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First-in-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors.

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Date
2013-07
ICR Author
Banerji, Udai
Turner, Lydia
Author
Sessa, C
Shapiro, GI
Bhalla, KN
Britten, C
Jacks, KS
Mita, M
Papadimitrakopoulou, V
Pluard, T
Samuel, TA
Akimov, M
Quadt, C
Fernandez-Ibarra, C
Lu, H
Bailey, S
Chica, S
Banerji, U
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Type
Journal Article
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Abstract
Purpose A phase I study was conducted with the primary objective of determining the maximum tolerated dose (MTD) of AUY922 in patients with advanced solid tumors. Secondary objectives included characterization of the safety, pharmacokinetic, and pharmacodynamic profiles.Patients and methods Patients with advanced solid tumors received 1-hour i.v. infusions of AUY922 once a week in a 28-day cycle. An adaptive Bayesian logistic regression model that employed observed dose-limiting toxicities (DLT) in the first treatment cycle was used to guide dose-escalation decisions, with the established MTD to be used in phase II studies.Results One hundred and one patients were enrolled and explored at doses in the range of 2 to 70 mg/m(2). DLTs occurred in 8 patients (22-70 mg/m(2)) and included diarrhea, asthenia/fatigue, anorexia, atrial flutter, and visual symptoms. At 70 mg/m(2), the AUY922 concentration achieved was consistent with active concentrations in a range of xenograft models. There was evidence of target inhibition in peripheral blood mononuclear cells (HSP70 induction) and tumor (client protein depletion and reduction of metabolic activity by (18)F-FDG PET). The recommended phase II dose (RP2D) of 70 mg/m(2) was proposed on the basis of toxicity and pharmacokinetic and pharmacodynamic profiles.Conclusions At the RP2D of 70 mg/m(2), AUY922 exhibited acceptable tolerability, and phase II single-agent and combination studies have been initiated in patients with HER2-positive breast, gastric, and non-small cell lung cancers.
URI
https://repository.icr.ac.uk/handle/internal/1981
DOI
https://doi.org/10.1158/1078-0432.ccr-12-3404
Collections
  • Cancer Therapeutics
  • Clinical Studies
Subject
Humans
Neoplasms
Resorcinols
Isoxazoles
Antineoplastic Agents
Neoplasm Staging
Treatment Outcome
Adult
Aged
Middle Aged
Female
Male
HSP90 Heat-Shock Proteins
Research team
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Language
eng
License start date
2013-07
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2013, 19 (13), pp. 3671 - 3680

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