Final Results of a Phase I Study of the Histone Deacetylase Inhibitor Vorinostat (Suberoyanilide Hydroxamic Acid, SAHA), in Patients with Leukemia and Myelodysplastic Syndrome.

Vorinostat, formerly known as suberoyl anilide hydroxamic acid, (SAHA) is a histone deacetylase inhibitor with potent in vitro antileukemia activity. We conducted a phase I study of two dose schedules of vorinostat: oral three times a day (TID) x 14 days every 21 days; or oral twice a day (BID) x 14 days every 21 days. Patients with relapsed or refractory chronic and acute leukemia or myelodysplastic syndrome (MDS), with adequate renal, hepatic functions and performance status were eligible. Older patients with untreated AML/MDS were also eligible. Forty-one patients were registered and dosed. Median age was 54 years (range 18 to 90), 31 (76%) had AML, 4 (10%) CLL, 3 (7%) MDS, 2 (5%) ALL and 1 (2%) CML. The median number of prior therapies was 2 (range 0–7). The starting dose of the oral TID schedule was 100 mg po TID and it was increased in 50 mg po steps using a 3+3 design. As these patients were thrombocytopenic at baseline due to their underlying disease, thrombocytopenia was not considered to be a dose-limiting toxicity. A dose of 300 mg po TID was considered above the maximally tolerated dose (MTD) with 2 out of 3 patients developing grade 3 toxicity (nausea, vomiting and diarrhea). Subsequently, 7 patients were treated at a dose of 300 mg po BID x 14 days every 21 days. Two patients developed gastrointestinal toxicity (typhlitis) in the setting of profound neutropenia, and the dose was reduced in the next 6 patients to 200 mg po BID x 14 days. No excess toxicity was observed at that dose level. Subsequently, 6 more patients were treated at a dose of 200 mg po TID x 14 days (The MTD of 250 mg po TID X 14 days could not be further evaluated as the 50 mg capsule was no longer available). Only one out 6 patients developed grade 3 toxicity (fatigue). More frequently observed toxicities, regardless of causality, were nausea, vomiting, diarrhea, anorexia, headache, fatigue, typhlitis, and dyspepsia that resolved upon cessation of therapy. Laboratory abnormalities included pancytopenia, hyperglycemia, hypokalemia, hypocalcemia and hypophosphatemia. Overall 9 patients (21%) had objective evidence of response: 1 CR, 2 CRp (CR criteria but no recovery of platelet counts), 1 partial response and 5 complete marrow responses (blasts less than 5%). All responses were observed in patients with AML, and 5 (41%) of these responses were observed at a dose of 200 mg po tid. Histone acetylation was observed in all patients at all dose levels. In summary, the MTD of oral vorinostat is either 200 mg po TID or 200 mg po BID x 14 days every 21 days in patients with leukemia. Significant activity was observed at a dose of 200 mg po TID x 14 days in patients with AML. This single agent activity warrants additional investigation of the role of vorinostat in the therapy of AML and may be guided by the development of informative biomarkers.