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: Updated Results
Authors: Holkova Beata , Kmieciak Maciej , Bose Prithviraj , Ma Shuo , Kimball Amy , Tombes Mary Beth , Shrader Ellen , Wan Wen , Weir-Wiggins Caryn , Stoddert Elizabeth , Singh Amanda Garnett , Dean April , Conine Sarah , Sankala Heidi , Roberts John D. , Shea Thomas C. , Grant Steven 
Published: November 2019

Abstract
The combination of proteasome and histone deacetylase (HDAC) inhibitors has shown synergistic interactions in pre-clinical studies involving diverse hematologic malignancies. We have previously reported that the combination of the proteasome inhibitor bortezomib and the HDAC inhibitor romidepsin, administered at extremely low concentrations (eg, ~3-5 nM), results in a striking increase in apoptosis in primary chronic lymphocytic leukemia (CLL) cells, including cells obtained from patients with CLL refractory to standard treatments (Dai Y et al. Clin Cancer Res. 2008). Romidepsin is an approved agent for both cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Based on these findings, a phase 1 trial was initiated, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and romidepsin in patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL), indolent B-cell lymphoma, PTCL, or CTCL.
Eighteen patients (13 with CLL/SLL, 1 with CTCL, 2 with indolent B-cell lymphoma, and 2 with PTCL; 15 male, 3 female) were enrolled and treated. The median age was 56.5 years (range 31-76); ECOG performance scores ranged from 0 to 1; and the median number of prior therapies was 3 (range 1-6). Bortezomib was administered as an intravenous bolus followed by a 4-hour intravenous infusion of romidepsin on days 1, 8, and 15 of 4-week cycles. The dose levels were: dose level 1 = bortezomib 1.3 mg/m2, romidepsin 8 mg/m2 (n = 3); dose level 2A = bortezomib 1.3 mg/m2, romidepsin 10 mg/m2 (n = 9); and dose level 2B = bortezomib 1.6 mg/m2, romidepsin 8 mg/m2 (n = 6).
Adverse events (AEs) and dose-limiting toxicities (DLTs) were determined using NCI-CTCAE version 4 and protocol guidelines. DLTs were determined in cycle 1 only. There was 1 DLT at dose level 2A (grade 3 fatigue), 2 DLTs at dose level 2B (grade 3 chills [associated with grade 2 cytokine release syndrome] and grade 3 vomiting), and no DLTs at dose level 1 (Table 1). Accrual to dose levels 2A and 2B took place using an alternating enrollment schema. Dose level 2A was identified as the MTD. Non-DLT grade 3 AEs for all treated patients possibly, probably, or definitely related to study treatment included anemia (6%), cytokine release syndrome (6%), fatigue (11%), leukopenia (6%), lymphopenia (6%), nausea (6%) neutropenia (11%), soft tissue infection (6%), vomiting (11%), and grade 4 neutropenia (17%). Common grade 2 AEs possibly, probably, or definitely related to study treatment included fatigue (44%), leukopenia (22%), nausea (44%), neutropenia (39%), and thrombocytopenia (39%).
All 18 patients treated in this study were evaluable for response. One partial response has been observed to date in a patient with CLL who was ZAP70 positive and had received 4 lines of prior chemotherapy. After 4 cycles of romidepsin and bortezomib, this patient proceeded to a stem cell transplant from an unrelated donor and has remained in complete remission since 2012. Nine patients had a best response of stable disease (CLL/SLL = 6; CTCL = 1; indolent B-cell lymphoma = 2 [1 patient still on treatment]) and 8 had progressive disease. Correlative studies examining pre- and post-treatment expression of NF-кB, XIAP, Bcl-xL, and Bim were performed for 3 patients and yielded variable results. Although the small sample size did not permit correlations to be made between protein expression of these markers and treatment outcome, the ability to obtain these data supports the feasibility of the correlative methodology.
The MTD was reached at dose level 2A (Table 1). The study is closed to accrual and one patient remains on treatment at dose level 2A. The safety profile is consistent with those reported for bortezomib and romidepsin, with reversible grade 2 to 4 AEs. The regimen appears to have modest activity in heavily pretreated patients with relapsed/refractory CLL/SLL, indolent B-cell lymphoma, or CTCL.
Table 1. Dose Level Enrollment and DLTs Dose Level Bortezomib (mg/m2) Romidepsin (mg/m2) Patients treated/# DLTs DLT 1 1.3 8 3/0 2A* 1.3 10 9/1 Grade 3 fatigue 2B** 1.6 8 6/2 Grade 3 chills (associated with cytokine release syndrome) Grade 3 vomiting
*MTD
**Exceeded MTD

Disclosures
Holkova: Seattle Genetics, Inc.: Research Funding. Bose:Celgene: Membership on an entity's Board of Directors or advisory committees. Roberts:Selexys: Research Funding.