A phase I study of the combination of a DNA topoisomerase inhibitor, idarubicin, with the histone deacetylase inhibitor vorinostat, in advanced acute leukemia

Abstract

7066 Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor (HDACi) with single agent activity in patients with advanced leukemia. HDACi lead to the acetylation of histones and facilitate an open chromatin configuration. Idarubicin potently inhibits DNA topoisomerase (topo) II by forming stable complexes with it, and eventually leading to ds-DNA breaks and apoptosis. Because of their effect on the chromatin of dividing cells, we postulated that the pairing of an HDACi with a topo II inhibitor, would have antileukemia activity. We tested this in vitro in leukemia cell lines and have shown that the combination of idarubicin and SAHA is synergistic. Methods: To test this clinically, we developed a phase I trial of the combination of idarubicin and SAHA, given in 2 different schedules, in advanced leukemia. In schedule A, idarubicin 12 mg/m2 daily for 3 days is given concurrently with SAHA, orally TID for 14 days (starting at 100 mg). In schedule B, SAHA is only given for 3 days. Only SAHA was dose-escalated, following a classic 3+3 schema, with the plan to treat 10 patients at the MTD. If both schedules were open at any given time, patients were randomized among them. Results: So far, 20 patients have been treated: 8 in schedule A and 12 in B. Median age of the patients is 56 (21–80). Of the patients enrolled thus far, 19 (95%) had relapsed, refractory AML, 1 had MDS, and 8 out of the 20 (40%) had diploid cytogenetics. In schedule A, a dose of idarubicin at 12 mg/m2 and SAHA at 100 mg was found to be above the MTD, with the DLT's being myelosuppression, encephalopathy, and dysphagia. Dose escalation of schedule B continues currently at a dose of SAHA at 400 mg. No severe grade 3 or 4 toxicities have been observed on this schedule. No cardiac toxicity has been observed. So far, 2 CR and 2 complete marrow responses have been observed. All of these patients had failed previous anthracycline-based chemotherapy. Induction of γ-H2AX, histone acetylation, and induction of topo II and p21CIP1 mRNA expression are being evaluated, as well as pharmacokinetic characteristics of both agents. Conclusion: The combination of idarubicin with SAHA is safe and active, and SAHA could be incorporated in the treatment of front-line AML. No significant financial relationships to disclose.