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A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies
BACKGROUND: Heat-shock protein 990 (HSP990) is a potent and selective synthetic small-molecule HSP90 inhibitor. The primary objectives of this phase I first-in-human study were to determine dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333497/ https://www.ncbi.nlm.nih.gov/pubmed/25625276 http://dx.doi.org/10.1038/bjc.2014.653 |
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author | Spreafico, A Delord, J-P De Mattos-Arruda, L Berge, Y Rodon, J Cottura, E Bedard, P L Akimov, M Lu, H Pain, S Kaag, A Siu, L L Cortes, J |
author_facet | Spreafico, A Delord, J-P De Mattos-Arruda, L Berge, Y Rodon, J Cottura, E Bedard, P L Akimov, M Lu, H Pain, S Kaag, A Siu, L L Cortes, J |
author_sort | Spreafico, A |
collection | PubMed |
description | BACKGROUND: Heat-shock protein 990 (HSP990) is a potent and selective synthetic small-molecule HSP90 inhibitor. The primary objectives of this phase I first-in-human study were to determine dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included characterisation of the safety profile, pharmacokinetics (PKs) and pharmacodynamics (PDs). METHODS: Heat-shock protein 990 was administered orally once or two times weekly on a 28-day cycle schedule in patients with advanced solid tumours. Dose escalation was guided by a Bayesian logistic regression model with overdose control. RESULTS: A total of 64 patients were enrolled. Fifty-three patients received HSP990 once weekly at 2.5, 5, 10, 20, 30, 50 or 60 mg, whereas 11 patients received HSP990 two times weekly at 25 mg. Median duration of exposure was 8 weeks (range 1–116 weeks) and 12 patients remained on treatment for >16 weeks. Dose-limiting toxicities occurred in seven patients and included diarrhoea, QTc prolongation, ALT/AST elevations and central neurological toxicities. The most common drug-related adverse events were diarrhoea, fatigue and decreased appetite. Further dose escalation beyond 60 mg once weekly was not possible owing to neurological toxicity. Rapid absorption, no drug accumulation and large interpatient variability in PK exposures were observed. No objective responses were seen; 25 patients had a best overall response of stable disease. CONCLUSIONS: Heat-shock protein 990 is relatively well tolerated, with neurological toxicity being the most relevant DLT. The single agent MTD/RP2D of HSP990 was declared at 50 mg once weekly. |
format | Online Article Text |
id | pubmed-4333497 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-43334972016-02-17 A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies Spreafico, A Delord, J-P De Mattos-Arruda, L Berge, Y Rodon, J Cottura, E Bedard, P L Akimov, M Lu, H Pain, S Kaag, A Siu, L L Cortes, J Br J Cancer Clinical Study BACKGROUND: Heat-shock protein 990 (HSP990) is a potent and selective synthetic small-molecule HSP90 inhibitor. The primary objectives of this phase I first-in-human study were to determine dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included characterisation of the safety profile, pharmacokinetics (PKs) and pharmacodynamics (PDs). METHODS: Heat-shock protein 990 was administered orally once or two times weekly on a 28-day cycle schedule in patients with advanced solid tumours. Dose escalation was guided by a Bayesian logistic regression model with overdose control. RESULTS: A total of 64 patients were enrolled. Fifty-three patients received HSP990 once weekly at 2.5, 5, 10, 20, 30, 50 or 60 mg, whereas 11 patients received HSP990 two times weekly at 25 mg. Median duration of exposure was 8 weeks (range 1–116 weeks) and 12 patients remained on treatment for >16 weeks. Dose-limiting toxicities occurred in seven patients and included diarrhoea, QTc prolongation, ALT/AST elevations and central neurological toxicities. The most common drug-related adverse events were diarrhoea, fatigue and decreased appetite. Further dose escalation beyond 60 mg once weekly was not possible owing to neurological toxicity. Rapid absorption, no drug accumulation and large interpatient variability in PK exposures were observed. No objective responses were seen; 25 patients had a best overall response of stable disease. CONCLUSIONS: Heat-shock protein 990 is relatively well tolerated, with neurological toxicity being the most relevant DLT. The single agent MTD/RP2D of HSP990 was declared at 50 mg once weekly. Nature Publishing Group 2015-02-17 2015-01-27 /pmc/articles/PMC4333497/ /pubmed/25625276 http://dx.doi.org/10.1038/bjc.2014.653 Text en Copyright © 2015 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/3.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ |
spellingShingle | Clinical Study Spreafico, A Delord, J-P De Mattos-Arruda, L Berge, Y Rodon, J Cottura, E Bedard, P L Akimov, M Lu, H Pain, S Kaag, A Siu, L L Cortes, J A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies |
title | A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies |
title_full | A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies |
title_fullStr | A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies |
title_full_unstemmed | A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies |
title_short | A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies |
title_sort | first-in-human phase i, dose-escalation, multicentre study of hsp990 administered orally in adult patients with advanced solid malignancies |
topic | Clinical Study |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333497/ https://www.ncbi.nlm.nih.gov/pubmed/25625276 http://dx.doi.org/10.1038/bjc.2014.653 |
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