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

Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00669669
• Other study ID #: 2000.00
• Secondary ID: NCI-2013-0070183
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: February 25, 2009
• Est. completion date: January 20, 2021

Study information

• Verified date: January 2022
• Source: Fred Hutchinson Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 12
• Est. completion date: January 20, 2021
• Est. primary completion date: July 6, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Glioblastoma
• Glioma
• Gliosarcoma

Intervention

Radiation:
• 3-Dimensional Conformal Radiation Therapy
Undergo 3D conformal IMRT

Procedure:
• Autologous Hematopoietic Stem Cell Transplantation
Undergo autologous in vitro-treated peripheral blood stem cell transplant

Drug:
• Carmustine
Given IV

Biological:
• Filgrastim
Given SC

Procedure:
• In Vitro-Treated Peripheral Blood Stem Cell Transplantation
Undergo autologous in vitro-treated peripheral blood stem cell transplant

Radiation:
• Intensity-Modulated Radiation Therapy
Undergo 3D conformal IMRT

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• O6-Benzylguanine
Given IV
• Plerixafor
Given SC

Radiation:
• Proton Beam Radiation Therapy
Undergo proton beam radiation therapy

Drug:
• Temozolomide
Given PO

Locations

Country	Name	City	State
United States	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Number of Participants With Retrovirus or Leukemia	Replication competent retrovirus or diagnosis of leukemia	Up to 2 years after infusion
Secondary	Response Rate	Number of patients with reduction in tumor burden of a predefined amount	Up to 66 months
Secondary	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
Secondary	Time to Progression	From the first day of treatment (transplant) until unequivocal progression is documented, assessed up to 66 months.	Up to 66 months.
Secondary	Number of Participants That Survived	From the first day of treatment until death, assessed up to 74 months.	Up to 74 months
Secondary	Number of Participants With Chemoprotection	assessed by the ability to increase the Temozolomide dose beyond 472 mg/m^2	Up to 66 months
Secondary	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
Secondary	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
Secondary	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