Bastian von Tresckow1, Cyrus Sayehli2, Walter E Aulitzky3, Maria-Elisabeth Goebeler2, Matthias Schwab4,5,6,7, Eunice Braz8, Babett Krauss8, Rolf Krauss8, Frank Hermann8, René Bartz8, Andreas Engert1. 1. Department of Internal Medicine I, University Hospital Cologne, Köln, Germany. 2. Early Clinical Trial Unit, Comprehensive Cancer Center Mainfranken, Würzburg, Germany. 3. Robert-Bosch-Hospital, Stuttgart, Germany. 4. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. 5. University of Tübingen, Tübingen, Germany. 6. Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany. 7. Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany. 8. 4SC AG, Planegg-Martinsried, Germany.
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.
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.
Authors: Yuan He; Shanshan Tai; Miao Deng; Zhaona Fan; Fan Ping; Lihong He; Chi Zhang; Yulei Huang; Bin Cheng; Juan Xia Journal: Cancer Med Date: 2019-04-25 Impact factor: 4.452