Phase I Study of Nintedanib Incorporating Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Patients With Advanced Solid Tumors
Mené sur 51 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la dose maximale tolérée du nintedanib et met en évidence ses effets à l'aide d'examens par IRM dynamique de contraste
Background. This open-label phase I dose-escalation study investigated the safety, efficacy, pharmacokinetics (PK), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) effects of the oral angiokinase inhibitor nintedanib in patients with advanced solid tumors. Methods. Nintedanib was administered once daily continuously, starting at 100 mg and later amended to allow evaluation of 250 mg b.i.d. The primary endpoint was maximum tolerated dose (MTD). DCE-MRI studies were performed at baseline and on days 2 and 28. Results. Fifty-one patients received nintedanib 100–450 mg once daily (n = 40) or 250 mg b.i.d. (n = 11). Asymptomatic reversible liver enzyme elevations (grade 3) were dose limiting in 2 of 5 patients at 450 mg once daily. At 250 mg b.i.d., 2 of 11 patients experienced dose-limiting toxicity (grade 3 liver enzyme elevation and gastrointestinal symptoms). Common toxicities included fatigue, diarrhea, nausea, vomiting, and abdominal pain (mainly grade ≤2). Among 45 patients, 22 (49%) achieved stable disease; 7 remained on treatment for >6 months. DCE-MRI of target lesions revealed effects in some patients at 200 and ≥400 mg once daily. Conclusion. Nintedanib is well tolerated by patients with advanced solid malignancies, with MTD defined as 250 mg b.i.d., and can induce changes in DCE-MRI. Disease stabilization >6 months was observed in 7 of 51 patients.