Relapsed/refractory malignant central nervous system tumors MedDRA version: 20.0 Level: SOC Classification code 10029104 Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps) System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: GD2-CART01
Product Code: [GD2-CART01]
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Linfociti T modificati geneticamente con fattore retrovirale SFG-iC9 CAR.GD2.CD28.41
Sponsors
IRCCS, OSPEDALE PEDIATRICO BAMBINO GESÙ DI ROMA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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) or diffuse intrinsic pontine glioma (DIPG) 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 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 =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 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 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 10, non-sterility, endotoxin contamination (> 1 EU/ml)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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 T-cells infused in pediatric and young adult patients affected by relapsed/refractory malignant central nervous system (CNS) tumors.;Secondary Objective: 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.;Primary end point(s): 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 (i.e. Lee grading for Cytokine Release Syndrome – CRS - and American Society for Transplantation and Cellular Therapy - ASTCT- Immune effector cell-associated neurotoxicity syndrome - ICANS - Consensus Grading). 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 most definitely related to the study cellular products: 1) Non-hematologic DLT is any grade 3 or 4 nonhematologic toxicity, non-responsive to AP1903 infusions; 2) Hematologic DLT is defined as any grade 4 hem | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 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 (Droplet 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 (Droplet PCR), whenever the tumor sample is available after the treatment 3. To assess the kinetic of GD2-CAR T-cells clearance after AP1903 infusion 4. To define the serum and CSF cytokine profile and its correlation with CRS in order to identify a possible predictive profile: • To dose IL-6, IL-2, IL-1, IL-1b, TNF-alpha, Interferon gamma in the microdialysate and in CSF samples to measure the CRS secondary to immunotherapy; to correlate cytokines trends in CSF and in microdialysis samples after GD2-CAR T-cells treatment • To dose glucose, lactate, pyruvate, lactate to pyruvate ratio (LPR), glycerol and glutamate to assess cerebral metabolism and oxidative damage and to correlate these with intracranial pressure (ICP) and cerebral perfusion pressure (CPP) after GD2-CAR T-cells infusion 5. To assess the clinical response and the kinetics of cytokine levels change in patients with CRS treated with AP1903 6. To assess the long-term antitumor effect of the infused GD2-CAR T-cells at 1, 3 and 5 years, without further therapy 7. To assess relapse rate, time to progression (TTP) and event free survival (EFS) and overall survival (OS) at 6 months 1, 3- and 5-years post cell infusion 8. To assess the disease outcome in patients treated with AP1903 9. To evaluate the ability of the response evaluation provided by the Response assessment in pediatric neuro-oncology (RAPNO) criteria to predict the disease outcome.;Timepoint(s) of evaluation of this end point: at 6 months, 1, 3 and 5 years | — |
Countries
Italy
Contacts
Public ContactDipartimento oncoematologia
IRCCS Ospedale Pediatrico Bambino Gesù
Outcome results
None listed