A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms
| Autor: | John Nemunaitis, Luis Paz-Ares, Amit Mahipal, Shaoyi Li, Pamela N. Munster, Tim Meyer, Hans A. de Haan, Kristen Hege, Monica M. Mita, Johanna C. Bendell, Edward M. Wolin, Ellen Filvaroff, Alain C. Mita |
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| Přispěvatelé: | Deming, Dustin A |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Physiology Kinase Inhibitors Cancer Treatment Phases of clinical research Administration Oral Neuroendocrine tumors Toxicology Pathology and Laboratory Medicine Gastroenterology Biochemistry Cohort Studies 0302 clinical medicine Drug Metabolism Medicine and Health Sciences Enzyme Inhibitors Stomatitis Cancer Gastrointestinal Neoplasms Multidisciplinary Middle Aged Body Fluids Neuroendocrine Tumors Blood Tolerability Oncology Research Design 6.1 Pharmaceuticals 030220 oncology & carcinogenesis Pyrazines Administration Toxicity Medicine Female Anatomy Research Article Oral Adult Diarrhea medicine.medical_specialty Maximum Tolerated Dose General Science & Technology Clinical Research Design Science Carcinoid Tumor Mechanistic Target of Rapamycin Complex 2 Gastroenterology and Hepatology Mechanistic Target of Rapamycin Complex 1 Research and Analysis Methods 03 medical and health sciences Rare Diseases Signs and Symptoms Pharmacokinetics Refractory Clinical Research Diagnostic Medicine Internal medicine medicine Humans Adverse effect Aged Pharmacology business.industry Evaluation of treatments and therapeutic interventions Biology and Life Sciences medicine.disease 030104 developmental biology Enzymology Adverse Events Digestive Diseases business Biomarkers |
| Zdroj: | PLoS ONE PloS one, vol 14, iss 9 Repisalud Instituto de Salud Carlos III (ISCIII) PLoS ONE, Vol 14, Iss 9, p e0221994 (2019) |
| ISSN: | 1932-6203 |
| Popis: | 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 Celgene who were involved in the operational aspects of the study, including Angela Joubert James and Torsten Trowe, who were employees of Celgene at the time of the study. The authors received medical writing assistance from Amy Agbonbhase, PhD, of The Lockwood Group, funded by Celgene Corporation. Sí |
| Databáze: | OpenAIRE |
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