TY - JOUR
T1 - First-in-human phase i trial of two schedules of OSI-930, a novel multikinase inhibitor, incorporating translational proof-of-mechanism studies
AU - Yap, Timothy A.
AU - Arkenau, Hendrik Tobias
AU - Camidge, D. Ross
AU - George, Suzanne
AU - Serkova, Natalie J.
AU - Gwyther, Stephen J.
AU - Spratlin, Jennifer L.
AU - Lal, Rohit
AU - Spicer, James
AU - Desouza, Nandita M.
AU - Leach, Martin O.
AU - Chick, Jon
AU - Poondru, Srinivasu
AU - Boinpally, Ramesh
AU - Gedrich, Richard
AU - Brock, Katie
AU - Stephens, Andrew
AU - Eckhardt, S. Gail
AU - Kaye, Stan B.
AU - Demetri, George
AU - Scurr, Michelle
PY - 2013/2/15
Y1 - 2013/2/15
N2 - Purpose: OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of OSI-930 in patients with advanced solid tumors. Experimental Design: OSI-930 was administered once or twice a day using a modified accelerated titration design. Pharmacokinetics and plasma soluble VEGFR2 (sVEGFR2) studies were undertaken. Dynamic contrast-enhanced MRI (DCE-MRI) and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) MTD expansion cohorts were conducted. Results: Fifty-eight patients received OSI-930 in 2 schedules; once a day schedule: 12 patients at doses up to 1, 600 mg without reaching MTD; twice a day schedule: 46 patients at 400 mg (n = 7), 500 mg (n = 31), and 600mg(n=8). Dose-limiting toxicities were observed at 600mgtwice a day (n=3):G3rash (n=2) and G4 g-glutamyltransferase, establishing the MTD at 500 mg twice a day. Common G1-2 toxicities included fatigue, diarrhea, nausea, and rash. Antitumor responses were seen in 2 patients with advanced ovarian cancer [Response Evaluation Criteria in Solid Tumors (RECIST) partial response (PR) (n=1); GCIG CA125 response (n = 1)]. Eleven of 19 heavily pretreated imatinib-resistant patients with gastrointestinal stromal tumors achieved RECIST stable disease (median duration: 126 days), with FDG-PET scans showing PRs in 4 of 9 patients. OSI-930 exposure increased with dose; substantial decreases in sVEGFR levels were observed with OSI-930 twice a day doses ≥400 mg, while DCE-MRI responses were shown in 4 of 6 patients. Conclusions: OSI-930 is safe and well tolerated, with pharmacokinetic- pharmacodynamic data supporting proof-of-mechanism with clinically relevant antitumor activity.
AB - Purpose: OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of OSI-930 in patients with advanced solid tumors. Experimental Design: OSI-930 was administered once or twice a day using a modified accelerated titration design. Pharmacokinetics and plasma soluble VEGFR2 (sVEGFR2) studies were undertaken. Dynamic contrast-enhanced MRI (DCE-MRI) and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) MTD expansion cohorts were conducted. Results: Fifty-eight patients received OSI-930 in 2 schedules; once a day schedule: 12 patients at doses up to 1, 600 mg without reaching MTD; twice a day schedule: 46 patients at 400 mg (n = 7), 500 mg (n = 31), and 600mg(n=8). Dose-limiting toxicities were observed at 600mgtwice a day (n=3):G3rash (n=2) and G4 g-glutamyltransferase, establishing the MTD at 500 mg twice a day. Common G1-2 toxicities included fatigue, diarrhea, nausea, and rash. Antitumor responses were seen in 2 patients with advanced ovarian cancer [Response Evaluation Criteria in Solid Tumors (RECIST) partial response (PR) (n=1); GCIG CA125 response (n = 1)]. Eleven of 19 heavily pretreated imatinib-resistant patients with gastrointestinal stromal tumors achieved RECIST stable disease (median duration: 126 days), with FDG-PET scans showing PRs in 4 of 9 patients. OSI-930 exposure increased with dose; substantial decreases in sVEGFR levels were observed with OSI-930 twice a day doses ≥400 mg, while DCE-MRI responses were shown in 4 of 6 patients. Conclusions: OSI-930 is safe and well tolerated, with pharmacokinetic- pharmacodynamic data supporting proof-of-mechanism with clinically relevant antitumor activity.
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U2 - 10.1158/1078-0432.CCR-12-2258
DO - 10.1158/1078-0432.CCR-12-2258
M3 - Article
C2 - 23403628
AN - SCOPUS:84874074235
SN - 1078-0432
VL - 19
SP - 909
EP - 919
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -