Phase 1b dose escalation study of erlotinib in combination with infusional 5-Fluorouracil, leucovorin, and oxaliplatin in patients with advanced solid tumors.

PURPOSE: Erlotinib (Tarceva) is a potent epidermal growth factor receptor (HER1) inhibitor. Infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) is a standard therapy for colorectal cancer. This trial assessed the maximum tolerated dose (MTD), safety, preliminary efficacy, and pharmacokinetics of erlotinib combined with FOLFOX. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were sequentially enrolled into three cohorts (cohort 1: 100 mg/d erlotinib, 65 mg/m(2) oxaliplatin, 200 mg/m(2) leucovorin, 400 mg/m(2) bolus 5-FU, and 400 mg/m(2) continuous infusion 5-FU; cohort 2: oxaliplatin increased to 85 mg/m(2) and 5-FU infusion increased to 600 mg/m(2); and cohort 3: erlotinib increased to 150 mg/d). RESULTS: Thirty-two patients were enrolled (23 with colorectal cancer): no dose-limiting toxicities (DLT) were observed in cohort 1. In cohort 2, two of nine patients experienced a DLT (both diarrhea). In cohort 3, two of nine patients had a DLT (diarrhea and staphylococcal septicemia). Cohort 3 determined the MTD cohort and expanded to 17 patients in total. The most common adverse events were diarrhea, nausea, stomatitis, and rash (primarily mild/moderate). No pharmacokinetics interactions were observed. One patient (colorectal cancer) had a complete response, seven patients had a partial response, and nine had stable disease. CONCLUSIONS: The MTD was defined as follows: 150 mg/d erlotinib, 85 mg/m(2) oxaliplatin; 200 mg/m(2) leucovorin, 400 mg/m(2) bolus 5-FU, and 600 mg/m(2) infusion 5-FU. At the MTD, the combination was well tolerated and showed antitumor activity, warranting further investigation in patients with advanced colorectal cancer and other solid tumors.

Pharmacokinetics of tilidine and naloxone in patients with severe hepatic impairment.

The objective of the present study was to evaluate the pharmacokinetics of tilidine (CAS 20380-58-9), naloxone (CAS 465-65-6) and tilidine metabolites after administration of a single oral dose of a solution containing 100 mg tilidine hydrochloride and 8 mg naloxone hydrochloride (equivalent to 1.44 ml Valoron N solution) to patients with severe hepatic impairment. The investigation was carried out as an open single-dose study in 8 patients suffering from liver cirrhosis. Patients qualified for study enrollment if they had a Child-Pugh score of > or = 7 and a mono-ethyl-glycine-xylidide (MEGX) 15-min test value < 50 ng/ ml. Blood samples were taken over a period of 28 h and analyzed for the prodrug tilidine, its active metabolite nortilidine, bisnortilidine, and naloxone (total and non-glucuronidated fraction). Pharmacokinetic parameters were compared with data from a previous study performed in healthy volunteers. Tilidine, nortilidine and unconjugated naloxone pharmacokinetic parameters showed a high variability between patients. Compared to previous results obtained in healthy volunteers, maximum plasma concentration (Cmax) of nortilidine was reduced by 44%, whereas elimination half-life (t1/2) was prolonged by factor 2. The area under the curve (AUC) showed a slight reduction of approximately 20%. For total naloxone, no relevant change was observed. However, in contrast to the results obtained in healthy subjects, unconjugated naloxone could be measured in plasma from patients with cirrhosis, possibly due to a reduced glucuronidation capacity of the liver in these patients. In conclusion, severe hepatic impairment has a relatively minor influence on the exposure (AUC) to the active metabolite of tilidine (i.e., nortilidine). However, a straightforward interpretation of the results was confounded by pronounced variability in nortilidine pharmacokinetics. In individual patients with severely affected liver function, satisfactory analgesia with tilidine/naloxone oral solution might not be achieved because of insufficient formation of nortilidine and insufficient inactivation of naloxone.