Phase I Study of Bortezomib and Romidepsin in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Indolent B-Cell Lymphoma, or Peripheral T-Cell Lymphoma
Authors: Holkova Beata , Shea Thomas C. , Bose Prithviraj , Tombes Mary Beth , Shrader Ellen , Wan Wen , Weir-Wiggins Caryn , Stoddert Elizabeth , Sankala Heidi , Kmieciak Maciej , Roberts John D. , Grant Steven 
Published: October 2019

Abstract
Abstract 1794
Preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors in diverse hematologic malignancies, including those of B-cell origin. We have previously shown that the combination of the proteasome inhibitor bortezomib and the HDAC inhibitor romidepsin, administered at extremely low concentrations (∼3–5 nM), results in a striking increase in apoptosis in primary CLL cells, including cells from patients with CLL refractory to standard treatments (Dai Y et al. Clin Cancer Res. 2008). These findings prompted initiation of a phase I trial, 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 chronic lymphocyte leukemia/small lymphocytic lymphoma (CLL/SLL), indolent B-cell lymphoma, or peripheral T-cell lymphoma (PTCL).
To date, 11 patients have been enrolled and treated. All of the patients treated have been diagnosed with CLL/SLL (n=11). The male:female ratio was n = 10 (91%):1 (9%); the median age was 56 (range 46–66) years; ECOG performance scores ranged from 0 to 1; and the median number of prior therapies was 4 (range 2–6). The schedule of administration was intravenous bolus bortezomib followed by a 4-hour intravenous infusion of romidepsin on days 1, 8, and 15; on a 28-day cycle. Dose level 1 = bortezomib 1.3 mg/m2, romidepsin 8 mg/m2 (n=3); level 2A = bortezomib 1.3 mg/m2, romidepsin 10 mg/m2 (n=5); and level 2B = bortezomib 1.6 mg/m2, romidepsin 8 mg/m2(n=3). The study is currently enrolling to dose levels 2A and 2B.
Adverse events were determined using CTCAE version 4. Dose limiting toxicities (DLTs) were determined per protocol and occur in cycle 1 only. Two DLTs have been observed: 1 at dose level 2A (grade 3 fatigue) and 1 at dose level 2B (grade 3 chills, associated with cytokine release syndrome). Both dose levels will be expanded to 6 DLT-evaluable patients. Non-DLT grade 3 or greater adverse events have included anemia (grade 3, 9%), fatigue (grade 3, 9%), leukopenia (grade 3, 9%), nausea (grade 3, 9%), neutropenia (grade 4, 18%), soft tissue infection (grade 3, 9%), and vomiting (grade 3, 9%). Serious adverse events that were deemed at least possibly related to treatment were grade 3 soft tissue infection with grade 4 neutropenia (1 patient); grade 2 fever/nausea/vomiting which precipitated hospitalization (1 patient); and grade 2 cytokine release syndrome with associated grade 3 shaking chills, and grade 2 nausea/vomiting/diarrhea/oral dysethesia/sweats/photophobia/macular rash (1 patient).
All 11 patients treated were evaluable for response. One partial response has been observed to date; the patient (positive for ZAP70; 4 lines of prior chemotherapy) proceeded, after 4 cycles of romidepsin and bortezomib, to allogeneic stem cell transplant. Five patients had a best response of stable disease and 5 had progressive disease. Correlative studies examining pre- and post-treatment expression of NF-κB (nuclear RelA and p52 as a marker of p100 processing), the NF-κB-dependent proteins XIAP and Bcl-xL, and Bim are currently underway.
Collectively, these findings indicate that the safety profile is consistent with those reported for bortezomib and romidepsin, with reversible grade 2 to 4 adverse events, in heavily pretreated patients with relapsed/refractory CLL/SLL. The MTD has not yet been reached. Pending identification of the MTD, phase II evaluation of this therapeutic strategy, if warranted, should determine its activity more definitively in this population.

Disclosures:
Shea: Millennium Pharmaceuticals: Research Funding.