Abstract B212: QTc study of picoplatin with emphasis on pharmacodynamics of cardiac repolarization
Authors: Earhart Robert H. , Rosen Lee , Mendelson David , Plaxe Steven , Gold Philip , Yee Lorrin , Mansoor Saleh , Verschraegen Claire , Phillips Angelica , Houston Scott , De Jager Robert 
Published: June 2012

Abstract
Introduction: Clinical studies have demonstrated that picoplatin (Pico), a new-generation platinum analogue designed to overcome platinum resistance, has activity when administered IV in solid tumors patients (pts); over 1,100 pts have received pico. The primary toxicity is hematological. Clinically significant nephro-, oto-, or neurotoxicity has rarely been observed (&lt;1% grade 3 and 0% grade 4), even in platinum-pretreated patients. Pico (150 mg/m2) Q3W is currently being studied in a Phase 3 trial as 2nd-line monotherapy for SCLC. Pico is also being studied in Phase 2 trials in combination with other chemotherapy drugs for colorectal and prostate cancers. In preclinical studies in dogs, pico had no effect on cardiovascular function, including the QT interval. In clinical trials to date, drug-related serious ventricular arrhythmias have not been observed. The purpose of this study was to assess cardiac effects of Pico in patients with advanced solid tumors.
Methods: The effect of pico on the QT/QTc interval as measured by the ECG was evaluated. The correlation between the QTcF interval and platinum concentration in plasma and plasma ultrafiltrate (PUF) was evaluated. ECG was recorded continuously with a Holter monitor. Triplicate 20 second ECG readings were extracted at 3 times before (baseline reference) and at 8 times in the 24 hrs after pico administration in Cycle 1. Triplicate 12-lead ECGs were obtained at the end of the pico infusion in subsequent cycles. Blood samples were collected before study drug administration and immediately after each ECG timepoint in Cycle 1 for pharmacokinetic analysis. The primary endpoint was the Fredericia corrected QT (QTcF). Time-averaged and time point analyses for QTcF were performed. Heart rate, PR, QRS, QT, QTcB (Bazett's) and morphological changes were also evaluated.
Results: 45 pts (28 women and 17 men), age 44–79 years (median = 60) received 150 mg/m2 pico as a 1-hr IV infusion. The time-averaged mean change from baseline of QTcF duration during Cycle 1 was +2.2 ms, which is considered a nonsignificant increase. At each time point in Cycle 1 and in subsequent cycles, there were only minimal changes from baseline in QTcF duration. Other ECG changes from baseline were unremarkable: ST depression was noted in 9% of pts at baseline and new T-wave changes in 7% of pts in Cycle 1. Mean ± SD Cmax in plasma and PUF were 5566 ± 1079 ng/mL and 4034 ± 674 ng/mL, respectively. The change in QTcF vs. platinum concentration in plasma or PUF showed a Cmax effect of 5–6 ms with an upper confidence interval of 8–9 ms, suggesting no clear effect of picoplatin on QTcF.
Conclusions: Pico had no effect on the QTcF interval or any other ECG parameter, supporting the clinical data showing that Pico does not increase the risk of serious ventricular arrhythmias.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B212.