A Study Of Naxitamab , Granulocyte Macrophage Colony Stimulating Factor For Patients With Relapsed /Refractory , Soft Tissue or Anti GD2 Immunotherapy Refractory Neuroblastoma

The anti-GD2 monoclonal antibody Naxitamab (also known as hu3F8) in combination with macrophage colony-stimulating factor (GM-CSF) is currently under pivotal phase 3 investigation for the treatment of High-Risk Neuroblastoma Patients with Primary or Secondary Refractory Osteomedullary Disease.

A subset of patients with high-risk, resistant disease, i.e., relapsed or refractory Neuroblastoma with soft tissue involvement as measured by 123I-Meta-iodobenzylguanidine (MIBG), 18F-FDG avid or measurable computed tomography (CT)/ magnetic resonance imaging (MRI) tumors outside of the bone marrow, or disease refractory to Naxitamab in combination with GM-CSF has shown significant response rates to a chemoimmunotherapy combination of Naxitamab, GM-CSF, irinotecan and temozolomide (HITS- Hu3F8, irinotecan, temozolomide and sargramostim) (NCT03189706). Treatment is administered on an outpatient basis and toxicities include those expected from I/T (myelosuppression and diarrhea) as well as pain and hypertension expected with Naxitamab. No other greater than grade 2 related toxicities occurred in this study (n=46). Early responses, assessed after 2 cycles, were documented in 18 (39%) patients and here complete (n = 9), partial (n = 8), and mixed (n = 1) and 13 patients had stable disease. Responses were achieved in refractory (3/7;43%) and progressive disease (15/39;38%) subgroups, in patients who had previously received I/T (12/34;35%) and/or anti-GD2 MoAb (14/36;39%), and in soft tissue (6/22; 27%) MIBG-avid skeletal sites (20/36;56%) and on bone marrow histology (9/12;75%). While encouraging, new strategies are warranted to further treat resistant disease.

A high-dose combination of ifosfamide, carboplatin, and etoposide (ICE) has activity against Neuroblastoma without cross-resistance to widely used chemotherapy regimens.

Through compassionate use, 4 patients with progression of disease or refractory disease after HITS therapy, have been further treated with two cycles of a combination of naxitamab, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and ifosfamide/Carboplatin/Etoposide (NICE). The first patient showed a complete response.

Toxicity included G2 prolonged aplasia and G3 hypertension, both expected from the chemotherapy agents and hu3F8. One patient progressed after the 2 cycles and the other 2 showed stable disease, according to the revised (2017) International Neuroblastoma Response Criteria (INRC).

In this formal trial, the investigators will investigate whether the combination of Naxitamab and GM-CSF with ifosfamide/Carboplatin/Etoposide (ICE) has a synergistic treatment effect in relapsed or refractory disease. The safety and efficacy of NICE (Naxitamab, Ifosfamide/Carboplatin/Etoposide) in patients that have not achieved complete remission with HITS chemo-immunotherapy will be assessed.

Inclusion criteria

• Diagnosis of neuroblastoma (NB) as defined per INRC as

• histopathology of tumor biopsy, or
• BM aspirate or biopsy indicative of NB by histology plus high blood or urine catecholamine metabolite levels or MYCN amplification, or
• Fluorodeoxyglucose (FDG), MIBG avid lesion(s)
• High-risk NB as defined as any of the following:

• Stage 4 with MYCN amplification
• Stage 4 without MYC amplification >1.5 y of age
• Stage 3 with MYCN amplification
• Relapsed/refractory Neuroblastoma with

• Evidence of soft tissue disease or
• Progessive disease/incomplete response/relapsed to previous treatment with Naxitamab plus GM-CSF
• Prior treatment with murine and hu3F8 is allowed
• Prior treatment with irinotecan or temozolomide or ICE is permitted
• Evaluable (microscopic marrow metastasis, elevated tumor markers, positive MIBG or PET scans) or measurable (CT, MRI) disease documented after completion of prior systemic therapy
• Age ≥18 months
• Acceptable hematological status defined as:

• Hemoglobin ≥8 g/dL (5.0 mmol/L)
• White blood cell count ≥1000/μL
• Absolute Neutrophil Count (ANC) ≥500/μL
• Platelet count ≥50,000/μL
• Acceptable liver function defined as:

• alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 times Upper Limit of Normal (ULN)
• 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 (≥ 12 years old).

Exclusion criteria

• Existing major organ dysfunction > grade 2, with the exception of hearing loss and hematologic toxicity (defined as suppression of all subtypes of WBCs, RBCs, and platelets).
• Active life-threatening infection.
• Pregnant women or women who are breast-feeding.
• Inability to comply with protocol requirements, including genetic studies.
• History of allergy to GM-CSF ≥ G4 (Common Terminology Criteria for Adverse Events- CTCAE) or does not respond to treatment.
• Absolute Neutrophil Count (ANC) < 500/uL .
• Platelet count <50,000/uL.
• Patients with relapsed/refractory Neuroblastoma with solely bone marrow/bone involvement. Only patients with B/BM compartiment disease who show progressive disease/incomplete response/relapsed to previous treatment with Naxitamab plus GM-CSF may be eligible (inclusion critèrium #3).