Phase I study of BAY 73-4506, an inhibitor of oncogenic and angiogenic kinases, in patients with advanced refractory colorectal carcinoma (CRC).

3560^ Background: BAY 73-4506 is a potent inhibitor of the receptor tyrosine kinases (VEGFR, KIT, RET, FGFR and PDGFR) and serine/threonine kinases (RAF and p38MAPK). In in-vivo models, BAY 73-4506 has demonstrated a broad spectrum of antitumor activity. METHODS This phase I study investigated the safety and pharmacokinetic (PK)/pharmacodynamic (PD) profiles of BAY 73-4506, given orally in repeating cycles of 21 days on/7 days off, in patients with refractory CRC. PK assessments were performed on days 1 and 21 of cycle 1. PD markers - including DCE-MRI and plasma levels of VEGF/soluble VEGFR-2 - were assessed at each cycle. Tumor response was evaluated per RECIST. RESULTS 38 patients with actively progressing CRC were treated with BAY 73-4506 at doses of 60 mg (n = 1), 120 mg (n = 4), 160 mg (n = 26), and 220 mg (n = 7) once daily. Median treatment duration was 56.5 days (range, 7-219 days). Drug-related adverse events (AEs) of all grades reported in >20% of patients were hand-foot skin reaction (HFSR) (61%; CTC 3-4, 32%), fatigue (45%; CTC 3, 11%), hoarseness (24%; CTC 3, 3%), mucositis (24%), diarrhea (24%; CTC 3, 3%), anorexia (24%), and hypertension (21%; CTC 3, 13%). Treatment-related AEs leading to dose reduction, interruption, or discontinuation (in ≥2 of patients) were HFSR (26%), fatigue (18%), thrombopenia (8%), and hypertension (5%). BAY 73-4506 showed a dose-dependent increase in exposure up to 160 mg, at which point a plateau was reached. One of 27 evaluable patients achieved a partial response (4%), 15 had stable disease (SD) at least 7 weeks after the start of treatment (55%), and 6 had SD for more than 23 weeks (22%). Patients had extensive previous antitumor treatment, including bevacizumab (44%) and cetuximab (59%). Decreases in soluble VEGFR-2 levels and iAUC60s of Gd-DTPA by DCE-MRI demonstrated that BAY 73-4506 was active on biologically relevant markers. CONCLUSIONS BAY 73-4506 dosing at 160 mg daily, using a treatment schedule of 21 days on/7 days off was feasible in patients with advanced refractory CRC. Promising clinical activity was shown, with a disease control rate (PR+SD) of 59% in evaluable patients. Mutational analysis of selected genes (KRAS, BRAF) is ongoing. [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco. org/conflictofinterest .