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Phase I Dose-Escalation Study of the Multikinase Inhibitor Lenvatinib in Patients with Advanced Solid Tumors and in an Expanded Cohort of Patients with Melanoma

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Phase I Dose-Escalation Study of the Multikinase Inhibitor Lenvatinib in Patients with Advanced Solid Tumors and in an Expanded Cohort of Patients with Melanoma Author Manuscript Published OnlineFirst on July 13, 2015; DOI: 10.1158/1078-0432.CCR-14-3063 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Title: 2 Phase I dose-escalation study of the multikinase inhibitor lenvatinib in patients with advanced 3 solid tumors and in an expanded cohort of patients with melanoma 4 5 Authors: 6 David S. Hong1, Razelle Kurzrock1, Jennifer J. Wheler1, Aung Naing1, Gerald S. Falchook2, 7 Siqing Fu1, Kevin B. Kim1, Michael A. Davies1, Ly M. Nguyen1, Goldy C. George1, Lucy Xu3, 8 Robert Shumaker3, Min Ren3, Jennifer Mink4, Cynthia Bedell5, Corina Andresen4, Pallavi 9 Sachdev3, James P. O’Brien4, John Nemunaitis5 10 11 Affiliations: 12 1The University of Texas MD Anderson Cancer Center, Houston, TX, United States 13 2Sarah Cannon Research Institute at HealthONE, Denver, CO, United States 14 3Eisai Inc., Oncology, Woodcliff Lake, NJ, United States 15 4Former employees of Eisai Inc., Woodcliff Lake, NJ, United States 16 5Mary Crowley Cancer Research Center, Dallas, TX, United States 17 18 Running Title: 19 Lenvatinib phase I safety, PK/PD, and mutational profiles 20 21 22 Key Words: lenvatinib, melanoma, pharmacodynamic, phase I, advanced solid tumors, E7080, 23 thyroid cancer, VEGFR, FGFR, PDGFR, RET, KIT 1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 13, 2015; DOI: 10.1158/1078-0432.CCR-14-3063 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 24 25 Funding: 26 This work was supported by Eisai Inc. and by the NIH Clinical and Translational Science Award 27 UL1 RR024148 and NIH Cancer Center Support Grant (CCSG) award CA016672 to The 28 University of Texas MD Anderson Cancer Center. 29 30 Corresponding Author: 31 David S. Hong, MD 32 The University of Texas MD Anderson Cancer Center 33 1515 Holcombe Boulevard, Box 455 34 Houston, TX 77030, USA 35 Tel: (713) 563-5844; Fax: (713) 792-0305 36 Email: [email protected] 37 38 Conflict of Interest Statement: 39 David S. Hong: Research funding, Eisai Inc. 40 Razelle Kurzrock: Nothing to disclose. 41 Jennifer J. Wheler: Nothing to disclose. 42 Aung Naing: Nothing to disclose. 43 Gerald S. Falchook: Nothing to disclose 44 Siqing Fu: Nothing to disclose. 45 Kevin B. Kim: Honorarium and research funding, Eisai Inc. 46 Michael A. Davies: Nothing to disclose. 2 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 13, 2015; DOI: 10.1158/1078-0432.CCR-14-3063 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 47 Ly M. Nguyen: Nothing to disclose. 48 Goldy C. George: Nothing to disclose. 49 Lucy Xu: Employee of Eisai Inc. 50 Robert Shumaker: Employee of Eisai Inc. 51 Min Ren: Employee of Eisai Inc. 52 Jennifer Mink: Nothing to disclose. 53 Cynthia Bedell: Nothing to disclose. 54 Corina Andresen: Nothing to disclose. 55 Pallavi Sachdev: Employee of Eisai Inc. 56 James P. O’Brien: Employee of Eisai Inc. 57 John Nemunaitis: Research funding from Eisai Inc. 58 59 60 61 Word Counts and Numbers of Figures/Tables: 62 Statement of translational relevance: 133 words (limit, 150 words) 63 Abstract: 250 words (limit, 250 words) 64 Manuscript text: 4674 words (limit, 5000 words) 65 Number of references: 37 (limit, 50) 66 Tables and figures: 6 (limit, 6), plus 2 Supplementary Tables 67 68 69 70 STATEMENT OF TRANSLATIONAL RELEVANCE 3 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 13, 2015; DOI: 10.1158/1078-0432.CCR-14-3063 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 71 Angiogenesis impacts the proliferation, growth, progression, migration, and metastasis of tumors 72 and surrounding stromal cells. Lenvatinib is an antiangiogenic agent that acts specifically against 73 tyrosine kinase receptors implicated in angiogenesis and related pathways (VEGFR 1–3, FGFR 74 1–3, and PDGFRα), as well as RET and KIT. This phase I study evaluated the maximum 75 tolerated dose (MTD), dose-limiting toxicities, safety, pharmacokinetics, pharmacodynamics, 76 and efficacy of lenvatinib given twice daily in patients with diverse tumor types, and in an 77 expansion cohort of patients with melanoma. The MTD for lenvatinib was established at 10 mg 78 twice daily. Encouraging antitumor activity was observed in patients with thyroid cancer and 79 melanoma. Pharmacodynamic analyses suggested that several serum biomarkers of apoptosis 80 and angiogenesis may potentially be predictive of clinical outcome in patients with advanced 81 melanoma treated with lenvatinib. 