Abstract
Histone deacetylase inhibitors (HDACi) such as vorinostat induce an open chromatin configuration and re-expression of epigenetically repressed genes. This can result in better chromatin access by DNA topoisomerase II (Topo II) inhibitors and/or increase the expression of Topo II. Preclinical studies using leukemia cell lines have demonstrated that the combination of vorinostat with a Topo II inhibitor has synergistic antileukemia effect (Sanchez-Gonzalez, Blood 2006). To test this concept clinically, we are conducting a CTEP sponsored clinical trial of the combination of idarubicin and vorinostat in advanced leukemia. Idarubicin was selected because it does not require age-based dose adjustment. Two different schedules of the combination are being studied. With schedule A, idarubicin 12 mg/m2 daily for 3 days is combined with vorinostat orally (PO) three times a day (TID) for 14 days (starting dose 100 mg PO TID). With schedule B, vorinostat is administered daily PO TID for only days. Cycles are repeated every 21 days. Both drugs are initiated simultaneously. Only vorinostat dose escalation is investigated, following a classic 3+3 dose escalation schema, with an expansion cohort of 10 patients at the MTD. If both schedules are open at any given time, patients are randomized among them. Thirty one patients (pts) have been treated: 15 in schedule A and 16 in B. Median age is 55 years (21–80); 28 pts (90%) had relapsed/refractory AML, 1 MDS, 1 ALL and 1 biphenotypic leukemia. 12 pts (39%) had poor risk cytogenetics and 8 (26%) had diploid cytogenetics. The median number of prior therapies was 3 (1–6). With schedule A, idarubicin at 12 mg/m2 with vorinostat at 100 mg was found to be above the MTD, with DLT’s being prolonged myelosuppression, encephalopathy, and mucositis. The expansion cohort has been completed with idarubicin at 9 mg/m2 and vorinostat at 100mg PO TID without significant toxicities. Dose escalation with schedule B continues at a dose of vorinostat at 500 mg PO TID. Grade 2 toxicities have been observed in 3 out of 3 patients at this dose. No serious cardiac toxicity has been observed on either schedule. The most common grade 1 and 2 toxicities include fatigue, nausea, diarrhea, cough, and mucositis. Thus far, 2 complete remissions and 4 complete marrow responses have been observed for an overall response rate of 23% in this refractory population. Most of these patients had failed previous anthracycline-based chemotherapy. In the samples tested thus far, histone acetylation by Western Blot and induction of p21 mRNA by RT-PCR was detected. Correlation of these biomarkers with response, as well as induction of γ-H2AX and topo II mRNA levels are being investigated. Pharmacokinetic analysis shows no significant interaction between the 2 agents and no significant differences between the 2 cohorts. There is an expected dose-dependent increase in the Cmax of vorinostat with escalating doses. Further analysis correlating serum level with response is ongoing. The combination of idarubicin and vorinostat is safe and active in AML. Histone hyperacetylation and induction of p21 is detected. Further dose escalation of the 3 day schedule and analysis of the optimal biological dose is ongoing.
Topoisomerase II and histone deacetylase inhibitors delay the G2/M transition by triggering the p38 MAPK checkpoint pathway