O6-Benzylguanine-Mediated Tumor Sensitization With Chemoprotected Autologous Stem Cell in Treating Patients With Malignant Gliomas
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| ClinicalTrials.gov Identifier: NCT00669669 |
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Recruitment Status :
Terminated
(Terminated due to loss in funding.)
First Posted : April 30, 2008
Results First Posted : December 28, 2018
Last Update Posted : May 18, 2022
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Glioblastoma Gliosarcoma | 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 | Phase 1 Phase 2 |
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 (Clinical Trial) |
| Actual Enrollment : | 12 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Benzylguanine-Mediated Tumor Sensitization With Chemoprotected Autologous Stem Cells for Patients With Malignant Gliomas |
| Actual Study Start Date : | February 25, 2009 |
| Actual Primary Completion Date : | July 6, 2018 |
| Actual Study Completion Date : | January 20, 2021 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment (chemotherapy, autologous stem cell transplant)
See Detailed Description
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Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo 3D conformal IMRT
Other Names:
Procedure: Autologous Hematopoietic Stem Cell Transplantation Undergo autologous in vitro-treated peripheral blood stem cell transplant
Other Name: Autologous Stem Cell Transplantation Drug: Carmustine Given IV
Other Names:
Biological: Filgrastim Given SC
Other Names:
Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation Undergo autologous in vitro-treated peripheral blood stem cell transplant
Other Names:
Radiation: Intensity-Modulated Radiation Therapy Undergo 3D conformal IMRT
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: O6-Benzylguanine Given IV
Other Names:
Drug: Plerixafor Given SC
Other Names:
Radiation: Proton Beam Radiation Therapy Undergo proton beam radiation therapy Drug: Temozolomide Given PO
Other Names:
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- Number of Participants Dose-limiting Toxicity (DLT) [ Time Frame: Up to 6 weeks after infusion ]Defined as any grade 4 nonhematopoietic toxicity that is likely related to the investigational procedures (Part I)
- Number of Participants With Retrovirus or Leukemia [ Time Frame: Up to 2 years after infusion ]Replication competent retrovirus or diagnosis of leukemia
- Response Rate [ Time Frame: Up to 66 months ]Number of patients with reduction in tumor burden of a predefined amount
- Duration of Response [ Time Frame: Up to 65 months ]From the onset of temozolomide to the date at which unequivocal disease progression, assessed up to 65 months.
- Time to Progression [ Time Frame: Up to 66 months. ]From the first day of treatment (transplant) until unequivocal progression is documented, assessed up to 66 months.
- Number of Participants That Survived [ Time Frame: Up to 74 months ]From the first day of treatment until death, assessed up to 74 months.
- Number of Participants With Chemoprotection [ Time Frame: Up to 66 months ]assessed by the ability to increase the Temozolomide dose beyond 472 mg/m^2
- Number of Participants With Chemoselection [ Time Frame: Up to 59 months ]assessed by the increase in peripheral blood Vector Copy Number (VCN), the average copies of integrated transgene per cell, after chemotherapy
- Gene Transfer Efficiency [ Time Frame: Up to 59 months ]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.
- Gene Transfer Efficiency After Chemotherapy [ Time Frame: Up to 59 months ]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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00669669
| United States, Washington | |
| Fred Hutch/University of Washington Cancer Consortium | |
| Seattle, Washington, United States, 98109 | |
| Principal Investigator: | Hans-Peter Kiem | Fred Hutch/University of Washington Cancer Consortium |
Documents provided by Fred Hutchinson Cancer Center:
| Responsible Party: | Fred Hutchinson Cancer Center |
| ClinicalTrials.gov Identifier: | NCT00669669 |
| Other Study ID Numbers: |
2000.00 NCI-2013-00701 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 8357 2000.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ) RG1709046 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ) |
| First Posted: | April 30, 2008 Key Record Dates |
| Results First Posted: | December 28, 2018 |
| Last Update Posted: | May 18, 2022 |
| Last Verified: | January 2022 |
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Glioblastoma Glioma Gliosarcoma Astrocytoma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Plerixafor Temozolomide Carmustine |
O(6)-benzylguanine Lenograstim Adjuvants, Immunologic Immunologic Factors Physiological Effects of Drugs Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Enzyme Inhibitors |