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

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.