A new concept of continuous gemcitabine infusion: Fixed-dose-rate gemcitabine plus Platinum in metastatic transitional cancer –preliminary results of a phase I study

Abstract

4641 Background: The intracellular accumulation rate of Gemcitabine (G) is saturated at a serum concentration of G of 15–20 micromol/l. A continuous infusion of 10 mg/m2/min achieves this level (26,5 +/- 9 micromol/l). Therefore we conducted a phase I study, where the standard infusion (30 min) in a 3-week schedule was replaced by the fixed-dose-rate infusion of 10mg/m2/min. Method: A phase I study was designed in cooperation with the GU-group of the german cancer society, which has two arms starting in each with G 800mg/m2/80min stepping up to 1600mg/m2/160min (d1+8) combined with Cisplatin (70mg/m2) or Carboplatin (AUC5) on day 2 dependent on renal function. A cohort of 3 patients /level was planned. Primary objectives are MTD and efficacy. DLT observed in the first cycle were defined. Between January 2002 and Sept 2003 we recruited 19 Patients with advanced or metastatic urothelium cancer. Measurable lesion, no prior chemo or radiation therapy were the most important inclusion criteria. Results: Of the 19 patients 9 started initially with G+Cis and 10 with G+Carbo. Due to decreased renal function we had to change from Cis- to Carbo after 3 cycles (800 level) in two patients with solitary kidney. Both completed 6 cycles. Mean number of cycles 4.4 (range 1–6). 6 Patients (46%) completed protocol with 6 cycles. Two DLT occurred: one grade 4 thrombopenia at the 800 level in the Carbo arm, so that 3 more patients have to be recruited; the other DLT was neutropenic fever plus grade 4 thrombopenia leading to a stop of the 1200 level in the cisplatin arm. 11 patients are evaluable for response: 2 CR, 3 PR,2 SD, 4 PD; resulting in an OR of 45%. Conclusion: The described 3-week schedule with the Fixed-Dose-Rate Gemcitabine of 10mg/m2/min is feasible. Toxicities are more frequent than in the standard infusion of 1200mg/m2/30min. Therefore the MTD for G (Cis-arm) is 1000mg/m2/100min. The recruitment for G (Carbo-arm) is ongoing but a reduced level of 800mg/m2/80min is the expected MTD due to more hematotoxicities of Carboplatin compared to Cisplatin. A randomized phase II will be planned if overall response is about 50%. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Germany