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First-In-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced

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First-In-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Author Manuscript Published OnlineFirst on April 5, 2019; DOI: 10.1158/1078-0432.CCR-18-1189 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced 2 Solid Tumors: Safety, Pharmacokinetics and Anti-Tumor Activity 3 Running title: Phase I Study of Savolitinib, a Selective MET Inhibitor 4 Hui Gan1–3, Michael Millward4, Ye Hua5, Chuan Qi5, Yang Sai5, Weiguo Su5, Jian Wang5, Lilin Zhang5, 5 Melanie M. Frigault6, Shethah Morgan7, Liu Yang8, Jason D. Lickliter9,10 6 1Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, 7 Melbourne, Victoria, Australia. 2School of Cancer Medicine, La Trobe University School of Cancer 8 Medicine, Melbourne, Australia. 3Department of Medicine, University of Melbourne, Melbourne, 9 Victoria, Australia. 4University of Western Australia, Perth, Australia and Linear Clinical Research, 10 Perth, Australia. 5Hutchison MediPharma Ltd, Shanghai, P.R. China. 6Oncology Translational Science, 11 IMED Biotech Unit, AstraZeneca, Boston, MA, USA. 7AstraZeneca, Cambridge, UK. 8AstraZeneca, 12 Shanghai, P.R. China. 9Monash Medical Center, Bentleigh East, Victoria, Australia. 10Nucleus 13 Network, Melbourne, Victoria, Australia. 14 Financial support 15 The research presented in this manuscript was funded by Hutchison MediPharma Ltd and 16 AstraZeneca. 17 Corresponding author: Dr Hui Gan, Austin Health and Olivia Newton-John Cancer Research Institute, 18 Melbourne, Victoria, Australia. Tel: + 61 3 9496 9925; Email: [email protected] 19 Disclosures 20 Hui Gan, Michael Millward and Jason Lickliter declare no potential conflicts of interest. At the time of 21 the study, Ye Hua, Chuan Qi, Yang Sai, Weiguo Su, Jian Wang and Lilin Zhang were employees of 22 Hutchison MediPharma Ltd. At the time of the study, Melanie M. Frigault, Shethah Morgan and Liu 23 Yang were employees of AstraZeneca. 24 Page 1 of 31 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 5, 2019; DOI: 10.1158/1078-0432.CCR-18-1189 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 25 Word count: 3545 (limit 5000 words) 26 Number of tables: 3 27 Number of figures: 3 28 Suggested Journal keyword options: clinical trials, small molecule agents (kinase and phosphatase 29 inhibitors) 30 Suggested author-defined keywords: savolitinib, volitinib, MET inhibitor 31 Page 2 of 31 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 5, 2019; DOI: 10.1158/1078-0432.CCR-18-1189 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 32 Abstract 33 Purpose: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is 34 implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability 35 and maximum tolerated dose (MTD) of the potent and selective MET inhibitor, savolitinib (AZD6094, 36 HMPL-504, volitinib). 37 Experimental design: This open-label, multi-center dose-escalation and -expansion study 38 evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3+3 design 39 assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose expansion phase 40 included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD and dose- 41 limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included 42 pharmacokinetics, biomarker research and anti-tumor activity. 43 Results: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib 44 (600 mg N=1, 800 mg N=1 and 1000 mg N=2); the MTD was 800 mg QD and not reached for BID 45 dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events 46 were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and 47 peripheral edema (15 patients, 31%). At 600 mg QD, Cmax was 2414.8 ng/mL, AUC was 48 17053.9 h·ng/mL and there was no apparent drug accumulation. Three patients with papillary renal 49 cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 50 weeks. 51 Conclusion: The tolerability profile of savolitinib was acceptable and the RP2D was 52 established as 600 mg QD. Preliminary anti-tumor activity was demonstrated supporting further 53 study in patients with PRCC. 54 Word count: 250 (limit 250 words) 55 Page 3 of 31 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 5, 2019; DOI: 10.1158/1078-0432.CCR-18-1189 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 56 Statement of Significance 57 This first-in-human study of savolitinib, a potent and highly selective inhibitor of MET 58 tyrosine kinase, established the recommended dose and confirmed the observed safety profile was 59 as expected for the drug based on its pharmacology. Early evidence of antitumor activity was 60 demonstrated; three partial responses were observed amongst patients with PRCC which tested 61 positive for MET gene copy number gain. 62 63 Translational Relevance 64 This first-in-human study of savolitinib (previously referred to as AZD6094, HMPL-504 and 65 volitinib) in patients with advanced solid malignancies established the recommended dose as 66 600 mg QD and confirmed the observed safety profile was as expected for the drug based on its 67 pharmacology. Evidence of antitumor activity with savolitinib was seen in some patients, in 68 particular, three partial responses were observed amongst patients with PRCC which tested positive 69 for MET gene copy number gain. A phase II trial of savolitinib in patients with advanced or metastatic 70 PRCC including analysis of treatment response by MET status biomarker was conducted based on 71 the data presented here (Clinicaltrials.gov identifier: NCT02127710) and has been published 72 (Choueiri TK, et al. J Clin Oncol 2017;35(26):2993-3001) and a phase III trial to assess the efficacy and 73 safety of savolitinib versus sunitinib in patients with MET-driven, unresectable and locally advanced, 74 or metastatic PRCC is underway (Clinicaltrials.gov identifier: NCT03091192). 75 Page 4 of 31 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 5, 2019; DOI: 10.1158/1078-0432.CCR-18-1189 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 76 Introduction 77 MET (hepatocyte growth factor [HGF] receptor) is a key regulator of angiogenesis, cell 78 survival, invasion and proliferation and is expressed on the epithelial cells in numerous organs 79 including the kidney, bone marrow and liver (1). Dysregulation of the HGF/MET signaling pathway 80 has been implicated in the tumorigenesis of a variety of human cancers (2). Binding of the ligand 81 HGF to its receptor activates the MET tyrosine kinase, leading to the initiation of a cascade of 82 downstream signals including activation of the Ras/Raf/MEK/ERK and phosphatidylinositol-3- 83 kinase/Akt pathways (1). Activating MET mutations and MET gene amplification have been reported 84 in various malignancies including gastric carcinomas, gliomas, and prostate cancer (3-5). MET 85 amplification is also a potential mechanism for the development of treatment resistance of 86 epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) with the EGFR 87 inhibitors, erlotinib, gefitinib and osimertinib (3,6,7). Recent studies have also linked MET 88 dysregulation with papillary renal cell carcinoma (PRCC) (8-10). 89 Various strategies to inhibit the HGF/MET signaling pathway have been explored. 90 Monoclonal antibodies directed against HGF and MET, such as rilotumumab, onartuzumab and 91 emibetuzumab, have demonstrated anti-tumor activity in early phase clinical trials (11,12). Further 92 developments include the small-molecule tyrosine kinase inhibitors crizotinib, cabozantinib and 93 foretinib, multi-kinase inhibitors that inhibit a number of intracellular pathways, including MET (13- 94 15). 95 Savolitinib (previously referred to as AZD6094, HMPL-504 and volitinib) is a potent and 96 highly selective small-molecule inhibitor of MET tyrosine kinase (16). Savolitinib effectively inhibited 97 the in vitro activity of recombinant MET (half maximal inhibitory concentration value of 4 nmol/L) 98 and the in vitro growth of gastric cell lines with dysregulated MET signaling (17). Also, MET signaling 99 was reduced and tumor regression observed following savolitinib treatment of in vivo human 100 xenograft tumor models of MET-amplified gastric cancer and PRCC (17,18). Page 5 of 31 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 5, 2019; DOI: 10.1158/1078-0432.CCR-18-1189 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 101 We present the results of the first-in-human phase I trial of savolitinib in patients with 102 advanced solid tumors. The study was designed to evaluate the safety, tolerability and maximum 103 tolerated dose (MTD) of savolitinib, with the additional exploratory objectives of evaluating 104 pharmacokinetics, biomarker research and anti-tumor activity. 105 106 Patients and Methods 107 Study design and objectives 108 This was a phase I, open-label, multi-center dose-escalation and -expansion study of oral 109 savolitinib in patients with locally advanced or metastatic solid tumors (Clinicaltrials.gov identifier: 110 NCT01773018). The dose escalation phase (Figure 1) determined the MTD. The starting dose of 111 100 mg was chosen based on pre-clinical studies of savolitinib.
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