دورية أكاديمية
A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms
| العنوان: | A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms |
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| المؤلفون: | Wolin, Edward, Mita, Alain, Mahipal, Amit, Meyer, Tim, Bendell, Johanna, Nemunaitis, John, Munster, Pam N, Paz Ares, Luis Gonzaga, Filvaroff, Ellen H, Li, Shaoyi, Hege, Kristen, de Haan, Hans, Mita, Monica |
| بيانات النشر: | Public Library of Science (PLOS) |
| سنة النشر: | 2019 |
| المجموعة: | REPISALUD (REPositorio Institucional en SALUD del Instituto de Salud Carlos III - ISCIII) |
| مصطلحات موضوعية: | Administration, Oral, Adult, Aged, Carcinoid Tumor, Cohort Studies, Female, Gastrointestinal Neoplasms, Humans, Male, Maximum Tolerated Dose, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Middle Aged, Neuroendocrine Tumors, Pyrazines |
| الوصف: | Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9-97.3%). Duration of PR was 125-401 days; median SD duration was 297 days (min-max, 50-1519 days). Median progression-free survival was 19.5 months (95% CI 10.4-28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development. ; We thank the patients and their families, and the principal investigator study teams, for enabling this study to complete successfully. We also thank the many support staff at ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1932-6203 |
| العلاقة: | Publisher's version; https://doi.org/10.1371/journal.pone.0221994Test.; PLoS One. 2019 ;14(9):e0221994.; http://hdl.handle.net/20.500.12105/9369Test; PloS one |
| DOI: | 10.1371/journal.pone.0221994 |
| الإتاحة: | https://doi.org/20.500.12105/9369Test https://doi.org/10.1371/journal.pone.0221994Test https://hdl.handle.net/20.500.12105/9369Test |
| حقوق: | http://creativecommons.org/licenses/by-nc-sa/4.0Test/ ; Atribución-NoComercial-CompartirIgual 4.0 Internacional ; info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.C0860345 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 19326203 |
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| DOI: | 10.1371/journal.pone.0221994 |