Clinical Trial Finder

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INCLUSION CRITERIA:

1. Patients with histologically proven glioblastomas or gliosarcomas that express epidermal growth factor receptor(EGFRv)III as assessed by immunohistochemistry (IHC) or polymerase chain reaction (PCR) confirmed by the National Cancer Institute (NCI) Laboratory of Pathology. 2. Patients must have progression of disease after radiotherapy (including patients that undergo surgery for recurrent disease and are rendered no evidence of disease (NED)). This includes recurrent glioblastoma (GBM) after receiving all standard first-line treatment, including surgery (if feasible due to neurosurgical and neuro-anatomical considerations) and adjuvant radiotherapy +/- chemotherapy. 3. Patients must either not be receiving steroids, or be on a stable dose of steroids for at least five days prior to registration. 4. Age greater than or equal to 18 years and less than or equal to age 70 years. 5. Ability of subject to understand and the willingness to sign a written informed consent document. 6. Willing to sign a durable power of attorney. 7. Karnofsky Performance Status (KPS) greater than or equal to 60. 8. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment. 9. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. 10. Serology.

• - Seronegative for human immunodeficiency virus (HIV) antibody.

(The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive may have decreased immune-competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)

• - Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody.

If hepatitis C antibody test is positive, then patients must be tested for the presence of antigen by Reverse transcription polymerase chain reaction (RT-PCR) and be Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) negative. 11. Hematology.

• - White blood cell (WBC) greater than or equal to 3000/mm(3) - Absolute neutrophil count (ANC) greater than or equal to 1000/mm(3) without the support of filgrastim.

• - Platelet count greater than or equal to 100,000/mm(3) - Hemoglobin greater than or equal to 8.0 g/dl.

Subjects may be transfused to reach this cut-off. 12. Chemistry.

• - Serum Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) less than or equal to 2.5 x ULN.

• - Serum creatinine less than or equal to 1.6 mg/dl.

• - Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome, who must have a total bilirubin equal to or less than 3.0 mg/dl.

13. Patients must be at least 4 weeks from radiation therapy. Additionally, patients must be at least 6 weeks from nitrosoureas, 4 weeks from temozolomide, 3 weeks from procarbazine, 2 weeks from vincristine and 4 weeks from last bevacizumab administration. Patients must be at least 4 weeks from other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic agents (e.g., interferon, tamoxifen) including investigative agents. All toxicities from prior therapies should be resolved to Common Terminology Criteria in Adverse Events (CTCAE) less than or equal to grade 1 (except for toxicities such as alopecia, or vitiligo). 14. Subject's must be co-enrolled on protocol 03-C-0277.

EXCLUSION CRITERIA:

1. A prior history of gliadel implantation in the past six months.. 2. Women of child-bearing potential who are pregnant or breast feeding because of the potentially dangerous effects of the treatment on the fetus or infant. 3. Active systemic infections, requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses. 4. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). 5. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities). 6. History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin. 7. History of coronary revascularization or ischemic symptoms. 8. Clinically significant hemorrhagic or ischemic stroke, including transient ischemic attacks and other central nervous system bleeding in the preceding 6 months that were not related to glioma surgery. History of prior intratumoral bleeding is not an exclusion criteria; patients who with history of prior intratumoral bleeding, however, need to undergo a non-contrast head computed tomography (CT) to exclude acute bleeding. 9. Other concomitant anti-cancer therapy except corticosteroids. 10. Any patient known to have left ventricular ejection fraction (LVEF) less than or equal to 45%. 11. Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted tested in patients with:

• - A prolonged history of cigarette smoking (greater than or equal to 20 pack-year smoking history, with cessation within the past two years).

• - Symptoms of respiratory dysfunction.

12. Patients who are receiving any other investigational agents. 13. Documented LVEF less than or equal to 45% tested in patients:

• - Age greater than or equal to 65 years.

• - With clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or have a history of ischemic heart disease and/or chest pain.

BACKGROUND:

• - Patients with recurrent gliomas have very limited treatment options.

Epidermal growth factor receptor (EGFR). (EGFRvIII) is the most common mutant variant of EGFR and is present in 24-67% of patients with glioblastoma.

• - EGFRvIII expression promotes oncogenesis and is associated with poor prognosis.

• - EGFRvIII is not expressed in normal tissue and is an attractive target for immunotherapy.

• - We have constructed a retroviral vector that contains a chimeric antigen receptor (CAR) that recognizes the EGFRvIII tumor antigen, which can be used to mediate genetic transfer of this CAR with high efficiency without the need to perform any selection.

OBJECTIVES: Primary Objectives.

• - To evaluate the safety of the administration of anti-EGFRvIII CAR engineered peripheral blood lymphocytes in patients receiving the non-myeloablative, lymphodepleting preparative regimen and aldesleukin.

• - Determine the six month progression free survival of patients receiving anti-EGFRvIII CAR-engineered peripheral blood lymphocytes and aldesleukin following a nonmyeloablative, lymphodepleting preparative regimen.

ELIGIBILITY:

• - Histologically proven glioblastoma or gliosarcoma expressing EGFRvIII as determined by immunohistochemistry (IHC) or Reverse transcription polymerase chain reaction (RT-PCR) - Failed prior standard treatment with radiotherapy with or without chemotherapy.

• - Karnofsky performance score (KPS) greater than or equal to 60.

• - Cardiac, pulmonary and laboratory parameters within acceptable limits.

DESIGN:

• - The study will be conducted using a Phase I/II design.

• - Patients will receive a non-myeloablative, lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumorreactive, CAR gene-transduced peripheral blood mononuclear cells (PBMC), plus intravenous (IV) aldesleukin.

• - Once the maximum tolerated cell dose (MTD) has been determined, the study will proceed to the phase II portion.

• - In the phase II portion of the trial, patients will be accrued to two cohorts: - Patients with recurrent malignant glioma receiving steroids at the time of treatment.

• - Patients with recurrent malignant glioma not receiving steroids at the time of treatment.

• - A total of 107 patients may be enrolled over a period of 7 years.

Arms

Experimental: 1/Phase I Arm

Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of epidermal growth factor receptor (EGFRv)III Chimeric antigen receptor (CAR) transduced peripheral blood lymphocytes (PBL) + aldesleukin

Experimental: 2/Phase II Arm

Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + maximum tolerated dose (MTD) of anti-EGFRvIII CAR transduced PBL established in Phase I + aldesleukin

Interventions

Biological: - Epidermal growth factor receptor(EGFRv)III Chimeric antigen receptor (CAR) transduced PBL

Day 0: Cells will be infused intravenously over 20-30 minutes. Patients will receive two cell doses, 2 hours apart.

Drug: - Aldesleukin

Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).

Drug: - Fludarabine

Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Drug: - Cyclophosphamide

Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr.