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

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.

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

Study Overview

• Status: Terminated
• Conditions: Neuroblastoma Recurrent
• Intervention / Treatment: Drug: Naxitamab and GM-CSF in combination with irinotecan and temozolomide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Hong Kong Children's Hospital
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Asan Medical Center Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Naxitamab and GM-CSF in combination with irinotecan and temozolomide; 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; 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)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Y-mAbs Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2021
• Primary Completion (Actual): September 21, 2022
• Study Completion (Actual): September 21, 2022

Study Registration Dates

• First Submitted: September 17, 2020
• First Submitted That Met QC Criteria: September 22, 2020
• First Posted (Actual): September 23, 2020

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Temozolomide; Irinotecan
• Other Study ID Numbers: 203 (UNIMIB Ethic Commettee)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No