Objectives
Domatinostat (4SCâ202) 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 1â14 with 7Â days off or continuously days 1â21 in a 3Â +Â 3 design at 7 dose levels from 25 to 400Â mg total daily dose (TDD). Twentyâfour patients were treated with domatinostat.
Results
No formal maximum tolerated dose (MTD) was determined. One doseâlimiting toxicity (DLT, grade 4 hypercalcemia) occurred during 200Â mg BID continuous treatment. Six patients were reported with â„ grade 3 treatmentârelated 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 200Â 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 200Â mg BID schedule (14Â +Â 7) is the recommended phase II dose for monotherapy.