Standard Immunotherapy with DFMO
    One of the following drugs will be chosen for each subject based on molecular guided results: ceritinib, dasatinib, sorafenib or vorinostat. This will be followed standard immunotherapy with Dinutuximab/GM-CSF/IL-2 and isotretinoin PLUS 1000mg/m2 BID of DFMO. At the end of immunotherapy, all subjects will go on to receive DFMO BID for 730 days.
    Interventions:
    • Drug: Ceritinib
    • Drug: dasatinib
    • Drug: sorafenib
    • Drug: vorinostat
    • Drug: DFMO
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 13, 2018)
500
Original Estimated Enrollment  ICMJE
 (submitted: September 23, 2015)
24
Estimated Study Completion Date  ICMJE September 2032
Estimated Primary Completion Date September 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Part A:

  1. Diagnosis: Subjects must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular or intermixed) verified by histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites. Subjects with the following disease stages at diagnosis are eligible, if they meet the other specified criteria:

    a) Subjects with newly diagnosed neuroblastoma with INSS Stage 4 are eligible with the following: i. Age > 18 months (> 547 days) regardless of biologic features or ii. Age 12-18 months (365-547 days) with any of the following 3 unfavorable biologic features (MYCN amplification, unfavorable pathology and/or DNA index = 1) or iii. MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features.

    b) Subjects with newly diagnosed neuroblastoma with INSS Stage 3 are eligible with the following: i. MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or ii. Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status.

    c) Subjects with newly diagnosed neuroblastoma with INSS Stage 2A/2B with MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features.

  2. Subjects must be age ≤ 21 years at initial diagnosis
  3. Subjects must not have had prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease and/or no more than 1 cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (as per P9641, A3961, ANBL0531, or similar) prior to determination of MYCN amplification status and histology.
  4. Specimens will be obtained only in a non-significant risk manner and not solely for the purpose of investigational testing.
  5. Ability to tolerate PBSC collection: No known contraindication to PBSC collection. Examples of contraindications would include a weight or size less than that determined to be feasible at the collecting institution, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure.

    Part A and B both:

  6. Adequate Cardiac Function Defined As:

    1. Shortening fraction of ≥ 27% by echocardiogram, or
    2. Ejection fraction of ≥ 50% by radionuclide evaluation or echocardiogram.
  7. Adequate liver function must be demonstrated, defined as:

    c. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age AND d. ALT (SGPT) < 10 x upper limit of normal (ULN) for age

  8. Subjects must have adequate renal function defined as a serum creatinine based on age/gender as follows:

    Age Maximum Serum Creatinine (mg/dL) Male Female 1 month to < 6 months 0.4 0.4 6 months to < 1 year 0.5 0.5 1 to < 2 years 0.6 0.6 2 to < 6 year 0.8 0.8 6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

    ≥ 16 years 1.7 1.4

  9. A negative serum pregnancy test is required for female participants of child bearing potential (≥13 years of age or after onset of menses)
  10. Both male and female post-pubertal study subjects need to agree to use one of the more effective birth control methods during treatment and for six months after treatment is stopped. These methods include total abstinence (no sex), oral contraceptives ("the pill"), an intrauterine device (IUD), levonorgestrol implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera shots). If one of these cannot be used, contraceptive foam with a condom is recommended.
  11. Informed Consent: All subjects and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines.

    Part B:

  12. All patients must have a pathologically confirmed diagnosis of neuroblastoma, be age ≤ 21 years at initial diagnosis, and classified as high risk by the criteria used by COG or SIOPEN at the time of diagnosis. Exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible.
  13. Previous Therapy- subjects must fit into one of the strata categories listed in section 10.5 to be eligible to enroll on Part B of this study.
  14. Pre-enrollment tumor survey:

    Prior to enrollment on Part B, a determination of mandatory disease staging must be performed. Tumor imaging studies including CT or MRI, MIBG or PET, and VMA/HVA (PET scan should be done for patients with prior disease that was MIBG non-avid). Bone marrow aspirates and biopsies are required.

    This disease assessment is required for eligibility and should be done preferably within 2 weeks, but must be done within a maximum of 4 weeks before first dose of study drug.

  15. Timing- Enrollment to occur prior to Day + 120 post-transplant, preferably when the subject is within 28 days after completing local radiation therapy (if given).

Exclusion Criteria (Part A and B)

  1. Subjects who are 12-18 months of age with INSS Stage 4 and all stage 3 subjects with favorable biologic features (ie, nonamplified MYCN, favorable pathology, and DNA index > 1) are not eligible.
  2. Lactating females are not eligible unless they have agreed not to breastfeed their infants.
  3. Subjects receiving any investigational drug concurrently.
  4. Subjects with any other medical condition, including but not limited to malabsorption syndromes, mental illness or substance abuse, deemed by the Investigator to be likely to interfere with the interpretation of the results or which would interfere with a subject's ability to sign or the legal guardian's ability to sign the informed consent, and subject's ability to cooperate and participate in the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 22 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Genevieve Bergendahl, MSN genevieve.bergendahl@atriumhealth.org
Contact: Michael Carpenter, MS Michael.Carpenter@atriumhealth.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02559778
Other Study ID Numbers  ICMJE NMTRC012
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Giselle SaulnierSholler, Atrium Health
Study Sponsor  ICMJE Giselle SaulnierSholler
Collaborators  ICMJE
  • Dell, Inc.
  • Beat NB Cancer Foundation
  • KC Pharma
Investigators  ICMJE
Study Chair: Giselle Sholler, MD Beat Childhood Cancer
PRS Account Atrium Health
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP