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Title: First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics and Anti-Tumor Activity.
Austin Authors: Gan, Hui K ;Millward, Michael J;Hua, Ye;Qi, Chuan;Sai, Yang;Su, Weiguo;Wang, Jian;Zhang, Lilin;Frigault, Melanie M;Morgan, Shethah;Yang, Liu;Lickliter, Jason D
Affiliation: Medical Oncology, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
School of Medicine, University of Western Australia
Department of Clinical Development and Regulatory Affairs, Hutchison MediPharma Limited..
Hutchison MediPharma Limited
Drug metabolism & Pharmacokinetics, Hutchison MediPharma Limited, Shanghai, China
Oncology Research, Hutchison MediPharma Ltd
Hutchison MediPharma Limited
Clinical Development, Hutchison MediPharma Limited
Oncology iMED, AstraZeneca (United States)
Early Clinical Development, AstraZeneca (United Kingdom)
Nucleus Network, Nucleus Network
Issue Date: 15-Aug-2019
Date: 2019-04-05
Publication information: Clinical Cancer Research 2019; 25(16): 4924-4932
Abstract: 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). 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. 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, Cmax 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. 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.
DOI: 10.1158/1078-0432.CCR-18-1189
ORCID: 0000-0001-7319-8546
Journal: Clinical Cancer Research
PubMed URL: 30952639
ISSN: 1078-0432
Type: Journal Article
Appears in Collections:Journal articles

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