AUTOLOGOUS T CELLS TRANSDUCED WITH A RETROVIRAL VECTOR ENCODING A CHIMERIC ANTIGEN RECEPTOR AGAINST GD2, EX-VIVO EXPANDED for Relapsed/refractory central nervous system tumors

Inclusion criteria

• {"criterion_text":"- 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)\n- 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.\n- 3. Age: 6 months – 30 years\n- 4. Adequate venous access for apheresis or eligible for appropriate catheter placement, and no other contraindications for leukapheresis\n- 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\n- 6. Karnofsky/Lansky = 60\n- Treatment eligibility 1. Imaging assessments performed within 14 days of start of treatment\n- 2. Age: 6 months – 30 years\n- 3. Measurable or evaluable disease on at least 2 dimensions on MRI at the time of treatment enrollment\n- 4. Karnofsky/Lansky = 60\n- 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\n- 6. Positioning of an implantable intraventricular access device\n- 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”\n- 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\n- 9. Females of childbearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus"}

Exclusion criteria

• {"criterion_text":"- 1. Severe, uncontrolled active infections\n- 2. HIV or active HCV and/or HBV infection\n- 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\n- Exclusion criteria: 1. Pregnant or lactating women\n- 2. Severe, uncontrolled active infections\n- 3. HIV or active HCV and/or HBV infection\n- 4. Rapidly progressive disease with life expectancy < 6 weeks\n- 5. History of grade 3 or 4 hypersensitivity to murine protein-containing products\n- 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\n- 7. Renal function: serum creatinine > 3x ULN for age\n- 8. Blood oxygen saturation < 90%\n- 9. Cardiac function: left ventricular ejection fraction lower than 45% by ECHO\n- 10.Bone marrow function: absolute neutrophils count (ANC) lower than 500/mm3 and/or platelets lower than 20.000 (not reached by transfusion)\n- 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.\n- 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\n- 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)"}

Primary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"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..."}

Secondary endpoints

• {"endpoint_text":"- 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\n- 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\n- 3. To assess the kinet","definition_or_measurement_approach":"1. Persistence/expansion: measured in PB and CSF using immunoassays and transgene detection (Real Time qPCR). 2. Tumor infiltration: assessed by IHC, flow cytometry and/or transgene detection (Real Time qPCR) when tumor samples available. 3. (truncated in source)"}

Italy

Earliest CTIS Part Ii Submission Date

21-10-2024

Latest Decision Or Authorization Date

03-10-2025

Processing Time Days

347

Number Of Sites

1

Number Of Participants

27

Primary sponsor

Full Name

Ospedale Pediatrico Bambino Gesu

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Italy