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Ref Type | Journal Article | ||||||||||||
PMID | (23403628) | ||||||||||||
Authors | Yap TA, Arkenau HT, Camidge DR, George S, Serkova NJ, Gwyther SJ, Spratlin JL, Lal R, Spicer J, Desouza NM, Leach MO, Chick J, Poondru S, Boinpally R, Gedrich R, Brock K, Stephens A, Eckhardt SG, Kaye SB, Demetri G, Scurr M | ||||||||||||
Title | First-in-human phase I trial of two schedules of OSI-930, a novel multikinase inhibitor, incorporating translational proof-of-mechanism studies. | ||||||||||||
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Abstract Text | 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.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.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 600 mg (n = 8). Dose-limiting toxicities were observed at 600 mg twice a day (n = 3): G3 rash (n = 2) and G4 γ-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.OSI-930 is safe and well tolerated, with pharmacokinetic-pharmacodynamic data supporting proof-of-mechanism with clinically relevant antitumor activity. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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OSI-930 | KIT Inhibitor 57 VEGFR2 Inhibitor 37 | OSI-930 binds and inhibits Kdr (Vegfr2) and Kit reducing cell proliferation and tumor growth (PMID: 16424037, PMID: 23403628). |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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