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

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.

Quantitative contrast-enhanced computed tomography: is there a need for system calibration?

The purpose of the study was to perform phantom studies to assess the impact of computed tomography (CT) system variability on quantitative measurements of contrast enhancement. A phantom containing tubes of contrast material at dilutions of 120, 1:35, 1:50, 1:100 and 1:200 arranged in air or water was imaged using 11 CT systems at 9 institutions. All systems had undergone routine calibration against air and water in accordance with the manufacturers' recommendations. For a given tube voltage, the relationship between the iodine concentration and CT attenuation value on a single system varied by 17 to 24% over 46-48 weeks. The coefficients of variance for iodine calibration factors across different CT systems were 8.9% in air and 5.1% in water. Calibration of individual CT systems for iodine response is required to allow comparison of quantitative measurements of contrast enhancement across different institutions. Using the iodine calibration factor to express contrast enhancement as iodine concentration would facilitate the universal application of diagnostic enhancement thresholds, especially if the necessary calculations were performed by software installed on the CT console.