Clinical trial NCT04196413: GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG)
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Glioma of Spinal Cord
Glioma of Brainstem
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: California Institute for Regenerative Medicine (CIRM)
name: CureSearch
name: National Institutes of Health (NIH)
First posted: 2019-12-12
Enrollment: 54
Sex: ALL
Minimum age (years): 2
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: INCLUSION CRITERIA

1. Disease Status: Diagnosis of H3K27M mutant diffuse midline glioma (DMG)
2. H3K27M or H3K27I mutation. Confirmed by CLIA test.
3. Age: Greater than or equal to 2 year of age and less than or equal to 60 years of age.
4. Prior Therapy:

   * At least 4 weeks following completion of standard upfront radiation therapy.
   * At least 3 weeks post chemotherapy or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy, except for systemic inhibitory/stimulatory immune checkpoint therapy that requires 3 months.
5. Performance Status:

   Subjects \> 16 years of age: Karnofsky ≥ 60% OR Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; Subjects ≤ 16 years of age: Lansky scale ≥ 60%.

   Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
6. Normal Organ and Marrow Function (supportive care is allowed per institutional standards, i.e. filgrastim, transfusion) i. ANC ≥ 1000/uL ii. Platelet count ≥ 100,000/uL iii. Absolute lymphocyte count ≥ 150/uL iv. Hemoglobin ≥ 8 g/dL v. Adequate renal, hepatic, pulmonary and cardiac function defined as:

   - Creatinine within institutional norms for age (i.e.

   ≤ 2 mg/dL in adults or according to table below in children \<18 years) OR creatinine clearance (as estimated by Cockcroft Gault Equation) ≥ 60 mL/min

   Serum ALT/AST ≤ 3.0 ULN (grade 1)
   * Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome.
   * Cardiac ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an ECHO, and no clinically significant ECG findings
   * Baseline oxygen saturation \> 92% on room air
7. Pregnancy Test Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization are not considered to be of childbearing potential) or NA
8. Contraception Subjects of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four (4) months after receiving the preparative regimen or for as long as GD2CART cells are detectable in peripheral blood or CSF.
9. Ability to give informed consent. All subjects ≥ 18 years of age must be able to give informed consent. For subjects \<18 years old their legal authorized representative (LAR) (i.e. parent or guardian) must give informed consent. Pediatric subjects will be included in age appropriate discussion and written assent will be obtained for those \> 7 years of age, when appropriate. If a minor becomes of age during participation of this study, he/she will be asked to reconsent as an adult.

EXCLUSION CRITERIA:

1. For Dose Escalation: 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.

   For Dose Expansion: Bulky disease that in the investigator's assessment place the subject at unacceptable risk for herniation. Thalamic DMG is permitted.
2. Clinically significant swallowing dysfunction/dysphagia or prominent medullary dysfunction, as determined by the clinical investigator.
3. Current systemic corticosteroid therapy above physiologic replacement levels.
4. Ongoing use of dietary supplements, alternative therapies or extreme diet modifications 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.

Primary outcomes:
measure: Rate of successful manufacture of GD2CART using a retroviral vector in the Miltenyi CliniMACS Prodigy system
timeFrame: 14 days after apheresis
measure: Maximum tolerated dose (MTD)/RP2D of GD2CART in subjects with H3K27M DIPG
timeFrame: 28 days after infusion
measure: Safety of GD2CART in subjects with spinal H3 K27M-mutant DMG treated at the RP2D
timeFrame: 28 days after infusion
Secondary outcomes:
measure: Radiographic Response Rate
timeFrame: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.
measure: Overall Survival (OS)
timeFrame: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.
measure: Progression-Free Survival (PFS)
timeFrame: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion
measure: Post-progression survival (PPS)
timeFrame: ime Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion
measure: Measure resolution of toxicity
timeFrame: 72 hours of administration of AP1903
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Lucile Packard Children's Hospital (LPCH)
state: California
Study officials:
affiliation: Stanford University
name: Michelle Monje
role: PRINCIPAL_INVESTIGATOR
References: