Responses to the combination of the glycolytic inhibitor 2-deoxy-glucose (2DG) and docetaxel (DC) in patients with lung and head and neck (H/N) carcinomas

Abstract

14025 Background: We demonstrated in mouse xenografts that the combination of docetaxel chemotherapy with 2DG is feasible and increases responses against tumors (CancerRes; 2004 64:31–4). Methods: 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, and to evaluate the pharmacokinetics (PK) of 2DG alone and in combination with weekly DC. 2DG was initially 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. A modified accelerated titration design was used. Following completion of the every other week (EOW) 2DG dosing regimen, 3 weeks on and 1 week off (3–1W) dosing; and then continuous (CW) 2DG dosing were investigated. Results: 21 pts were enrolled in the EOW dosing at 2DG doses up to 88 mg/kg/day; another 10 pts were enrolled in the other dosing regimens. 5 pts had lung cancer (4 NSCLC + 1 SCLC); and another 6 pts had H/N cancers. One pt discontinued for DC-related sensory neuropathy. Single cases of DLT occurred - asymptomatic (64mg/kg) and symptomatic (88 mg/kg) Grade 3 hyperglycemia. The MTD was not reached with the EOW regimen. 2DG is rapidly absorbed (Tmax 0.5–1h) with a 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 and DC PK do not alter each other. One of 18 evaluable pts in the EOW dosing with breast cancer had a partial response (PR). Another 8 pts achieved disease stabilization (SD) among them: 2 of 4 pts with NSCLC, 2 of 6 pts with H/N cancers, 1 pt with thyroid cancer, and 1 of 3 pts with adenoidcystic carcinoma. The others were unknown primary and a breast lymphoma. Also the MTD was not reached at 63mg/kg (3–1W) dosing where one patient with H/N cancer achieved stabilization of his disease. Enrollment of pts in the CW regimen is ongoing now. 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 in patients with NSCLC and H/N cancers. No significant financial relationships to disclose.