Phase I Dose Escalation Trial of 2-Deoxy-D-Glucose (2DG) Alone and in Combination With Docetaxel in Subjects With Advanced Solid Malignancies
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
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.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Luis Raez, MD
University of Miami Sylvester Comprehensive Cancer Center
United States: Food and Drug Administration
|Indiana University Cancer Center||Indianapolis, Indiana 46202-5265|
|University of Miami Sylvester Comprehensive Cancer Center||Miami, Florida 33136|
|Institute for Drug Development Cancer Therapy & Research Center||San Antonio, Texas 78229|