data for afatinib (a second patient also received a few days’ treatment at the dose of 70 mg due to an administrative error). The first pre-planned safety assessment was Mocetinostat performed when 24 patients had been included; the results confirmed adequacy of dosing, and the trial continued to full recruitment. The incidence of AEs regardless of relatedness to the study drugs is presented in Table V. Overall, the AEs reflected the known tolerability profiles of the drugs, as well as the nature of the underlying disease with primarily intra-abdominal spread. Gastrointestinal (GI), asthenia and skin events represented the largely predominating AEs. GI and skin AEs, as well as increases in liver laboratory parameters, were also the most frequent AEs considered to be related to the study drugs (Table VI), with the exception of asthenia – probably as most patients suffered from end-stage disease. No other CTCAE of grade 3 or 4 that was kinase inhibition reported as likely to be drug-related occurred in more than a single patient (Table VII).
Dose reductions were most frequently prompted by GI AEs (reduction of BIBF 1120, or afatinib, or both) and increases of liver enzymes (BIBF 1120 only; Table VIII). Few patients only discontinued the drug due to AEs (AEs not related to progressive disease), with drug-related AEs being the reason for discontinuation in only two patients (4.3%) – one suffering from worsening of diarrhoea that had been present and requiring therapy at baseline, the other experiencing CTCAE Grade 4 asthenia. Increases in liver laboratory kinase inhibitor drug parameters (liver enzymes, bilirubin; Table VIII) occurred in several patients.
Most patients with relevant changes (increases to CTCAE grades 3 or 4) suffered from liver, or, occasionally, liver hilus lymph node metastases of increasing size during the trial, and also had elevated levels of liver parameters at baseline. However, the data were suggestive of a clear relationship with hepatic progressive disease only for bilirubin kinase pathway inhibitor increases. Even though almost all patients with increased liver transaminases, the most common side-effect limiting the dosing of BIBF 1120, also suffered from liver metastases, most of which also progressed until the end of the trial, this increase occurred relatively early (six patients within the first 4 weeks; in the seventh patient after ~8 weeks), and were reversible down to at least grade 1 in five out of seven patients (the other two had progressing liver metastases). One patient had an increase of bilirubin from baseline grade 0 to grade 4 that was not considered to be drug related; the patient had been classified as having no liver metastases at baseline but had a ‘liver node’ that remained present as a non-target lesion throughout the trial. One patient with multiple large liver metastases was included in the trial 17 days after having received the last dose of bevacizumab; this patient was included despite relevant increased liver parameters at baseline.
These were found to be due to thrombosis of the portal vein, with a fatal outcome after 2 weeks of trial participation; the maximum grade of transaminases and bilirubin during trial treatment of this patient was CTCAE grade 3 and 4, respectively. None of the 25 deaths that occurred during the study, including 17 patients (40.0%) with additionally reported unrelated AEs, were considered to be related to the study drug, and AEs reported in the context of death in most cases were attributed to progressive disease. One patient with pulmonary metastases died due to pulmonary haemorrhage. Pharmacokinetics. On study inclusion, no plasma levels were detectable in the blood samples for either drug prior to first intake of study medication (data not shown; for the PK sampling scheme, refer to Figure 1). In the samples obtained on day 8 prior to the very first intake of afatinib, no plasma levels of afatinib were detectable, with the exception of three patients who had measurable levels in the range otherwise observed shortly after
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