Phase I study of high-dose bi-weekly gemcitabine at a constant rate infusion (CRI) without growth factor support in advanced solid tumors, including prior standard gemcitabine treated patients

Abstract

2067 Background:Phosphorylation of gemcitabine by deoxycytidine kinase is the rate-limiting step in the accumulation of the active triphosphate metabolite. This enzyme is saturable and the optimal infusion dose rate that maximizes amount of gemcitabine triphosphate is 10 mg/m2/min. Previous experience of weekly gemcitabine at this CRI produced a maximum tolerated dose (MTD) close to the already recommended 30-minute infusion. We are investigating the MTD of gemcitabine at a CRI in patients with solid tumors using a biweekly regimen. Methods: Metastatic patients failing standard therapy (1 or no prior chemotherapy including standard 30-minute gemcitabine) were eligible. Gemcitabine was infused at a CRI of 10 mg/m2/minute every 2 weeks starting at 2,400 mg/m2 with 9 predefined dose-level (DL). In the absence of dose-limiting toxicity (DLT) dose was increased 600 mg/m2 at each DL. Results: Twenty patients (6 female, 14 male); median age 54 (range 38–74); ECOG 0 (10), 1 (10); diagnoses: cholangiocarcinoma (3), unknown primary (2), pancreas (2), bladder (2), head and neck (2), soft-tissue sarcoma (2), cervix (2), prostate (2),breast (2) and kidney (1) received a total of 89 cycles (range 1–17). Up to now MTD has not been reached at dose level 6. Main non-hematologic toxicity was grade 2 alopecia in all patients and grade 3 astenia in 6 patients. Grade 3–4 anemia and neutropenia ocurred in 4 (20%) and 11 (55%) of patients, with no febrile neutropenia. Objective responses (PR) have been observed in 4 patients: unknown primary, cholangiocarcinoma, bladder,and prostate cancer. In 2 patients after previous gemcitabine treatment. Conclusions: Biweekly CRI of gemcitabine is feasible and can be given safely up to a dose of 5400 mg/m2 in 9 hours infusion every 15 days without growth factor support. Activity has been seen in patients pretreated with gemcitabine. MTD has not been reached. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly