A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors.
Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral foretinib once daily. Dose escalation was planned as a conventional "3+3" design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P<0.003) and soluble VEGFR2 plasma levels significantly decreased from baseline (P<0.03). The MTD of foretinib bisphosphate salt was determined to be 80 mg once daily.
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Geoffrey I
GI
Shapiro
Stewart
S
McCallum
Laurel M
LM
Adams
Laurie
L
Sherman
Steve
S
Weller
Suzanne
S
Swann
Harold
H
Keer
Dale
D
Miles
Thomas
T
Müller
Patricia
P
Lorusso
D000328:Adult; D000368:Aged; D000813:Anilides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019859:Proto-Oncogene Proteins c-met / Q000097:blood; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood
D000813:Anilides; C544831:GSK 1363089; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D042461:Vascular Endothelial Growth Factor A; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2