Naxitamab and GM-CSF in Combination With IT in Patients With High-Risk Neuroblastoma

An International, Single-Arm, Multicenter Phase 2 Trial.

This is an international, single-arm, multicenter phase 2 trial, in patients ≥ 12 months of age with high-risk NB with primary refractory disease or in first relapse. Patients will receive naxitamab + GM-CSF + irinotecan/temozolomide. The Follow-Up period ends 2 years after End of Treatment.

Eligibility Criteria:
Inclusion Criteria:

* Neuroblastoma (NB)
* Documented high-risk disease
* Receipt of Standard of Care (SoC) frontline induction/consolidation therapy (including surgery, chemotherapy, ASCT, MIBG, radiotherapy, immunotherapy, or retinoids)
* Active disease despite previous aggressive multi-drug chemotherapy, defined as one of the following:

  * verified first progression during multi-drug frontline treatment or
  * verified first episode of relapse, defined as recurrence after response to frontline treatment, or
  * verified first designation of refractory disease, defined as persistent metastatic disease (SD or minor response by INRC and MIBG curie score ≥3) detected at conclusion of at least 4 cycles of multi-drug induction chemotherapy on or according to a high-risk NB treatment protocol as defined above
* The patients must have one of the following (locally assessed) obtained within 3 weeks prior to enrollment and at least 10 calendar days after end of any prior anti-cancer treatment:

  * Measurable tumor on CT/MRI scan that is MIBG-avid or demonstrates increased FDG uptake on PET scan
  * MIBG (Metaiodobenzylguanidine) scan with positive uptake at a minimum of one site. This site must represent disease recurrence after completion of therapy, progressive disease on therapy, or refractory disease during induction
* Age ≥ 12 months at enrollment
* Written informed consent

Exclusion Criteria:

* Myelodysplastic syndrome or any malignancy other than NB
* Any systemic anti-cancer therapy within 3 weeks
* Autologous stem cell transplant (ASCT) within 6 weeks prior to enrollment or ongoing toxicity due to the stem cell transplant at the discretion of the investigator
* Therapeutic 131I-MIBG within 6 weeks prior to enrollment
* Radiotherapy (RT) within 4 weeks prior to enrollment at any lesion site that will be identified as a target lesion to measure tumor response
* Prior treatment with anti-GD2 if the patient experienced Progressive Disease (PD) while on anti-GD2 treatment
* Receipt of second line chemotherapy after designation of primary refractory disease or first relapse or PD
* NB in Bone Marrow (BM) only
* NB in the Central Nervous System (CNS) or leptomeningeal disease within 6 months prior to enrollment
* Performance status of \< 50% as per the Lansky scale (patients less than 16 years of age) or Karnofsky scale (for patients aged 16 years or older)
* Life expectancy of less than 6 months
* Left ventricular ejection fraction \< 50% by echocardiography
* Inadequate pulmonary function
* Diarrhea Grade ≥ 2
* Treatment with long-acting myeloid growth factor within 14 days or short-acting myeloid growth factor within 7 days prior to first dose of GM-CSF
* Receipt of immunosuppressive treatment (local steroids excluded) within 4 weeks prior to enrollment
* Life threatening infection(s)
* Uncontrolled seizure disorders despite anticonvulsant therapy (defined as a seizure event within 3 months prior to enrollment)
* Treatment with enzyme-inducing anticonvulsants including phenytoin, phenobarbital, or carbamazepine for at least 7 days prior to enrollment
* Concomitant use with St John's wort
* Allogeneic hematopoietic stem cell transplantation (allo-SCT) or donor-lymphocyte-infusion (defined as any kind of active allogeneic lymphocyte suspension)
* Treatment with Hematopoietic Progenitor Cell (HPC) boost within 2 months prior to enrollment
* History of allergy or known hypersensitivity to GM-CSF, yeast-derived products, or any component of GM-CSF, naxitamab, irinotecan or temozolomide
* History of anaphylactic reactions CTCAE Grade 4 related to prior anti-GD2 antibody therapy
* Unacceptable hematological status at screening, defined as one of the following:

  * Hemoglobin \<5.0 mmol/L (\<8 g/dL)
  * White blood cell count \<1000/µL
  * Absolute neutrophil count \<750/µL
  * Platelet count \< 75,000/µL
* Unacceptable liver function at screening, defined as one of the following:

  * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \>5 times upper normal limit (UNL)
  * Total bilirubin \>1.5 x UNL
* Unacceptable kidney function at screening, defined as estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73 m2 calculated by the 2009 revised Bedside Schwartz Equation
* Inability to comply with protocol
* Significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the action of trial agents or to significantly increase the severity of the toxicities experienced from trial treatment
* Females of childbearing potential who are pregnant, breast feeding, intend to become pregnant, or are not using adequate contraceptive methods or males who are not using adequate contraceptive methods