Evaluation Of Safety, Tolerability And Pharmacokinetics (Pk) Of Patupilone In Patients (Pts) With Advanced Solid Tumors And Varying Degrees Of Hepatic Function: An Open-Label Phase I Study

2557 Background: Patupilone is a novel epothilone with activity in a wide range of solid tumors. Early phase I studies suggest its systemic levels may be elevated in pts with impaired hepatic function. This study investigates patupilone’s PK profile and optimal doses for varying degrees of hepatic dysfunction. Methods: The study is a multicenter, open-label, 3+3 design for pts with advanced solid tumors and varying degrees of hepatic function: Normal (N), Mildly impaired (M) (T. bilirubin <1.5xULN and SGOT >ULN), and Moderately impaired (Mod) (T. bilirubin >1.5 to 3xULN and any SGOT). Patupilone is given as 10 mg/m2 to pts in N group or as 5 mg/m2 to M group in a single 20-min IV infusion every 3 weeks. PK samples are drawn during cycles 1 and 2. Results: To date 18 pts have enrolled (10 N, 8 M, 0 Mod). Median age is 60 yrs (range 35–79). Median cycles received are 2 (range 1- 14). A DLT (unexplained death) for the M arm lead to this arm’s expansion. The most common reported adverse events (AEs) regardless of relationship were diarrhea 71%, fatigue 41%, nausea 35% and abdominal pain 29%. Most frequent G3/4 AEs reported were diarrhea, GI hemorrhage, and hypokalemia, each 23%, and fatigue, hyponatremia, spinal cord compression and vomiting, each 11%. Of the 16 evaluable pts, 9 (56%) had stable disease: pancreas (3), colon (2) and glioma (1). Preliminary PK data suggest clearance, apparent Vss and elimination t1/2 are similar in both the N and M arm. The mean AUC of the Mild arm at 5mg/m2 (1086 + 410 ng.h/mL, n=3) was approximately half of the Normal (1962 + 469 ng.h/mL, n=9). Conclusions: The pharmacokinetic parameters (clearance, apparent Vss and elimination t1/2) of patupilone were similar between patients with mild hepatic dysfunction at 5 mg/m2 and patients with normal hepatic function at 10 mg/m2. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis