Phase I study of BAY 73–4506, an inhibitor of oncogenic and angiogenic kinases, in patients with advanced solid tumors: Final results of a dose-escalation study

Abstract

2558 Background: BAY 73–4506 is a potent inhibitor of the receptors of tyrosine kinases (VEGFR, KIT, RET, FGFR and PDGFR) and serine/threonine kinases (RAF and p38MAPK). In tumor xenograft models, BAY 73–4506 demonstrated a broad spectrum antitumor activity. Methods: This phase I study was a dose-escalation trial investigating the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profile of BAY 73–4506, given orally in 21 days on/7 days off cycles, until discontinuation due to toxicity or tumor progression. PK was assessed on days 1 and 21 of cycle 1. PD markers including DCE-MRI, soluble VEGFR-2 (sVEGFR-2) and VEGF plasma levels were assessed at each cycle. Tumor response was evaluated as per RECIST. Results: 52 patients (pts) with solid tumors and progressive disease were enrolled and treated with doses of 10 to 220 mg once daily. Frequent tumor types included CRC (31%), malignant melanoma (10%), and ovarian cancer (10%). The median treatment duration was 49.5 days (min. 3, max. 609). Drug-related adverse events (AEs) of all grades reported in >20% of pts were hoarseness (54%), dermatological toxicities (50%; CTC 3–4: 13%), mucositis (35%), diarrhea (25%; CTC 3: 2%), fatigue (23%; CTC 3: 2%), and hypertension (23%; CTC 3: 6%). Treatment-related AEs leading to dose reduction, interruption or discontinuation were hand foot skin reaction (15%), diarrhea (8%), and thrombopenia (6%). BAY 73–4506 showed dose-dependent increase in exposure up to 160 mg where it reached a plateau. The major metabolites (active in vitro and in vivo) also showed dose-dependent increases in exposure up to 220 mg and reached similar AUC(0–24)ss to the parent drug at 220 mg. Of the 33 evaluable pts, 9% achieved a partial response (PR), 64% had stable disease (SD), at least 7 weeks after start of treatment, and 48% had SD or PR for more than 11 weeks. Decrease in sVEGFR-2 level or iAUC60s of Gd-DTPA by DCE-MRI correlated with drug exposure. Conclusions: The recommended phase II dose for BAY 73–4506 is 160 mg daily, using the 21 days on/7 days off treatment schedule. Clinical activity (PR+SD) has been demonstrated in 73% of the evaluable pts. An extension cohort (dose level 160 mg) has been started. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Bayer Bayer Bayer Bayer Bayer