M.A. Gouda , J. Shunyakova , A. Naing , E. Dumbrava , D.S. Hong , Y. Yuan , P. Yang , A. Myers , Y. Liang , J. Peng , D. Karp , A.M. Tsimberidou , J. Rodon , T.A. Yap , S.A. Piha-Paul , F. Meric-Bernstam , S. Fu
{"title":"TAK-659 和紫杉醇治疗紫杉类药物难治性晚期实体瘤患者的 I 期研究","authors":"M.A. Gouda , J. Shunyakova , A. Naing , E. Dumbrava , D.S. Hong , Y. Yuan , P. Yang , A. Myers , Y. Liang , J. Peng , D. Karp , A.M. Tsimberidou , J. Rodon , T.A. Yap , S.A. Piha-Paul , F. Meric-Bernstam , S. Fu","doi":"10.1016/j.esmoop.2024.103486","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors.</p></div><div><h3>Patients and methods</h3><p>Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1.</p></div><div><h3>Results</h3><p>Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (<em>n</em> = 31; 63%), increased alanine aminotransferase (<em>n</em> = 26; 53%), decreased neutrophil count (<em>n</em> = 26; 53%), and decreased white blood cell count (<em>n</em> = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response.</p></div><div><h3>Conclusions</h3><p>The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.</p></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1000,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2059702924012559/pdfft?md5=e6c1a0a4356eb28803380a9a2f802530&pid=1-s2.0-S2059702924012559-main.pdf","citationCount":"0","resultStr":"{\"title\":\"A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors\",\"authors\":\"M.A. Gouda , J. 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A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors
Background
Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors.
Patients and methods
Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1.
Results
Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response.
Conclusions
The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.
期刊介绍:
ESMO Open is the online-only, open access journal of the European Society for Medical Oncology (ESMO). It is a peer-reviewed publication dedicated to sharing high-quality medical research and educational materials from various fields of oncology. The journal specifically focuses on showcasing innovative clinical and translational cancer research.
ESMO Open aims to publish a wide range of research articles covering all aspects of oncology, including experimental studies, translational research, diagnostic advancements, and therapeutic approaches. The content of the journal includes original research articles, insightful reviews, thought-provoking editorials, and correspondence. Moreover, the journal warmly welcomes the submission of phase I trials and meta-analyses. It also showcases reviews from significant ESMO conferences and meetings, as well as publishes important position statements on behalf of ESMO.
Overall, ESMO Open offers a platform for scientists, clinicians, and researchers in the field of oncology to share their valuable insights and contribute to advancing the understanding and treatment of cancer. The journal serves as a source of up-to-date information and fosters collaboration within the oncology community.