von Tresckow, Bastian, Sayehli, Cyrus, Aulitzky, Walter E., Goebeler, Maria-Elisabeth, Schwab, Matthias, Braz, Eunice, Krauss, Babett, Krauss, Rolf, Hermann, Frank, Bartz, Rene and Engert, Andreas (2019). Phase I study of domatinostat (4SC-202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies. Eur. J. Haematol., 102 (2). S. 163 - 174. HOBOKEN: WILEY. ISSN 1600-0609

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Abstract

Objectives Domatinostat (4SC-202) is a selective class I histone deacetylase inhibitor (HDACi). This phase I study investigated safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity in patients with advanced hematological malignancies. Methods Domatinostat was administered orally once (QD) or twice daily (BID) on days 1-14 with 7 days off or continuously days 1-21 in a 3 + 3 design at 7 dose levels from 25 to 400 mg total daily dose (TDD). Twenty-four patients were treated with domatinostat. Results No formal maximum tolerated dose (MTD) was determined. One dose-limiting toxicity (DLT, grade 4 hypercalcemia) occurred during 200 mg BID continuous treatment. Six patients were reported with >= grade 3 treatment-related adverse events (TRAE; grade 3 hematological in three patients, grade 3 and grade 4 liver enzyme increase in 2 patients, grade 4 pulmonary embolism, and grade 4 hypercalcemia in one patient each). Higher grade hepatic TRAE occurred in the 200 mg BID continuous treatment cohort. Out of 24 patients, 1 achieved a complete response, 1 achieved a partial response, and 18 had stable disease as best response. Conclusion Administration of domatinostat was safe, well tolerated with signs of antitumor activity. Four hundred milligram TDD in a 200 mg BID schedule (14 + 7) is the recommended phase II dose for monotherapy.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
von Tresckow, BastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sayehli, CyrusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aulitzky, Walter E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goebeler, Maria-ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwab, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braz, EuniceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krauss, BabettUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krauss, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hermann, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartz, ReneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engert, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-158551
DOI: 10.1111/ejh.13188
Journal or Publication Title: Eur. J. Haematol.
Volume: 102
Number: 2
Page Range: S. 163 - 174
Date: 2019
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1600-0609
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HDAC INHIBITORS; CANCER; IMMUNOTHERAPY; RESISTANCEMultiple languages
HematologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15855

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