Therapy for Children With Advanced Stage Neuroblastoma

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).

Sex

All

Maximum age

18 Years

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.

• DERIVEDFurman WL, McCarville B, Shulkin BL, Davidoff A, Krasin M, Hsu CW, Pan H, Wu J, Brennan R, Bishop MW, Helmig S, Stewart E, Navid F, Triplett B, Santana V, Santiago T, Hank JA, Gillies SD, Yu A, Sondel PM, Leung WH, Pappo A, Federico SM. Improved Outcome in Children With Newly Diagnosed High-Risk Neuroblastoma Treated With Chemoimmunotherapy: Updated Results of a Phase II Study Using hu14.18K322A. J Clin Oncol. 2022 Feb 1;40(4):335-344. doi: 10.1200/JCO.21.01375. Epub 2021 Dec 6. PMID 34871104
• DERIVEDNguyen R, Sahr N, Sykes A, McCarville MB, Federico SM, Sooter A, Cullins D, Rooney B, Janssen WE, Talleur AC, Triplett BM, Anthony G, Dyer MA, Pappo AS, Leung WH, Furman WL. Longitudinal NK cell kinetics and cytotoxicity in children with neuroblastoma enrolled in a clinical phase II trial. J Immunother Cancer. 2020 Mar;8(1):e000176. doi: 10.1136/jitc-2019-000176. PMID 32221013