{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T23:30:40Z","timestamp":1794007840199,"version":"4.8.0"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Dialectic Therapeutics"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Hematol Oncol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Small molecule inhibition of BCL-XL with navitoclax resulted in on-target dose-limiting thrombocytopenia. DT2216 was more effective than navitoclax and reduced platelet toxicity in preclinical models by selectively degrading BCL-XL via the VHL E3 ligase, which is minimally expressed in platelets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A dose escalation study using a 3\u2009+\u20093 design with doses ranging from 0.04 to 0.4\u00a0mg\/kg IV twice weekly (BIW) was performed. Eligible subjects had solid tumors of any histology that had progressed on standard treatment and had measurable tumor by RECIST v1.1. Tumor assessment was performed at 8-week intervals. BCL-XL levels were measured in peripheral leukocytes by western blotting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Twenty patients were enrolled, with a median age of 60.5\u00a0year; 60% were female. Only one dose-limiting toxicity was observed, grade 4 thrombocytopenia that resolved within 48\u00a0h. Stable disease, observed in 20% of the patients. The lowest platelet count in the first cycle ranged from 24,000 to 297,000. In all cases, the platelet count recovered to &gt;\u200950,000 within 4 days and &gt;\u200975,000 within 1 week. There were no episodes of bleeding or treatment emergent adverse events leading to death. The median overall survival was 7.9 months. The plasma AUC of DT2216 was dose proportional with no dose accumulation. Patients receiving 0.4\u00a0mg\/kg DT2216 demonstrated rapid and sustained degradation of BCL-XL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Based on the rapid recovery of transient thrombocytopenia that occurred only in the first cycle and the degradation of BCL-XL in peripheral leukocytes, the RP2D of DT2216 is 0.4\u00a0mg\/kg IV BIW. (NCT04886622)<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13045-025-01753-8","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T14:29:45Z","timestamp":1762957785000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["First in human phase 1 study of DT2216, a selective BCL-xL degrader, in patients with relapsed\/refractory solid malignancies"],"prefix":"10.1186","volume":"18","author":[{"given":"Daruka","family":"Mahadevan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minal","family":"Barve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devalingam","family":"Mahalingam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Parekh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kurman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Strauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry","family":"Tremaine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Hromas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Sills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"McCulloch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Harkey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacy","family":"Suberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Zimmerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangrong","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daohong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"1753_CR1","doi-asserted-by":"crossref","unstructured":"Vela L, Marzo I. 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The methods were performed in accordance with relevant guidelines and regulations and approved by the Food and Drug Administration (FDA). Written informed consent was obtained from all study participants. The Institutional Review Boards (IRBs) of all participating institutions approved the study protocol. The institutions participating in the study were Northwestern University Medical School, Chicago, IL; Mary Crowley Cancer Research, Dallas, TX; and Mays Cancer Center, UT Health San Antonio, TX.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"98"}}