Phase I/II study of anti-GD2 Chimeric Antigen Receptor-Expressing T cells in pediatric patients affected by High Risk and/or relapsed/refractory Neuroblastoma and other relapsed/refractory GD2+ tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ospedale Pediatrico Bambino Gesu

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

18 Feb 2025 → ongoing

Decision date (initial)

2025-02-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AIFA (bandi per la ricerca indipendente) · Ministero della Salute, Ricerca Finalizzata

External identifiers

EU CT number

2024-520436-15-00

EudraCT number

2017-002475-26

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

The primary objective of this study is to evaluate the safety and feasibility of iC9-GD2-CAR T cells infused in pediatric patients affected by relapsed/refractory NBL. The phase II extension is aimed at testing the efficacy of the treatment at the optimal dose defined in the phase I, including the patients with extremely High-Risk NBL, at greater risk of relapse (namely patients with stage III/IV and Myc-N amplification) at the end of the first-line treatment, even if they reached CR.

Conditions and MedDRA coding

High Risk and/or relapsed/refractory Neuroblastoma and other relapsed/refractory GD2+ tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. Phase I - Patient Inclusion Criteria The patient must meet the following eligibility inclusion criteria to be enrolled to receive treatment in the Phase I study. 1. Diagnosis of NBL that have been treated with frontline therapy and is judged to be incurable, based upon the following criteria: a. Relapse after first-line treatment, proved by a positive 123-I-mMIBG-scan b. Persistence/progression of disease after the initiation of the upfront treatment 2. Patients must have measurable or evaluable disease at the time of treatment enrollment, as shown by bone marrow biopsy/aspirate, US or CT/MRI scan or by 123-I-mMIBG scan. 3. Recover from the toxic effect of previous chemotherapies: grade 4 and or 3 non-hematologic toxicities must have resolved to grade ≤2; if some effects of the therapies have become chronic (i.e. treatment associated thrombocytopenia), the patient must be clinically stable, according to the opinion of the treating physicians, and meet all other eligibility criteria. 4. Age: 12 months – 18 years. 5. Voluntary informed consent is given. For subjects < 18 years old their legal guardian must give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate. 6. Clinical performance status: Patients > 16 years of age: Karnofsky greater than or equal to 60%; Patients less than or equal to 16 years of age: Lansky scale greater than or equal to 60%. 7. Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen. 8. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus.
2. Phase II - Patients Inclusion criteria The patient must meet the following eligibility inclusion criteria to be enrolled to receive treatment in the Phase II study. 1. Diagnosis of NBL that have been treated with frontline therapy and is judged to be incurable, based upon the following criteria: a. Relapse after first-line treatment, proved by a positive MIBG-scan b. Persistence/progression of disease after the initiation of the upfront treatment OR 2. Diagnosis of extremely High Risk NBL at high risk of relapse, defined by stage III/IV and Myc-N amplification, at the end of the first-line treatment according to the Standard of Care, even if NED. OR 3. Diagnosis of GD2+ tumors other than Neuroblastoma, considered incurable with conventional treatments by the treating physician (Phase II only). 4. Patients with relapsed/refractory disease must have measurable or evaluable disease at the time of treatment enrollment, as shown by bone marrow biopsy/aspirate, US or CT/MRI scan or by MIBG-scan. 5. Recover from the toxic effect of previous chemotherapies: grade 4 and or 3 non-hematologic toxicities must have resolved to grade ≤2; if some effects of the therapies have become chronic (i.e. treatment associated thrombocytopenia), the patient must be clinically stable, according to the opinion of the treating physicians, and meet all other eligibility criteria. 6. Age: 12 months –35 years. 7. Voluntary informed consent is given. For subjects < 18 years old their legal guardian must give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate. 8. Clinical performance status: Patients > 16 years of age: Karnofsky greater than or equal to 60%; Patients less than or equal to 16 years of age: Lansky scale greater than or equal to 60%. 9. Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen. 10. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus

