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

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

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.

Study Overview

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

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (chemotherapy, autologous stem cell transplant); See Detailed Description

Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Filgrastim; Given SC; Other Names: G-CSF; r-metHuG-CSF; Neupogen; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; Filgrastim XM02; Tbo-filgrastim; Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Drug: Carmustine; Given IV; Other Names: BCNU; BiCNU; Becenum; Becenun; Bis(chloroethyl) Nitrosourea; Bis-Chloronitrosourea; Carmubris; Carmustin; Carmustinum; FDA 0345; N,N'-Bis(2-chloroethyl)-N-nitrosourea; Nitrourean; Nitrumon; SK 27702; SRI 1720; WR-139021; Gliadel; Radiation: Proton Beam Radiation Therapy; Undergo proton beam radiation therapy; Drug: Plerixafor; Given SC; Other Names: Mozobil; AMD 3100; JM-3100; SDZ SID 791; Drug: O6-Benzylguanine; Given IV; Other Names: O(6)-Benzylguanine; 6-O-BENZYLGUANINE; Radiation: 3-Dimensional Conformal Radiation Therapy; Undergo 3D conformal IMRT; Other Names: 3-dimensional radiation therapy; 3D CONFORMAL RADIATION THERAPY; 3D CRT; 3D-CRT; Conformal Therapy; Radiation Conformal Therapy; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Undergo autologous in vitro-treated peripheral blood stem cell transplant; Other Names: Autologous Stem Cell Transplantation; Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation; Undergo autologous in vitro-treated peripheral blood stem cell transplant; Other Names: in vitro-treated PBPC transplantation; in vitro-treated peripheral blood progenitor cell transplantation; Radiation: Intensity-Modulated Radiation Therapy; Undergo 3D conformal IMRT; Other Names: IMRT; Intensity Modulated RT; Intensity-Modulated Radiotherapy

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center

Publications and helpful links

General Publications

• Adair JE, Johnston SK, Mrugala MM, Beard BC, Guyman LA, Baldock AL, Bridge CA, Hawkins-Daarud A, Gori JL, Born DE, Gonzalez-Cuyar LF, Silbergeld DL, Rockne RC, Storer BE, Rockhill JK, Swanson KR, Kiem HP. Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. J Clin Invest. 2014 Sep;124(9):4082-92. doi: 10.1172/JCI76739. Epub 2014 Aug 8.

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2009
• Primary Completion (Actual): July 6, 2018
• Study Completion (Actual): January 20, 2021

Study Registration Dates

• First Submitted: April 29, 2008
• First Submitted That Met QC Criteria: April 29, 2008
• First Posted (Estimate): April 30, 2008

Study Record Updates

• Last Update Posted (Actual): May 18, 2022
• Last Update Submitted That Met QC Criteria: April 29, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Glioma; Gliosarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Adjuvants, Immunologic; Temozolomide; Lenograstim; Carmustine; Plerixafor; O(6)-benzylguanine
• Other Study ID Numbers: 2000.00 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); NCI-2013-00701 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 8357; RG1709046 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)