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

  • STATUS
    Recruiting
  • End date
    Dec 22, 2023
  • participants needed
    54
  • sponsor
    Crystal Mackall, MD
Updated on 22 August 2021

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.

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.

Details
Condition Glioma of Brainstem, Brainstem Glioma, Glioma of Spinal Cord, spinal cord glioma
Treatment cyclophosphamide, Fludarabine, GD2 CAR T cells
Clinical Study IdentifierNCT04196413
SponsorCrystal Mackall, MD
Last Modified on22 August 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Disease Status
Currently accepting US patients only
Tissue diagnosis of H3K27M-mutated Diffuse Intrinsic Pontine Glioma (DIPG) with radiographically evident tumor restricted to the brainstem, OR
Tissue diagnosis of H3K27M-mutated Diffuse Midline Glioma (DMG) of the spinal cord
Age: Greater than or equal to 2 year of age and less than or equal to 30 years of age
Prior Therapy
At least 6 weeks following completion of front line 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, which requires 5 half-lives
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%
Normal Organ and Marrow Function (supportive care is allowed per institutional standards, i.e. filgrastim, transfusion)
Absolute neutrophil count (ANC) 1,000/uL
Platelet count 100,000/uL
Absolute lymphocyte count 150/uL
Hemoglobin 8 g/dL
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
Age (Years) -- Maximum Serum Creatinine (mg/dL)
Years ---------------- 0.8mg/dL
< age 10 Years ----1.0mg/dL
>10-18 Years -----------1.2mg/dL
>18 Years -----------2.0mg/dL
Serum Alanine aminotransferase( ALT)/Aspartate Aminotransferase (AST) 3.0 Upper limit of normal (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 echocardiogram (ECHO), and no clinically significant ECG findings
Baseline oxygen saturation > 92% on room air
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)
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 lymphodepletion regimen or for as long as GD2-CAR T cells are detectable in peripheral blood or cerebrospinal fluid (CSF)
Ability to give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those > 7 years of age, when appropriate

Exclusion Criteria

Tumor involvement of cerebellar vermis or hemispheres (pontocerebellar peduncle involvement is allowed), thalamic lesions, or supratentorial lesions
Clinically significant swallowing dysfunction
Current systemic corticosteroid therapy
Prior CAR therapy
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
Ongoing infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus (anti Hepatitis C Virus (HCV) positive). A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative polymerase chan reaction (PCR) and/or nucleic acid testing
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
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
Known sensitivity or allergy to any agents/reagents used in this study
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
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