The primary purpose of this study is to test whether GD2-CAR T cells can be successfully made from immune cells collected from children and young adults with H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) or spinal H3K27M-mutant diffuse midline glioma (DMG). H3K27Mmutant testing will occur as part of standard of care prior to enrollment.
Name: GD2 CAR T cells
Name: Fludarabine
Name: Cyclophosphamide
Description: The percentage of apheresis samples (fresh or frozen) will be determined for each dose cohort.
Measure: Rate of successful manufacture of GD2CART using a retroviral vector in the Miltenyi CliniMACS Prodigy system Time: 14 days after apheresisDescription: Severity of dose limiting toxicities (DLTs) following chemotherapy and infusion of GD2CART cells, will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 at each dose level tested in subjects with H3K27M-mutant DIPG following standard upfront radiation therapy.
Measure: Maximum tolerated dose (MTD)/RP2D of GD2CART in subjects with H3K27M DIPG Time: 28 days after infusionDescription: Severity of dose limiting toxicities (DLTs) following chemotherapy and infusion of GD2CART cells will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 in subjects with spinal H3K27M-mutant DMG following standard upfront radiation therapy
Measure: Safety of GD2CART in subjects with spinal H3 K27M-mutant DMG treated at the RP2D Time: 28 days after infusionDescription: Radiographic Response will be evaluated using tumor response criteria: Complete Response (CR): disappearance on MR of all evaluable tumor and mass effect; stable or improving neurologic examination. If CSF was positive, it must be negative. Partial Response (PR): ≥ to 50% reduction in tumor size; stable or improving neurologic examination. Stable Disease (SD): at least stable and maintenance corticosteroid dose not increased, and MR/CT imaging meets neither PR nor PD Progressive Disease (PD): Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression; OR a > 25% increase in the bi-dimensional measurement, OR the appearance of a new tumor lesion.
Measure: Radiographic Response Rate Time: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.Description: OS is defined as the time from the start of the lymphodepleting chemotherapy preparative regimen to the date of death from any cause
Measure: Overall Survival (OS) Time: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.Description: PFS is defined as the time from the start of the lymphodepleting chemotherapy preparative regimen to the date of radiographic progression or death from any cause.
Measure: Progression-Free Survival (PFS) Time: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusionDescription: PPS is measured for each subject with DIPG as OS minus PFS, and for each patient with recorded progression as OS minus Time to Progression (TTP)
Measure: Post-progression survival (PPS) Time: ime Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusionDescription: Resolution of toxicity ≤ grade2, in the event unacceptable toxicity considered possibly, probably or definitely related to GD2CART cells within 72 hours
Measure: Measure resolution of toxicity Time: 72 hours of administration of AP1903Allocation: N/A
Single Group Assignment
There is one SNP
Severity of dose limiting toxicities (DLTs) following chemotherapy and infusion of GD2CART cells, will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 at each dose level tested in subjects with H3K27M-mutant DIPG following standard upfront radiation therapy.. Safety of GD2CART in subjects with spinal H3 K27M-mutant DMG treated at the RP2D. --- K27M ---
Crohns, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years Glioma of Spinal Cord Glioma of Brainstem Glioma Primary Objectives: - Determine the feasibility of manufacturing autologous T cells transduced with 14g2a-CD8-BBz-iCasp9 retroviral vector expressing GD2 Chimeric Antigen Receptor (GD2CART) for administration in subjects with H3K27M+ diffuse intrinsic pontine glioma (DIPG) or subjects with spinal H3 K27M-mutant diffuse midline glioma (DMG) using a retroviral vector and dasatinib in the Miltenyi CliniMACS Prodigy® system. --- K27M ---
Secondary Objectives: - In a preliminary manner, assess clinical benefit of GD2CART at the RP2D in subjects with H3K27M DIPG or spinal H3 K27M-mutant DMG. - If unacceptable toxicity occurs that is possibly, probably or likely related to GD2CART, assess the capacity for AP1903, a dimerizing agent, to mediate clearance of the genetically engineered cells and resolve toxicity. --- K27M ---