GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT04196413|
Recruitment Status : Recruiting
First Posted : December 12, 2019
Last Update Posted : November 13, 2020
|Condition or disease||Intervention/treatment||Phase|
|Glioma of Spinal Cord Glioma of Brainstem||Drug: GD2 CAR T cells Drug: Fludarabine Drug: Cyclophosphamide||Phase 1|
- 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.
- Assess the safety and identify the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of GD2CART in subjects with H3K27M+ DIPG administered after cyclophosphamide/fludarabine-based lymphodepletion regimen using the following dose escalation schedule: DL1: 1e6 transduced T cells/kg; DL2: 3e6 transduced T cells/kg; DL3: 10e6 transduced T cells/kg.
- Assess the safety of the MTD/RP2D of GD2CART in subjects with spinal H3K27M mutant DMG.
- 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||54 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase 1 Clinical Trial of Autologous GD2 Chimeric Antigen Receptor (CAR) T Cells (GD2CART) for Diffuse Intrinsic Pontine Gliomas (DIPG) and Spinal Diffuse Midline Glioma (DMG)|
|Actual Study Start Date :||June 4, 2020|
|Estimated Primary Completion Date :||December 2023|
|Estimated Study Completion Date :||December 2023|
Experimental: GD2-CAR T
Dose escalation in subjects with DIPG:
A standard 3+3 dose escalation design will test GD2-CAR T cells in subjects with H3K27M-mutant DIPG, starting with Dose
Dose Level -1 will be explored if the first subject treated experiences dose limiting toxicity (DLT) or if >2 of 6 subjects treated at Dose Level 1 experiences DLT.
Dose expansion in subjects with DIPG and spinal DMG: Once the MTD or RP2D is determined, up to 20 evaluable subjects with H3K27M-mutant DIPG and 10 evaluable subjects with H3K27M-mutant spinal DMG will be treated at the RP2D (including subjects treated during dose escalation).
Drug: GD2 CAR T cells
Autologous T-Cells transduced with retroviral vector (14g2a-CD8.BB.z.iCasp9) expressing GD2-chimeric antigen receptor
Fludarabine 25 mg/m2 per day IV for days -4, -3, -2
Cyclophosphamide 500 mg/m2 per day IV for days -4, -3, -2
- Rate of successful manufacture of GD2CART using a retroviral vector in the Miltenyi CliniMACS Prodigy system [ Time Frame: 14 days after apheresis ]The percentage of apheresis samples (fresh or frozen) will be determined for each dose cohort.
- Maximum tolerated dose (MTD)/RP2D of GD2CART in subjects with H3K27M DIPG [ Time Frame: 28 days after infusion ]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 [ Time Frame: 28 days after infusion ]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
- Radiographic Response Rate [ Time Frame: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion. ]
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.
- Overall Survival (OS) [ Time Frame: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion. ]OS is defined as the time from the start of the lymphodepleting chemotherapy preparative regimen to the date of death from any cause
- Progression-Free Survival (PFS) [ Time Frame: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion ]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.
- Post-progression survival (PPS) [ Time Frame: ime Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion ]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 resolution of toxicity [ Time Frame: 72 hours of administration of AP1903 ]Resolution of toxicity ≤ grade2, in the event unacceptable toxicity considered possibly, probably or definitely related to GD2CART cells within 72 hours
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04196413
|Contact: Courtney Ericksonemail@example.com|
|United States, California|
|Lucile Packard Children's Hospital (LPCH)||Recruiting|
|Stanford, California, United States, 94304|
|Contact: Anne C. Marcy 650-721-9994 firstname.lastname@example.org|
|Principal Investigator: Michelle Monje, MD|
|Principal Investigator:||Michelle Monje||Stanford University|