{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T22:11:54Z","timestamp":1793657514580,"version":"4.5.1"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T00:00:00Z","timestamp":1706659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"TransThera Sciences (Nanjing), Inc"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1\/2, vascular endothelial growth factor receptors, and Aurora A\/B, in patients with advanced solid tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Patients and Methods<\/jats:title>\n                    <jats:p>Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Forty-eight patients were enrolled (dose escalation, n\u2005=\u200540; dose expansion, n\u2005=\u20058). MTD was not reached; DRDE was 12 mg daily. DLTs were palmar-plantar erythrodysesthesia syndrome (8 mg, n\u2005=\u20051) and hypertension (15 mg, n\u2005=\u20052). The most common treatment-related adverse event was hypertension (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; n\u2005=\u20057) or stable disease (SD)\u2005\u2265\u200524 weeks (n\u2005=\u20056), including 4\/11 (36.4%) with FGFR2 mutations\/fusions and cholangiocarcinoma (PR n\u2005=\u20053; SD\u2005\u2265\u200524 weeks n\u2005=\u20051), 3\/3 (100.0%) with hormone receptor (HR)-positive\/HER2-negative breast cancer (PR n\u2005=\u20052; SD\u2005\u2265\u200524 weeks n\u2005=\u20051), 2\/5 (40.0%) with triple-negative breast cancer (TNBC; PR n\u2005=\u20051; SD\u2005\u2265\u200524 weeks n\u2005=\u20051), and 1\/1 (100.0%) with castrate-resistant prostate cancer (CRPC; PR). Four of 12 patients (33.3%; HR-positive\/HER2-negative breast cancer, TNBC, prostate cancer, and cholangiocarcinoma) treated at DRDE had PRs. Tinengotinib\u2019s half-life was 28-34 hours.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Tinengotinib was well tolerated with favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit in FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative breast cancer (including TNBC), and CRPC. Continued evaluation of tinengotinib is warranted in phase II trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/oncolo\/oyad338","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T09:46:09Z","timestamp":1704275169000},"page":"e514-e525","source":"Crossref","is-referenced-by-count":27,"title":["First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients With Advanced Solid Tumors"],"prefix":"10.1093","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9455-1660","authenticated-orcid":false,"given":"Sarina A","family":"Piha-Paul","sequence":"first","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4195-337X","authenticated-orcid":false,"given":"Binghe","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, National Cancer Center\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ecaterina E","family":"Dumbrava","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqing","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel D","family":"Karp","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Funda","family":"Meric-Bernstam","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi A","family":"Rodon","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apostolia M","family":"Tsimberidou","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanwal","family":"Raghav","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9946-0629","authenticated-orcid":false,"given":"Jaffer A","family":"Ajani","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony P","family":"Conley","sequence":"additional","affiliation":[{"name":"Department of Sarcoma Medical Oncology, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Mott","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Head and Neck Medical Oncology, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, National Cancer Center\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Fan","sequence":"additional","affiliation":[{"name":"Clinical Department, TransThera Sciences (US), Inc. , Gaithersburg, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Peng","sequence":"additional","affiliation":[{"name":"Project Management Department, TransThera Sciences (Nanjing), Inc. , Nanjing , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Clinical Department, TransThera Sciences (Nanjing), Inc. , Nanjing , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumao","family":"Ni","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics