Therapy for Children With Advanced Stage Neuroblastoma

Sponsor
St. Jude Children's Research Hospital (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT01857934
Collaborator
Cookies for Kids' Cancer (Other), CURE Childhood Cancer, Inc. (Other)
153
1
1
124.9
1.2

Study Details

Study Description

Brief Summary

Neuroblastoma is the most common extracranial solid tumor in childhood, with nearly 50% of patients presenting with widespread metastatic disease. The current treatment for this group of high-risk patients includes intensive multi-agent chemotherapy (induction) followed by myeloablative therapy with stem-cell rescue (consolidation) and then treatment of minimal residual disease (MRD) with isotretinoin. Recently a new standard of care was established by enhancing the treatment of MRD with the addition of a monoclonal antibody (ch14.18) which targets a tumor-associated antigen, the disialoganglioside GD2, which is uniformly expressed by neuroblasts. Despite improvement in 2-year event-free survival (EFS) of 20%, more than one-third of children with high-risk neuroblastoma (HR defined in) still cannot be cured by this approach. Therefore, novel therapeutic approaches are needed for this subset of patients. This study will be a pilot Phase II study of a unique anti-disialoganglioside (anti-GD2) monoclonal antibody (mAb) called hu14.18K322A, given with induction chemotherapy.

PRIMARY OBJECTIVE:
  • To study the efficacy [response: complete remission + partial remission (CR+PR)] to two initial courses of cyclophosphamide and topotecan combined with hu14.18K322A (4 doses/course followed by GM-CSF) in previously untreated children with high-risk neuroblastoma.

  • To estimate the event-free survival of patients with newly diagnosed high-risk neuroblastoma treated with the addition of hu14.18K322A to treatment.

SECONDARY OBJECTIVES:
  • To study the feasibility of delivering hu14.18K322A to 6 cycles induction chemotherapy and describe the antitumor activity (CR+PR) of this 6 course induction therapy.

  • To estimate local control and pattern of failure associated with focal intensity modulated or proton beam radiation therapy dose delivery in high-risk abdominal neuroblastoma.

  • To describe the tolerability of four doses of hu14.18K322A with allogeneic natural killer (NK) cells from an acceptable parent, in the immediate post-transplant period [day +2 - +5 after peripheral blood stem cell (PBSC) infusion] in consenting participants.

  • To describe the tolerability of hu14.18K322A with interleukin-2 and GM-CSF as treatment for minimal residual disease (MRD).

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

The phases of the study are:
  1. Screening phase: Tests and evaluations will be done before treatment starts.

  2. Induction phase: Includes chemotherapy plus hu14.18K322A mAb. Participants will also have surgery during this part of the study to remove as much tumor as possible.

  3. Consolidation/Intensification phase: Includes high doses of chemotherapy and blood stem cell transplantation with additional, experimental "minimal residual disease" (MRD) treatment. Participants will also get radiation treatment to all sites of the tumor(s) after recovery from the stem cell transplant.

  4. Maintenance/MRD treatment phase: With immune therapy in addition to the standard treatment with the drug isotretinoin.

Study Design

Study Type:
Interventional
Actual Enrollment :
153 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Neuroblastoma Protocol 2012: Therapy for Children With Advanced Stage High-Risk Neuroblastoma
Actual Study Start Date :
Jul 5, 2013
Actual Primary Completion Date :
Oct 21, 2021
Anticipated Study Completion Date :
Dec 1, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment

Participants receive IV hu14.18K322A with each course of chemotherapy (cyclophosphamide, topotecan, cyclophosphamide, doxorubicin, vincristine, cisplatin, and etoposide). Mesna will be given prior to and after cyclophosphamide infusion. Peripheral blood stem cell harvest (PBSC) and surgical resection of primary tumor will be performed, if feasible. Intensification therapy includes busulfan, melphalan, and levetiracetam with peripheral blood stem cell transplantation. A course of hu14.18K322A with natural killer cell infusion will be given to consenting participants. Radiation therapy will follow PBSC transplant with the exception of any patient requiring emergent radiotherapy. MRD treatment includes hu14.18K322A, G-CSF, GM-CSF, interleukin-2 and isotretinoin. Cells for infusion are prepared using the CliniMACS System.

