First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics and Anti-Tumor Activity.

Purpose: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability and maximum tolerated dose (MTD) of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib). Experimental design: This open-label, multi-center dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3+3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research and anti-tumor activity. Results: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N =1, 800 mg N =1 and 1000 mg N =2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, C max was 2414.8 ng/mL, AUC was 17053.9 h·ng/mL and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks. Conclusion: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary anti-tumor activity was demonstrated supporting further study in patients with PRCC.