The primary purpose of this study is to test whether CAR T cells targeting GD2 (GD2CART) can be successfully made and safely given to children and adults with H3K27M-mutant diffuse midline glioma (DMG). Eligible subjects may have DMG arising in the pons (called difuse intrinisic pontine glioma, DIPG), the spinal cord, or other areas of the brain such as a thalamus
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-mutant diffuse midline glioma (DMG) using a retroviral vector and dasatinib in the Miltenyi CliniMACS Prodigy® system. * Assess the safety and identify the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), route and schedule of GD2CART and lymphodepleting chemotherapy in subjects with H3K27M-mutant DMG. * Assess the safety of the MTD/RP2D, route and schedule of GD2CART in expansion cohorts of subjects with H3K27M-mutant DMG. Secondary Objectives: * In a preliminary manner, assess clinical benefit and Patient Reported Outcomes (PROs) of GD2CART at the RP2D in children and adults with H3K27M-mutant DMG. * Evaluate the safety and impact on clinical benefit of repeat intracerebroventricular (ICV) administrations of GD2CART according to Arms A, B, C or D. * 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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
97
Autologous T-Cells transduced with retroviral vector (14g2a-CD8.BB.z.iCasp9) expressing GD2-chimeric antigen receptor
Fludarabine 30 mg/m2 per day IV for days -4, -3, -2
Cyclophosphamide 500 mg/m2 per day IV for days -4, -3, -2
Lucile Packard Children's Hospital (LPCH)
Stanford, California, United States
RECRUITINGRate of successful manufacture of GD2CART using a retroviral vector in the Miltenyi CliniMACS Prodigy system
The percentage of apheresis samples (fresh or frozen) will be determined for each dose cohort.
Time frame: 14 days after apheresis
Safety of the dose, route and schedule of GD2CART and lymphodepleting chemotherapy in subjects with H3K27M-mutant DMG
Incidence and severity of dose limiting toxicities (DLTs) after initial dose of GD2.BB.z.iCasp9-CAR T cells (GD2CART) in each Arm, at each dose level tested by disease cohort
Time frame: 28 days after infusion
Safety of GD2CART at RP2D, route and schedule of GD2CART in expansion cohorts of subjects with H3K27M-mutant DMG
Suspected adverse events and serious adverse events following chemotherapy preparative regimen and infusion of GD2CART."
Time frame: 28 days after infusion
Radiographic Response Rate
Radiographic Response will be evaluated using the RANO 2.0 tumor response criteria.
Time frame: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.
Overall Survival (OS)
Overall survival (OS) is defined as the time from date of initial diagnosis to date of death from any cause. Treatment OS is defined as the time from Cycle 1 Day 0 to date of death from any cause.
Time frame: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.
Progression-Free Survival (PFS)
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.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
First round: 750 mg/m2 per day IV for days -6 and -5. Subsequent rounds: 750 mg/m2 per day IV for day -5.
Time frame: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion
Post-progression survival (PPS)
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)
Time frame: ime Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion
Measure resolution of toxicity
Resolution of toxicity ≤ grade2, in the event unacceptable toxicity considered possibly, probably or definitely related to GD2CART cells within 72 hours
Time frame: 72 hours of administration of AP1903