Drug: cyclophosphamide
Given intravenously (IV)
Other Names:
  • Cytoxan(R)
  • Drug: topotecan
    Given IV
    Other Names:
  • Hycamtin(R)
  • Biological: hu14.18K322A
    Given IV
    Other Names:
  • humanized anti-GD2 antibody
  • monoclonal antibody
  • dinutuximab
  • Procedure: peripheral blood stem cell harvest
    Following evaluation and approval by a member of the transplant staff and completion of the consent form by the participant, collection of peripheral blood stem cells (PBSC) may take place.
    Other Names:
  • PBSCH
  • Procedure: surgical resection
    The primary tumor will be resected surgically following two initial courses of chemotherapy, if feasible. Patients who are unable to have their primary tumor resected after the initial two courses of induction chemotherapy will undergo surgery for resection of the primary tumor mass and careful lymph node staging.

    Drug: cisplatin
    Given IV
    Other Names:
  • Platinol-AQ(R)
  • Drug: etoposide
    Given IV
    Other Names:
  • VP16
  • Vepesid(R)
  • Etopophos(R)
  • Drug: doxorubicin
    Given IV
    Other Names:
  • Adriamycin(R)
  • Drug: vincristine
    Given IV
    Other Names:
  • Oncovin(R)
  • Drug: busulfan
    Given IV
    Other Names:
  • Busulfex(R)
  • Drug: melphalan
    Given IV
    Other Names:
  • L-phenylalanine mustard
  • Phenylalanine mustard
  • L-PAM
  • L-sarcolysin
  • Alkeran(R)
  • Biological: peripheral blood stem cell transplantation
    Transplantation of previously harvested peripheral blood stem cells.
    Other Names:
  • PBSCT
  • Biological: natural killer cell infusion
    Natural killer (NK) cells obtained from a suitable donor will be given together with hu14.18K322A prior to early hematopoietic cell recovery. In the event there is not a suitable parental donor, consenting participants will receive an additional course of hu14.18K322A.
    Other Names:
  • NK cell infusion
  • Radiation: radiation therapy
    Radiation therapy to the primary and metastatic disease sites will follow peripheral blood stem cell transplant with the exception of any patient requiring emergent radiotherapy. External beam radiotherapy will be delivered to the primary site and select metastatic and bulky nodal sites.

    Biological: GM-CSF
    Given subcutaneously (SQ)
    Other Names:
  • sargramostim
  • Leukine(R)
  • granulocyte macrophage colony stimulating factor
  • Biological: G-CSF
    Given subcutaneously (SQ)
    Other Names:
  • Granulocyte colony stimulating factor
  • Neupogen(R)
  • Filgrastim
  • Drug: mesna
    Given IV
    Other Names:
  • Mesnex(R)
  • Drug: levetiracetam
    Given IV
    Other Names:
  • Keppra
  • Biological: interleukin-2
    Given by continuous infusion during MRD maintenance, and SQ during induction.
    Other Names:
  • IL-2
  • aldesleukin
  • Proleukin(R)
  • Drug: Isotretinoin
    Given orally (PO)
    Other Names:
  • 13-cis retinoic acid
  • Device: CliniMACS
    The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.
    Other Names:
  • Cell Selection System
  • Outcome Measures

    Primary Outcome Measures

    1. Number of participants with complete or partial response [after two initial courses of chemotherapy (approximately 6 weeks after enrollment)]

      To study the efficacy [response: complete remission + partial remission (CR+PR)] to two initial courses of cyclophosphamide and topotecan combined with hu14.18K322A (4 doses/course followed by GM-CSF) in previously untreated children with high-risk neuroblastoma.

    2. Event-free survival (EFS) [3 years after last participant enrollment]

      EFS will be estimated for patients with newly diagnosed high-risk neuroblastoma treated with the addition of hu4.18K322A to each phase of treatment.

