Therapy for Children With Advanced Stage Neuroblastoma
Condition: Neuroblastoma
MeSH terms: Neuroblastoma
Intervention: cyclophosphamide; topotecan; hu14.18K322A; peripheral blood stem cell harvest; surgical resection; cisplatin; etoposide; doxorubicin; vincristine; busulfan; melphalan; peripheral blood stem cell transplantation; natural killer cell infusion; radiation therapy; GM-CSF; G-CSF; mesna; levetiracetam; interleukin-2; Isotretinoin; CliniMACS
Intervention description: Given intravenously (IV); Given IV; Given IV; 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.; 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.; Given IV; Given IV; Given IV; Given IV; Given IV; Given IV; Transplantation of previously harvested peripheral blood stem cells.; 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.; 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.; Given subcutaneously (SQ); Given subcutaneously (SQ); Given IV; Given IV; Given by continuous infusion during MRD maintenance, and SQ during induction.; Given orally (PO); 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.
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Melphalan; Busulfan; Mechlorethamine; Doxorubicin; Etoposide; Vincristine; Topotecan; Interleukin-2; Molgramostim; Dinutuximab; Levetiracetam; Isotretinoin; Antibodies; Immunoglobulins; Sargramostim; Lenograstim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 153.0
Sex: All
Maximum age: 18 Years
Healthy volunteers: No
Keywords: Anti-GD2 monoclonal antibody; hu14.18K322A; High-risk neuroblastoma; Phase II; Allogeneic NK cells

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).
    

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.