Phase I study of anti-GD2 Chimeric Antigen Receptor-Expressing T cells in pediatric and young adult patients affected by relapsed/refractory central nervous system 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

5 Feb 2025 → ongoing

Decision date (initial)

2025-02-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-519168-42-00

EudraCT number

2021-004729-55

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

The primary objective of this study is to evaluate the safety and feasibility and establish the maximum tolerated dose (MTD)/recommended dose (RD) of iC9-GD2-CAR Tcells infused in pediatric and young adult patients affected by relapsed/refractory malignant central nervous system (CNS) tumors.

Secondary objectives 1

1. The secondary objectives of the protocol will be aimed at characterizing the kinetics of expansion and distribution of the infused iC9-GD2-CAR-T cells, document CRS features and obtain preliminary data on the efficacy of the treatment. The same features will be analyzed in the subgroup of patients receiving AP1903, in order to define the impact of the activation of the safety switch. Intracerebral microdialysate analysis will be performed to monitor cerebral metabolism after GD2-CAR T-cells treatment. Furthermore, microdialysate cerebrospinal fluid (CSF) samples will be used to obtain local cytokines profile after GD2-CAR T-cells treatment and to monitor CRS in the CNS in response to immunotherapy.

Conditions and MedDRA coding

Relapsed/refractory malignant central nervous system tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Procurement eligibility 1. Histological diagnosis of relapsed/refractory CNS tumors, including: a. Medulloblastoma (MB)/other embryonal tumor (ARM A) b. Hemispheric high-grade glioma (HGG) (ARM B) c. Thalamic HGG, diffuse midline glioma (DMG) and other rare CNS tumors not included in Arm A and B (ARM C) 2. Eligibility according to GD2 expression: - GD2-positivity: the patient will be considered eligible and will be enrolled in the present protocol since there is not any other effective treatment to be explored - GD2-negativity: the patient will be considered NOT eligible for the treatment: an alternative treatment of rescue, whenever possible, or palliation will be proposed to the patient in this case - Impossibility of obtaining tumor samples: the patient will be considered eligible and will be enrolled in the present protocol since there is not any other effective treatment to be explored, considering the available scientific data published on GD2 expression for the majority of highly malignant brain tumors. 3. Age: 6 months – 30 years 4. Adequate venous access for apheresis or eligible for appropriate catheter placement, and no other contraindications for leukapheresis 5. Written and signed informed consent from patients, parents or legal guardians. For subjects < 18 year-old their legal guardian must give informed consent. In addition, pediatric subjects will be included in age-appropriate discussion and written informed assent will be obtained for those greater than or equal to 7 years of age, when appropriate 6. Karnofsky/Lansky = 60 Treatment eligibility 1. Imaging assessments performed within 14 days of start of treatment 2. Age: 6 months – 30 years 3. Measurable or evaluable disease on at least 2 dimensions on MRI at the time of treatment enrollment 4. Karnofsky/Lansky = 60 5. Recover from the toxic effects of previous radiation and chemotherapies: grade 4 and or 3 non-hematologic toxicities must have resolved to grade = 2; in presence of chronic complications (e.g. treatment-associated thrombocytopenia), patient must be clinically stable, according to the opinion of the treating physicians, and meet all other eligibility criteria 6. Positioning of an implantable intraventricular access device 7. “Written and signed informed consent from patients, parents or legal guardians. For subjects < 18 year-old their legal guardian must give informed consent. In addition, pediatric subjects will be included in age-appropriate discussion and written informed assent will be obtained for those greater than or equal to 7 years of age, when appropriate” 8. Patients of childbearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for six months after receiving the preparative regimen 9. Females of childbearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus

Exclusion criteria 1

1. 1. Severe, uncontrolled active infections 2. HIV or active HCV and/or HBV infection 3. Concurrent or recent prior therapies, before apheresis: a. If receiving glucocorticoids, patient must be on a stable or weaning dose for at least 7 days prior to apheresis. Recent or current use of inhaled/topical/nonabsorbable steroids is not exclusionary. 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 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 6 weeks prior to apheresis Exclusion criteria: 1. Pregnant or lactating women 2. Severe, uncontrolled active infections 3. HIV or active HCV and/or HBV infection 4. Rapidly progressive disease with life expectancy < 6 weeks 5. History of grade 3 or 4 hypersensitivity to murine protein-containing products 6. 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 7. Renal function: serum creatinine > 3x ULN for age 8. Blood oxygen saturation < 90% 9. Cardiac function: left ventricular ejection fraction lower than 45% by ECHO 10.Bone marrow function: absolute neutrophils count (ANC) lower than 500/mm3 and/or platelets lower than 20.000 (not reached by transfusion) 11.Congestive heart failure, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the principal investigator (PI) would pose an unacceptable risk to the subject. 12.Concurrent or recent prior therapies, before infusion: a. If receiving glucocorticoids, patient must be on a stable or weaning dose for at least 7 days prior to infusion. Recent or current use of inhaled/topical/nonabsorbable steroids is not exclusionary. 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 b. Systemic chemotherapy in the 3 weeks preceding infusion c. Immunosuppressive agents less than or equal to 30 days d. Radiation therapy must have been completed at least 6 weeks prior to enrollment e. Other anti-neoplastic investigational agents currently or within 30 days prior to start of protocol therapy 13.Patient-derived GD2-CART01 production failure: vitality <80%, CD3+ cells <80%, CD3+ CAR+ cells <20%, CD3+ CAR+ antitumor activity <60% in functional co-culture assay at an Effector: Target ratio 1:1, viable CAR+ cells upon AP1903 exposition >20%, Replication Competent Retrovirus (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. 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, both systemic and neurological, will be evaluated according to the Common Terminology Criteria for Adverse Event scale, version 5.0, and to specific grading scales. 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 pos

Secondary endpoints 1

1. 1. To assess the in vivo persistence and expansion of the infused CAR T-cells in the peripheral blood (PB) and CSF using immunoassays and transgene detection (Real Time q Polymerase Chain Reaction (PCR)) both for the whole population and the specific T cells subsets 2. To evaluate the tumor infiltration of the infused T cells by immunohistochemistry (IHC), flow cytometry and/or transgene detection (Real Time qPCR), whenever the tumor sample is available after the treatment 3. To assess the kinet

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

Application history

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