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

Study Overview
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Brief Summary
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An International, Single-Arm, Multicenter Phase 2 Trial.

Detailed Description
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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.

Official Title
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Naxitamab and Granulocyte-Macrophage Colony Stimulating Factor in Combination With Irinotecan and Temozolomide in Patients With High-Risk Neuroblastoma With Primary Refractory Disease or in First Relapse. An International, Single-Arm, Multicenter Phase 2 Trial.

Conditions
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Neuroblastoma Recurrent

Intervention / Treatment
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* Drug: Naxitamab and GM-CSF in combination with irinotecan and temozolomide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Naxitamab and GM-CSF in combination with irinotecan and temozolomide<br>A treatment cycle is 21 days. The patients will receive irinotecan 50 mg/m2/day IV and temozolomide 100 mg/m2/day orally (both on Days 1-5) in combination with naxitamab 2.25 mg/kg/day IV (Days 2, 4, 8 and 10) (total 9 mg/kg per cycle), and GM-CSF 250 ug/m2/day sc, (Days 6-10). Patients will receive up to 18 IT cycles after enrollment. Naxitamab and GM-CSF will be given for at least 8 cycles. | Drug: Naxitamab and GM-CSF in combination with irinotecan and temozolomide<br>* Irinotecan, solution for infusion (20 mg/mL) Temozolomide, capsules (5 mg, 20 mg and 100 mg) The humanized immunoglobulin isotype G (IgG1) monoclonal antibody (mAb) naxitamab, solution for infusion (4 mg/mL) Sargramostim (GM-CSF), lyophilized 250 µg single use vial (250 µg/vial)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | The proportion of patients obtaining a centrally assessed complete response (CR) or partial response (PR) according to the International Neuroblastoma Response Criteria (INRC) | 84 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR after 2 cycles | The proportion of patients obtaining a centrally assessed CR or PR according to the INRC | 42 days | 
| Duration of response (DoR) | The time from first centrally assessed overall response (OR) (CR or PR according to the INRC) to PD or death | 2 years | 
| Complete response (CR) rate | the proportion of patients obtaining a centrally assessed CR according to the INRC | 84 days | 
| Time to first subsequent therapy | the time from initiation of IMP treatment until death or start of new anti-cancer treatment (prohibited as per protocol) | 3 years | 
| Progression free survival (PFS) | the time from enrollment until progressive disease or death, whichever comes first | 3 years | 
| PFS at 1 year | The proportion of patients alive and with no PD | 1 year | 
| PFS at 2 years | The proportion of patients alive and with no PD | 2 year | 
| Overall survival (OS) | the time from enrollment until death | 3 years | 
| Overall survival (OS) | the time from enrollment until death | 1 year | 
| Overall survival (OS) at 2 years | The proportion of patients alive | 2 year |