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A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas

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 pati...

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Autores principales: 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
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360568/
https://www.ncbi.nlm.nih.gov/pubmed/17031397
http://dx.doi.org/10.1038/sj.bjc.6603419
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author 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
author_facet 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
author_sort Duran, I
collection PubMed
description 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.
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spelling pubmed-23605682009-09-10 A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas 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 Br J Cancer Clinical Study 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. Nature Publishing Group 2006-11-06 2006-10-10 /pmc/articles/PMC2360568/ /pubmed/17031397 http://dx.doi.org/10.1038/sj.bjc.6603419 Text en Copyright © 2006 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Clinical Study
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
A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas
title A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas
title_full A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas
title_fullStr A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas
title_full_unstemmed A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas
title_short A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas
title_sort phase ii clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas
topic Clinical Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360568/
https://www.ncbi.nlm.nih.gov/pubmed/17031397
http://dx.doi.org/10.1038/sj.bjc.6603419
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