Clinical Trials /

Pediatric Precision Laboratory Advanced Neuroblastoma Therapy

NCT02559778

Description:

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.

Related Conditions:
  • Ganglioneuroblastoma, Intermixed
  • Ganglioneuroblastoma, Nodular
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pediatric Precision Laboratory Advanced Neuroblastoma Therapy
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: NMTRC012
  • NCT ID: NCT02559778

Conditions

  • Neuroblastoma

Interventions

DrugSynonymsArms
CeritinibZykadiaStandard Immunotherapy with DFMO
dasatinibSprycelStandard Immunotherapy with DFMO
sorafenibNexavarStandard Immunotherapy with DFMO
vorinostatZOLINZAStandard Immunotherapy with DFMO
DFMOEflornithine, α-difluoromethylornithineStandard Immunotherapy with DFMO

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Standard Immunotherapy without DFMOActive ComparatorOne 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.
  • Ceritinib
  • dasatinib
  • sorafenib
  • vorinostat
Standard Immunotherapy with DFMOActive ComparatorOne 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.
  • Ceritinib
  • dasatinib
  • sorafenib
  • vorinostat
  • DFMO

Eligibility Criteria

        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
      
Maximum Eligible Age:22 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of days from start of therapy to date of first relapse
Time Frame:Up to 8 years
Safety Issue:
Description:To measure the response of treatments chosen based on: • Event free survival (EFS)

Secondary Outcome Measures

Measure:Number of days that subjects remain alive
Time Frame:3 years plus 5 years follow up
Safety Issue:
Description:To measure the response of treatments chosen based on: Overall response rate (ORR) after induction therapy Overall survival (OS)
Measure: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
Safety Issue:
Description:To measure the response of treatments chosen based on: • Overall response rate (ORR) after induction therapy
Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Amount of pain medicine required by Arm A versus Arm B
Time Frame:3 years
Safety Issue:
Description: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.
Measure:Number of subjects required to go off therapy due to treatment-related adverse events as assessed by CTCAE v4.0.
Time Frame:1 year
Safety Issue:
Description: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: Subject has a targeted agent identified Receives 75% of dosing of medications while on study protocol during cycles 3-6 Subject is not removed from study due to targeted agent drug related toxicity.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Giselle Sholler

Last Updated

July 23, 2019