Exclusion criteria 2

1. Phase I/II Exclusion Criteria 1. Severe, uncontrolled active intercurrent infections 2. HIV, or active HCV and/or HBV infection 3. Concurrent or recent prior therapies, before apheresis: a. Systemic steroids (at a dose equivalent to or greater 2 mg/kg prednisone) in the 2 weeks before apheresis collection. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary. b. Systemic chemotherapy in the 3 weeks preceding apheresis collection. c. Immunosuppressive agents in the 2 weeks preceding apheresis collection d. Radiation therapy must have been completed at least 3 weeks prior to apheresis. e. I131 MIBG therapy must have been completes at least 6 weeks prior to apheresis f. Anti-GD2 murine monoclonal antibody (ch14.18 antibody) in the 2 weeks preceding apheresis collection g. Other anti-neoplastic investigational agents currently or within 30 days prior to apheresis (i.e. start of protocol therapy); h. Exceptions: Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis
2. Phase I/II - Patient Exclusion criteria 1. Pregnant or lactating women 2. Severe, uncontrolled active intercurrent infections 3. Active hepatitis B or hepatitis C infection 4. HIV infection 5. Rapidly progressive disease with life-expectancy < 6 weeks 6. History of grade 3 or 4 hypersensitivity to murine protein-containing products 7. Hepatic function: Inadequate liver function defined as total bilirubin > 4x upper limit of normal (ULN) or transaminase (ALT and AST) > 6 x ULN based on age and laboratory specific normal ranges 8. Renal function: serum creatinine > 3x ULN for age. 9. Blood oxygen saturation < 90%. 10. Cardiac function: Left ventricular ejection fraction lower than 45% by ECHO. 11. Marrow function: ANC lower than 500/mm3 and/or platelets lower than 20.000 (not reached by transfusion). 12. Congestive heart failure, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject. 13. Untreated CNS metastasis; patients with previous CNS tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are eligible. 14. Concurrent or recent prior therapies, before infusion: a. Systemic steroids (at a dose equivalent to or greater 2 mg/kg prednisone) in the 2 weeks before infusion. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary. b. Systemic chemotherapy in the 2 weeks preceding infusion. c. Immunosuppressive agents less than or equal to 30 days. d. Radiation therapy must have been completed at least 3 weeks prior to enrollment. e. I131-MIBG therapy must have been completes at least 6 weeks prior to enrollment f. Anti-GD2 murine monoclonal antibody (ch14.18 antibody) in the 2 weeks preceding infusion g. Other anti-neoplastic investigational agents currently or within 30 days prior to start of protocol therapy; h. Exceptions: ii. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis 15. Patient-derived GD2-CART01 production failure: vitality <80%, CD3+ cells <80%, CD3+ CAR+ cells <20%, CD3+ CAR+ antitumor activity <60% in functional coculture assay at an Effector:Targetratio 1:1, viable CAR+ cells upon AP1903 exposition >20%, RCR positivity, Vector Copy Number >10, non-sterility, endotoxin contamination (> 1 EU/ml).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Phase I primary end-points 1. To evaluate the safety of the infusion of iC9-GD2-CAR T cells at different escalating/de-escalating doses and establish the dose limiting toxicity (DLT) of the cellular product. Toxicity will be evaluated according to the Common Terminology Criteria for Adverse Event (CTC AE) scale, version 4.0. DLT will be defined as any of the following that is not pre-existing, due to infection or to underlying malignancy and that may be considered possibly, probably or definite

Secondary endpoints 1

1. Phase I and II secondary end-points 1. To assess the in vivo persistence and expansion of the infused T cells in the peripheral blood (PB), BM and in the Cerebro-Spinal Fluid (CSF) using immunoassays and transgene detection (Real Time qPCR), both for the whole population and the specific T cells subsets. 2. To evaluate the tumor infiltration of the infused T cells through Immunohistochemistry (IHC), flow cytometry and/or transgene detection (Real Time qPCR), whenever the tumor sample is availa

Investigational products

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

Test 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ospedale Pediatrico Bambino Gesu

Sponsor organisation

Ospedale Pediatrico Bambino Gesu

Address

Piazza Di Sant'onofrio 4

City

Rome

Postcode

00165

Country

Italy

Scientific contact point

Organisation

Ospedale Pediatrico Bambino Gesu

Contact name

Locatelli Franco

Public contact point

Organisation

Ospedale Pediatrico Bambino Gesu

Contact name

Locatelli Franco

Locations

1 EU/EEA country · 1 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 11 files

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

Application history

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