Cardiovascular safety profile of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor: Results from two independent phase I trials in patients with advanced cancer

Abstract

e14539 Background: Heat shock protein 90 (Hsp90) is a protein chaperone that regulates the proper folding, stability, and function of multiple mutated and wild type signaling proteins that promote malignant phenotypes. Numerous clinical trials are investigating the activity of the Hsp90 inhibitor IPI-504. Since Hsp90 is a novel cancer target that is ubiquitously expressed in normal cells, a comprehensive evaluation of potential cardiac effects, including the risk of ventricular arrhythmia, was performed in two Phase I trials. Methods: ECG data were pooled and analyzed from 60 pts in two-open label Phase I trials of patients with advanced cancers. Pts received 90 to 400 mg/m2 of IPI-504 IV twice weekly for 2 out of 3 weeks. Subset analyses for 35 pts who received the MTD of 400 mg/m2 were performed. ECGs were obtained in triplicate at 5, 60, and 360 minutes after IPI-504 infusion. Interpretation was conducted at a central, independent laboratory. Results: Over 6,500 ECGs were obtained from 60 pts. At the MTD 3,000 ECGs were obtained from 35 patients. No ventricular arrhythmias or changes in QTcF of ≥60 msec were noted, and no statistically significant relationship between the concentration or dose of IPI-504 and QTcF was observed. At the MTD 5 minutes post infusion, changes from baseline were observed in QTcF (5.4 ms increase), heart rate (15.2 bpm decrease), and PR interval (27.9 ms increase). All of these changes reversed by 6 hours post-infusion and no clinical hemodynamic disturbances were observed. Conclusions: In phase I studies, IPI-504 was not associated with any significant ventricular arrhythmia and no clinically significant QTcF interval changes were noted. These studies did show however that IPI-504 administration was associated with transient, dose-related bradycardia and PR interval lengthening, suggestive of autonomic effects associated with the drug infusion. No clinically significant and IPI-504 related cardiac safety events were observed at the MTD dose of 400 mg/m2. Given these findings, appropriate monitoring of heart rate immediately post-infusion is recommended during further studies with IPI-504. [Table: see text]