Phase I study of BAY 73–4506, an inhibitor of oncogenic and angiogenic kinases, in patients with advanced refractory colorectal carcinoma (CRC)
Authors: Strumberg D. , Scheulen M. E. , Frost A. , Büchert M. , Christensen O. , Wagner A. , Heinig R. , Fasol U. , Mross K. 
Published: August 2020

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.

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