{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:13:04Z","timestamp":1791231184451,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T00:00:00Z","timestamp":1603756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 CA016672"],"award-info":[{"award-number":["P30 CA016672"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Deregulated Notch signaling is implicated in T\u2010cell acute lymphoblastic leukemia (T\u2010ALL)\/T\u2010cell lymphoblastic lymphoma (T\u2010LBL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed\/refractory T\u2010ALL\/T\u2010LBL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>JJCB was a multicenter, nonrandomized, open\u2010label, dose\u2010escalation, phase 1 study in adult patients with relapsed\/refractory T\u2010ALL\/T\u2010LBL. Eligible patients received Crenigacestat orally 3 times per week plus dexamethasone at 24 mg twice daily on days 1 to 5 every other week in a 28\u2010day cycle. The starting level of Crenigacestat was 50 mg, and dose escalation was performed with a modified 3+3 scheme for the estimation of dose\u2010limiting toxicity (DLT) at the recommended dose level.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In total, 36 patients with T\u2010ALL (n\u00a0=\u00a031 [86.1%]) or T\u2010LBL (n\u00a0=\u00a05 [13.9%]) were treated with Crenigacestat and dexamethasone. Six patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75\u2010mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100\u2010mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125\u2010mg cohort (grade 3 diarrhea, nausea, and vomiting). The maximum tolerated dosewas 75 mg plus 24 mg of dexamethasone daily on days 1 to 5. Twenty\u2010eight patients (77.8%) experienced 1 or more treatment\u2010emergent adverse events related to the study treatment. The best overall response was a confirmed response, with 1 patient (2.8%) having a duration of response of 10.51 months. Six patients (16.7%) achieved stable disease, and 12 patients (33.3%) experienced progressive disease. The remaining 17 patients (47.2%) were not evaluable. The median event\u2010free survival was 1.18 months (95% confidence interval, 0.76\u20102.14 months) among all groups. A pharmacodynamic analysis showed decreased plasma amyloid \u03b2 levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Crenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed\/refractory T\u2010ALL\/T\u2010LBL.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.33188","type":"journal-article","created":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T13:40:39Z","timestamp":1603806039000},"page":"372-380","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Phase 1 study to evaluate Crenigacestat (LY3039478) in combination with dexamethasone in patients with T\u2010cell acute lymphoblastic leukemia and lymphoma"],"prefix":"10.1002","volume":"127","author":[{"given":"Gautam","family":"Borthakur","sequence":"first","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Department of Specialized, Diagnostic, and Experimental Medicine University of Bologna Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Raffoux","sequence":"additional","affiliation":[{"name":"Saint Louis Hospital Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3142-5581","authenticated-orcid":false,"given":"Patrice","family":"Chevallier","sequence":"additional","affiliation":[{"name":"Central University Research Hospital (CHRU) De Nantes, Hotel\u2010Dieu Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Chromik","sequence":"additional","affiliation":[{"name":"University Hospital Frankfurt Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Lithio","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Indianapolis Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire L.","family":"Smith","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Surrey United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunice","family":"Yuen","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Surrey United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Gerard Joseph","family":"Oakley","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Indianapolis Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim A.","family":"Benhadji","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Indianapolis Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"DeAngelo","sequence":"additional","affiliation":[{"name":"Dana\u2010Farber Cancer Institute Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,10,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3816\/CLM.2009.s.015"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.05.047"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2404302"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-11-056754"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.145"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.23.021704.115747"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.2789"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/2040620712471368"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1900"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1102160"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2009.07607.x"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.3230"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.09.2403"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2018.08.012"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy244"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2003.04.036"},{"key":"e_1_2_8_18_1","first-page":"1834","article-title":"Dose\u2010dependent serum concentration of ISDN and its metabolites following administration of ISDN\u2010retard. 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