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The safety and antitumor activity of sitravatinib are reported in patients from two histologic cohorts (anti-angiogenesis-refractory clear cell renal cell carcinoma [RCC] and castrate-resistant prostate cancer [CRPC] with bone metastases) who participated in a Phase 1\/1b study. The patients were enrolled using a 3-stage design that was based on observed objective responses. Objective response rate (ORR) was the primary endpoint. Duration of response, progression-free survival (PFS), overall survival (OS), and safety were also assessed. Overall, 48 patients (RCC n\u2009=\u200938, CRPC n\u2009=\u200910) received\u2009\u2265\u20091 dose of sitravatinib. Both cohorts were heavily pretreated (median number of prior systemic therapies: RCC cohort 3, CRPC cohort 6). In the RCC cohort, ORR was 25.9%, <jats:italic>P<\/jats:italic>\u2009=\u20090.015 (null hypothesis [ORR\u2009\u2264\u200910%] was rejected). Responses were durable (median duration 13.2 months). Median PFS was 9.5 months and median OS was 30.0 months. No objective responses were seen in the CRPC cohort; median PFS and OS were 5.8 months and 10.1 months, respectively. Across both cohorts, diarrhea (72.9%), fatigue (54.2%), and hypertension (52.1%) were the most frequent all-cause treatment-emergent adverse events (TEAEs). Diarrhea and vomiting (both, 6.3%) were the most frequent serious TEAEs considered related to study treatment. Sitravatinib demonstrated an acceptable safety profile and promising clinical activity in patients with clear cell RCC refractory to prior angiogenesis inhibitor therapy. Strong indicators for clinical activity were not seen in patients with CRPC and bone metastases. <\/jats:p><jats:p><jats:bold>Clinical trial registration<\/jats:bold>:ClinicalTrials.gov NCT02219711.<\/jats:p>","DOI":"10.1007\/s10637-024-01465-9","type":"journal-article","created":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T08:24:50Z","timestamp":1724401490000},"page":"547-558","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting multiple receptor tyrosine kinases with sitravatinib: A Phase 1b study in advanced renal cell carcinoma and castrate-resistant prostate cancer"],"prefix":"10.1007","volume":"42","author":[{"given":"Shubham","family":"Pant","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byoung Chul","family":"Cho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christos E.","family":"Kyriakopoulos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Spira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nizar","family":"Tannir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theresa L.","family":"Werner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohong","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saskia","family":"Neuteboom","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Chao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2798-7568","authenticated-orcid":false,"given":"Sanjay","family":"Goel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,8,21]]},"reference":[{"key":"1465_CR1","doi-asserted-by":"publisher","first-page":"2957","DOI":"10.1200\/JCO.22.00868","volume":"40","author":"WK Rathmell","year":"2022","unstructured":"Rathmell WK, Rumble RB, Van Veldhuizen PJ et al (2022) Management of metastatic clear cell renal cell carcinoma: ASCO Guideline. 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The study was approved by the institutional review board at each participating site.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Shubham Pant: research support to institution for Elicio, Amal Therapeutics, Janssen, Arcus, Astellas, Biontech, Boehringer Ingelheim, Mirati Therapeutics, Bristol Myers Squibb, 4D Pharma, Framewave, ImmunoMET, Ipsen, Lilly, NGM Pharmaceuticals, Novartis; Pfizer, Xencor, Immuneering, and Zymeworks; and consulting\/advisory fees from USWorldmeds, Alligator Bioscience, Boehringer Ingelheim, Novartis, BPGBio, Ipsen, AstraZeneca, Janssen, Jazz Pharmaceuticals, AskGene Pharma, Nihon Medi-Physics Co, Ltd, and Zymeworks. Byoung Chul Cho: research funding from Cyrus, Abbvie, AstraZeneca, Dizal Pharma, Bayer, Blueprint