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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
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.
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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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