O6-Benzylguanine-Mediated Tumor Sensitization With Chemoprotected Autologous Stem Cell in Treating Patients With Malignant Gliomas

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of temozolomide when given together with radiation therapy, carmustine, O6-benzylguanine, and patients' own stem cell (autologous) transplant in treating patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Giving chemotherapy, such as temozolomide, carmustine, and O6-benzylguanine, and radiation therapy before a peripheral stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as filgrastim or plerixafor, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy or radiation therapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy and radiation therapy.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the safety and feasibility of infusing autologous granulocyte colony-stimulating factor (G-CSF) (filgrastim) mobilized stem cells transduced with a Phoenix-gibbon ape leukemia virus (GALV)-pseudotype vector expressing methylguanine methyltransferase (MGMT) (P140K). II. Define the dose of BCNU (carmustine) that results in efficient engraftment of gene modified cells when given with peripheral blood stem cell support. SECONDARY OBJECTIVES: I. Determine the engraftment of gene-modified cells after conditioning with BCNU. II. Determine the ability to select gene-modified cells in vivo with this regimen. III. Evaluate the molecular and clonal composition of gene-modified cells after chemotherapy with temozolomide. IV. Observe patients for clinical anti-tumor response. V. Determine the correlation of the level of MGMT (P140K) marking with toxicity, temozolomide dose achieved, and response. VI. Characterize the toxicity associated with this regimen. OUTLINE: This is a phase I, dose-escalation study of temozolomide followed by a phase II study. PART I: Within 35 days of surgery, patients undergo 3 dimensional (3D) conformal intensity-modulated radiation therapy (IMRT) or proton beam radiation therapy daily 5 days per week for 6 weeks. Patients receive filgrastim subcutaneously (SC) on days -7 to -3 and begin stem cell collection on the 4th day of filgrastim administration (up to 3 apheresis). Patients may also receive plerixafor SC on days -5 to -3. The CD34+ stem cells are separated from the patient's stem cells and they are transduced with Phoenix-RD114 pseudotype vector (retrovirus). One day after apheresis is completed, patients receive carmustine intravenously (IV) over 3 hours followed 2 hours later by temozolomide orally (PO). At least twenty-four hours after completion of carmustine and temozolomide, patients undergo reinfusion of genetically-modified stem cells. PART II: Beginning approximately 4 weeks after completion of Phase 1 of the study, patients receive O6-benzylguanine IV continuously over 48 hours followed by temozolomide PO within 1 hour. Treatment may repeat at least every 28 days for a total of 24 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 1-3 months for 2 years, every 3-6 months for 3 years, and then annually thereafter for 10 years.

Official Title
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Benzylguanine-Mediated Tumor Sensitization With Chemoprotected Autologous Stem Cells for Patients With Malignant Gliomas

Conditions
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Glioblastoma, Gliosarcoma

Intervention / Treatment
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* Radiation: 3-Dimensional Conformal Radiation Therapy
* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Drug: Carmustine
* Biological: Filgrastim
* Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation
* Radiation: Intensity-Modulated Radiation Therapy
* Other: Laboratory Biomarker Analysis
* Drug: O6-Benzylguanine
* Drug: Plerixafor
* Radiation: Proton Beam Radiation Therapy
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with glioblastoma multiforme or gliosarcoma The patient or legal guardian must be able to comprehend the informed consent form and sign prior to patient enrollment Karnofsky performance status at time of study entry must be >= 70% Life expectancy of >= 3 months Patients must agree to undergo repeat clinical neurological examinations and brain magnetic resonance imaging (MRI) with appropriate contrast after every other cycle of chemotherapy White blood cell (WBC) > 3000/ul Absolute neutrophil count (ANC) > 1500/ul Platelets > 100,000/ul Hemoglobin > 10 gm/100ml Total and direct bilirubin < 1.5 times upper limit of laboratory normal Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =< 3 times upper limit of laboratory normal Alkaline phosphatase =< 3 times upper limit of laboratory normal Blood urea nitrogen (BUN) < 1.5 times upper limit of laboratory normal Serum creatinine < 1.5 times upper limit of laboratory normal Left ventricular ejection fraction (LVEF) >= 40%, however, subjects with a LVEF in the range of 40-49% should have cardiology clearance prior to intervention MGMT promoter methylation analysis of surgically resected tumor or tumor biopsy must demonstrate an unmethylated or hypomethylated MGMT promoter status Exclusion Criteria: Patients with cardiac insufficiency and a LVEF of < 40%; history of coronary artery disease or arrhythmia, which has required or requires ongoing treatment Patients with active pulmonary infection and/or pulse oximetry < 90% and a corrected diffusion capacity of the lung for carbon monoxide (DLCO) < 70% of predicted Active systemic infection Patients who are human immunodeficiency virus (HIV) positive Pregnant or lactating women; a beta-human chorionic gonadotropin (HCG) level will be obtained from women of childbearing potential; fertile men and women should use effective contraception Previous chemotherapy for any malignancy including temozolomide, dacarbazine (DTIC) or prior nitrosourea Diabetes mellitus Bleeding disorder Methylated or hypermethylated MGMT promoter status within tumor tissue Medical or psychiatric condition which in the opinion of the protocol chairman would compromise the patient's ability to tolerate this protocol Prior interstitial radiotherapy, stereotactic or gamma knife surgery or implanted BCNU-wafers

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, autologous stem cell transplant)<br>See Detailed Description | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Undergo 3D conformal IMRT<br>* Other names: Radiation Conformal Therapy;Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous in vitro-treated peripheral blood stem cell transplant<br>* Other names: Autologous Stem Cell Transplantation;Drug: Carmustine<br>* Given IV<br>* Other names: WR-139021;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation<br>* Undergo autologous in vitro-treated peripheral blood stem cell transplant<br>* Other names: in vitro-treated peripheral blood progenitor cell transplantation;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo 3D conformal IMRT<br>* Other names: Intensity-Modulated Radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: O6-Benzylguanine<br>* Given IV<br>* Other names: O(6)-Benzylguanine;Drug: Plerixafor<br>* Given SC<br>* Other names: SDZ SID 791;Radiation: Proton Beam Radiation Therapy<br>* Undergo proton beam radiation therapy<br>Drug: Temozolomide<br>* Given PO<br>* Other names: Temomedac;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Dose-limiting Toxicity (DLT) | Defined as any grade 4 nonhematopoietic toxicity that is likely related to the investigational procedures (Part I) | Up to 6 weeks after infusion | 
| Number of Participants With Retrovirus or Leukemia | Replication competent retrovirus or diagnosis of leukemia | Up to 2 years after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Number of patients with reduction in tumor burden of a predefined amount | Up to 66 months | 
| Duration of Response | From the onset of temozolomide to the date at which unequivocal disease progression, assessed up to 65 months. | Up to 65 months | 
| Time to Progression | From the first day of treatment (transplant) until unequivocal progression is documented, assessed up to 66 months. | Up to 66 months. | 
| Number of Participants That Survived | From the first day of treatment until death, assessed up to 74 months. | Up to 74 months | 
| Number of Participants With Chemoprotection | assessed by the ability to increase the Temozolomide dose beyond 472 mg/m^2 | Up to 66 months | 
| Number of Participants With Chemoselection | assessed by the increase in peripheral blood Vector Copy Number (VCN), the average copies of integrated transgene per cell, after chemotherapy | Up to 59 months | 
| Gene Transfer Efficiency | Assessed by gene marking in peripheral blood prior to chemoselection. Gene marking is assessed in whole blood by quantitative PCR and reported as a vector copy number (VCN) or the average copies of integrated transgene per cell. The units here will be reported as copies/cell. | Up to 59 months | 
| Gene Transfer Efficiency After Chemotherapy | Assessed by gene marking in peripheral blood after chemoselection. Gene marking is assessed in whole blood by quantitative PCR and reported as a vector copy number (VCN) or the average copies of integrated transgene per cell. The units here will be reported as copies/cell. | Up to 59 months |