{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T20:02:56Z","timestamp":1788984176156,"version":"build-2803163510"},"reference-count":22,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2017,6,19]],"date-time":"2017-06-19T00:00:00Z","timestamp":1497830400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:p>The hedgehog signaling pathway regulates multiple morphogenetic processes during embryogenesis. Aberrant activation of the hedgehog pathway signal transduction in adult tissues is associated with the pathogenesis of hematologic malignancies and solid tumors. We report findings from an open\u2010label, multicenter phase I trial of the selective, small\u2010molecule hedgehog signaling inhibitor glasdegib (<jats:styled-content style=\"fixed-case\">PF<\/jats:styled-content>\u201004449913) in Japanese patients with select advanced hematologic malignancies. Glasdegib was administered as once\u2010daily oral doses (25, 50 and 100\u00a0mg) in 28\u2010day cycles after a lead\u2010in dose on Day \u22125. The primary objectives were to determine first\u2010cycle dose\u2010limiting toxicities, safety, vital signs and laboratory test abnormalities. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics and preliminary evidence of clinical activity of glasdegib. No dose\u2010limiting toxicities were noted in the 13\u00a0patients in the present study. All patients experienced at least one treatment\u2010emergent, all\u2010causality adverse event. The most frequent treatment\u2010related adverse events (observed in \u22653\u00a0patients) were dysgeusia (<jats:italic>n\u00a0<\/jats:italic>=\u00a09), muscle spasms (<jats:italic>n\u00a0<\/jats:italic>=\u00a05), alopecia, decreased appetite (<jats:italic>n\u00a0<\/jats:italic>=\u00a04 each), and increased blood creatinine phosphokinase, constipation and diarrhea (<jats:italic>n\u00a0<\/jats:italic>=\u00a03 each). Two deaths occurred during the study and were deemed not to be treatment\u2010related due to disease progression. Glasdegib demonstrated dose\u2010proportional pharmacokinetics, marked downregulation of the glioma\u2010associated transcriptional regulator <jats:styled-content style=\"fixed-case\">GLI<\/jats:styled-content>1 expression in normal skin, and evidence of preliminary clinical activity, although data are limited. Glasdegib was safe and well tolerated across the dose levels tested. It is confirmed that the 100\u2010mg dose is safe and tolerable in Japanese patients, and this dose level will be examined in the future clinical trial.<\/jats:p>","DOI":"10.1111\/cas.13285","type":"journal-article","created":{"date-parts":[[2017,5,27]],"date-time":"2017-05-27T01:36:42Z","timestamp":1495849002000},"page":"1628-1633","source":"Crossref","is-referenced-by-count":50,"title":["Phase I study of glasdegib (<scp>PF<\/scp>\u201004449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies"],"prefix":"10.1111","volume":"108","author":[{"given":"Yosuke","family":"Minami","sequence":"first","affiliation":[{"name":"National Cancer Center Hospital East Kashiwa Chiba Japan"},{"name":"Kobe University Hospital Kobe Hyogo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironobu","family":"Minami","sequence":"additional","affiliation":[{"name":"Kobe University Hospital Kobe Hyogo 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