Medicines, Bridgebio Therapeutics, CHA Bundang Medical Center, Champions Oncology, CJ Blossom Park, Dong-A ST, Genexine, GI-Cell, CJ Bioscience, GI-ImmuneOncia, Hanmi, Abion, Illumina, Innovation, Interpark Bio Convergence Corp, Janssen, JINTSbio, Kanaph Therapeutics, LG Chem, Boehringer Ingelheim, Lilly, MOGAM Institute, MSD, Novartis, Nuvalent, Ono, Oscotec, Regeneron, Therapex, Vertical Bio AG, Oncternal, and Yuhan; consulting fees from AstraZeneca, Janssen, BeiGene, Novartis, Boehringer-Ingelheim, CJ, CureLogen, Cyrus Therapeutics, Abion, Eli Lilly, GI-Cell, Guardant, Hanmi, Bristol Myers Squibb, HK Inno-N, Imnewrun Biosciences Inc., Medpacto, MSD, Ono, Onegene Biotechnology, Pfizer, RandBio, Takeda, Blueprint Medicines, and Yuhan; honoraria from Chinese Thoracic Oncology Society, International Association for the Study of Lung Cancer, American Society of Clinical Oncology, European Society of Medical Oncology, Guardant, Pfizer, AstraZeneca, Korean Cancer Study Group, Korean Society of Medical Onoclogy, Korean Society of Thyroid, Head and Neck Surgery, MSD, Novartis, Roche, and Korean Cancer Association; advisory board roles for Cyrus Therapeutics, Bridgebio Therapeutics, Guardant Health, J INTS BIO, Gilead, KANAPH Therapeutic Inc, Oscotec Inc, Amgen, and Therapex; royalties from Crown Bioscience, Bio GmbH, Champions Oncology, PearlRiver, Imagen, and Roche; member of the board of directors for J INTS BIO; founder of DAAN Biotherapeutics; and stock ownership for Cyrus Therapeutics, Gencurix Inc, Interpark Bio Convergence Corp., J INTS BIO, KANAPH Therapeutics, Bridgebio Therapeutics, and TheraCanVac Inc. Christos E. Kyriakopoulos: research support from Bristol Myers Squibb, Merck, AstraZeneca, Gilead Sciences, Pionyr Immunopharma, Incyte Corporation, and Sanofi-Aventis; participation in Advisory Boards for Janssen, AVEO Pharmaceuticals, Exelixis, and Sanofi-Aventis; stock for EPIC Systems Inc. Alexander Spira: honoraria from Bristol Myers Squibb, Amgen, Novartis, Bayer, CytomX Therapeutics, Janssen Oncology, Merck, AstraZeneca\/MedImmune, and Takeda; consulting\/advisory roles for Incyte,Amgen, Blueprint Medicines, Array Biopharma, AstraZeneca\/MedImmune, Black Diamond Therapeutics, Janssen Research & Development; Bristol Myers Squibb, Mersana, Daiichi Sankyo, Sanofi, Gritstone Oncology, Jazz Pharmaceuticals, Lilly, Merck, Mirati Therapeutics, Novartis, Regeneron, and Takeda; research funding from Abbvie, Bristol Myers Squibb, ADCT, Alkermes, Arch Therapeutics, Arrivent Biopharma, Astellas Pharma, AstraZeneca\/MedImmune, Ignyta, Astex Pharmaceuticals, Plexxikon,Black Diamond Therapeutics, Gritstone Oncology, Blueprint Medicines, Boehringer Ingelheim, Roche, CytomX Therapeutics, Revolution Medicines, Amgen, Daiichi Sankyo, Incyte, LAM Therapeutics, Loxo, Macrogenics, Medikine, Mersana, Mirati Therapeutics, Synthekine, Janssen Oncology, Nalo Therapeutics, Novartis, Regeneron, Rubius, Scorpion Therapeutics, and Takeda; leadership role for NEXT Oncology (Virginia); and stock ownership for Eli Lilly Nizar Tannir: clinical grants from Exelixis, Bristol Myers Squibb, Nektar Pharmaceuticals, Calithera Biosciences, and Novartis; honoraria for consultancy\/advisory roles from Exelixis, AstraZeneca, Eisai, Intellisphere, Merck, Nektar Therapeutics, Bristol Myers Squibb, and Oncorena; and stock or stock options for Biocryst Pharmaceuticals, Merck, Surface Oncology, Amgen, Vanguard Healthcare, Johnson & Johnson\/Janssen, and SPDR S&P Pharmaceuticals. Theresa L. Werner: research support to institution for Mersana Therapeutics, Abbvie, GSK-Tesaro, Acrivon, BluePrint Medicines, Clovis Oncology, Genmab, Repare Therapeutics, AstraZeneca, and Roche Genetech; and honoraria for advisory roles from Mersana Therapeutics Xiaohong Yan: employment, stock ownership and support for meeting attendance for Mirati Therapeutics Inc. Saskia Neuteboom: prior employment and stock ownership for Mirati Therapeutics Inc. Richard Chao: employment, stock ownership and support for meeting attendance for Mirati Therapeutics Inc. Sanjay Goel: research support to institution from Mirati Therapeutics Inc.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}