82 83 4 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 13, 2015; DOI: 10.1158/1078-0432.CCR-14-3063 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 84 ABSTRACT 85 Purpose: This “3+3” phase I study evaluated the safety, biologic, and clinical activity of 86 lenvatinib, an oral multikinase inhibitor, in patients with solid tumors. 87 Experimental Design: Ascending doses of lenvatinib were administered po bid in 28-day 88 cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were 89 tested as possible biomarkers in an expanded melanoma cohort. 90 Results: Seventy-seven patients were treated in 3 cohorts: 18 with intermittent bid dosing (7 91 days on, 7 days off) of 0.1–3.2 mg; 33 with bid dosing of 3.2–12 mg; and 26 with bid dosing of 92 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg po bid. 93 Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), 94 and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. 95 Twelve patients (15.6%) achieved partial response (PR, n=9) or unconfirmed PR (uPR, n=3), and 96 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD≥23 weeks was 40.3% 97 (n=31). Responses (PR/uPR) by disease were: melanoma, 5/29 patients (includes 1 patient with 98 NRAS mutation); thyroid, 3/6; pancreatic, 1/2; lung, 1/1; renal, 1/1; endometrial, 1/4; and 99 ovarian, 1/5. AUC0-24 and Cmax increased dose-proportionally. In multivariate Cox proportional 100 hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 101 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the 102 expanded melanoma cohort (P=0.041 and P=0.03, respectively). 103 Conclusions: The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are 104 encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma 105 patients. 106 107 5 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 13, 2015; DOI: 10.1158/1078-0432.CCR-14-3063 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 108 INTRODUCTION 109 Angiogenesis is required for tumor growth, progression, and metastasis, making it a 110 logical target for antitumor drug development. Several growth factors are positive regulators of 111 angiogenesis, including vascular endothelial growth factor (VEGF), basic and acidic fibroblast 112 growth factor (FGF), and platelet-derived growth factor (PDGF). Each of these factors signal 113 through specific transmembrane tyrosine kinase receptors: VEGFRs 1 and 2 (FMS-like tyrosine 114 kinase [FLT-1] and fetal liver kinase 1/kinase insert domain receptor [FLK-1/KDR]), FGFR, and 115 PDGFR (1-3). 116 Lenvatinib is an oral, multi–tyrosine kinase inhibitor active against RET, VEGFR1–3, 117 FGFR1–3, KIT, and PDGFRα (4-6). Lenvatinib inhibits VEGF-driven human umbilical vein 118 endothelial cell proliferation and tube formation and significantly inhibits tumor growth in 119 various murine tumor models, including human lung (H146) and breast cancer (MDA-MB-231) 120 mouse xenograft models (4, 5). Based on a population pharmacokinetics/pharmacodynamics 121 analysis of lenvatinib, agents that modify gastric pH levels do not have a significant effect on the 122 absorption of lenvatinib (Eisai, data on file). Earlier studies have shown that lenvatinib exposure 123 is neither affected by food intake (7) or co-administration of CYP3A4 inhibitors and inducers (8, 124 9). Lenvatinib is rapidly and well-absorbed; it is also extensively metabolized, with predominant 125 excretion in feces, and to a smaller extent in urine (10). The primary objectives of this study 126 were to identify the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and the 127 pharmacokinetic (PK) profile of lenvatinib. 128 129 MATERIALS AND METHODS 130 Ethics 6 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 13, 2015; DOI: 10.1158/1078-0432.CCR-14-3063 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 131 The study followed the International Conference on Harmonization
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