    Secondary Outcome Measures

    1. Feasibility of delivering hu14.18K322A to 6 cycles of induction therapy [After 6 cycles of induction therapy (approximately 24 weeks after enrollment)]

      A patient will be considered as a failure for the 6 cycles of induction therapy if the patient failed to complete induction therapy within 155 days due to toxicity or has disease progression during the induction therapy, unless delay is a result of non-medical issues (e.g. not due to protocol toxicity).

    2. Local failure rate [End of study - about 4- 5 years]

      Local failure is defined as relapse or progression of disease at the primary site.

    3. Dose limiting toxicity (DLT) or severe (grade 3 or 4) VoD [During the recovery phase after busulfan/melphalan and PBSC rescue (approximately 24-26 weeks after enrollment)]

      Participants will be considered evaluable for tolerability if they receive four doses of hu14.18K322A with allogeneic NK cells in the immediate post-transplant period, or if hu14.18K322A is discontinued early for presumed toxicity.

    4. Dose limiting toxicity (DLT) [During the second MRD treatment cycle (approximately 8-12 months after enrollment)]

      Participants will be considered evaluable for tolerability if they receive at least one dose of hu14.18K322A with course 2 of MRD treatment (the first course given with IL-2).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 18 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    PARTICIPANT Inclusion Criteria:
    • Participants <19 years of age (eligible until 19th birthday).

    • Newly diagnosed, advanced stage, high-risk neuroblastoma defined as one of the following:

    • Children < 1 year with International Neuroblastoma Staging System (INSS) stage 2a, 2b, 3, 4 or 4S disease AND MYCN amplification (>10 copies, or greater than four-fold increase in MYCN signal as compared to reference signal).

    • INSS 2a or 2b disease AND MYCN amplification, regardless of age or additional biologic features

    • INSS stage 3 AND:

    1. MYCN amplification (>10 copies, or greater than four-fold increase in MYCN signal as compared to reference signal, regardless of age or additional biologic features

    2. Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status

    • INSS stage 4 and:
    1. MYCN amplification, regardless of age or additional biologic features

    2. Age > 18 months (> 547 days) regardless of biologic features

    3. Age 12 - 18 months (365 - 547 days) with any of the following three unfavorable biologic features (MYCN amplification, unfavorable pathology and/or DNA index =1) or any biologic feature that is indeterminant/unknown

    • Children at least 365 days initially diagnosed with: INSS stage 1, 2, 4S who progressed to a stage 4 without interval chemotherapy.

    • Histologic proof of neuroblastoma or positive bone marrow for tumor cells with increased urine catecholamines.

    • Adequate renal and hepatic function (serum creatinine <3 x upper limit of normal for age, AST< 3 x upper limit of normal).

    • No prior therapy, unless an emergency situation requires local tumor treatment (discuss with principal investigator).

    • Written, informed consent according to institutional guidelines.

    PARTICIPANT Exclusion Criteria:
    • Any evidence, as judged by the investigator, of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease).

    • Pregnant or breast feeding (female of child-bearing potential).

    • Children with INSS 4 disease, age <18 months with all 3 favorable biologic features (non-amplified MYCN, favorable pathology and DNA index >1).

    DONOR Inclusion Criteria:
    • Potential donor is a biologic parent

    • Potential donor is at least 18 years of age.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 St. Jude Children's Research Hospital Memphis Tennessee United States 38105

    Sponsors and Collaborators

    • St. Jude Children's Research Hospital
    • Cookies for Kids' Cancer
    • CURE Childhood Cancer, Inc.

    Investigators

    • Principal Investigator: Sara M. Federico, MD, St. Jude Children's Research Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    St. Jude Children's Research Hospital
    ClinicalTrials.gov Identifier:
    NCT01857934
    Other Study ID Numbers:
    • NB2012
    • NCI-2013-00034
    First Posted:
    May 20, 2013
    Last Update Posted:
    Apr 11, 2022
    Last Verified:
    Apr 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    Yes
    Keywords provided by St. Jude Children's Research Hospital
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Apr 11, 2022