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

• ClinicalTrials.gov Identifier: NCT03363373
• Recruitment Status: Recruiting
• First Posted: December 6, 2017
• Last Update Posted: March 7, 2023
• Sponsor: Y-mAbs Therapeutics
• Information provided by (Responsible Party): Y-mAbs Therapeutics

Tracking Information

• First Submitted Date: November 6, 2017
• First Posted Date: December 6, 2017
• Last Update Posted Date: March 7, 2023
• Actual Study Start Date: April 3, 2018
• Estimated Primary Completion Date: May 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 5, 2017)

Response rate during Naxitamab treatment [ Time Frame: 101 weeks ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 10, 2021)

• Incidence of adverse events and serious adverse events [ Time Frame: 101 weeks ]
  Safety will be evaluated by the incidence of adverse events (AE) and serious adverse events (SAEs) graded according to CTCAE, version 4.0.
• Duration of Response (DoR) [ Time Frame: 101 weeks ]
  Length of time from patient response to disease progression.
• Complete Response Rate [ Time Frame: 101 weeks ]
  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.
• Assessment of the maximum serum concentration (cmax) of naxitamab [ Time Frame: Pre-naxitamab dose - 552 hours ]
  Calculation of maximum serum concentration of naxitamab will be calculated and summarized with descriptive statistics.
• Assessment of the minimum serum concentration (cmin) of naxitamab [ Time Frame: Pre-naxitamab dose - 552 hours ]
  Calculation of minimum serum concentration of naxitamab will be calculated and summarized with descriptive statistics.
• Assessment of the clearance of naxitamab [ Time Frame: Pre-naxitamab dose - 552 hours ]
  Calculation of clearance of naxitamab will be calculated and summarized with descriptive statistics.
• Assessment of the volume of distribution of naxitamab [ Time Frame: Pre-naxitamab dose - 552 hours ]
  Calculation of the volume of distribution of naxitamab will be calculated and summarized with descriptive statistics.
• Assessment of the Area under the Curve (AUC) of naxitamab [ Time Frame: Pre-naxitamab dose - 552 hours ]
  Calculation of the AUC of naxitamab will be calculated and summarized with descriptive statistics.
• Assessment of the terminal half-life (t½) of naxitamab [ Time Frame: Pre-naxitamab dose - 552 hours ]
  Calculation of the t½ of naxitamab will be calculated and summarized with descriptive statistics.
• Assessment of anti-drug antibody (ADA) formation [ Time Frame: Pre-naxitamab dose - 552 hours ]
  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.
• Intravenous (IV) opioid use (cycle 1) [ Time Frame: 6 hours ]
  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
• Intravenous (IV) opioid use (all cycles) [ Time Frame: 101 weeks ]
  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
• Hospitalization days (cycle 1) [ Time Frame: 4 weeks ]
  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
• Safety of patients with positive human anti-drug antibody (ADA) [ Time Frame: 101 weeks ]
  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
• Number of infusions done in an outpatient setting [ Time Frame: 101 weeks ]
  Number of infusions done in an outpatient setting
• Percentage of infusions done in an outpatient setting [ Time Frame: 101 weeks ]
  Percentage of infusions done in an outpatient setting
• Incidence of adverse events and serious adverse events in ADA positive patients [ Time Frame: 101 weeks ]
  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.
• Progression Free Survival (PFS) [ Time Frame: 5 years ]
  PFS, defined as the time from the first 1st infusion of naxitamab until progressive disease or death, whichever comes first
• Overall Survival [ Time Frame: 5 years ]
  The interval from the date of first dose of Naxitamab until the date of death due to any cause.
• Happiness and activity levels [ Time Frame: 39 days ]
  Happiness and activity levels will be measured over time and assessed by caretaker

Original Secondary Outcome Measures (submitted: December 5, 2017)

• Incidence of adverse events and serious adverse events [ Time Frame: 101 weeks ]
  Safety will be evaluated by the incidence of adverse events (AE) and serious adverse events (SAEs) graded according to CTCAE, version 4.0.
• Duration of Response (DoR) [ Time Frame: 101 weeks ]
  Length of time from patient response to disease progression.
• Progression Free Survival (PFS) [ Time Frame: 101 weeks ]
  The interval from the date of first dose of Naxitamab until the date of disease progression
• Overall Survival [ Time Frame: 101 weeks ]
  The interval from the date of first dose of Naxitamab until the date of death due to any cause.
• Assessment of peak plasma concentration (Cmax) of Naxitamab [ Time Frame: 101 weeks ]
  Cmax will be calculated and summarized with descriptive statistics.
• Assessment of trough plasma concentration (Cmin) of Naxitamab [ Time Frame: 101 weeks ]
  Cmin will be calculated and summarized with descriptive statistics.
• Assessment of clearance of Naxitamab [ Time Frame: 101 weeks ]
  Clearance will be calculated and summarized with descriptive statistics.
• Assessment of volume of distribution (Vd) of Naxitamab [ Time Frame: 101 weeks ]
  Volume of distribution will be calculated and summarized with descriptive statistics.
• Assessment of area under the plasma concentration versus time curve (AUC) of Naxitamab [ Time Frame: 101 weeks ]
  AUC will be calculated and summarized with descriptive statistics.
• Assessment of half life (T1/2) of Naxitamab [ Time Frame: 101 weeks ]
  T1/2 will be calculated and summarized with descriptive statistics.
• Assessment of HAHA formation [ Time Frame: 101 weeks ]
  Human Anti-Human Antibody formation
• Opioid use [ Time Frame: 2 weeks ]
  Intravenous opioid use during cycle 1
• Number of hospitalization days [ Time Frame: 2 weeks ]
  Hospitalization days related to Naxitamab infusion during cycle 1

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Naxitamab for High-Risk Neuroblastoma Patients With Primary Refractory Disease or Incomplete Response to Salvage Treatment in Bone and/or Bone Marrow
• Official Title: A Pivotal Phase 2 Trial of Antibody Naxitamab (hu3F8) and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in High-Risk Neuroblastoma Patients With Primary Refractory Disease or Incomplete Response to Salvage Treatment in Bone and/or Bone Marrow

Brief Summary

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

Detailed Description

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
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Patients will receive cycles of GM-CSF and Naxitamab every 4 weeks up to a total of 101 weeks. Safety and efficacy will be investigated with short-term follow-up at minimum 4 weeks after last treatment and with long-term follow-up for up to 3 years after end of treatment visit.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Neuroblastoma

Intervention

Biological: GM-CSF + Naxitamab

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

Study Arms

Experimental: GM-CSF + Naxitamab

Each investigational cycle is started with 5 days of 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 until CR or PR 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. After end of treatment patients will enter a long-term follow up for up to 3 years after end of treatment visit.

Intervention: Biological: GM-CSF + Naxitamab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 6, 2023): 122
• Original Estimated Enrollment (submitted: December 5, 2017): 37
• Estimated Study Completion Date: April 2028
• Estimated Primary Completion Date: May 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Joris Wilms; +4570261414; clinicaltrials@ymabs.com

• Listed Location Countries: Canada, Denmark, France, Germany, Hong Kong, Italy, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03363373
• Other Study ID Numbers: 201
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Y-mAbs Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Y-mAbs Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Y-mAbs Therapeutics
• Verification Date: March 2023