A phase II study of a 1-hour infusion of romidepsin combined with bortezomib for multiple myeloma (MM) patients with relapsed or refractory disease

Abstract

e19508 Background: Nonclinical studies have demonstrated that histone deacetylase inhibitors (HDACi) significantly reduce the growth of MM cells and enhance cytotoxicity of the proteasome inhibitor bortezomib (Velcade). Romidepsin, a pan-HDACi, has previously shown activity for patients (pts) with relapsed or refractory MM when administered as a 4-hr infusion in combination with dexamethasone and bortezomib. Methods: This open-label, multi-center, phase II study (GPI-08–0006) was initiated to evaluate the activity and safety of a 1-hr infusion of romidepsin in combination with bortezomib for MM pts with relapsed or refractory disease and to evaluate the safety and single dose pharmacokinetics (PK)/pharmacodynamics of romidepsin in the first 5 pts. Pts received 10 mg/m2 romidepsin on days 1, 8 and 15 and 1.0 mg/m2 bortezomib on days 1, 4, 8 and 11 of a 28-day cycle. PK sampling and triplicate ECGs were performed at 0, 0.25, 0.5, 1, 2, 3, 4, 6 and 24 hrs after initiation of the first 1-hr infusion of romidepsin. Results: To date, 5 pts have been enrolled (median age 68 [range, 65–72]) 2 pts who relapsed from recent bortezomib-containing regimens experienced minimal responses after 2 cycles. 2 pts have experienced grade 3 thrombocytopenia. No pt had a QTcF value of >480 ms the mean change in QTcF from baseline to Cmax was 4.2 ms (-10 to 13). Values for PK parameters are included in the table . When compared with data from pts who were treated with a 4-hr infusion of 14 mg/m2, the Cmax of the 1-hr infusion of romidepsin 10 mg/m2 was ∼ 20% higher and exposure (AUC0–24hr) was reduced by 70%. Conclusions: Preliminary data suggest that the 1-hr infusion of romidepsin combined with bortezomib is active for pts with MM relapsed or refractory to bortezomib. Based on the initial incidence of grade 3 thrombocytopenia and PK data, additional pts are being treated on the same schedule but with a reduced dose of romidepsin (8 mg/m2). This study continues to enroll pts. [Table: see text] [Table: see text]