Combining glycolytic inhibitors with chemotherapy: Phase I trial of 2-deoxyglucose and docetaxel in patients with solid tumors

Abstract

3190 Background: Although hypoxia is known to contribute to tumor cell resistance to chemotherapeutic agents by slowing growth, it also provides a window of selectivity for glycolytic inhibitors, such as 2-deoxy-D-glucose (2DG). Thus, the combination of chemotherapy and 2DG (to selectively kill slowly dividing cells) 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: We designed a phase I clinical trial with the following aims: (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 solid malignancies who failed chemotherapy previously; (2) To evaluate the pharmacokinetics (PK) of 2DG after single and multiple doses when given alone and in combination with weekly DC and (3) To evaluate the biologic effect of 2DG alone and in combination with weekly DC on tumor uptake of 18F-fluorodeoxyglucose using positron-emission tomography. 2DG was administered daily for 7 days every other week starting at a dose of 2mg/kg, and DC was administered at 30mg/m2 for 3 of every 4 weeks beginning Day 1/Week 2. Results: To date 12 pts with various types of malignancies. i.e. breast, head and neck, lung, and adenoid cystic carcinoma have entered the trial. A modified accelerated titration design was used where single subjects were enrolled at different dose levels and each dose level was increased by 100% until dose-limiting toxicity (DLT) occurred in one subject at 64mg/kg (transient asymptomatic Grade 3 hyperglycemia). However this patient was found to be glucose intolerant. Nonetheless, 3 pts began 2DG treatment at one dose level lower (32mg/kg) and dose escalations were reduced to a 40% increase. No DLT or serious adverse events have occurred in the cohort at 32 mg/kg and dose escalation is continuing. PK analysis did not reveal any interaction between 2DG and DC to date. Two pts have achieved disease stabilization (1 NSCLC and 1 adenoid cystic carcinoma). Conclusions: The combination of 2DG and DC appears to be feasible and safe. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Threshold Aventis, Threshold Threshold Aventis Aventis