GD2-CAR T Cells for Pediatric Brain Tumours

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

The purpose of this study is to test the safety and efficacy of iC9-GD2-CAR T-cells, a third generation (4.1BB-CD28) CAR T cell treatment targeting GD2 in paediatric or young adult patients affected by relapsed/refractory malignant central nervous system (CNS) tumors. In order to improve the safety of the approach, the suicide gene inducible Caspase 9 (iC9) has been included.

Study Overview

• Status: Recruiting
• Conditions: High Grade Glioma; Medulloblastoma, Childhood; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma; Embryonal Tumor; Brain Tumor Adult; Brain Tumor, Pediatric
• Intervention / Treatment: Biological: GD2-CART01 (iC9-GD2-CAR T-cells)

Detailed Description

The study will consist of a Phase I, dose escalation phase aimed at evaluating the safety and feasibility of intravenous injections of autologous iC9-GD2-CAR T-cells in patients with refractory/relapsed malignant CNS tumors.

Considering the peculiar potential risks associated with the treatment of CNS tumors, the study has been designed to enrol patients in 3 different arms depending on the histology and location of the disease. This model of enrollment is aimed at testing the safety sequentially, starting from categories of patients at lower risk of severe intracranial hypertension first, and subsequently proceeding with patients at proportionally increased risk. In particular, the three arms explored will be relapsed or refractory:

• ARM A: MB/other embryonal tumor
• ARM B: Hemispheric HGG
• ARM C: Thalamic HGG, DMG, DIPG and other rare CNS tumors not included in Arm A and B

Eligible patients will undergo leukapheresis in order to harvest T cells, which will be manufactured to obtain the autologous CAR T product iC9-GD2-CAR T-cells, a GD2-targeting CAR T product. Briefly, the patients will be treated with a lymphodepleting regimen containing conventional chemotherapic agents and subsequently will receive a single infusion of GD2-CART01.

Moreover, the product contains a suicide gene safety switch (namely inducible Caspase 9): in case of relevant toxicities, the patient will receive the dimerizing agent in order to activate the apoptotic pathway in the infused T cells.

After infusion of CAR T cells, the patients will enter a 5-year active follow-up period (for disease follow-up). A conventional 15-year follow-up will be performed as per regulatory requirements in patients receiving gene therapy.

• Study Type: Interventional
• Enrollment (Estimated): 54
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Francesca Del Bufalo, MD; Phone Number: 2739 00396859; Email: francesca.delbufalo@opbg.net
• Study Contact Backup: Name: Angela Mastronuzzi, MD, PhD; Phone Number: 4647 00396859; Email: angela.mastronuzzi@opbg.net

Study Locations

• Italy
  • Roma, Italy, 00165
    • Recruiting
    • Ospedale Pediatrico Bambino Gesù
    • Principal Investigator: Franco Locatelli, MD PhD
    • Contact: Francesca del Bufalo, MD PhD; Phone Number: 2739 0039-066859; Email: francesca.delbufalo@opbg.net
    • Contact: Angela Mastronuzzi, MD PhD; Phone Number: 4647 0039-066859; Email: angela.mastronuzzi@opbg.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 30 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Imaging assessments performed within 14 days of start of treatment
2. Age: 6months-30years
3. Measurable or evaluable disease on at least 2 dimensions on MRI at the time of treatment enrollment
4. Karnofsky/Lansky≥60
5. Recoverfromthetoxiceffectsofpreviousradiationandchemotherapies:grade4and or 3 non-hematologic toxicities must have resolved to grade ≤ 2; in presence of chronic complications (i.e. 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 (CodmanHolterRickham reservoir, Integra LifeSciences, NJ, U.S.A) and a microdialysis probe (71 high cutoff microdialysis bolt catheter, M Dialysis AB, Stockholm Sweden)
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 four 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. Pregnant or lactating women
2. Severe,uncontrolledactiveinfections
3. HIV or active HCV and/or HBV infection
4. Rapidly progressive disease with life expectancy < 6 weeks
5. Historyofgrade3or4hypersensitivitytomurineprotein-containingproducts
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. 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:

