Abstract A108: A phase I and pharmalogical study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327, administered to subjects with advanced or refractory solid tumors

Abstract

Abstract Background: JNJ-26483327 is a potent reversible multi-targeted tyrosine kinase inhibitor. Tyrosine kinases of Epidermal Growth Factor Receptor (EGFR), Her2, Her4, RET receptor, Vascular Epidermal Growth Factor Receptor (VEGFR)-3, and Src family (Lyn, Fyn, Yes) are inhibited at low nanomolar concentrations. Methods: Objectives were to (1) determine safety, maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), (2) characterize the pharmacokinetic (PK) profile, (3) explore preliminary evidence of antitumor activity, and (4) explore pharmacodynamic (PD) effects in skin biopsies and blood. Results: 19 patients, 16 M/3F, median age 61 yrs (47-74) received JNJ-26483327 twice daily (BID) continuously at 100 mg (n=1), 200 mg (n=1), 400 mg (n=1), 800 mg (n=3), 1200 mg (n=3), 1500 mg (n=6) and 2100 mg (n=4). JNJ-26483327 was administered as oral solution (dose ≤ 1200 mg) or capsules (dose ≥ 1500 mg, 300 mg capsule). Skin biopsies were taken at days 0 and 28. At 2100 mg DLT consisted of a combination of grade 3 anorexia and fatigue in one patient, and due to substantial difficulty in intake in most patients, pill load at 2100 mg was dose limiting. JNJ-26483327 was well tolerated up to 1500 mg BID, with most common reported toxicities being nausea, vomiting, diarrhea, fatigue, skin rash. Plasma concentrations of JNJ-26483327 rapidly increased till about 3–4h post dose. PK showed significant inter-individual variability, but no marked deviation in dose-proportionality was observed up to 1500 mg BID. At 1500 mg BID, steady state plasma concentrations were 2–6 µg/l and AUCs 13–53 µg.h/ml and were in the active range as observed in xenograft mouse models. PD evaluation failed to show a substantial effect on expression of Ki-67, p27kip1, pMAPK, pAKT, and EGFR in paired skin biopsies. Serum levels of sVEGFR-2, VEGF-C and VEGF-D remained unchanged. No antitumor activity was observed in this study. Conclusion: The recommended dose of JNJ-26483327 is 1500 mg BID. JNJ-26483327 shows a predictable pharmacokinetic profile. Additional PD research is planned to demonstrate biological activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A108.