Phase I trial of glycolitic inhibition with 2-deoxyglucose and docetaxel for patients with solid tumors
Authors: Luis E. Raez, Virginia K. Langmuir, Kyriakos Papadopoulus, Alejandro Ricart, Caio M. Rocha-Lima, Joseph Rosenblatt, James Schlesselman, Allan Colowick, Don Jung, Theodore Lampidis
Journal: Cancer Research (2006)

515  Background: The slow growing cell population of solid tumors that is associated with hypoxia presents a formidable mode of resistance to chemotherapeutic agents; however anaerobic metabolism of these tumor cells also provides a window of selectivity for glycolytic inhibitors, such as 2-deoxy-D-glucose (2DG). Thus, the combination of chemotherapy (targets rapidly dividing cells) and 2DG (selectively killing the slow growing population) is expected to be more effective than either agent alone. We previously demonstrated this in mouse xenografts of human osteosarcoma and lung cancer cell lines with 2DG + adriamycin and 2DG + paclitaxel (CancerRes;.2004 64:31-4). Methods: The objectives of this Phase I dose escalation clinical trial were: (1) To determine the maximum tolerated dose (MTD) of daily oral doses of 2DG given alone and in combination with weekly docetaxel (DC) in patients (pts) with advanced malignancies who had relapsed after chemotherapy or for whom there was no curative standard treatment available; (2) To evaluate the pharmacokinetics (PK) of 2DG after single and multiple doses when given alone and in combination with weekly DC; (3) To evaluate the effect on tumor uptake of 18F-fluorodeoxyglucose using positron-emission tomography (PET). 2DG was administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg, and DC was administered at 30mg/m2 for 3 of every 4 weeks beginning Day 1/Week 2. A modified accelerated titration design was used where single subjects were enrolled at each dose level and dose increases were 100% until dose-limiting toxicity (DLT) occurred. Cohorts of 3-6 pts were then enrolled at dose increases of 40%. Results: To date 22 pts with a variety of malignancies have enrolled at 2DG doses up to 88 mg/kg. One pt discontinued for an adverse event (docetaxel-related sensory neuropathy). Single cases of DLT occurred - transient asymptomatic (64mg/kg) and symptomatic (88 mg/kg) Grade 3 hyperglycemia. The MTD has not been reached. 2DG is rapidly absorbed (Tmax 0.5-1h) with a terminal half-life of 5-10h. 2DG exhibits linear PK following single and multiple doses with minimal accumulation after multiple doses at 63 and 88 mg/kg. 2DG PK are not altered by docetaxel nor are docetaxel PK altered by 2DG. Six of 18 pts with post-treatment tumor assessments have achieved disease stabilization (NSCLC, SCC soft palate, non-Hodgkins lymphoma, thyroid cancer, adenoid cystic carcinoma of trachea and unknown primary). One pt with breast cancer had a partial response and PET showed decreased standard uptake values in all 4 lesions after one week of 2DG alone. Conclusions: The combination of 2DG and DC appears to be feasible and safe with no evidence of PK interactions. Evidence of anti-tumor activity was observed. To maximize the potential efficacy of 2-DG, we are pursuing a continuous daily dosing schedule of 2-DG in combination with weekly docetaxel.