Universität zu Köln

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:	Creators Email ORCID ORCID Put Code von Tresckow, Bastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Sayehli, Cyrus UNSPECIFIED UNSPECIFIED UNSPECIFIED Aulitzky, Walter E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goebeler, Maria-Elisabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwab, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Braz, Eunice UNSPECIFIED UNSPECIFIED UNSPECIFIED Krauss, Babett UNSPECIFIED UNSPECIFIED UNSPECIFIED Krauss, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermann, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartz, Rene UNSPECIFIED UNSPECIFIED UNSPECIFIED Engert, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language HDAC INHIBITORS; CANCER; IMMUNOTHERAPY; RESISTANCE Multiple languages Hematology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15855