Naxitamab for High-Risk Neuroblastoma Patients With Primary Refractory Disease or Incomplete Response to Salvage Treatment in Bone and/or Bone Marrow
Study Details
Study Description
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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. |
Biological: GM-CSF + Naxitamab
Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Humanized IgG1 monoclonal GD2 antibody
|
Outcome Measures
Primary Outcome Measures
- Response rate during Naxitamab treatment [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.
Secondary Outcome Measures
- Incidence of adverse events and serious adverse events [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) [101 weeks]
Length of time from patient response to disease progression.
- Complete Response Rate [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 [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 [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 [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 [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 [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 [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 [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) [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) [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) [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) [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 [101 weeks]
Number of infusions done in an outpatient setting
- Percentage of infusions done in an outpatient setting [101 weeks]
Percentage of infusions done in an outpatient setting
- Incidence of adverse events and serious adverse events in ADA positive patients [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) [5 years]
PFS, defined as the time from the first 1st infusion of naxitamab until progressive disease or death, whichever comes first
- Overall Survival [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 [39 days]
Happiness and activity levels will be measured over time and assessed by caretaker
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Florida | Gainesville | Florida | United States | 32611 |
| 2 | University of Chicago | Chicago | Illinois | United States | 60637 |
| 3 | Riley Hospital for Children | Indianapolis | Indiana | United States | 46202 |
| 4 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
| 5 | Nationwide Children's Hospital | Columbus | Ohio | United States | 43205 |
| 6 | M.D. Anderson Cancer Center | Houston | Texas | United States | 77030 |
| 7 | The Hospital for Sick Children | Toronto | Canada | M5G 1X8 | |
| 8 | Rigshospitalet | København | Denmark | 2100 | |
| 9 | University Medical Center Hamburg-Eppendorf | Hamburg | Germany | ||
| 10 | Johannes Gutenberg-Universität | Mainz | Germany | ||
| 11 | University Hospital Regensburg | Regensburg | Germany | ||
| 12 | Hong Kong Children's Hospital | Hong Kong | Hong Kong | ||
| 13 | Queen Mary Hospital | Hong Kong | Hong Kong | ||
| 14 | Istituto Tumori di Milano | Milan | Lombardia | Italy | 20133 |
| 15 | Giannina Gaslini Hospital | Genoa | Italy | 16147 | |
| 16 | Fondazione IRCCS Istituto Nazionale dei Tumori | Milan | Italy | 20133 | |
| 17 | Hospital Sant Joan de Déu | Barcelona | Spain | 08950 | |
| 18 | Hospital Infantil Universitario Niño Jesús | Madrid | Spain | 28009 | |
| 19 | Hospital Universitario y Politécnico La Fe | Valencia | Spain | 46026 | |
| 20 | The Royal Glasgow Children's Hospital | Glasgow | United Kingdom | G51 4TF | |
| 21 | Leeds General Infirmary | Leeds | United Kingdom | LS1 3EX | |
| 22 | The Royal Marsden | London | United Kingdom | SW3 6JJ | |
| 23 | University Hospital Southampton | Southampton | United Kingdom | SO16 6YD |
Sponsors and Collaborators
- Y-mAbs Therapeutics
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 201