A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies
Spreafico, A. (University of Toronto. Princess Margaret Cancer Centre. Division of Medical Oncology and Hematology (Canada))
Delord, Jean-Pierre (Institut Claudius Regaud (France))
Mattos Arruda, Leticia de (Hospital Universitari Vall d'Hebron)
Berge, Y. (Institut Claudius Regaud (France))
Pérez-Rodón, Jordi (Hospital Universitari Vall d'Hebron)
Cottura, E. (Institut Claudius Regaud (France))
Bedard, Philippe L (University of Toronto. Princess Margaret Cancer Centre. Division of Medical Oncology and Hematology (Canada))
Akimov, Mikhail (Novartis Pharma AG (Switzerland))
Lu, H. (Novartis Pharmaceuticals Corp (USA))
Pain, S. (Novartis Pharmaceuticals Corp (USA))
Kaag, A. (Novartis Pharma AG (Switzerland))
Siu, L. L. (University of Toronto. Princess Margaret Cancer Centre. Division of Medical Oncology and Hematology (Canada))
Cortés, Javier (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Date:	2015
Abstract:	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). 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. 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. 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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra, i la creació d'obres derivades, sempre que no sigui amb finalitats comercials i que es distribueixin sota la mateixa llicència que regula l'obra original. Cal que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	HSP90 inhibitors ; Molecular chaperone ; Phase I study
Published in:	British journal of cancer, Vol. 112 (February 2015) , p. 650-659, ISSN 1532-1827

DOI: 10.1038/bjc.2014.653
PMID: 25625276

10 p, 426.6 KB

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