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Open Access Highly Accessed Research article

Vascular effects, efficacy and safety of nintedanib in patients with advanced, refractory colorectal cancer: a prospective phase I subanalysis

Klaus Mross1*, Martin Büchert2, Annette Frost1, Michael Medinger1, Peter Stopfer3, Matus Studeny3 and Rolf Kaiser3

Author Affiliations

1 Tumor Biology Center, Department of Medical Oncology, Breisacherstrasse 117, D-79106 Freiburg in Breisgau, Germany

2 Magnetic Resonance Development and Application Center, Department of Radiology, University Medical Center Freiburg, Freiburg, Germany

3 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany

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BMC Cancer 2014, 14:510  doi:10.1186/1471-2407-14-510

Published: 11 July 2014

Abstract

Background

Nintedanib is a potent, oral angiokinase inhibitor that targets VEGF, PDGF and FGF signalling, as well as RET and Flt3. The maximum tolerated dose of nintedanib was evaluated in a phase I study of treatment-refractory patients with advanced solid tumours. In this preplanned subanalysis, the effect of nintedanib on the tumour vasculature, along with efficacy and safety, was assessed in 30 patients with colorectal cancer (CRC).

Methods

Patients with advanced CRC who had failed conventional treatment, or for whom no therapy of proven efficacy existed, were treated with nintedanib ranging from 50–450 mg once-daily (n = 14) or 150–250 mg twice-daily (n = 16) for 28 days. After a 1-week rest, further courses were permitted in the absence of progression or undue toxicity. The primary objective was the effect on the tumour vasculature using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and expressed as the initial area under the DCE-MRI contrast agent concentration–time curve after 60 seconds (iAUC60) or the volume transfer constant between blood plasma and extravascular extracellular space (Ktrans).

Results

Patients received a median of 4.0 courses (range: 1–13). Among 21 evaluable patients, 14 (67%) had a ≥40% reduction from baseline in Ktrans and 13 (62%) had a ≥40% decrease from baseline in iAUC60, representing clinically relevant effects on tumour blood flow and permeability, respectively. A ≥40% reduction from baseline in Ktrans was positively associated with non-progressive tumour status (Fisher’s exact: p = 0.0032). One patient achieved a partial response at 250 mg twice-daily and 24 (80%) achieved stable disease lasting ≥8 weeks. Time to tumour progression (TTP) at 4 months was 26% and median TTP was 72.5 days (95% confidence interval: 65–114). Common drug-related adverse events (AEs) included nausea (67%), vomiting (53%) and diarrhoea (40%); three patients experienced drug-related AEs ≥ grade 3. Four patients treated with nintedanib once-daily had an alanine aminotransferase and/or aspartate aminotransferase increase ≥ grade 3. No increases > grade 2 were seen in the twice-daily group.

Conclusions

Nintedanib modulates tumour blood flow and permeability in patients with advanced, refractory CRC, while achieving antitumour activity and maintaining an acceptable safety profile.

Keywords:
Angiogenesis inhibitor; Clinical trial; Phase I; Nintedanib; Colorectal cancer; Magnetic resonance imaging