Safety Study of Dinutuximab Combined With Immunotherapy to Treat Neuroblastoma

Assess toxicity and safety of subcutaneous GM-CSF and iv IL-2 in enhancing Dinutuximab-mediated ablation of Bone Marrow (BM) disease in patients with high-risk neuroblastoma who have achieved a Complete Response or Very Good Partial Response of the macroscopic disease in the investigators institution.

Assess response of minimal residual disease (MRD) of the anti-GD2 monoclonal antibody Dinutuximab combined with granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-2 in patients with high-risk neuroblastoma (NB). More precisely, to apply real-time quantitative RT-PCR to test the hypothesis that minimal residual disease content of BM after the first treatments with dinutuximab/GM-CSF has significant prognostic impact on relapse-free survival.

Inclusion criteria

• Diagnosis of neuroblastoma as defined by international criteria by histopathology or bone marrow metastases. Patients age must be less than 18 years at the time of initial diagnosis.
• Neuroblastoma, as defined by risk-related treatment guidelines and the International Neuroblastoma Staging System, stage 4 with (any age) or without (>18 months) MYCN-amplification, or MYCN-amplified neuroblastoma other than stage 1, or high-risk neuroblastoma defined based on the 3-gene molecular profile developed at our institution (Garcia I, et al. CCR 2012).

• Group 1 patients have neuroblastoma (as defined above) resistant to standard therapy, as evidenced by incomplete response in bone marrow, but no MIBG-avid soft tissue or bone tumor and no progressive disease.
• Group 2 patients have no evidence of measurable disease

3 - Patients must have a Lansky or Karnofsky Performance Scale score of > 50% and patients must have a life expectancy of > 2 months.

4- Pre-enrollment tumor survey: Prior to enrollment a determination of residual disease must be Performed (Tumor imaging studies including CT or MRI, MIBG scan, bone marrow aspiration & biopsy, and blood and bone marrow samples). This disease assessment is required for eligibility.

5 - Patients must have adequate organ functions at the time of registration:

• Hematological: Total absolute phagocyte count (APC = neutrophils + monocytes) is at least 1000/microL
• Renal: Adequate Renal Function Defined As: Creatinine clearance or radioisotope GFR > 70 mL/min/1.73 m2 or serum creatinine based on age/gender.
• Hepatic- total bilirubin < 1.5 x normal, and SGPT (ALT) < 5 x normal. Veno-occlusive disease, if present, should be stable or improving.
• Cardiac- shortening fraction of > 30% by echocardiogram, or if shortening fraction abnormal, ejection fraction of > 55% by gated radionuclide study.
• Pulmonary- FEV1 and FVC > 60% of predicted by pulmonary function test. For children who are unable to do PFTs, no evidence of dyspnea at rest, no exercise intolerance.
• Central nervous system- Patients with seizure disorder may be enrolled if on anticonvulsants and wellcontrolled. CNS toxicity < Grade 2.

6 - Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.

7 - Signed informed consent indicating awareness of the investigational nature of this program.

Exclusion criteria

• - Existing severe major organ dysfunction, i.e., renal., cardiac, hepatic, neurologic, pulmonary, or gastrointestinal toxicity ≥ grade 3.
• - Progressive disease or MIBG-avid soft tissue/bone tumor.
• - Active life-threatening infection.
• - Inability to comply with protocol requirements.
• - Patient is eligible for SIOP HR-NB-01 protocol (= newly diagnosed high-risk neuroblastoma patient in a center where the SIOP protocol is open for enrollment).