e15037 Background: Nintedanib (BIBF 1120), an angiokinase inhibitor of VEGFR 1–3, PDGFR-α/-β, and FGFR 1–3, has shown clinical activity with a good safety profile in patients (pts) with solid tumors in previous Phase II clinical trials. Several classes of targeted agents are associated with QT prolongation, including the multi-targeted tyrosine kinase inhibitors. Here, we prospectively evaluated the cardiac safety of nintedanib, specifically assessing the QT liability in an open-label, randomized, phase II efficacy and safety study of nintedanib vs sunitinib in pts with previously untreated RCC. Methods: Eligible pts (advanced, measurable, unresectable, recurrent RCC, ECOG PS 0–1, chemo-naïve, life expectancy >3 months) were randomized to receive either nintedanib 200 mg bid or sunitinib 50 mg od in a 2:1 ratio. Time-matched electrocardiograms of patients treated with nintedanib were collected over 12 hrs. Primary endpoint was the time-matched change from baseline (Day –1 prior nintedanib dosing) to Day 15 (steady-state) in the QTcF interval (QT interval corrected for heart rate dependency by the Fridericia formula) observed at each timepoint. PK parameters were determined and AEs were reported until Day 15. Results: 64 pts were treated with nintedanib. Estimated mean time-matched changes in the QTcF interval (ms) from baseline to Day 15 ranged from –1.7 (90% CI: –4.9, 1.6) at 2 hrs to 3.1 (90% CI: –0.2, 6.4) at 7 hrs. Upper CIs at all timepoints were <10 ms, the ICH E14 guideline threshold level of regulatory concern. Changes from baseline to Day 1 and changes in QT interval were also within the threshold of 10 ms. No pts showed a QTcF or a QT value >500 ms at baseline, Day 1 or Day 15, and no patient experienced an increase from baseline in QTcF >60 ms on Days 1 and 15. PK/QTc analyses did not indicate any relationship between exposure to nintedanib and a change from baseline in QTcF or the QT interval. The most frequently reported drug-related AEs were nausea (14.1%), diarrhea (12.5%) and vomiting (6.3%). Conclusions: Single and multiple doses of 200 mg nintedanib administered until steady-state did not prolong the QTcF interval compared with baseline in pts with RCC.
Rate Dependency in Steady-State Upscaling