Department, TransThera Sciences (Nanjing), Inc. , Nanjing , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caixia","family":"Sun","sequence":"additional","affiliation":[{"name":"Clinical Department, TransThera Sciences (Nanjing), Inc. , Nanjing , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Qiang","sequence":"additional","affiliation":[{"name":"Biology Department, TransThera Sciences (Nanjing), Inc. , Nanjing , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy J","family":"Levin","sequence":"additional","affiliation":[{"name":"Clinical Department, CRC Oncology , San Diego, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Ngo","sequence":"additional","affiliation":[{"name":"Clinical Department, CRC Oncology , San Diego, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinhua Cindy","family":"Ru","sequence":"additional","affiliation":[{"name":"Clinical Department, CRC Oncology , San Diego, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Wu","sequence":"additional","affiliation":[{"name":"Project Management Department, TransThera Sciences (Nanjing), Inc. , Nanjing , People\u2019s Republic of China"},{"name":"Drug Metabolism and Pharmacokinetics Department, TransThera Sciences (Nanjing), Inc. , Nanjing , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milind M","family":"Javle","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, The University of Texas, MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,1,31]]},"reference":[{"key":"2024041017280984700_CIT0001","first-page":"1780","article-title":"Targeting cancer with kinase inhibitors","volume-title":"J Clin Invest.","author":"Gross","year":"2015"},{"key":"2024041017280984700_CIT0002","first-page":"551","article-title":"Kinase drug discovery 20 years after imatinib: progress and future directions","volume-title":"Nat Rev Drug Discov.","author":"Cohen","year":"2021"},{"key":"2024041017280984700_CIT0003","first-page":"205","article-title":"Tinengotinib (TT-00420), a novel spectrum-selective small-molecule kinase inhibitor, is highly active against triple-negative breast cancer","volume-title":"Mol Cancer Ther.","author":"Peng","year":"2023"},{"key":"2024041017280984700_CIT0004","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2021.39.15_suppl.3090","article-title":"Phase I study of TT-00420, a multiple kinase inhibitor, as a single agent in advanced solid tumors","volume":"39","author":"Piha-Paul","year":"2021","journal-title":"J Clin Oncol."},{"key":"2024041017280984700_CIT0005","doi-asserted-by":"crossref","first-page":"5869","DOI":"10.1158\/1538-7445.AM2018-5869","article-title":"TT-00420, a dual mechanism kinase inhibitor targeting both mitosis and tumor microenvironment, is highly active against TNBC both in vitro and in vivo","volume":"78","author":"Peng","year":"2018","journal-title":"Cancer Res."},{"key":"2024041017280984700_CIT0006","first-page":"2420","article-title":"Critical aspects of the Bayesian approach to phase I cancer trials","volume-title":"Stat Med.","author":"Neuenschwander","year":"2008"},{"key":"2024041017280984700_CIT0007","first-page":"1103","article-title":"Cancer phase I clinical trials: efficient dose escalation with overdose control","volume-title":"Stat Med.","author":"Babb","year":"1998"},{"key":"2024041017280984700_CIT0008","first-page":"2105","article-title":"Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology\/College of American Pathologists clinical practice guideline focused update","volume-title":"J Clin Oncol.","author":"Wolff","year":"2018"},{"key":"2024041017280984700_CIT0009","first-page":"228","article-title":"New response evaluation criteria in solid tumours: revised recist guideline (version 11)","volume-title":"Eur J Cancer.","author":"Eisenhauer","year":"2009"},{"key":"2024041017280984700_CIT0010","first-page":"522","article-title":"Fight-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF\/FGFR alterations and advanced malignancies","volume-title":"Ann Oncol.","author":"Subbiah","year":"2022"},{"key":"2024041017280984700_CIT0011","first-page":"e0231877","article-title":"INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models","volume-title":"PLoS One.","author":"Liu","year":"2020"},{"key":"2024041017280984700_CIT0012","first-page":"843","article-title":"Lenvatinib in patients with advanced or metastatic thymic carcinoma (remora): a multicentre, phase 2 trial","volume-title":"Lancet