A Phase 3 Trial of Antibody hu3F8 and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in High-Risk Neuroblastoma Patients with Primary or Secondary Refractory Osteomedullary Disease

Prior treatment

• History of anaphylactic reactions CTCAE grade 4 related to prior GD2 antibody therapy
• Prior treatment with omburtamab (mu8H9) within 6 months of 1st dose of GM-CSF
• Any clinically meaningful abnormal finding in physical examination, vital signs, ECG, hematology, clinical chemistry, or urinalysis prior to inclusion into the trial, which in the opinion of the investigator, may put the subject at risk because of his/her participation in the study.
• Treatment with immunosuppressive agents (local steroids excluded) within a month prior to 1st dose of GM-CSF.
• Prior treatment with naxitamab
• Pregnancy or a woman who is breast-feeding (women of child-bearing potential must have a negative pregnancy test at screening). A woman of child-bearing potential is excluded if she does not agree to use highly effective contraception for a period of 42 days after the last naxitamab infusion according to section 9.2.5. A sterilized or infertile woman is exempt from the requirement to use contraception after naxitamab treatment: she must have undergone surgical sterilization (hysterectomy, or bilateral ovariectomy).

Other illness

• Any systemic anti-cancer therapy, including chemotherapy or immunotherapy, within 3 weeks of 1st dose of GM-CSF
• History of allergy or known hypersensitivity to GM-CSF, yeast-derived products, or any component of GM-CSF or naxitamab
• Actively progressing disease at trial entry according to Park criteria (Park et al. 2017) (see section 6.7)
• Active life-threatening infection

Lab values

• Patients who have had allogeneic hematopoietic stem cell transplantation (allo-SCT) or donor-lymphocyte-infusion (DLI). DLI or buffy coat infusion is defined as any kind of active allogenic lymphocyte suspension a. within 6 months of 1st dose of GM-CSF or b. with a lymphocyte count < 0.2 x109/L
• Patients who received Hematopoietic Progenitor Cell (HPC) boost or “top-up” of allogenic stem cells (lymphocyte-depleted) within 2 months of 1st dose GM-CSF
• Inadequate cardiac function defined as either left ventricular ejection fraction of < 50% by echocardiography or other clinically relevant cardiac disorders at the discretion of the investigator.

Other

• NB in central nervous system (CNS) within 6 months of 1st dose of GM-CSF
• Evaluable NB outside bone and BM defined as follows: • MIBG-avid tumor: Definite MIBG uptake in tumor tissues outside bone and BM • MIBG nonavid tumor: Definite uptake in tumor tissues outside bone and BM on FDG-PET
• Existing major organ dysfunction CTCAE >Grade 2, with the exception of hearing loss, hematological status, kidney and liver function.
• Karnofsky/Lansky score <50%
• Inability to comply with protocol requirements, including PK studies, as determined by the investigator

• Documented diagnosis of neuroblastoma (NB) as defined per INRC as a. histopathology of tumor biopsy, or b. bone marrow (BM) aspirate or biopsy indicative of NB by histology, plus high blood or urine catecholamine metabolite levels or Myelocytomatosis Viral-Related Oncogene, Neuroblastoma derived (MYCN) amplification, or c. MIBG-avid lesion(s)
• High-risk NB patients with either primary refractory disease or incomplete response to salvage treatment (in both cases including SD, MR and PR) evaluable in bone and/or BM as defined in section 6.7. If disease is only present in bone the patient must have evaluable disease outside the radiation areas for being eligible in the trial, please see section 7.2.1. If disease is only present in the BM the involvement must be >5%.
• Life expectancy ≥6 months
• Age ≥12 months
• Acceptable hematological status at screening, (hematological support is allowed if administered ≥1 week before first screening procedure), defined as: a. Hemoglobin ≥8 g/dL (5.0 mmol/L) b. White blood cell count ≥1000/μL (1.0 x109/L) c. Absolute neutrophil count (ANC) ≥500/μL (0.5 x109/L) d. Platelet count ≥25,000/μL (25 x109/L)
• Acceptable liver function defined as: a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 times upper limit of normal (ULN) b. Bilirubin ≤1.5 x ULN
• Acceptable kidney function defined as: a. Estimated Glomerular Filtration Rate (eGFR) >60 mL/min/1.73 m2 calculated by the 2009 revised Bedside Schwartz Equation
• Written informed consent from legal guardian(s) and/or patient in accordance with local regulations. Children must provide assent as required by local regulations.