Modified T-cells in Treating Patients with Glioblastoma

Inclusion Criteria

• Inclusion Criteria Step 1:
• Pathological criteria: Glioblastoma (GBM) that is histologically confirmed by pathology review of surgically resected tissue
• Tumor cells from resected tissue must be available for EGFRvIII testing; patients who have previously been treated with an EGFRvIII-targeted therapy and recurred, must have a tumor sample obtained after their recurrence available for EGFRvIII testing
• If the patient is on dexamethasone, the anticipated dose must be 4 mg/day or less for at least 5 days prior to apheresis
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• White blood count >= 2500/mm^3 without transfusion or growth factor support
• Platelets >= 100,000/mm^3 without transfusion or growth factor support
• Hemoglobin >= 9.0 g/dL without transfusion or growth factor support
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) within 2.5 x upper normal limit
• Gamma-glutamyl transpeptidase (GGT) within 2.5 x upper normal limit
• Lactate dehydrogenase (LDH) within 2.5 x upper normal limit
• Alkaline phosphatase within 2.5 x upper normal limit
• Total bilirubin =< 2.0 mg/dL
• Serum creatinine =< 1.5 x upper limit of normal
• Coagulation tests prothrombin time (PT) and partial thromboplastin time (PTT) have to be within normal limits, unless the patient has been therapeutically anti-coagulated for previous venous thrombosis
• Provide voluntary informed consent for tissue screening and apheresis
• Inclusion Criteria Step 2:
• Subject met all Step 1 eligibility criteria
• Tumor cells test positive for EGFRvIII expression (by real time [RT]-PCR, next generation sequencing, or immunohistochemistry) and a CART EGFRvIII product has been manufactured and formulated; patients who have previously been treated with an EGFRvIII-targeted therapy and recurred are only eligible if a tumor sample obtained after their recurrence tests positive for EGFRvIII
• Stage of disease: * Cohort 1: Patients with recurrent primary glioblastoma; recurrence may be determined by imaging and clinical criteria alone * Cohort 2: Patients with newly diagnosed glioblastoma with a < 95% resection or >/= 1 cm^3 of residual disease on the post-operative MRI (typically post-operative day 1)
• If the patient is on dexamethasone, the dose must be 4 mg/day or less prior to CART-EGFRvIII infusion
• It is anticipated that all patients in Cohort 2 will have completed standard of care external beam radiotherapy and chemotherapy with temozolomide (TMZ) at the time of the pre-infusion safety visit
• Life expectancy > 3 months
• Adequate cardiac function (ejection fraction [EF] > 55%)
• Provide voluntary informed consent for study treatment
• Female subjects of reproductive potential must agree to use a reliable method of contraception

Exclusion Criteria

• Exclusion Criteria Step 1:
• Female subjects of reproductive potential who are pregnant or lactating; female study participants of reproductive potential must have a negative serum pregnancy test as part of Step 1 eligibility confirmation
• Uncontrolled active infection
• Active or latent hepatitis B or active hepatitis C infection
• Human immunodeficiency virus (HIV) infection
• Previous treatment with any gene therapy products
• Known addiction to alcohol or illicit drugs
• History of allergy or hypersensitivity to study product excipients (human serum albumin, dimethyl sulfoxide [DMSO], and Dextran 40)
• Exclusion Criteria Step 2:
• Female subjects of reproductive potential who are pregnant or lactating; female study participants of reproductive potential must have a negative serum pregnancy test within two weeks prior to the CART-EGFRvIII cell infusion
• Use of immunosuppressive agents such as cyclosporine, mycophenolate mofetil (MMF), tacrolimus, or rapamycin within 4 weeks of enrollment on Step 2; a minimal dose of corticosteroid (dexamethasone up to 4 mg/day) is permitted; recent or current use of inhaled steroids is not exclusionary
• Subjects or their physicians anticipate use of any of the following concurrent treatment or medications including: * Radiosurgery (except for the standard of care fractionated external radiation therapy is a part of the protocol regimen in Cohort 2) * Chemotherapy (except for the standard of care temozolomide therapy in Cohort 2) * Interferon (e.g. Intron-A) * Allergy desensitization injections * Any ongoing investigational therapeutic medication * Bevacizumab
• Participants who have another cancer diagnosis with history of visceral metastases at the time of pre-entry evaluation; the following diagnoses are examples that will be allowed: * Squamous cell cancer of the skin without known metastasis * Basal cell cancer of the skin without known metastasis * Carcinoma in situ of the breast (ductal carcinoma in situ [DCIS] or lobular carcinoma in situ [LCIS]) * Carcinoma in situ of the cervix * Prostate cancer with only prostate specific antigen (PSA) recurrence * Any cancer that has not required systemic therapy (other than hormonal therapies) for the past three (3) years.
• Any uncontrolled active medical disorder that would preclude participation as outlined
• Unstable angina and/or myocardial infarction within 6 months prior to screening
• History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)