Therapie für Kinder mit Neuroblastom im fortgeschrittenen Stadium

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.

Given IV

• VP16
• Vepesid(R)
• Etophophos(R)

Given intravenously (IV)

• Cytoxan®

Given IV

• Hycamtin(R)

Given IV

• monoklonaler Antikörper
• humanisierter Anti-GD2-Antikörper
• Dinutuximab

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.

• PBSCH

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

• Platinol-AQ(R)

Given IV

• Adriamycin(R)

Given IV

• Oncovin(R)

Given IV

• Busulfex®

Given IV

• Phenylalaninsenf
• L-PAM
• L-Phenylalanin-Senf
• L-Sarcolysin
• Alkeran®

Transplantation of previously harvested peripheral blood stem cells.

• PBSCT

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.

• NK-Zell-Infusion

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)

• sargramostim
• Granulozyten-Makrophagen-Kolonie-stimulierender Faktor
• Leukin(R)

Given subcutaneously (SQ)

• Filgrastim
• Granulozyten-Kolonie-stimulierender Faktor
• Neupogen(R)

Given IV

• Mesnex(R)

Given IV

• Keppra

Given by continuous infusion during MRD maintenance, and SQ during induction.

• IL-2
• aldesleukin
• Proleukin®

Given orally (PO)

• 13-cis-Retinsäure

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.

• Zellenauswahlsystem

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.

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

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

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.

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).

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.