    1. 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/non- absorbable 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
    2. Systemic chemotherapy in the 3 weeks preceding infusion
    3. Immunosuppressive agents less than or equal to 30 days
    4. Radiation therapy must have been completed at least 6 weeks prior to enrollment
    5. Otheranti-neoplasticinvestigationalagentscurrentlyorwithin30dayspriorto 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%, RCR positivity, Vector Copy Number >10, non-sterility, endotoxin contamination (> 1 EU/ml)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ARM A: MB/other embryonal tumor; After a lymphodepleting regimen, patients affected by relapsed/refractory MB/other embryonal tumor will receive 1.0 to 6.0 x 10⁶/kg GD2 Chimeric Antigen Receptor (CAR) positive T cells.	Biological: GD2-CART01 (iC9-GD2-CAR T-cells); Following a lymphodepleting treatment with conventional chemotherapy, patients will be treated with 1.0 to 6.0 x 10⁶/kg GD2 Chimeric Antigen Receptor (CAR) positive T cells, infused i.v. as a single dose
Experimental: ARM B: Hemispheric HGG; After a lymphodepleting regimen, patients affected by relapsed/refractory hemispheric high grade glioma will receive 1.0 to 6.0 x 10⁶/kg GD2 Chimeric Antigen Receptor (CAR) positive T cells.	Biological: GD2-CART01 (iC9-GD2-CAR T-cells); Following a lymphodepleting treatment with conventional chemotherapy, patients will be treated with 1.0 to 6.0 x 10⁶/kg GD2 Chimeric Antigen Receptor (CAR) positive T cells, infused i.v. as a single dose
Experimental: ARM C: Thalamic HGG, DMG, DIPG and other rare CNS tumors not included in Arm A and B; After a lymphodepleting regimen, patients affected by relapsed/refractory thalamic HGG, DMG, DIPG and other rare CNS tumors not included in Arm A and B will receive 1.0 to 6.0 x 10⁶/kg GD2 Chimeric Antigen Receptor (CAR) positive T cells.	Biological: GD2-CART01 (iC9-GD2-CAR T-cells); Following a lymphodepleting treatment with conventional chemotherapy, patients will be treated with 1.0 to 6.0 x 10⁶/kg GD2 Chimeric Antigen Receptor (CAR) positive T cells, infused i.v. as a single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and definition of the MTD/RD	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) and the maximum tolerated dose/recommended dose (MTD/RD) of the cellular product	4 weeks after CAR T cell infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
In vivo expansion and persistence	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 (Droplet PCR), both for the whole population and the specific T cells subsets	Up to 5 years
Tumor infiltration	To evaluate the tumor infiltration of the infused T cells by immunohistochemistry (IHC), flow cytometry and/or transgene detection (Droplet PCR), whenever the tumor sample is available after the treatment	Up to 5 years
iC9-GD2-CAR-T cells clearance after AP1903 infusion	To assess the kinetic of iC9-GD2-CAR-T cells clearance after AP1903 infusion	Up to 5 years
Serum cytokine profiling	To define the serum and CSF cytokine profile and its correlation with CRS in order to identify a possible predictive profile	Up to 3 months
Time to progression (TTP)	To evaluate the TTP after infusion	Up to 5 years
Event-free survival (EFS)	To evaluate the EFS after infusion	Up to 5 years
Overall survival (OS)	To evaluate the OS after infusion	Up to 5 years
Disease outcome according to the Response assessment in pediatric neuro-oncology (RAPNO) criteria	umor response assessment through the RAPNO criteria	Up to 5 years

Collaborators and Investigators

• Sponsor: Bambino Gesù Hospital and Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2023
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2038

Study Registration Dates

• First Submitted: March 18, 2022
• First Submitted That Met QC Criteria: March 18, 2022
• First Posted (Actual): March 28, 2022

Study Record Updates

• Last Update Posted (Estimated): November 17, 2023
• Last Update Submitted That Met QC Criteria: November 16, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: CAR T cell; Immunotherapy; medulloblastoma; high grade glioma; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma; Brain tumors; GD2-antigen; Pediatric Central Nervous System tumours; Central nervous system tumour young adults
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Neuroectodermal Tumors, Primitive; Brain Stem Neoplasms; Infratentorial Neoplasms; Neoplasms; Glioma; Brain Neoplasms; Central Nervous System Neoplasms; Medulloblastoma; Diffuse Intrinsic Pontine Glioma
• Other Study ID Numbers: GD2CAR02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No