A Phase 3 Trial of Antibody hu3F8 and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in High-Risk Neuroblastoma Patients with Primary or Secondary Refractory Osteomedullary Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Y-mAbs Therapeutics A/S

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

3 Apr 2018 → ongoing

Decision date (initial)

2023-12-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2023-508587-29-00

EudraCT number

2017-001829-40

ClinicalTrials.gov

NCT03363373

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy, Pharmacokinetic

To evaluate the centrally assessed objective response rate (ORR) to naxitamab + GM-CSF

Secondary objectives 8

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)

Conditions and MedDRA coding

Treatment of high-risk neuroblastoma patients with primary refractory disease or incomplete response to salvage treatment in bone and/or bone marrow

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002346-PIP01-18

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

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 (1.0 x109/L) c. Absolute neutrophil count (ANC) ≥500/μL (0.5 x109/L) d. Platelet count ≥25,000/μL (25 x109/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.

Exclusion criteria 18

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 progressing 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 according to section 9.2.5. A sterilized or infertile woman is exempt from the requirement to use contraception after naxitamab 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 months 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, hematology, 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective Response Rate (ORR) during the naxitamab treatment period, centrally assessed according to the International Neuroblastoma Response Criteria (INRC)

Secondary endpoints 13

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 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 infusions done in an outpatient setting
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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Y-mAbs Therapeutics A/S

Sponsor organisation

Y-mAbs Therapeutics A/S

Address

Agern Alle 11

City

Hoersholm

Postcode

2970

Country

Denmark

Scientific contact point

Organisation

Y-mAbs Therapeutics A/S

Contact name

Director Clinical Operations

Public contact point

Organisation

Y-mAbs Therapeutics A/S

Contact name

Director Clinical Operations

Third parties 9

Locations

5 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 57 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications