A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms
Autoři:
Edward Wolin aff001; Alain Mita aff001; Amit Mahipal aff002; Tim Meyer aff003; Johanna Bendell aff004; John Nemunaitis aff005; Pam N. Munster aff006; Luis Paz-Ares aff007; Ellen H. Filvaroff aff008; Shaoyi Li aff009; Kristen Hege aff008; Hans de Haan aff008; Monica Mita aff001
Působiště autorů:
Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
aff001; Phase 1 Clinical Trials Program, Mayo Clinic, Rochester, MN, United States of America
aff002; Experimental Cancer Medicine, University College Hospital, London, United Kingdom
aff003; GI Oncology Research, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, United States of America
aff004; Department of Oncology, Mary Crowley Cancer Research Center, Dallas, TX, United States of America
aff005; Early Phase Clinical Research Program, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, United States of America
aff006; Medical Oncology Department, Hospital Universitario 12 de Octubre, CNIO, Universidad Complutense and CiberOnc, Madrid, Spain
aff007; Translational Medicine, Celgene Corporation, San Francisco, CA, United States of America
aff008; Department of Statistics, Celgene Corporation, Summit, NJ, United States of America
aff009
Vyšlo v časopise:
PLoS ONE 14(9)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0221994
Souhrn
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.
Klíčová slova:
Biology and life sciences – Toxicology – Toxicity – Biochemistry – Biomarkers – Enzymology – Enzyme inhibitors – Kinase inhibitors – Anatomy – Body fluids – Blood – Physiology – Medicine and health sciences – Pathology and laboratory medicine – Diarrhea – Oncology – Cancer treatment – Gastroenterology and hepatology – Diagnostic medicine – Signs and symptoms – Pharmacology – Pharmacokinetics – Drug metabolism – Research and analysis methods – Research design – Clinical research design – Adverse events
Zdroje
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Článek vyšel v časopise
PLOS One
2019 Číslo 9
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