- 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.
International patients are not currently eligible to enroll.
- Currently accepting US patients only
- Disease Status:
- 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
- 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)
1. Absolute neutrophil count (ANC) ≥ 1,000/uL
2. Platelet count ≥ 100,000/uL
3. Absolute lymphocyte count ≥ 150/uL
4. Hemoglobin ≥ 8 g/dL
5. 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)
- ≤5 Years ---------------- 0.8mg/dL
- 5 < 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,
- 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