Therapy for Children With Advanced Stage Neuroblastoma

Study Overview
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Brief Summary
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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).

Detailed Description
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The phases of the study are: Screening phase: Tests and evaluations will be done before treatment starts. 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. 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. Maintenance/MRD treatment phase: With immune therapy in addition to the standard treatment with the drug isotretinoin.

Official Title
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Neuroblastoma Protocol 2012: Therapy for Children With Advanced Stage High-Risk Neuroblastoma

Conditions
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Neuroblastoma

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: topotecan
* Biological: hu14.18K322A
* Procedure: peripheral blood stem cell harvest
* Procedure: surgical resection
* Drug: cisplatin
* Drug: etoposide
* Drug: doxorubicin
* Drug: vincristine
* Drug: busulfan
* Drug: melphalan
* Biological: peripheral blood stem cell transplantation
* Biological: natural killer cell infusion
* Radiation: radiation therapy
* Biological: GM-CSF
* Biological: G-CSF
* Drug: mesna
* Drug: levetiracetam
* Biological: interleukin-2
* Drug: Isotretinoin
* Device: CliniMACS


Participation Criteria
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Eligibility Criteria
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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: 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 Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status INSS stage 4 and: MYCN amplification, regardless of age or additional biologic features Age > 18 months (> 547 days) regardless of biologic features 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.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>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<br>* Given intravenously (IV)<br>* Other names: Cytoxan(R);Drug: topotecan<br>* Given IV<br>* Other names: Hycamtin(R);Biological: hu14.18K322A<br>* Given IV<br>* Other names: dinutuximab;Procedure: peripheral blood stem cell harvest<br>* 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.<br>* Other names: PBSCH;Procedure: surgical resection<br>* 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.<br>Drug: cisplatin<br>* Given IV<br>* Other names: Platinol-AQ(R);Drug: etoposide<br>* Given IV<br>* Other names: Etopophos(R);Drug: doxorubicin<br>* Given IV<br>* Other names: Adriamycin(R);Drug: vincristine<br>* Given IV<br>* Other names: Oncovin(R);Drug: busulfan<br>* Given IV<br>* Other names: Busulfex(R);Drug: melphalan<br>* Given IV<br>* Other names: Alkeran(R);Biological: peripheral blood stem cell transplantation<br>* Transplantation of previously harvested peripheral blood stem cells.<br>* Other names: PBSCT;Biological: natural killer cell infusion<br>* 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.<br>* Other names: NK cell infusion;Radiation: radiation therapy<br>* 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.<br>Biological: GM-CSF<br>* Given subcutaneously (SQ)<br>* Other names: granulocyte macrophage colony stimulating factor;Biological: G-CSF<br>* Given subcutaneously (SQ)<br>* Other names: Filgrastim;Drug: mesna<br>* Given IV<br>* Other names: Mesnex(R);Drug: levetiracetam<br>* Given IV<br>* Other names: Keppra;Biological: interleukin-2<br>* Given by continuous infusion during MRD maintenance, and SQ during induction.<br>* Other names: Proleukin(R);Drug: Isotretinoin<br>* Given orally (PO)<br>* Other names: 13-cis retinoic acid;Device: CliniMACS<br>* 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.<br>* Other names: Cell Selection System;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate [Complete Response + Very Good Partial Response + Partial Response (CR + VGPR + PR)] | Per the 1993 INRC: measurable tumor defined as product of the longest x widest perpendicular diameter, elevated catecholamine levels and tumor cels in bone marrow. Complete Response (CR)-no evidence of primary tumor or metastases. Very Good Partial Response (VGPR)->90% reduction of primary tumor; no metastases; no new bone lesions, all pre-existing lesions improved. Partial Response (PR)-50-90% reduction of primary tumor; >50% reduction in measurable sites of metastases; 0-1 bone marrow samples with tumor; number of positive bone sites decreased by >50%. Mixed Response (MR)->50% reduction of any measurable lesion with <50% reduction in other sites; no new lesions; <25% increase in any existing lesion. No Response (NR)-no new lesions; <50% reduction but <25% increase in an any existing lesion. No Response (NR)-no new lesions; <50% reduction but <25% increase in any existing legions. Progressive Disease (PD)-any new/increased measurable lesion by >25%; previous negative marrow positive. | After two initial courses of chemotherapy (approximately 6 weeks after enrollment) | 
| Event-free Survival (EFS) | EFS was estimated as time to relapse, progressive disease, secondary neoplasm, or death from any cause from enrollment. The EFS was estimated by Kaplan-Meier method | 3 years, from time of enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of Delivering hu14.18K322A to 6 Cycles of Induction Therapy | The study is designed to monitor the feasibility of delivering hu14.18K332A to 6 cycles of Induction chemotherapy. The feasibility of Induction therapy for this study will be to target no worse than 75%. A patient was considered as a failure for the 6 cycles of Induction therapy if the patient failed to complete Induction therapy within 155 days since treatment initiation due to toxicity or disease progression, unless the delay was a result of non-medical issues (e.g. not due to protocol toxicity). The proportion of patients who successfully received hu14.18K322A with 6 cycles of induction chemotherapy was estimated together with a 95% confidence interval. The response rate (CR + VGPR + PR) to 6 cycles of Induction chemoimmunotherapy was estimated together with the 95% confidence intervals | After 6 cycles of induction therapy (approximately 24 weeks after enrollment) | 
| Local Failure Rate and Pattern of Failure | Local failure is defined as relapse or progression of disease at the primary site. The cumulative incidence of local failure will be estimated; competing events will include distant failure or death prior to local failure. | Up to 3 years | 
| Dose Limiting Toxicity (DLT) or Severe (Grade 3 or 4) VOD With hu14.18K322A With Allogeneic NK Cells in Consolidation | Number of patients who experience an unacceptable dose limiting toxicity (per CTCAE v 4.0) including the following toxicities: 1) toxicity requiring the use of pressors, including Grade 4 acute capillary leak syndrome or Grade3 and 4 hypotension; 2) Toxicity requiring ventilation support, including Grade 4 respiratory toxicity; 3) Grade 3 or 4 neurotoxicity with MRI evidence of new CNS thrombi, infarction or bleeding in any subject receiving the hu14.18K322A with NK cell combination; 4) Failure of recovery of ANC > 500/mm3 by day 35 after PBSC infusion. Number of patients who experience Grade 3 or Grade 4 (per Common Toxicity Criteria v 4.0) veno occlusive disease (VOD). | During the recovery phase after busulfan/melphalan and PBSC rescue (approximately 24-26 weeks after enrollment) | 
| Dose Limiting Toxicity (DLT) | Number of patients who experience an unacceptable dose limiting toxicity (per CTCAE v 4.0) including the following toxicities: 1) Toxicity requiring the use of pressors, including Grade 4 acute capillary leak syndrome or Grade 3 and 4 hypotension; 2) Toxicity requiring ventilation support, including Grade 4 respiratory toxicity; 3) Grade 3 or 4 neurotoxicity with MRI evidence of new CNS thrombi, infarction or bleeding. | During MRD treatment cycle (approximately 8-12 months after enrollment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-GD2 monoclonal antibody, hu14.18K322A, High-risk neuroblastoma, Phase II, Allogeneic NK cells