Clinical Trials /

Therapy for Children With Advanced Stage Neuroblastoma

NCT01857934

Description:

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).

Related Conditions:
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Therapy for Children With Advanced Stage <span class="go-doc-concept go-doc-disease">Neuroblastoma</span>

Title

  • Brief Title: Therapy for Children With Advanced Stage Neuroblastoma
  • Official Title: Neuroblastoma Protocol 2012: Therapy for Children With Advanced Stage High-Risk Neuroblastoma
  • Clinical Trial IDs

    NCT ID: NCT01857934

    ORG ID: NB2012

    NCI ID: NCI-2013-00034

    Trial Conditions

    Neuroblastoma

    Trial Interventions

    Drug Synonyms Arms
    cyclophosphamide Cytoxan(R) Treatment
    topotecan Hycamtin(R) Treatment
    cisplatin Platinol-AQ(R) Treatment
    etoposide VP16, Vepesid(R), Etopophos(R) Treatment
    doxorubicin Adriamycin(R) Treatment
    vincristine Oncovin(R) Treatment
    busulfan Busulfex(R) Treatment
    melphalan L-phenylalanine mustard, Phenylalanine mustard, L-PAM, L-sarcolysin, Alkeran(R) Treatment
    mesna Mesnex(R) Treatment
    levetiracetam Keppra Treatment
    Isotretinoin 13-cis retinoic acid Treatment

    Trial Purpose

    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.

    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 intensity modulated
    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).

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

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

    Trial Arms

    Name Type Description Interventions
    Treatment Experimental Participants receive intravenous 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. cyclophosphamide, topotecan, cisplatin, etoposide, doxorubicin, vincristine, busulfan, melphalan, mesna, levetiracetam, Isotretinoin

    Eligibility Criteria

    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.

    Minimum Eligible Age: N/A

    Maximum Eligible Age: 18 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Number of participants with complete or partial response

    Secondary Outcome Measures

    Failure rate for the 6 cycles of induction therapy.

    Local failure rate

    Dose limiting toxicity (DLT) or severe (grade 3 or 4) VoD

    Dose limiting toxicity (DLT)

    Trial Keywords

    Anti-GD2 monoclonal antibody

    hu14.18K322A

    High-risk neuroblastoma

    Phase II

    Allogeneic NK cells