Phase I study of nintedanib incorporating dynamic contrast-enhanced magnetic resonance imaging in patients with advanced solid tumors

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02182206.

©AlphaMed Press; the data published online to support this summary is the property of the authors.

Figures

Figure 1.

Change from baseline in dynamic contrast-enhanced magnetic resonance imaging kinetic parameters in patients with liver metastases and those with other (nonliver) metastases: Ktrans on day 2 (24 hours after dose) (A) and kep on day 28 (±1 day) (B). Open circles and error bars represent mean pretreatment values and calculated repeatability ranges, respectively, whereas crossed boxes represent treatment-related changes. A statistically significant antiangiogenic effect was deemed to have occurred when the crossed box lay below the repeatability limits of the pretreatment values. *, statistically significant change from pretreatment value. Abbreviations: kep, rate constant; Ktrans, transfer constant.