Pharmacokinetics and biomarkers
tumor, tumors, (C1D4).Tumor, Cancer
TUMOR, TUMORS, INFLAMMATION, CANCER
PK of galunisertib were measured using validated liquid chromatography-atmospheric pressure ionization/tandem mass spectrometry methods at Intertek Pharmaceutical Services (El Dorado Hills and San Diego, California, USA). There were 293 PK galunisertib observations in 41 patients on Days 1, 14, and 15 in Cycles 1 and 2 as well as pre-dose, Cycle 4 Day 1 (C1D4).Tumor cell membrane PD-L1 was measured by immunohistochemistry using the Dako PD-L1 (28–8) kit at Mosaic Laboratories (Cancer gene sequencing (Ribonucleic acid (RNA) extraction and Illumina TruSeq RNA Exome sequencing was performed by Almac for gene expression profiling of 12 baseline tumor samples, 4 tumors collected on C1D15, and 3 tumors collected on C2D1. Six baseline samples were paired with treatment biopsies. Formalin fixed paraffin embedded tumor samples were macrodissected and RNA extraction was performed using the Qiagen RNeasy extraction kit followed by quality assessments using Nanodrop, Agilent Bioanalyzer & RNA-Seqability (an Almac proprietary quality control step). Paired-end sequencing with a read length of 100 base pairs and targeted read depth of 50 million reads/sample was performed. Read counts were quantified using an in-house Perl script and summarized at the gene level (National Center for Biotechnology Information [NCBI] h37.p13 annotation). The resulting data were quantile-normalized and filtered to remove genes with fewer than 5 counts across 80% of the samples from the analysis. Baseline expression of TGF-β pathway genes included Differentially expressed gene analysis was conducted using the DESeq2 package [Serum proteins (51 analytes) were assessed at baseline, C1D8, C1D15, C2D1, and C2D15 using the Inflammation Multi-Analyte Immunoassay panel developed by Myriad RBM. Paired t-tests were used to compare post-dose levels with baseline at each time point for each biomarker.