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GD2CART for the Treatment of H3K27M Mutated Diffuse Intrinsic Pontine Glioma or Spinal Diffuse Midline Glioma

Trial Status: Active

This phase I trial investigates the side effects and best dose of autologous GD2 chimeric antigen receptor (CAR) T cells (GD2CART) and how well it works in treating patients with diffuse intrinsic pontine glioma or spinal diffuse midline glioma. The chimeric antigen receptor (CAR) is a genetically-engineered receptor made so that immune cells can recognize and respond to a specific molecule, which in this trial is the GD2 protein. This uses a portion of an antibody to GD2 and part of a molecule that activates or ‘turns on’ the immune cell. The CAR molecule is combined with a patient's T cells, to help the T cells find cancer in the body. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine, are given before GD2CART to help prepare the immune system to accept GD2CART, and may help let the GD2CART grow in the body and attack cancer cells. The purpose of this trial is to test the safety of giving GD2CART to children and young adults with diffuse intrinsic pontine glioma or diffuse midline glioma, and determine its effects, both good and bad, and to test how the cancer responds to GD2CART after chemotherapy.

Inclusion Criteria

  • FOR DOSE ESCALATION: Diagnosis of H3K27M mutated diffuse intrinsic pontine glioma (DIPG)
  • FOR DOSE EXPANSION: Diagnosis of H3K27M mutated diffuse intrinsic pontine glioma (DIPG), OR
  • FOR DOSE EXPANSION: Diagnosis of spinal H3K27M mutated diffuse midline glioma (DMG)
  • At least 6 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 5 half-lives
  • 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%
  • Absolute neutrophil count (ANC) >= 1000/uL (supportive care is allowed per institutional standards, i.e. filgrastim, transfusion)
  • Platelet count >= 100,000/uL (supportive care is allowed per institutional standards, i.e. filgrastim, transfusion)
  • Absolute lymphocyte count >= 150/uL (supportive care is allowed per institutional standards, i.e. filgrastim, transfusion)
  • Hemoglobin >= 8 g/dL (supportive care is allowed per institutional standards, i.e. filgrastim, transfusion)
  • Creatinine within institutional norms for age (i.e. =< 2 mg/dL in adults or according to below in children < 18 years) OR creatinine clearance (as estimated by Cockcroft Gault equation) >= 60 mL/min * Age (years); maximum serum creatinine (mg/dL) ** Age =< 5; 0.8 mg/dL ** 5 < age =< 10; 1.0 mg/dL ** > Age 10-18; 1.2 mg/dL ** Age >18; 2.0 mg/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 echocardiography (ECHO), and no clinically significant electrocardiogram (ECG) findings
  • Baseline oxygen saturation > 92% on room air
  • 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)
  • 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
  • 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 verbal 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

  • Tumor involvement of cerebellar vermis or hemispheres (pontocerebellar peduncles involvement is acceptable), thalamic lesions, or supratentoral lesions
  • Clinically significant swallowing dysfunction or prominent dysphagia, as determined by the clinical investigator
  • 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: * Human immunodeficiency virus (HIV), * Hepatitis B (hepatitis B surface antigen [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 chain 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
  • Women who are pregnant or breastfeeding
  • 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

California

Palo Alto
Lucile Packard Children's Hospital Stanford University
Status: ACTIVE
Contact: Michelle Monje
Phone: 650-721-5750

PRIMARY OBJECTIVES:

I. Determine the feasibility of manufacturing autologous T cells transduced with 14g2a-CD8-BBz-iCasp9 retroviral vector expressing GD2 chimeric antigen receptor (autologous anti-GD2-CAR-BBz-iCasp9 retroviral vector-transduced T lymphocytes [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.

II. 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: dose level (DL) 1: 1e6 transduced T cells/kg; DL2: 3e6 transduced T cells/kg; DL3: 10e6 transduced T cells/kg.

III. Assess the safety of the MTD/RP2D of GD2CART in subjects with spinal H3K27M mutant DMG.

SECONDARY OBJECTIVES:

I. In a preliminary manner, assess clinical benefit of GD2CART at the RP2D in subjects with H3K27M DIPG or spinal H3 K27M-mutant DMG.

II. If unacceptable toxicity occurs that is possibly, probably or likely related to GD2CART, assess the capacity for rimiducid (AP1903), a dimerizing agent, to mediate clearance of the genetically engineered cells and resolve toxicity.

EXPLORATORY OBJECTIVES:

I. Measure expansion/persistence/phenotype of adoptively transferred GD2CART in the cerebrospinal (CSF) and blood and correlate this with antitumor effects.

II. Conduct analyses of the manufactured T cell product and blood and CSF post-infusion to identify biomarkers associated with enhanced CAR T cell expansion, persistence and/or phenotype.

III. Assess whether changes in the level of circulating tumor deoxyribonucleic acid (ctDNA) in the cerebrospinal fluid can provide prognostic information and/or information regarding clonal evolution of DIPG over time.

IV. Evaluate whether antigen expression or tumor microenvironment are correlated with response to CAR T cell.

OUTLINE: This is a dose-escalation study of autologous anti-GD2-CAR-BBz-iCasp9 retroviral vector-transduced T lymphocytes.

CONDITIONING LYMPHODEPLETION CHEMOTHERAPY: Patients receive cyclophosphamide intravenously (IV) over 60 minutes and fludarabine phosphate IV over 30 minutes on daily on days -4 to -2.

GD2CART INFUSION: Patients receive autologous anti-GD2-CAR-BBz-iCasp9 retroviral vector-transduced T lymphocytes (GD2CART) IV over 10-30 minutes on day 0. Beginning on day 30, patients who had a partial response or stable disease with clinical benefit may receive another infusion of cells.

After completion of study treatment, patients are followed up for 28 days, at 2 months, 3 months, 6 months, 9 months, 12 months, every 6-12 months until year 5, and then annually for years 6-15.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Lucile Packard Children's Hospital Stanford University

Principal Investigator
Michelle Monje

  • Primary ID PEDSCCT6005
  • Secondary IDs NCI-2020-05891, IRB-52934
  • Clinicaltrials.gov ID NCT04196413