Neuroblastoma Recurrent
Conditions
Brief summary
An International, Single-Arm, Multicenter Phase 2 Trial.
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.
Interventions
DRUGNaxitamab 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)
Sponsors
Y-mAbs Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Months to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 84 days | The proportion of patients obtaining a centrally assessed complete response (CR) or partial response (PR) according to the International Neuroblastoma Response Criteria (INRC) |
Countries
Hong Kong, South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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) | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | Naxitamab and GM-CSF in Combination With Irinotecan and Temozolomide |
|---|---|
| Age, Categorical <=18 years | 2 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 4.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment South Korea | 2 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 2 / 2 |
Outcome results
Primary
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)
Time frame: 84 days
Population: The trial was terminated prematurely and no results from primary or secondary efficacy outcomes are available because images and bone marrow pathology were never submitted for central response assessment.