A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas Journal Article
| Authors: | Duran, I.; Kortmansky, J.; Singh, D.; Hirte, H.; Kocha, W.; Goss, G.; Le, L.; Oza, A.; Nicklee, T.; Ho, J.; Birle, D.; Pond, G. R.; Arboine, D.; Dancey, J.; Aviel-Ronen, S.; Tsao, M. S.; Hedley, D.; Siu, L. L. |
| Article Title: | A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas |
| Abstract: | Standard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity. A phase II study was designed to evaluate the efficacy, safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma (NEC). Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus. Patients were evaluated for tumour response, time to progression (TTP), overall survival (OS) and adverse events (AE). Twenty-two archival specimens, as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers. The intent-to-treat response rate was 5.6% (95% CI 0.6-18.7%), median TTP 6 months and 1-year OS rate 71.5%. The most frequent drug-related AE of all grades as percentage of patients were: fatigue (78%), hyperglycaemia (69%) and rash/desquamation (64%). Temsirolimus effectively inhibited the phosphorylation of S6 (P = 0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P = 0.01) predicted for a better response. Increases in pAKT (P = 0.041) and decreases in pmTOR (P = 0.048) after treatment were associated with an increased TTP. Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC. Pharmacodynamic analysis revealed effective mTOR pathway downregulation. © 2006 Cancer Research UK. |
| Keywords: | adult; cancer survival; clinical article; controlled study; treatment outcome; aged; middle aged; survival analysis; clinical trial; drug tolerability; fatigue; advanced cancer; cancer growth; dose response; drug efficacy; drug safety; antineoplastic agents; pancreatic neoplasms; follow-up studies; controlled clinical trial; pharmacodynamics; phase 2 clinical trial; protein kinases; tumor biopsy; phosphorylation; temsirolimus; hyperglycemia; neuroendocrine tumor; pneumonia; rash; pneumothorax; disease progression; mammalian target of rapamycin; proto-oncogene proteins c-akt; phase ii; infusions, intravenous; carcinoid tumor; sirolimus; mtor; bronchospasm; desquamation; exanthema; neuroendocrine carcinoma; carcinoma, neuroendocrine; ribosomal protein s6; ps6 |
| Journal Title: | British Journal of Cancer |
| Volume: | 95 |
| Issue: | 9 |
| ISSN: | 0007-0920 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2006-11-06 |
| Start Page: | 1148 |
| End Page: | 1154 |
| Language: | English |
| DOI: | 10.1038/sj.bjc.6603419 |
| PUBMED: | 17031397 |
| PROVIDER: | scopus |
| PMCID: | PMC2360568 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 June 2012" - "CODEN: BJCAA" - "Source: Scopus" |
