Phase I pharmacokinetic (PK) and safety study of intravenous (IV) CI-1033 in patients with advanced solid tumors

Abstract

3057 Background: CI-1033 is a pan-erbB tyrosine kinase inhibitor. In phase 1 oral (PO) studies, dose limiting toxicities were primarily gastrointestinal (GI), which supported the exploration of IV dosing to achieve higher drug exposures. Methods: Forty-eight patients (pts) with advanced nonhematologic malignancies received IV CI-1033 via 30 min infusions (10–500 mg) on a 3-day weekly (MWF) schedule. PK samples were collected on Days 1 and 8 and evaluated using compartmental analysis (NONMEM ADVAN3). Results: 28M/20F, ECOG PS 0 & 1, median age 54 (42–73), tumors: lung 11, colorectal 10, mesothelioma 9, melanoma 4, unknown primary 2, others 12. Despite a 5 to 10-fold increase in IV Cmax and a 3-fold increase in AUC compared to PO at equivalent doses, treatment-related GI AEs were notably less frequent with this IV regimen than with once weekly dosing of PO CI-1033 (100–1000 mg; n=55; Proc. ASCO 2001,283:72a). The incidences of the most common GI AEs when given IV were Gr 1–2 nausea (15%), vomiting (11%), diarrhea (7%) vs 60%, 40%, and 49%, respectively, with PO dosing. Whereas Gr 3 GI AEs occurred in 2% of pts on the PO study, none were reported in the IV study to date. The incidences of Gr 3 hypersensitivity were comparable for IV and PO regimens (each 2%). Systemic exposure was dose proportional with bi-phasic elimination. The initial distribution phase had a 2 to 3 minute half-life while the terminal elimination phase half-life was approx 3 hrs. Central volume of distribution (18.5 liters) approximated extravascular water volume. Systemic clearance was rapid at 3 L/min. Systemic exposure was not dependent upon age, gender, race, renal function, body weight or surface area in this IV study. Conclusions: Gastrointestinal AEs were less frequent following IV dosing relative to PO dosing at comparable systemic exposures and hence higher drug exposures could be acheived by the IV route. Oral bioavailability of CI-1033 is about one-third that observed following IV dosing. The clinical significance of the higher drug exposures achieved by the IV route is yet to be determined but warrants further investgation. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer