GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG)

Phase 1

Recruiting

• Conditions: Glioma of Brainstem; Glioma of Spinal Cord
• Interventions: Drug: GD2 CAR T cells; Drug: Fludarabine; Drug: Cyclophosphamide

• Registration Number: NCT04196413
• Lead Sponsor: Crystal Mackall, MD

Brief Summary

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.

Detailed Description

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.

* 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.

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.

Study Timeline

• Study First Submitted: 2019-12-10
• Study First Submitted QC: 2019-12-10
• Study First Posted: 2019-12-12
• Study Start: 2020-06-04
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-15
• Last Update Posted: 2024-10-17
• Primary Completion: 2028-07-31
• Study Completion: 2043-07-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 54

Inclusion Criteria

Not provided

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Exclusion Criteria

1. Bulky tumor involvement of cerebellar vermis or hemispheres (pontocerebellar peduncles involvement is acceptable), or thalamic lesions that in the investigator's assessment place the subject at unacceptable risk for herniation.

2. Clinically significant swallowing dysfunction/dysphagia or prominent medullary dysfunction, as determined by the clinical investigator.

3. Current systemic corticosteroid therapy.

4. Ongoing use of dietary supplements, alternative therapies or extreme diets or any medication not approved by the investigators

5. Prior CAR therapy.

6. Prior GD2 antibody therapy

7. Uncontrolled fungal, bacterial, viral, or other infection. Previously diagnosed infection for which the patient continues to receive antimicrobial therapy is permitted if responding to treatment and clinically stable.

8. Diagnosed ongoing infection with:

   • HIV,
   • Hepatitis B (HBsAg positive) or
   • Hepatitis C virus (anti HCV positive). A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing.

9. Clinically significant systemic illness or medical condition (e.g. significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgement of the principal investigator is likely to interfere with assessment of safety or efficacy of the investigational regimen and its requirements.

10. Women who are pregnant or breastfeeding.

11. In the investigator's judgment, the subject is unlikely to complete all protocol required study visits or procedures, including follow up visits, or comply with the study requirements for participation.

12. Known sensitivity or allergy to any agents/reagents used in this study.

13. Primary immunodeficiency or history of autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years

All subject files must include supporting documentation to confirm subject eligibility. The method of confirmation can include, but is not limited to, laboratory test results, radiology test results, subject self report, and medical record review.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
GD2-CAR T	GD2 CAR T cells	Rolling-6 dose escalation design will test GD2-CAR T cells in subjects with H3K27M-mutant DIPG. GD2CART will be administered in escalating doses on Day 0 in hospitalized subjects with either DIPG or spinal DMG Intravenously * Dose Level -1: 3x10\^5 transduced T cells/kg(± 20%) * Dose Level 1: 1x10\^6 transduced T cells/kg (± 20%) * Dose Level 2: 3x10\^6 transduced T cells/kg (± 20%) Intracerebroventricularly, without conditioning lymphodepletion chemotherapy * Dose Level -1: 10x10\^6 transduced T cells (±20%) * Dose Level 1: 30x10\^6 transduced T cells (±20%) * Dose Level 2: 50x10\^6 transduced T cells (±20%) * Dose Level 3: 100x10\^6 transduced T cells (±20%) Intracerebroventricularly after administration of conditioning lymphodepletion chemotherapy regimen with cyclophosphamide and fludarabine * Dose Level -1: 10x10\^6 transduced T cells (±20%) * Dose Level 1: 30x10\^6 transduced T cells (±20%) * Dose Level 2: 50x10\^6 transduced T cells (±20%)
GD2-CAR T	Fludarabine	Rolling-6 dose escalation design will test GD2-CAR T cells in subjects with H3K27M-mutant DIPG. GD2CART will be administered in escalating doses on Day 0 in hospitalized subjects with either DIPG or spinal DMG Intravenously * Dose Level -1: 3x10\^5 transduced T cells/kg(± 20%) * Dose Level 1: 1x10\^6 transduced T cells/kg (± 20%) * Dose Level 2: 3x10\^6 transduced T cells/kg (± 20%) Intracerebroventricularly, without conditioning lymphodepletion chemotherapy * Dose Level -1: 10x10\^6 transduced T cells (±20%) * Dose Level 1: 30x10\^6 transduced T cells (±20%) * Dose Level 2: 50x10\^6 transduced T cells (±20%) * Dose Level 3: 100x10\^6 transduced T cells (±20%) Intracerebroventricularly after administration of conditioning lymphodepletion chemotherapy regimen with cyclophosphamide and fludarabine * Dose Level -1: 10x10\^6 transduced T cells (±20%) * Dose Level 1: 30x10\^6 transduced T cells (±20%) * Dose Level 2: 50x10\^6 transduced T cells (±20%)
GD2-CAR T	Cyclophosphamide	Rolling-6 dose escalation design will test GD2-CAR T cells in subjects with H3K27M-mutant DIPG. GD2CART will be administered in escalating doses on Day 0 in hospitalized subjects with either DIPG or spinal DMG Intravenously * Dose Level -1: 3x10\^5 transduced T cells/kg(± 20%) * Dose Level 1: 1x10\^6 transduced T cells/kg (± 20%) * Dose Level 2: 3x10\^6 transduced T cells/kg (± 20%) Intracerebroventricularly, without conditioning lymphodepletion chemotherapy * Dose Level -1: 10x10\^6 transduced T cells (±20%) * Dose Level 1: 30x10\^6 transduced T cells (±20%) * Dose Level 2: 50x10\^6 transduced T cells (±20%) * Dose Level 3: 100x10\^6 transduced T cells (±20%) Intracerebroventricularly after administration of conditioning lymphodepletion chemotherapy regimen with cyclophosphamide and fludarabine * Dose Level -1: 10x10\^6 transduced T cells (±20%) * Dose Level 1: 30x10\^6 transduced T cells (±20%) * Dose Level 2: 50x10\^6 transduced T cells (±20%)

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose (MTD)/RP2D of GD2CART in subjects with H3K27M DIPG	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.
Rate of successful manufacture of GD2CART using a retroviral vector in the Miltenyi CliniMACS Prodigy system	14 days after apheresis	The percentage of apheresis samples (fresh or frozen) will be determined for each dose cohort.
Safety of GD2CART in subjects with spinal H3 K27M-mutant DMG treated at the RP2D	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

Secondary Outcome Measures

Name	Time	Method
Radiographic Response Rate	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.
Progression-Free Survival (PFS)	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)	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)
Overall Survival (OS)	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
Measure resolution of toxicity	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

Trial Locations

Locations (1)

Lucile Packard Children's Hospital (LPCH); 🇺🇸 Stanford, California, United States