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

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.

• Authors: Cristiana Sessa, Geoffrey I Shapiro, Kapil N Bhalla, Carolyn Britten, Karen S Jacks, Monica Mita, Vali Papadimitrakopoulou, Tim Pluard, Thomas A Samuel, Mikhail Akimov, Cornelia Quadt, Cristina Fernandez-Ibarra, Hong Lu, Stuart Bailey, Sandra Chica, Udai Banerji
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 13 Pg. 3671-80 (Jul 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23757357 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Isoxazoles
• Resorcinols

Topics

• Adult
• Aged
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Female
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Isoxazoles (adverse effects, pharmacokinetics, therapeutic use)
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms (drug therapy, pathology)
• Resorcinols (adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome