No patient had received bevacizumab or cetuximab prior to study inclusion. one patient had received sorafenib which at the time of the study was considered an RAF kinase inhibitor rather than a multikinase angiogenesis selleck catalog inhibitor. One patient had previously received adjuvant chemo radiotherapy and was included in the study after rejecting all stand ard treatments. The patient was subject to two dose re ductions and subsequently excluded from the study due to DLT. Patients on the once daily schedule of nintedanib re ceived doses of between 50 and 450 mg once daily, while those on the twice daily schedule received doses of between 150 and 250 mg twice daily. Overall, patients were treated for a median of 4. 0 cycles with 15 of the 30 patients receiving 2 cycles.

Of the 30 patients who were enrolled, 15 contin ued study treatment until disease progression. Dynamic contrast enhanced magnetic resonance imaging Twenty one patients with CRC were evaluable for DCE MRI. In total, 14 of the 21 patients with evaluable DCE MRI data had a 40% reduction from baseline in tumour Ktrans, representing a clinically relevant antivas cular effect. Similarly, 13 of the 21 patients had a 40% decrease from baseline in tumour iAUC60. In the correlative analyses, a 40% reduction from baseline in Ktrans was shown to be positively associated with non progressive tumour status. Figure 1 shows parameter maps of Ktrans, taken pretreat ment, and on days 2 and 28, from a patient with liver me tastases who received nintedanib 250 mg once daily.

As shown in Figure 2a, Ktrans and iAUC60 decreased relative to baseline over time in this patient who had stable disease according to RECIST. A strong reduction in contrast agent uptake was observed relative to baseline in the target tumour lesion from this patient on both day 2 and day 28. Efficacy One patient with CRC and liver metastasis who was treated with nintedanib 250 mg twice daily achieved a partial response, while 24 patients treated with either schedule at various dose levels had a best response of stable disease lasting 8 weeks. Based on Kaplan Meier estimates, median TTP was 71 days among patients who received once daily ninteda nib and 106 days among patients who received the twice daily schedule. The difference between the two dosing schedules was not statistically significant.

The majority of drug related AEs were CTC grade 1 or 2 in intensity, including all gastrointestinal AEs, and mostly occurred during the first treatment cycle independently of the dos ing schedule. Drug related AEs CTC grade Entinostat 3 were only seen in three patients, all of whom had received the twice daily schedule of nintedanib. Two patients experienced CTC grade 1 drug related hyper tension. No treatment related deaths were reported. Four of the 14 patients treated with once daily ninteda nib experienced an increase in ALT and/or AST CTC grade 3.