Clinical Trials /

GD2 CAR T Cells in DiffuseIntrinsicPontine Gliomas(DIPG) & Spinal DiffuseMidline Glioma(DMG)

NCT04196413

Description:

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.

Related Conditions:
  • Diffuse Intrinsic Pontine Glioma
  • Diffuse Midline Glioma, H3 K27M-Mutant
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: GD2 CAR T Cells in DiffuseIntrinsicPontine Gliomas(DIPG) & Spinal DiffuseMidline Glioma(DMG)
  • Official Title: Phase 1 Clinical Trial of Autologous GD2 Chimeric Antigen Receptor (CAR) T Cells (GD2.BB.z.iCasp9-CAR T Cells) for Diffuse Intrinsic Pontine Gliomas (DIPG) and Spinal Diffuse Midline Glioma (DMG)

Clinical Trial IDs

  • ORG STUDY ID: IRB-52934
  • SECONDARY ID: PEDSCCT6005
  • NCT ID: NCT04196413

Conditions

  • Glioma of Spinal Cord
  • Glioma of Brainstem

Interventions

DrugSynonymsArms
GD2 CAR T cellsGD2-CAR T
FludarabineGD2-CAR T
CyclophosphamideGD2-CAR T

Purpose

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 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.

      Secondary Objectives:

        -  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.
    

Trial Arms

NameTypeDescriptionInterventions
GD2-CAR TExperimentalA standard 3+3 dose escalation design will test GD2-CAR T cells in subjects with H3K27M-mutant DIPG or spinal DMG, starting with Dose Level 1: Dose Level 1: 1x10^6 CAR+ T cells/kg body weight (+/- 20%) Dose Level 2: 3x10^6 CAR+ T cells/kg body weight (+/- 20%) Dose Level 3: 10x10^6 CAR+ T cells/kg body weight (+/- 20%) Dose Level -1 will be explored if the first subject treated experiences dose limiting toxicity (DLT) or if >2 of 6 subjects treated at Dose Level 1 experiences DLT. DOSE EXPANSION Once the MTD or RP2D is determined, up to 20 evaluable subjects with H3K27M-mutant DIPG and 10 evaluable subjects with H3K27M-mutant spinal DMG will be treated at the RP2D (including subjects treated during dose escalation).
  • GD2 CAR T cells
  • Fludarabine
  • Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

          -  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

        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% (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,
             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

          -  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
             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.

          -  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
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of successful manufacture of GD2.BB.z.iCasp9-CAR T cells using a retroviral vector in the Miltenyi CliniMACS Prodigy system
Time Frame:14 days after apheris
Safety Issue:
Description:The percentage of apheresis samples (fresh or frozen) will be determined for each dose cohort.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.
Safety Issue:
Description:OS is defined as the time from the start of the lymphodepleting chemotherapy preparative regimen to the date of death from any cause
Measure: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.
Safety Issue:
Description: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.
Measure:Post-progression survival (PPS)
Time Frame:Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.
Safety Issue:
Description: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)
Measure:Radiographic Response Rate
Time Frame:Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion.
Safety Issue:
Description: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.
Measure:Measure resolution of toxicity
Time Frame:72 hours of administration of AP1903
Safety Issue:
Description:Resolution of toxicity ≤ grade2, in the event unacceptable toxicity considered possibly, probably or definitely related to GD2.BB.z.iCasp9-CAR T cells within 72 hours

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Stanford University

Last Updated

December 10, 2019