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69947F Gordon MS Fig2 V1d Author Manuscript Published OnlineFirst on April 23, 2020; DOI: 10.1158/1078-0432.CCR-19-3239 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-cell Lymphoma Running title: Phase I study of TAK-659 in lymphoma Leo I Gordon1, Jason Kaplan1*, Rakesh Popat2, Howard A. Burris III3, Silvia Ferrari4, Sumit Madan5, Manish R. Patel6, Giuseppe Gritti4, Dima El-Sharkawi2†, Ian Chau7, John Radford8, Jaime Perez de Oteyza9, Pier Luigi Zinzani10, Swaminathan Iyer11, William Townsend2, Reem Karmali1, Harry Miao12, Igor Proscurshim12, Shining Wang12, Yujun Wu12, Kate Stumpo12, Yaping Shou12, Cecilia Carpio13, and Francesc Bosch13 1Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois. 2NIHR/UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, United Kingdom. 3Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee. 4Ospedale Papa Giovanni XXIII, Bergamo, Italy. 5Cancer Therapy and Research Center at University of Texas Health Science Center, San Antonio, Texas. 6Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida. 7Royal Marsden Hospital, Sutton, Surrey, United Kingdom. 8The University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom. 9Hospital Universitario Madrid Sanchinarro, Universidad CEU San Pablo, Madrid, Spain. 10Institute of Hematology “Seragnoli”, University of Bologna, Bologna, Italy. 11Houston Methodist Cancer Center, Houston, Texas. 12Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. 13University Hospital Vall d’Hebron, Barcelona, Spain. *Current affiliation: NorthShore University Hospitals, Evanston, Illinois. 1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 23, 2020; DOI: 10.1158/1078-0432.CCR-19-3239 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. †Current affiliation: Royal Marsden Hospital, Sutton, Surrey, United Kingdom. Corresponding Author: Leo I. Gordon, Northwestern University Feinberg School of Medicine, 676 N St Clair Street, Suite 850, Chicago, IL 60611. Phone: (312) 695-4546; Fax: (312) 695-6189; E-mail: [email protected] Disclosure of potential conflicts of interest This study was sponsored by Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. L.I. Gordon is a co-founder of Zylem, has received research support from Juno/Celgene, had a consultancy with Takeda, and has received honoraria from Juno/Celgene, Bayer, and Gilead. J. Kaplan has received research support from Seattle Genetics and Janssen. R. Popat had a consultancy for Takeda, has received honoraria from Takeda, Amgen, Janssen, and Roche, and is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. S. Madan has received payment for expert testimony from Celgene, Takeda, Amgen, and Onyx. M.R. Patel has received honoraria from Gilead, Exelixis, BMS, Genentech, and Medivation. G. Gritti declares research support from Gilead and consultancy with Autolus. D. El-Sharkawi has received honoraria from AbbVie, Roche, and Janssen. I. Chau has participated in advisory boards for Eli Lilly, Bristol-Myers Squibb, MSD, Bayer, Roche, Merck Serono, Five Prime Therapeutics, AstraZeneca, Oncologie International, and Pierre Fabre, has received research funding from Eli Lilly, Janssen-Cilag, Sanofi Oncology, and Merck Serono, and has received an honorarium from Eli Lilly. J. Radford declares consultancy for Takeda, Seattle Genetics, Novartis, Bristol-Myers Squibb, Cell Medica, and ADC Therapeutics, has received research support from Takeda, has received honoraria from Takeda, Seattle Genetics, Novartis, Bristol-Myers Squibb, and Cell Medica, and his spouse has ownership interest in AstraZeneca and GlaxoSmithKline. J. Perez de Oteyza has received research support from Takeda and Millennium 2 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 23, 2020; DOI: 10.1158/1078-0432.CCR-19-3239 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. P.L. Zinzani declares membership on advisory boards for Roche, Celgene, Janssen, Gilead, Takeda, Bayer, Merck, Servier, and TG Pharmaceuticals. S. Iyer has received research support from Seattle Genetics, Takeda, Rhizen, Acrotech/Spectrum, Amgen, Celgene, Daichi Sankyo, Cellectis, and CrisprRx. W. Townsend has received honoraria and consultancy fees from Roche, Takeda, and Gilead. R. Karmali has participated in advisory boards for Celgene/Juno, Gilead/Kite, and Karyopharm, and has received honoraria for speaker bureaus with AstraZeneca, BeiGene, and Gilead/Kite. S. Wang, Y. Wu, K. Stumpo, Y. Shou, H. Miao, and I. Proscurshim are employed by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. S. Wang has ownership interests in Takeda Pharmaceutical Company Limited. K. Stumpo has equity ownership in Astra Zeneca and Teva, and has family members with stock ownership in Bristol-Myers Squibb, AstraZeneca, GSK. I. Proscurshim is a former employee of Agenus. F. Bosch declares consultancy for, and has received honoraria and paid expert testimony from Roche, Novartis, Janssen, AbbVie, Gilead, and Mundipharma, and has received research support from Roche, Celgene, Karyopharm, and Takeda, and declares membership on the board of directors or its advisory committees for Roche, Janssen, and AbbVie. All other authors have nothing to disclose (H.A. Burris III, S. Ferrari, and C. Carpio). Key words (up to five): TAK-659, diffuse large B-cell lymphoma, Phase I, SYK, follicular lymphoma Provide chemical structure(s) either in the manuscript or through a Web link to a publicly available source: https://www.sciencedirect.com/science/article/pii/S0960894X16311350 3 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 23, 2020; DOI: 10.1158/1078-0432.CCR-19-3239 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Translational Relevance: In this phase I study, the maximum tolerated dose (MTD) of TAK-659 was 100 mg once-daily. The safety and activity of TAK-659 at the MTD was evaluated in an additional 69 patients with lymphoma (expansion phase). Common treatment-emergent adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. TAK-659 showed single-agent activity across different histological subtypes. Responses occurred in both de-novo and transformed disease and appeared independent of cell-of-origin classification. These data suggest that targeting SYK (the role of FLT3 is unclear) with TAK-659 has clinical activity in B-cell malignancies. Further studies are needed to elucidate the exact mechanism of this effect and to further evaluate TAK-659 monotherapy or combination therapy in patients with relapsed/refractory B-cell malignancies. 4 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 23, 2020; DOI: 10.1158/1078-0432.CCR-19-3239 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Purpose: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, maximum tolerated dose (MTD)/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. Experimental Design: Patients received continuous, once-daily oral TAK-659 60– 120 mg in 28-day cycles until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in 5 disease cohorts at the MTD. Results: Overall, 105 patients were enrolled (dose escalation, n=36 [solid tumors n=19, lymphoma n=17]; expansion, n=69). The MTD was 100 mg once-daily. TAK-659 absorption was fast (Tmax ~2 hours) with a long terminal half-life (~37 hours). Exposure generally increased with dose (60–120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% (23% intent-to-treat [ITT]). Responses were seen in both de-novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57%
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