Treatment of Newly Diagnosed Brain Tumors With Chemotherapy and Radiation Using Cells Modified for Chemoprotection and an Experimental Drug to Decrease the Tumor Cell Resistance to Chemotherapy
|Glioblastoma Multiforme (WHO Grade IV) Anaplastic Astrocytoma (WHO Grade III)||Drug: 06Benzylguanine Genetic: MGMT P140K Device: Meltenyi CliniMacs||Phase 1|
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
|Official Title:||A Pilot Study of Temozolomide and 06Benzylguanine for Treatment of Newly Diagnosed High Grade Glioma, Using Autologous Peripheral Blood Stem Cells Genetically Modified for Chemoprotection|
- To assess the safety and feasibility of infusing autologous PBSC transduced with MSCV-MGMTP140K construct, using the fibronectin component CH-296 to assist gene transfer. [ Time Frame: 5 years ]
- Assess the efficiency of gene transfer and durability of transgene expression in this clinical setting. [ Time Frame: 5 years ]
- Assess the degree of chemotherapy resistance in transduced cells, and the ability to enrich the population of transduced stem cells with subsequent courses of chemotherapy. [ Time Frame: 5 years ]
|Study Start Date:||December 2005|
|Study Completion Date:||August 2012|
|Primary Completion Date:||December 2008 (Final data collection date for primary outcome measure)|
The use of temozolomide (TEM) both during and after irradiation is a promising new approach for the treatment of patients with high-grade glioma. However, this treatment is limited by tumor cell resistance and therapy-related hematologic toxicity. To overcome TEM resistance, in this study we will add the chemotherapy sensitizing drug O6-Benzylguanine (BG). To overcome hematologic toxicity, patients will receive autologous hematopoietic stem cells transduced with a chemotherapy resistance gene designed to protect these cells from subsequent therapy with this drug combination.
The potential benefit of using transduced blood stem cells is the possibility for dose escalation of TEM, since hematologic toxicity has heretofore limited higher doses. Transduction will be accomplished with a retroviral vector carrying MGMTP140K, which codes for a mutated form of the resistance protein methylguanine-DNA methyltransferase (MGMT). Successful transduction of hematopoietic cells with MGMTP140K makes them resistant to the toxic effects of both TEM + BG. Repeated doses of these drugs should therefore result in an increase in the percentage of transduced (and thus protected) blood stem cells, thus reducing the likelihood of hematologic toxicity with further therapy. Accordingly, patients who are tolerating therapy well and who have laboratory evidence of chemoprotection will receive intrapatient dose escalation of TEM + BG during courses 2-6.
Eligible patients must be between 5 and 55 years of age and have newly-diagnosed high-grade glioma (anaplastic astrocytoma or glioblastoma multiforme) which cannot be completely resected. No prior therapy other than surgery is allowed, and patients must have adequate performance status and organ function as defined in the protocol.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00272870
|United States, Ohio|
|Cincinnati Children's Hospital Medical Center|
|Cincinnati, Ohio, United States, 45229|
|Study Director:||Punam Malik, MD||Cincinnati Childrens Hospital Medical Center|