Genetically Engineered Cells (C7R-GD2.CAR T Cells) for the Treatment of Patients with GD2-Expressing High Grade Glioma or Diffuse Intrinsic Pontine Glioma, The GAIL-B Trial

Status: active

This phase I trial evaluates the best dose and possible benefits and/or side effects of C7R-GD2.CAR T cells in treating patients with GD2-expressing high grade glioma or diffuse intrinsic pontine glioma. GD2 is a protein found on almost all high grade glioma/diffuse intrinsic pontine glioma cells. Another purpose is to find out how long these cells can be detected in the blood. This trial combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Previous studies suggest that putting a new antibody gene into T cells may make them recognize tumor cells and kill them. In this trial, the C7R-GD2.CAR T cells are grown in the laboratory by infecting T cells with a retroviral vector (a special virus that can carry a new gene into cells) containing one gene that can recognize and kill tumor cells (GD2.CAR) and another gene called C7R that may help these cells survive longer. Giving C7R-GD2.CAR T cells with standard of care chemotherapy may allow the T cells to expand and stay longer in the body, potentially killing tumor cells more effectively.

Inclusion Criteria

PROCUREMENT (COHORT I): * Histologically confirmed, GD2-expressing newly diagnosed diffuse midline glioma (DMG) / high-grade glioma (HGG) (including pontine) or confirmation of positive H3K27M alteration status if sufficient tissue for GD2 staining by immunohistochemistry (IHC) is not available. Newly diagnosed is defined as prior to radiographic progression or recurrence, OR * Histologically confirmed, GD2-expressing recurrent, refractory, or progressive DMG/HGG (except pontine) or confirmation of positive H3K27M alteration status if sufficient tissue for GD2 staining by IHC is not available. OR * Recurrent, refractory, or progressive CNS embryonal tumor, or ependymal tumor with confirmed GD2-expression. Examples of embryonal tumors include: medulloblastoma, "PNET", AT/RT
PROCUREMENT (COHORT II): Recurrent, refractory, or progressive pontine DMG/HGG with confirmed GD2-expression (or H3K27M-altered for HGG)
PROCUREMENT: Tumors less than 5 cm in maximum dimension at enrollment * Tumors with =< 25% increase in size (on any dimension) on magnetic resonance imaging (MRI) 4-8 weeks post-radiotherapy remain eligible for study * Tumors with > 25% increase in size on post-radiation imaging may be reassessed with repeat MRI in 4-6 weeks, and are eligible if tumor size is subsequently =< 25% increased compared with pre-irradiation MRI * Tumors with sizes between 5 and 5.5 cm are eligible if the tumor was surgically debulked
PROCUREMENT: Measurable disease on at least 2 dimensions on MRI
PROCUREMENT: Age 12 months to 22 years
PROCUREMENT: Functional score (Karnofsky/Lansky) >= 50 expected at infusion (≥ 60 for cohort 2)
TREATMENT (COHORT I): * Histologically confirmed, GD2-expressing newly diagnosed DMG/ HGG (including pontine) or confirmation of positive H3K27M alteration status if sufficient tissue for GD2 staining by IHC is not available. Newly diagnosed is defined as prior to radiographic progression or recurrence. OR * Histologically confirmed, GD2-expressing recurrent, refractory, or progressive HGG/DMG (excluding pontine) or confirmation of positive H3K27M alteration status if sufficient tissue for GD2 staining by IHC is not available. OR * Recurrent, refractory, or progressive CNS embryonal tumor, or ependymal tumor with confirmed GD2-expression. Examples of embryonal tumors include: medulloblastoma, "PNET", AT/RT.
TREATMENT (COHORT II): Recurrent, refractory, or progressive pontine DMG/HGG with confirmed GD2-expression (or H3K27M-altered for HGG)
TREATMENT: Tumors less than 5 cm in maximum dimension at enrollment * Tumors with =< 25% increase in size (on any dimension) on MRI 4-8 weeks post-radiotherapy remain eligible for study * Tumors with > 25% increase in size on post-radiation imaging may be reassessed with repeat MRI in 4-6 weeks, and are eligible if tumor size is subsequently =< 25% increased compared pre-irradiation MRI * Tumors with sizes between 5 and 5.5 cm are eligible if the tumor was surgically debulked
TREATMENT: Measurable disease on at least 2 dimensions on MRI
TREATMENT: Central line (peripherally inserted central catheter [PICC] or other) in place or planned to be placed
TREATMENT: Age 12 months to 22 years
TREATMENT: Functional score (Karnofsky/Lansky) >= 50 (≥ 60 for cohort 2)
TREATMENT: Patients must have completed radiation therapy at least 4 weeks prior to administration of investigational agent. Radiation therapy and (if applicable) bevacizumab treatment for radiation necrosis must be completed at least 4 weeks prior to administration of investigational agent
TREATMENT: Stable neurologic exam for 7 days prior to enrollment
TREATMENT: Stable or decreasing dose of steroids (maximum [max.] allowable dose of dexamethasone is 0.1 mg/kg/day over the past 7 days prior to infusion of investigational therapy)
TREATMENT: ANC > 1000 cells/ul (within 10 days prior to initiation of study related treatment)
TREATMENT: Platelet count > 100,000 cells/ul (within 10 days prior to initiation of study related treatment)
TREATMENT: Total bilirubin < 1.5 x ULN (within 10 days prior to initiation of study related treatment)
TREATMENT: ALT and AST < 5 x ULN (within 10 days prior to initiation of study related treatment)
TREATMENT: Serum creatinine or kidney within 2 x ULN for age (within 10 days prior to initiation of study related treatment)

