The main exclusion criteria included surgery, radiother apy or investigational anticancer therapy during the previous 4 weeks. selleck chemicals active ulcers or infectious disease. injuries with incomplete wound healing. pregnancy or breastfeeding. brain metastases requiring therapy. absolute neutrophil count 1,500/mm3. platelet count 100,000/mm3. bilirubin 1. 5 mg/dL. aspartate amino transferase and/or alanine amino transfer ase 3 the upper limit of normal . serum creatinine 1. 5 mg/dL. uncontrolled severe hyper tension. and gastrointestinal disorders anticipated to inter fere with the resorption of study medication. Study design The phase I trial was an open label, single and multiple dose study, with accelerated, toxicity guided dose escal ation.

The first treatment cycle comprised a single oral dose of nintedanib on day 1, followed by a 1 day washout and 28 days of continuous once or twice daily oral ad ministration of fixed dose nintedanib. After a 1 week rest period, further cycles were permitted in the absence of major tumour progression or dose limiting toxicity. The full dose escalation protocol has been described previously. Among patients with CRC, the following dose levels were evaluated once daily doses of 50, 100, 200, 250, 300 and 450 mg. and twice daily doses of 2 150, 150 200, 2 200 and 2 250 mg. Dose tiers were evaluated in separ ate patient cohorts, and intrapatient dose escalation was not permitted. Antiemetic prophylaxis was not allowed. The primary objective of this preplanned subanalysis was to assess the effect of continuous daily dosing with nintedanib on the tumour vasculature in patients with CRC using DCE MRI.

Additional objectives included evaluation of tumour response, time Drug_discovery to first tumour pro gression and safety/tolerability. The protocol was approved by the local medical eth ics committee, and the trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent prior to engaging in study procedures. Assessments Dynamic contrast enhanced magnetic resonance imaging Full details of the DCE MRI protocol that was used have been published previously. In brief, coronal slice images through one or more measurable, clearly defined, non necrotic target lesions were obtained at baseline, on day 2 for once daily dosing or day 3 for twice daily dosing, and on day 29/30 of the first treatment cycle immediately prior to and following intra venous administration of contrast agent via a standard power injector. Additional images were obtained on day 28 of each re peated cycle for all patients remaining in the trial. All imaging data were acquired using a clinical 1.