Oncol.","author":"Sato","year":"2020"},{"key":"2024041017280984700_CIT0013","first-page":"1569","article-title":"Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: the alter 0303 phase 3 randomized clinical trial","volume-title":"JAMA Oncol","author":"Han","year":"2018"},{"key":"2024041017280984700_CIT0014","first-page":"e1","article-title":"Mechanisms of VEGF (vascular endothelial growth factor) inhibitor-associated hypertension and vascular disease","volume-title":"Hypertension.","author":"Pandey","year":"2018"},{"key":"2024041017280984700_CIT0015","first-page":"5186","article-title":"Aurora kinase inhibition: a new light in the sky","volume-title":"J Med Chem.","author":"Linardopoulos","year":"2015"},{"key":"2024041017280984700_CIT0016","first-page":"232","article-title":"Adverse event management of oral mucositis in patients with breast cancer","volume-title":"Breast Care (Basel)","author":"Seiler","year":"2014"},{"key":"2024041017280984700_CIT0017","first-page":"539","article-title":"Phase II study of FGFR1-3 inhibitor tinengotinib as monotherapy in patients with advanced or metastatic cholangiocarcinoma: interim analysis","volume-title":"J Clin Oncol.","author":"Javle","year":"2023"},{"key":"2024041017280984700_CIT0018","first-page":"3","article-title":"Fgfr inhibitors: effects on cancer cells, tumor microenvironment and whole-body homeostasis (review)","volume-title":"Int J Mol Med.","author":"Katoh","year":"2016"},{"key":"2024041017280984700_CIT0019","first-page":"326","article-title":"Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib","volume-title":"Cancer Discov","author":"Silverman","year":"2021"},{"key":"2024041017280984700_CIT0020","first-page":"671","article-title":"Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study","volume-title":"Lancet Oncol.","author":"Abou-Alfa","year":"2020"},{"key":"2024041017280984700_CIT0021","first-page":"228","article-title":"Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma","volume-title":"N Engl J Med.","author":"Goyal","year":"2023"},{"key":"2024041017280984700_CIT0022","first-page":"803","article-title":"Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study","volume-title":"Lancet Gastroenterol Hepatol","author":"Javle","year":"2021"},{"key":"2024041017280984700_CIT0023","doi-asserted-by":"crossref","first-page":"4009","DOI":"10.1200\/JCO.2022.40.16_suppl.4009","article-title":"Updated results of the FOENIX-CCA2 trial: efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions\/rearrangements","volume":"40","author":"Goyal","year":"2022","journal-title":"J Clin Oncol."},{"key":"2024041017280984700_CIT0024","first-page":"252","article-title":"Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma","volume-title":"Cancer Discov","author":"Goyal","year":"2017"},{"key":"2024041017280984700_CIT0025","first-page":"2750","article-title":"Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies","volume-title":"J Clin Invest.","author":"Lehmann","year":"2011"},{"key":"2024041017280984700_CIT0026","first-page":"569","article-title":"The FGF\/FGFR system in the physiopathology of the prostate gland","volume-title":"Physiol Rev.","author":"Giacomini","year":"2021"},{"key":"2024041017280984700_CIT0027","first-page":"1180","article-title":"Lineage plasticity in prostate cancer depends on JAK\/STAT inflammatory signaling","volume-title":"Science.","author":"Chan","year":"2022"},{"key":"2024041017280984700_CIT0028","first-page":"23","article-title":"Lineage plasticity enables low-ER luminal tumors to evolve and gain basal-like traits","volume-title":"Breast Cancer Res.","author":"Mohamed","year":"2023"},{"key":"2024041017280984700_CIT0029","first-page":"466","article-title":"Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity","volume-title":"Cancer Cell","author":"Dravis","year":"2018"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/29\/4\/e514\/57210430\/oyad338.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/29\/4\/e514\/57210430\/oyad338.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T14:16:09Z","timestamp":1712758569000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/29\/4\/e514\/7595477"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,31]]},"references-count":29,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,1,31]]},"published-print":{"date-parts":[[2024,4,4]]}},"URL":"https:\/\/doi.org\/10.1093\/oncolo\/oyad338","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,4,1]]},"published":{"date-parts":[[2024,1,31]]}}}