Effect of lurbinectedin on the QTc interval in patients with advanced solid tumors: an exposure-response analysis.

PURPOSE: This study assessed the effect of lurbinectedin, a highly selective inhibitor of oncogenic transcription, on the change from baseline in Fridericia's corrected QT interval (∆QTcF) and electrocardiography (ECG) morphological patterns, and lurbinectedin concentration-∆QTcF (C-∆QTcF) relationship, in patients with advanced solid tumors. METHODS: Patients with QTcF ≤ 500 ms, QRS < 110 ms, PR < 200 ms, and normal cardiac conduction and function received lurbinectedin 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks. ECGs were collected in triplicate via 12-lead digital recorder in treatment cycle 1 and 2 and analyzed centrally. ECG collection time-matched blood samples were drawn to measure lurbinectedin plasma concentration. No effect on QTc interval was concluded if the upper bound (UB) of the least square (LS) mean two-sided 90% confidence intervals (CI) for ΔQTcF at each time point was < 20 ms. C-∆QTcF was explored using linear mixed-effects analysis. RESULTS: A total of 1707 ECGs were collected from 39 patients (females, 22; median age, 56 years). The largest UB of the 90% CI of ΔQTcF was 9.6 ms, thus lower than the more conservative 10 ms threshold established at the ICH E14 guideline for QT studies in healthy volunteers. C-∆QTcF was better fit by an effect compartment model, and the 90% CI of predicted ΔQTcF at Cmax was 7.81 ms, also below the 10 ms threshold of clinical concern. CONCLUSIONS: ECG parameters and C-ΔQTcF modelling in this prospective study indicate that lurbinectedin was not associated with a clinically relevant effect on cardiac repolarization.

Long-Term Follow-Up of Desmoid Fibromatosis Treated with PF-03084014, an Oral Gamma Secretase Inhibitor.

BACKGROUND: Desmoid fibromatosis is a fibroblastic neoplasm driven by aberrations within the WNT pathway, exhibiting mutations in ß-catenin or APC. We review the long-term follow-up of patients in a phase I study treated with an oral gamma secretase inhibitor, PF-03084014. METHODS: PF-03084014 was administered orally at doses ranging from 20 to 330 mg twice daily. Tumor assessments were performed using computed tomography/magnetic resonance imaging (CT/MRI) within 4 weeks of study entry, and every other cycle through cycle 9. After cycle 9, patients were evaluated as clinically indicated. RESULTS: Seven patients with desmoid fibromatosis were treated between December 2009 and December 2016 at the University of Colorado. Five patients (71.4%, 95% confidence interval [CI] 29.0-96.3%) achieved a partial response (PR), with a mean time to achieving response of 11.9 months (95% CI 2.5-21.4 months). All patients who achieved a PR continue to maintain responses between 47.9 and 73+ months. Four patients stopped treatment yet remain free of progression between 11 and 53+ months. One patient had PFS of 42+ months, with a 17% decrease in the target lesion. A biopsy performed at the end of the study showed decreased tumoral cellularity compared with previous biopsies. Effective treatment doses ranged from 80 to 330 mg administered orally twice daily. CONCLUSIONS: PF-03084014 was effective in treating desmoid tumors, with an objective response rate of 71.4% (95% CI 29.0-96.3%) in this small cohort of patients. PF-03084014 exhibits promising activity, even at relatively low doses (80 mg twice daily), with high tolerability leading to prolonged disease control even after therapy discontinuation.