Exclusion Criteria

PROCUREMENT: Patients who are pregnant or breastfeeding
PROCUREMENT: Any patient with other risk factors for whom administration of investigational agent is deemed not in the patient’s best interest, in the opinion of the investigator
TREATMENT: Patients who received any other forms of immunotherapy =< 42 days before administration of investigational agent
TREATMENT: Patients who received colony-stimulating factors within 14 days prior to administration of lymphodepletion
TREATMENT: Patients receiving any concurrent anti-cancer therapy (it is preferable for patients to stop any concurrent anti-cancer therapy at least three half-lives prior to treatment)
TREATMENT: Patients who are pregnant or breast feeding
TREATMENT: Any patient with other risk factors for whom administration of investigational agent is deemed not in the patient’s best interest, in the opinion of the investigator

PRIMARY OBJECTIVE:

I. To determine the safety of escalating doses of autologous T cells modified to express a second-generation GD2.CAR combined with a constitutively active IL7 receptor (C7R-GD2.CAR T cells) administered via intravenous (IV) infusion with subsequent intracerebroventricularly (ICV) administration to patients with GD2-expressing pediatric brain tumors.

SECONDARY OBJECTIVE:

I. To estimate the anti-tumor response of autologous C7R-GD2.CAR T cells in children with GD2-expressing pediatric brain tumors.

EXPLORATORY OBJECTIVES:

I. To evaluate the fate and immunologic effects of (C7R)-GD2.CART cells administered both intracerebroventricularly and intravenously to patients with GD2-expressing pediatric brain tumors.

II. To evaluate the impact on overall survival.

III. To evaluate the impact on progression free survival.

OUTLINE: This is a dose-escalation study of C7R-GD2.CAR T cells with fixed-dose cyclophosphamide and fludarabine. Patients are assigned to 1 of 2 cohorts.

COHORT I: Patients receive standard of care lymphodepletion chemotherapy consisting of cyclophosphamide IV on days -4 and -3 and fludarabine IV on days -4 to -2. Patients then receive C7R-GD2.CAR T cells IV over 1-10 minutes on day 0 of cycle 1 and ICV over 1-10 minutes of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Lymphodepletion may be omitted after cycle 1. Clofarabine IV may be substituted for fludarabine in case of critical shortage. Additionally, patients undergo blood sample and cerebrospinal fluid (CSF) collection and magnetic resonance imaging (MRI) on study.

COHORT II: Patients receive standard of care lymphodepletion chemotherapy consisting of cyclophosphamide IV on days -4 and -3 and fludarabine IV on days -4 to -2. Patients then receive C7R-GD2.CAR T cells IV over 1-10 minutes on day 0. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Clofarabine IV may be substituted for fludarabine in case of critical shortage. Additionally, patients undergo blood sample and CSF collection and MRI on study.

After completion of study treatment, patients are followed up at 1, 2, 3, 4, 6, and 8 weeks, then at 3, 6, 9, and 12 months, then twice a year for the next 4 years, then annually for the next 10 years up to 15 years.

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Genetically Engineered Cells (C7R-GD2.CAR T Cells) for the Treatment of Patients with GD2-Expressing High Grade Glioma or Diffuse Intrinsic Pontine Glioma, The GAIL-B Trial

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Genetically Engineered Cells (C7R-GD2.CAR T Cells) for the Treatment of Patients with GD2-Expressing High Grade Glioma or Diffuse Intrinsic Pontine Glioma, The GAIL-B Trial

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