Phase I study of oral suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, in patients (pts) with advanced leukemias or myelodysplastic syndromes (MDS)

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Abstract
3027 Background: SAHA is a histone deacetylase inhibitor with in vitro antileukemia activity. Methods: We present results of a phase I study in pts with leukemia/MDS given SAHA orally three times a day (TID) x 14 consecutive days every 21days. The TID schedule was developed to induce continuous histone hyperacetylation for 14 days. The initial dose level was 100 mg po TID with dose escalation in increments of 50 mg TID, using a 3+3 design. Eligibility included: relapsed/refractory leukemia/MDS, or untreated disease if pt not willing to proceed with standard therapy, preserved organ function and performance status. Results: 15 pts have been treated and are evaluable for toxicity. At dose level 1, 2 pts with AML and 1 CMML. At level 2, 1 pt with AML, 1 with ALL and 1 with CLL. At level 3, 4 with AML, 1 with MDS and 1 with ALL, at level 4, 2 with AML and 1 with CML. Median age is 71 years; median number of prior therapies 2. Dose level 3 was expanded from 3 to 6 pts, to better assess toxicity. No pt has experienced grade 3- 4 toxicity or death related to SAHA. The most commonly reported adverse events, regardless of causality, are nausea, vomiting, diarrhea, anorexia, headache, fatigue, dyspepsia, that resolved during the week of rest. Lab abnormalities included pancytopenia, hyperglycemia, hypokalemia, hypocalcemia, hypophosphatemia. Histone hyperacetylation was detected in pts treated at all dose levels. On dose level 1, one pt with AML achieved hematological improvement (marrow blasts less than 5%, ANC > 1x 109k/UL, but no recovery of platelets) and progressed in the marrow after 6 courses. On dose level 2, one CLL pt had reduction in the size of lymph nodes. On dose level 3, one elderly pt with untreated AML achieved a complete remission after 2 courses of therapy, now maintained after 4; two additional AML pts and one MDS pt had a decrease in marrow blasts to less than 10% without peripheral blood recovery. Conclusions: These results indicate that single agent SAHA is well tolerated up to doses of 250 mg po TID x 14 days every 21 days and has promising activity in pts with AML/MDS. Dose escalation continues.

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