Naxitamab for High-Risk Neuroblastoma Patients With Primary Refractory Disease or Incomplete Response to Salvage Treatment in Bone and/or Bone Marrow

Phase 2Active Not RecruitingNCT03363373

Y-mAbs Therapeutics122 enrolled

Overview

Children and adults diagnosed with high-risk neuroblastoma patients with primary refractory disease or incomplete response to salvage treatment in bone and/or bone marrow will be treated for up to 101 weeks with naxitamab and granulocyte-macrophage colony stimulating factor (GM-CSF). Patients will be followed for up to five years after first dose. Naxitamab, also known as hu3F8 is a humanised monoclonal antibody targeting GD2

Each patient will receive treatment for up to 101 weeks following the first Naxitamab administration. After the end of trial visit, each patient will enter a long-term follow-up where they will be monitored for up to 5 years after first treatment cycle. Each investigational cycle is started with 5 days, days -4 to 0, of Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) administered at 250 µg/m2/day in advance of the start of Naxitamab administration. GM-CSF is thereafter administered at 500 µg/m2/day on days 1 to 5. As standard treatment, Naxitamab is administered at 3 mg/kg/day on days 1, 3, and 5, totalling 9 mg/kg per cycle. Treatment cycles are repeated every 4 weeks (±1 week) until complete response or partial response followed by 5 additional cycles every 4 weeks (±1 week). Subsequent cycles are repeated every 8 weeks (±2 weeks) through 101 weeks from first infusion at the discretion of the investigator. End of treatment will take place around 8 weeks after the last cycle and thereafter long-term follow-up will continue.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

122

Conditions

Neuroblastoma

Interventions

GM-CSF + NaxitamabBIOLOGICAL

Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Humanized IgG1 monoclonal GD2 antibody

Eligibility

Sex: ALLMin age: 1 Year

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of neuroblastoma as defined per International Neuroblastoma Response Criteria * High-risk neuroblastoma patients with either primary refractory disease or incomplete response to salvage treatment (in both cases including stable disease, minor response and partial response) evaluable in bone and/or bone marrow. * Life expectancy ≥ 6 months Exclusion Criteria: * Any systemic anti-cancer therapy, including chemotherapy or immunotherapy, within 3 weeks before 1st dose of GM-CSF * Evaluable neuroblastoma outside bone and bone marrow * Existing major organ dysfunction \> Grade 2, with the exception of hearing loss, hematological status, kidney and liver function * Active life-threatening infection

Locations (20)

Riley Hospital for Children

Indianapolis, Indiana, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Outcomes

Primary Outcomes

Response rate during Naxitamab treatment

Overall objective response rate (ORR) during the Naxitamab treatment period that will be centrally assessed according to the International Neuroblastoma Response Criteria (INRC) modified with 123I-MIBG criteria and following the use of 18F FDG-PET for MIBG non-avid lesions.

Time frame: 101 weeks

Secondary Outcomes

Incidence of adverse events and serious adverse events

Safety will be evaluated by the incidence of adverse events (AE) and serious adverse events (SAEs) graded according to CTCAE, version 4.0.

Time frame: 101 weeks

Duration of Response (DoR)

Length of time from patient response to disease progression.

Time frame: 101 weeks

Complete Response Rate

The complete response (CR) rate is defined as the fraction of patients experiencing a CR according to International Neuroblastoma Response Criteria (INRC) criteria during the treatment period.

Time frame: 101 weeks

Assessment of the maximum serum concentration (cmax) of naxitamab

Calculation of maximum serum concentration of naxitamab will be calculated and summarized with descriptive statistics.

Time frame: Pre-naxitamab dose - 552 hours

Assessment of the minimum serum concentration (cmin) of naxitamab

Calculation of minimum serum concentration of naxitamab will be calculated and summarized with descriptive statistics.

Time frame: Pre-naxitamab dose - 552 hours

Assessment of the clearance of naxitamab

Data from ClinicalTrials.gov

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The Hospital for Sick Children

Toronto, Canada

Rigshospitalet

Copenhagen, Denmark

University Medical Center Hamburg-Eppendorf

Hamburg, Germany

Johannes Gutenberg-Universität

Mainz, Germany

University Hospital Regensburg

Regensburg, Germany

Hong Kong Children's Hospital

Hong Kong, Hong Kong

Queen Mary Hospital

Hong Kong, Hong Kong

Tata Memorial Centre

Mumbai, India

...and 10 more locations

Calculation of clearance of naxitamab will be calculated and summarized with descriptive statistics.

Time frame: Pre-naxitamab dose - 552 hours

Assessment of the volume of distribution of naxitamab

Calculation of the volume of distribution of naxitamab will be calculated and summarized with descriptive statistics.

Time frame: Pre-naxitamab dose - 552 hours

Assessment of the Area under the Curve (AUC) of naxitamab

Calculation of the AUC of naxitamab will be calculated and summarized with descriptive statistics.

Time frame: Pre-naxitamab dose - 552 hours

Assessment of the terminal half-life (t½) of naxitamab

Calculation of the t½ of naxitamab will be calculated and summarized with descriptive statistics.

Time frame: Pre-naxitamab dose - 552 hours

Assessment of anti-drug antibody (ADA) formation

ADA formation will be investigated following a multi-tiered approach: A screening confirmation-titration analysis plus a ligand binding assay to examine a potential neutralizing effect of anti-naxitamab antibodies.

Time frame: Pre-naxitamab dose - 552 hours

Intravenous (IV) opioid use (cycle 1)

IV opioid use during cycle 1 defined as total dosage of IV morphine (or equivalent opioid) administered 2 hours before infusion until 4 hours after end of infusion of naxitamab

Time frame: 6 hours

Intravenous (IV) opioid use (all cycles)

IV opioid use for each cycle during the trial defined as total dosage of IV morphine (or equivalent opioid) administered 2 hours before infusion until 4 hours after end of infusion of naxitamab

Time frame: 101 weeks

Hospitalization days (cycle 1)

Number of hospitalization days related to naxitamab during cycle 1, defined as number of overnight stays. Hospitalizations required solely for protocol-specified assessments (e.g., PK sampling) or non-medical circumstances are excluded

Time frame: 4 weeks

Safety of patients with positive human anti-drug antibody (ADA)

In patients with positive ADA at trial inclusion, safety will be evaluated by the incidence of AEs and SAEs graded according to CTCAE, version 4.0

Time frame: 101 weeks

Number of infusions done in an outpatient setting

Time frame: 101 weeks

Percentage of infusions done in an outpatient setting

Time frame: 101 weeks

Incidence of adverse events and serious adverse events in ADA positive patients

Safety will be evaluated by the incidence of adverse events (AE) and serious adverse events (SAEs) graded according to CTCAE, version 4.0 in ADA positive patients.

Time frame: 101 weeks

Progression Free Survival (PFS)

PFS, defined as the time from the first 1st infusion of naxitamab until progressive disease or death, whichever comes first

Time frame: 5 years

Overall Survival

The interval from the date of first dose of Naxitamab until the date of death due to any cause.

Time frame: 5 years

Happiness and activity levels

Happiness and activity levels will be measured over time and assessed by caretaker

Time frame: 39 days