Dose Escalation Trial of 2-Deoxy-D-Glucose (2DG) in Subjects With Advanced Solid Tumors
The objectives of this study are to evaluate the safety, tolerability, pharmacokinetics, and biologic effect (FDG PET, preliminary efficacy) of daily oral doses of 2DG with and without weekly docetaxel in subjects with advanced solid tumors.
Head and Neck Cancer
Drug: 2-deoxy-D-glucose (2DG)
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Dose Escalation Trial of 2-Deoxy-D-Glucose (2DG) Alone and in Combination With Docetaxel in Subjects With Advanced Solid Malignancies|
- Significant Toxicity
- Disease Progression
- Response Rate
|Study Start Date:||February 2004|
|Study Completion Date:||July 2008|
|Primary Completion Date:||July 2008 (Final data collection date for primary outcome measure)|
2-deoxy-D-glucose (2DG) is a synthetic glucose analog under development by Threshold Pharmaceuticals, Inc. that exploits the differences in metabolism between normal and malignant cells. Malignant cells utilize glucose at a much higher rate than normal cells and are therefore more dependent on aerobic and anaerobic glycolysis. If glycolysis could be blocked preferentially in malignant cells, 2DG would have potential for anti-tumor therapy. Hypoxic cells are especially dependent on anaerobic glycolysis and are generally resistant to anti-tumor therapies such as chemotherapy and radiotherapy. Therefore, combining 2DG with chemotherapy may be a way to simultaneously target both hypoxic and aerobic cells in tumors.
Four factors may play a role in the preferential toxicity of 2DG in malignant cells: (1) increased uptake and retention of glucose analogs by malignant cells; (2) relative hypoxia of tumor cells relative to normal cells; (3) malignant cells may be more sensitive to glucose deprivation than normal cells; and (4) inhibition of glycolysis may increase sensitivity to some cytotoxic agents. Preliminary data in human tumor xenografts support this hypothesis.
Because 2DG is most likely to be effective in combination with chemotherapy, this trial was designed to evaluate the maximum tolerated dose (MTD) of 2DG both alone and in combination with chemotherapy. Docetaxel was chosen because there is evidence in human tumor xenografts of delayed tumor growth for 2DG in combination with paclitaxel compared to paclitaxel alone and it has been reported that taxanes may enhance uptake of 2DG into malignant cells. Patients with advanced solid tumors were chosen because they are appropriate candidates for a Phase I clinical trial and because their tumors are likely to have areas of hypoxia.
|United States, Florida|
|University of Miami Sylvester Comprehensive Cancer Center|
|Miami, Florida, United States, 33136|
|United States, Indiana|
|Indiana University Cancer Center|
|Indianapolis, Indiana, United States, 46202|
|United States, Texas|
|Institute for Drug Development Cancer Therapy & Research Center|
|San Antonio, Texas, United States, 78229|
|Principal Investigator:||Luis Raez, MD||University of Miami Sylvester Comprehensive Cancer Center|