Phase I trial of a new schedule of romidepsin in patients with advanced cancers

Abstract

Purpose: Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 romidepsin schedule was evaluated. A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers.

Experimental design: Open-label, single-arm, phase I, 3 + 3 dose escalation study. Romidepsin was administered as a 4-hour infusion on days 1, 3, and 5 of a 21-day cycle. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMC), RAI uptake in refractory thyroid cancer, and HDI-related ECG changes.

Results: Twenty-eight patients with solid tumors, including 11 patients with thyroid cancer were enrolled. Six dose levels were explored, and 7 mg/m(2) on days 1, 3, and 5 was identified as tolerable. No Response Evaluation Criteria In Solid Tumors-defined objective responses were recorded although 9 patients had stable disease a median 30 weeks (range, 21-112) including 6 with thyroid cancer a median of 33 weeks. PD studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels. Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases.

Conclusions: A romidepsin dose of 7 mg/m(2) administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs. Although there were no objective responses with romidepsin alone, this schedule may be useful for developing combination studies in solid tumors.

Figure 1

Pharmacokinetics of romidepsin. The area under the concentration-time curves up to the last quantifiable point (AUC_LAST) was calculated in WinNonlin v5 using the linear trapezoidal rule. Maximum plasma concentrations (C_MAX) at the end of the 4-hr infusion were recorded as observed values. (A) Log-transformed C1D1 concentration-time profiles of all 28 patients. Relationship between dose and (B) C_MAX or (C) exposure, defined as AUC_LAST. A linear regression analysis was performed to determine the significance of the linear relationship. (D) Dose proportionality of romidepsin in dose-normalized romidepsin plasma exposure on C1D1, C1D3, and C1D5.

Figure 2

Pharmacodynamic endpoints of romidepsin. The fold-increase in acetylated histone H3 at the 4 h and 24 h timepoints compared to baseline in patient PBMCs was determined by an immunodot-blot. A linear regression analysis was used to detemine the relationship between fold-increase and (A) C_max or (B) AUC_LAST. (C) Fold-increase relative to baseline in acetylated histone H3 at the 4 and 24 h time points grouped by dose level as noted. Bar represents median value. Five of six patients studied at dose level 1 or 2 had no measurable increase in AcH3 (although increases over 2-fold were noted in these patients on subsequent cycles when higher doses were administered, data not shown). In contrast, 14 of 16 patients treated at 3.3 mg/m² or greater had > 2-fold increase in histone acetylation. (D) Stacked bar graph denoting incidence of ST segment and T wave changes in 650 ECGs obtained in 120 cycles, according to dose administered. These are a subset of the ECGs reported in Supplementary Table 4. ECG data from patients whose dose was escalated to a higher dose level or de-escalated to a lower dose level than their entry dose are included at the actual dose administered, not at the entry dose. “Pre” indicates ECGs obtained prior to the first dose of a cycle, “4 h” and “24 h” indicate ECGs obtained at infusion end or on the following day, respectively, on days 1, 3 or 5. White segment depicts grade 0, gray segment depicts grade 1 and black segment depicts grade 2 ST and T wave changes.