A phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma

Abstract

A phase 1 study was conducted to determine the dose-limiting toxicities and maximum-tolerated dose (MTD) for bortezomib followed by romidepsin on days 1, 8, and 15 in patients with relapsed/refractory CLL/SLL or B- or T-cell lymphoma. Eighteen treated patients were evaluable for response. The MTD was 1.3 mg/m2 bortezomib and 10 mg/m2 romidepsin; median treatment duration was 3 cycles at this dose. The dose-limiting toxicities were grade 3 fatigue, vomiting, and chills. Two patients had partial responses, one lasting >2 years, 8 had stable disease, and 8 had progressive disease. The median duration of stable disease was 3.5 cycles. Correlative studies examining expression of NF-кB, XIAP, Bcl-xL, and Bim yielded variable results. The safety profile was consistent with that reported for single-agent bortezomib and romidepsin. This regimen has modest activity in heavily pretreated patients with relapsed/refractory CLL or B- or T-cell lymphoma. NCT00963274.

Keywords: Bortezomib; lymphoma; phase 1 clinical trial; romidepsin.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest:

No potential conflicts of interest were disclosed. Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

Figures

Fig. 1

Pharmacodynamic analysis of pre- and post-treatment blood samples. Relative expression levels of total XIAP, Bcl-XL, Bim (A–C), and nuclear RelA (D) in PBMC from 3 patients were measured by Western blot analysis. Samples were obtained prior to the first dose of study treatment (pre-treatment) and 20 to 24 hours following the first dose of study treatment (post-treatment). Biomarker expression levels were normalized to GAPDH and the normalized pre-treatment value for each sample was defined as 100%. E) p100 to p50 processing pre- and post-treatment is shown as the ratio of p52 to p100 expression, as determined by Western blot. The pre-treatment samples were normalized to 1 prior to calculation of the p100/p52 ratio. All samples were run in triplicate and data are shown as the mean ± SD.