- Determine the feasibility of manufacturing GD2.BB.z-iCasp9-CAR T cells for
administration in children and young adults with H3K27M-mutant DIPG and spinal
H3K27M-mutant DMG using a retroviral vector in the Miltenyi CliniMACS Prodigy® system.
- Assess the safety and identify the MTD and/or recommended phase 2 dose (RP2D) of
GD2.BB.z-iCasp9-CAR T cells in children and young adults with H3K27M-mutant DIPG or
spinal H3K27M-mutant DMG 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.
- In a preliminary manner, assess clinical benefit of GD2.BB.z-iCasp9-CAR T cells at the
RP2D in children and young adults with H3K27M-mutant DIPG or spinal H3K27M-mutant DMG.
- If unacceptable toxicity, occurs that is possibly, probably or likely related to
GD2.BB.z.iCasp9-CAR T cells, assess the capacity for AP1903, a dimerizing agent, to
mediate clearance of the genetically engineered cells and resolve toxicity.
- 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 25 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% (See section 13.1, Appendix A)
- 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 ≤ 10Years ----1.0mg/dL
- >10-18Years -----------1.2mg/dL
- >18Years ----------------2.0mg/dL
- Serum Alalnine 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
- No 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
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
- 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.
- May not have 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