Phase I study of domatinostat (4 SC ‐202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies

Objectives Domatinostat (4 SC ‐202) is a selective class I histone deacetylase inhibitor ( HDAC i). 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.