Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study

• Published in: Investigational new drugs 2013-10, Vol.31 (5), p.1283-1293
• Main Authors: Eisen, Tim, Shparyk, Yaroslav, Macleod, Nicholas, Jones, Robert, Wallenstein, Gudrun, Temple, Graham, Khder, Yasser, Dallinger, Claudia, Studeny, Matus, Loembe, Arsene-Bienvenu, Bondarenko, Igor
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Analysis; Angiogenesis; Antineoplastic agents; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Cancer therapies; Carcinoma, Renal Cell - blood; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - physiopathology; Drug dosages; Electrocardiography; Electrocardiography - drug effects; Female; Fibroblasts; General aspects; Heart rate; Humans; Hypertension; Indoles - blood; Indoles - pharmacology; Indoles - therapeutic use; Inhibitor drugs; Kidney cancer; Kidney Neoplasms - blood; Kidney Neoplasms - drug therapy; Kidney Neoplasms - physiopathology; Kidneys; Kinases; Leukemia; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Nephrology. Urinary tract diseases; Oncology; Pharmaceutical sciences; Pharmacokinetics; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phase II Studies; Protein Kinase Inhibitors - blood; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Risk assessment; Studies; Tumors; Tumors of the urinary system; Vascular endothelial growth factor
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-013-9962-7

Summary Purpose Some targeted anticancer agents are associated with serious ventricular tachyarrhythmias, which may be predicted by electrocardiographic evaluation of drug-related QT prolongation. We studied the effects of nintedanib (BIBF 1120; an oral, triple angiokinase inhibitor targeting vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors) on the QT interval in patients with renal cell carcinoma (RCC) participating in an open-label phase II trial. Methods Treatment-naïve, adult patients with unresectable/metastatic, clear cell RCC received nintedanib 200 mg twice daily. QT intervals were evaluated at baseline (day −1), on day 1 (after the first dose), and on day 15 (steady state) by 12-lead electrocardiograms (ECGs) performed in triplicate. Pharmacokinetic sampling was also undertaken. Results Among 64 evaluable patients, the upper limits of the 2-sided 90 % confidence intervals for the adjusted mean time-matched changes in QTcF interval (corrected for heart rate by Fridericia’s method) from baseline to day 1 and 15 (primary ECG endpoint) were well below the regulatory threshold of 10 ms at all times. No relationship between nintedanib exposure and change from baseline in QTcF was seen. Nintedanib was generally well tolerated with no drug-related cardiovascular adverse events. Conclusion Nintedanib administered at 200 mg twice daily was not associated with clinically relevant QT prolongation.