A Safety and Efficacy Study of hu14 in High-Risk Neuroblastoma Patients

A Phase 2/3 Study to Characterize and Evaluate the Efficacy, Safety, and Tolerability of hu14.18K322A Treatment Given in Combination With Chemotherapy in Participants With High-Risk Neuroblastoma

Neuroblastoma is the most common type of solid cancer found outside the brain in young children. Generally, it affects children younger than 5 years old, with the average age when it is found being just 2 years. Most patients have 'high-risk' disease, with spread of the disease to different sites (metastases). This multinational study aims to find out how effective and safe the treatment of a monoclonal anti-GD2 antibody hu14.18K322A (daretabart) is when used together with chemotherapy to treat children and young people who have high-risk neuroblastoma.

This is a Phase 2/3, open label, single arm study, evaluating how well hu14.18K322A works and how safe it is in combination with chemotherapy, in relapsed and refractory high-risk neuroblastoma (HRNB) patients.

The study is in 2 parts. The first part of the study will test two doses of hu14.18K322A to give with chemotherapy in 12 patients to confirm the best dose. Once the best dose is found, Part 2 of the study will recruit up to an additional 66 participants with relapsed disease and 66 participants with refractory disease.

Children and young people who take part in the study must be between 18 months and 18 years old at the time of consent and have confirmed HRNB that has spread to other parts of the body. It is expected that participants will receive up to 12 cycles of treatment. Once the treatment has finished, participants will be followed up to study long-term effects.

Inclusion Criteria

1. Are ≥18 months to <18 years of age at time of informed consent or assent.

2. Are initially diagnosed with histologically proven HRNB with metastatic disease.

3. Have evaluable or measurable disease per International Neuroblastoma Response Criteria (INRC)

4. Have a Lansky performance status of ≥50 (≤16 years ) or Karnofsky performance status ≥50% (for >16 years).

5. Have recovered from the toxic effects of prior chemotherapies

6. Are at least 2 weeks beyond any major tumor surgery

7. Meet the following organ function criteria, as measured within 1 week prior to Investigational Medicinal Product (IMP) dosing:

   1. BM function: i. Platelets ≥50 × 109/L ii. Absolute neutrophil count (ANC) ≥0.50 × 109/L
   2. Renal function: i. Age-adjusted serum creatinine ≤1.5 × upper limit of normal (ULN) for age. ii. Estimated glomerular filtration rate (eGFR) at least 60 mL/min using the Schwartz formula.
   3. Liver function: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤3 × ULN and total bilirubin ≤1.5 × ULN.
   4. Cardiac function: i. Shortening fraction ≥27% or ejection fraction of ≥50% on echocardiogram. ii. Corrected QT Interval on electrocardiogram (ECG) using the Fridericia formula (QTcF) ≤ 480 msec.
   5. Lung function: i. Pulse oximetry considered normal in room air. No evidence of dyspnea at rest.
   6. Central nervous system (CNS) function: i. Participants with a history of CNS disease must have no clinical or radiological evidence of active CNS disease at the time of study enrollment.

8. If a fertile and sexually active woman of child-bearing potential (WOCBP), have a negative serum pregnancy test at Screening and then either a negative serum or urine test prior to each cycle and agree to use an acceptable and highly effective contraception method during the study and for at least 6 months after the last day of study treatment .

9. If a fertile and sexually active male, agree to use condoms during the study and for at least 6 months after the last dose of study treatment

10. If applicable based on age, are willing and able to provide voluntary written informed assent for participation in the study (as per local Institutional Review Board [IRB]/Independent Ethics Committee [IEC] requirements and if applicable based on regional age of consent) and to comply with all protocol requirements.

11. Their parent or legal guardian (if applicable based on regional age of consent) is willing and able to provide voluntary written informed consent for the participant's involvement in the study.

Exclusion Criteria

1. Any active uncontrolled infection at the time of enrollment. Any known history of infection with human immunodeficiency virus (HIV), or active or chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).

2. Any contraindications to any of the study treatments.

3. Patients with >Grade 2 diarrhea.

4. Patients with disease of any major organ system that would compromise their ability to withstand chemoimmunotherapy.

5. Patients who have undergone a prior allogeneic stem cell transplant < 6 months ago or have undergone a solid organ transplant.

6. Patients who are on hemodialysis.

7. Patients who require or are likely to require pharmacologic doses of systemic corticosteroids while receiving treatment on this study except to manage allergic reactions

8. Patients on any other immunosuppressive medications

9. Patients who have received enzyme-inducing anticonvulsants including phenytoin, phenobarbital, or carbamazepine for at least 7 days prior to study enrollment.

10. Patients who have been diagnosed with any malignancy other than neuroblastoma.

11. Patients with symptoms of congestive heart failure.

12. Patients with a history of Grade 4 allergic reactions to anti-GD2 antibodies or reactions that required permanent discontinuation of the anti-GD2 therapy.

13. Patients participating in or planning to participate in another study that is either blinded or involves an IMP

14. If female, are breastfeeding, pregnant, or planning to become pregnant, or, if sexually active and of child-bearing potential, are unwilling to use an effective birth control method until 6 months after the last dose of study medication

15. Do not meet the following required washout periods prior to the administration of the first dose of hu14.18K322A:

    1. 14 days from prior systemic myelosuppressive chemotherapy.
    2. 7 days from prior systemic biologic antineoplastic agents (e.g. anti-cancer agents not known to be myelosuppressive - not associated with reduced platelet or ANC counts).
    3. 14 days from systemic steroids.
    4. ≥12 weeks from large field radiation therapy (i.e., total body irradiation, whole abdominal, total lung, ≥50% pelvis).
    5. 6 weeks from prior craniospinal radiotherapy or Iodine-131-metaiodobenzylguanidine (131I-MIBG) therapy.
    6. 2 weeks from radiotherapy to the primary tumor bed.
    7. ≥7 days from small treatment field radiation.
    8. 14 days or 5 half-lives (whichever is longer) from last administration of an IMP.
    9. >7 days prior to study enrollment for drugs that are strong inducers or inhibitors of Cytochrome P450 3A4 (CYP3A4).
    10. ≥21 days and with recovery of all associated toxicities from receiving cellular therapy (e.g., modified T lymphocyte cells, Natural Killer (NK) cells, dendritic cells).

16. Ongoing need for any medication known or suspected to interfere with study treatment.