{'fraction_non_alphanumeric': 0.049235181644359464, 'fraction_numerical': 0.0607074569789675, 'mean_word_length': 4.9460227272727275, 'pattern_counts': {'":': 0, '<': 2, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Phase I clinical and biomarker study of BIBF 1120, an oral multitarget tyrosine kinase inhibitor, in patients with advanced solid tumors (ST): Impact of CD133- and CD117-positive cells on a biomarker of an antiangiogenic inhibitor.

3572 Background: BIBF 1120 (Vargatef) is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptors.


METHODS
BIBF 1120 (150-250 mg) was administered orally twice-daily (bid) to heavily pre-treated solid tumor (ST) patients to determine safety, tolerability, maximum tolerated dose (MTD) and pharmacokinetics (PK). CD133- and/or CD117 (c-kit)-positive cells from CD34+CD45dim peripheral blood cells were evaluated using flow-cytometry on pre-treatment, Day 2, Day 8 and Day 29.


RESULTS
Twenty-one patients were treated at doses of 150 mg bid (n=3), 200 mg bid (n=12) and 250 mg bid (n=6). Dose-limiting toxicities (DLTs) of reversible Grade 3/4 elevated liver enzymes occurred in three of 12 patients at 200 mg bid and three of six patients at 250 mg bid; 200 mg bid was declared as the MTD. Best observed responses were stable disease in 16 (76.2%) patients and median progression-free survival was 113 days (95% CI: 77-119 days). PK analysis indicated that Cmax and AUC increased with increased dose within the dose range tested. Flow cytometry analysis revealed that BIBF 1120 treatment significantly increased the percentage of CD133+CD117- cells (p<0.001) on Day 29 compared with pre-treatment, and conversely decreased that of CD133-CD117+ cells (p<0.01). In addition, CD133+CD117+ cells tended to decrease in responders (stable disease) to a greater extent than in non- responders after treatment.


CONCLUSIONS
BIBF 1120 dosed continuously at 200 mg bid was well tolerated and appeared to provide some clinical benefit. Our biomarker study provides a novel insight into CD133- and CD117-positive cells as a pharmacodynamic biomarker for an antiangiogenic inhibitor. [Table: see text].