| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of high-risk neuroblastoma patients with primary refractory disease or incomplete response to salvage treatment in bone and/or bone marrow |
| Behandlung von Hochrisiko-Neuroblastompatienten mit primärer refraktärer Erkrankung oder unvollständigem Ansprechen auf eine Salvage-Behandlung in Knochen und / oder Knochenmark. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of high-risk neuroblastoma patients with primary refractory disease or incomplete response to salvage treatment in bone and/or bone marrow |
| Behandlung von Hochrisiko-Neuroblastompatienten mit primärer refraktärer Erkrankung oder unvollständigem Ansprechen auf eine Salvage-Behandlung in Knochen und / oder Knochenmark. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066595 |
| E.1.2 | Term | Neuroblastoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 1. To evaluate the centrally assessed objective response rate (ORR) to naxitamab + GM-CSF |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety of naxitamab + GM-CSF
2. To evaluate Duration of Response (DoR) to naxitamab + GM-CSF
3. To evaluate the complete response (CR) rate with naxitamab + GM-CSF
4. To evaluate the investigator assessed objective response rate to
naxitamab + GM-CSF
5. To evaluate the pharmacokinetics (PK) of naxitamab
6. To investigate the formation of Anti-Drug antibodies (ADAs)
7. To evaluate the safety of naxitamab + GM-CSF in patients with positive ADA at trial entry
8. To evaluate quality of life (QoL)
Secondary objectives in long-term follow-up:
1. To evaluate Progression-Free Survival (PFS) with naxitamab + GM-CSF
2. To evaluate overall survival (OS) with naxitamab + GM-CSF |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Documented diagnosis of neuroblastoma (NB) as defined per INRC as
a. histopathology of tumor biopsy, or
b. Bone marrow (BM) aspirate or biopsy indicative of NB by histology, plus high blood or urine catecholamine metabolite levels or Myelocytomatosis Viral-Related Oncogene, Neuroblastoma derived (MYCN) amplification, or
c. MIBG-avid lesion(s)
2. High-risk NB patients with either primary refractory disease or incomplete response to salvage treatment (in both cases including SD, MR and PR) evaluable in bone and/or BM as defined in section 6.7. If disease is only present in bone the patient must have evaluable disease outside the radiation areas for being eligible in the trial, please see section 7.2.1. If disease is only present in the BM the involvement must be >5%.
3. Life expectancy ≥6 months
4. Age ≥12 months
5. Acceptable hematological Status at screening, (hematological support is allowed if administered ≥1 week before first screening procedure), defined as:
a. Hemoglobin ≥8 g/dL (5.0 mmol/L)
b. White blood cell count ≥1000/μL (1.0e9/L)
c. Absolute neutrophil count (ANC) ≥500/μL (0.5e9/L)
d. Platelet count ≥25,000/μL (25e9/L)
6. Acceptable liver function defined as:
a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 times upper limit of normal (ULN)
b. Bilirubin ≤1.5 x ULN
7. Acceptable kidney function defined as:
a. Estimated Glomerular Filtration Rate (eGFR) >60 mL/min/1.73 m2
calculated by the 2009 revised Bedside Schwartz Equation
8. Written informed consent from legal guardian(s) and/or patient in accordance with local regulations. Children must provide assent as required by local regulations. |
|
| E.4 | Principal exclusion criteria |
1. Any systemic anti-cancer therapy, including chemotherapy or immunotherapy, within 3 weeks of 1st dose of GM-CSF
2. Evaluable NB outside bone and BM defined as follows:
• MIBG-avid tumor: Definite MIBG uptake in tumor tissues outside bone and BM
• MIBG nonavid tumor: Definite uptake in tumor tissues outside bone and BM on FDG-PET
3. Actively Progressive Disease at trial entry according to Park criteria (Park et al. 2017) (see section 6.7)
4. Existing major organ dysfunction CTCAE >Grade 2, with the exception of hearing loss, hematological status, kidney and liver function.
5. Active life-threatening infection
6. Prior treatment with naxitamab
7. Karnofsky/Lansky score <50%
8. Pregnancy or a woman who is breast-feeding (women of child-bearing potential must have a negative pregnancy test at screening). A woman of child-bearing potential is excluded if she does not agree to use highly effective contraception for a period of 42 days after the last naxitamab infusion section 9.2.5 in protocol. A sterilized or infertile woman is exempt from the requirement to use contraception after hu3F8 treatment: she must have undergone surgical sterilization (hysterectomy, or bilateral ovariectomy)
9. Inability to comply with protocol requirements, including PK studies, as determined by the investigator
10. History of allergy or known hypersensitivity to GM-CSF, yeast-derived products, or any component of GM-CSF or naxitamab
11. History of anaphylactic reactions CTCAE grade 4 related to prior GD2 antibody therapy
12. NB in central nervous system (CNS) within 6 months of 1st dose of GM-CSF
13. Prior treatment with omburtamab (mu8H9) within 6 months of 1st dose of GM-CSF
14. Patients who have had allogeneic hematopoietic stem cell transplantation (allo-SCT) or donor-lymphocyte-infusion (DLI). DLI or buffy coat infusion is defined as any kind of active allogenic lymphocyte suspension
a. within 6 month of 1st dose of GM-CSF or
b. with a lymphocyte count < 0.2 x109/L
15. Patients who received Hematopoietic Progenitor Cell (HPC) boost or "top-up" of allogenic stem cells (lymphocyte-depleted) within 2 months of 1st dose GM-CSF.
16. Any clinically meaningful abnormal finding in physical examination, vital signs, ECG, haematology, clinical chemistry, or urinalysis prior to inclusion into the trial, which in the opinion of the investigator, may put the subject at risk because of his/her participation in the study
17. Treatment with immunosuppressive agents (local steroids excluded) within a month prior to 1st dose of GM-CSF.
18. Inadequate cardiac function defined as either left ventricular ejection fraction of < 50% by echocardiography or other clinically relevant cardiac disorders at the discretion of the investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Objective Response Rate (ORR), during the naxitamab Treatment period, centrally assessed according to the International Neuroblastoma Response Criteria (INRC) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During and up to 101 weeks following the first naxitamab treatment |
|
| E.5.2 | Secondary end point(s) |
1. Safety will be evaluated by the incidence of adverse events (AEs) and serious adverse events (SAEs) graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
2. DoR, defined as the time from first objective response (CR or partial response (PR)) to PD; data will be censored at the date of last disease evaluation before new anti-NB treatment
3. Complete response rate, during the naxitamab treatment period, centrally assessed according to the INRC
4. ORR, during the naxitamab treatment period, investigator assessed according to the International Neuroblastoma Response Criteria (INRC)
5. Assessment of the PK of naxitamab
6. Assessment of ADA formation
7. Intravenous (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
8. Intravenous (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
9. 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
10. Number and percentage of infusion done in an outpatient settings
11. 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
12. Happiness and activity levels measured over time assessed by caretaker
13. Pain during naxitamab infusion as assessed by Wong Baker- and FLACC scales
Secondary endpoints for long term follow-up:
1. PFS, defined as the time from the 1st infusion of naxitamab until PD or death, whichever comes first; data will be censored at the date of last disease evaluation before new anti-NB treatment or last assessment during long-term follow-up, whichever comes first
2. OS, defined as the time from the 1st infusion of naxitamab until death; data censored at last date known to be alive during long-term follow-up |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During and up to 101 weeks following the first naxitamab treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Hong Kong |
| Canada |
| United Kingdom |
| United States |
| Denmark |
| France |
| Germany |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of trial is defined as last patient last visit in the long-term follow-up period |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
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