First-in-human phase I trial of two schedules of OSI-930, a novel multikinase inhibitor, incorporating translational proof-of-mechanism studies

Purpose: OSI-930 is a novel, potent oral small-molecule inhibitor of receptor tyrosine kinases, primarily targeting VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I clinical trial was conducted to evaluate its safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity in patients with advanced solid tumors.
Experimental Design: OSI-930 was administered once or twice daily using a modified accelerated titration design. Pharmacokinetic analyses and plasma soluble VEGFR2 (sVEGFR2) assessments were performed. Additionally, MTD expansion cohorts were evaluated using dynamic contrast-enhanced MRI (DCE-MRI) and 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET).
Results: A total of 58 patients received OSI-930 across two dosing schedules. In the once-daily regimen, 12 patients received doses up to 1,600 mg without reaching the MTD. In the twice-daily regimen, 46 patients were treated at doses of 400 mg (n = 7), 500 mg (n = 31), and 600 mg (n = 8). Dose-limiting toxicities at 600 mg twice daily included grade 3 rash (n = 2) and grade 4 γ-glutamyltransferase elevation (n = 1), establishing the MTD at 500 mg twice daily. Common grade 1–2 adverse events included fatigue, diarrhea, nausea, and rash. Antitumor activity was observed in two patients with advanced ovarian cancer, including one partial response per RECIST criteria and one CA125 response per GCIG guidelines. Among 19 heavily pretreated, imatinib-resistant patients with gastrointestinal stromal tumors, 11 achieved RECIST stable disease (median duration: 126 days), while FDG-PET scans indicated partial responses in 4 of 9 patients. OSI-930 exposure increased with dose, and substantial reductions in sVEGFR levels were observed at doses of ≥400 mg twice daily. DCE-MRI responses were documented in 4 of 6 patients.
Conclusions: OSI-930 demonstrated a favorable safety profile and was well tolerated. Pharmacokinetic and pharmacodynamic findings support its mechanism of action, with evidence of clinically meaningful antitumor activity.