Responses to Romidepsin in Patients with Cutaneous T-Cell Lymphoma (CTCL) and Prior Treatment with Systemic Chemotherapy: Subanalysis from the Pivotal Phase 2 Study
Authors: Duvic Madeleine , Kim Youn H , Rook Alain H , Lerner Adam , Robak Tadeusz , Samtsov Alexey , McCulloch William , Waksman Joel , Whittaker Sean 
Published: October 2019

Abstract
Background: CTCL is a primarily indolent, heterogeneous group of non-Hodgkin lymphomas that arise in the skin but can progress to systemic disease (blood, lymph nodes, viscera). For patients who require systemic treatment, nonchemotherapeutic agents are currently preferred, and multiagent chemotherapies are typically reserved for patients with disease that is particularly aggressive or relapsed/refractory to multiple prior systemic therapies. Durable clinical responses are difficult to achieve, and selection of the best treatment following chemotherapy is unclear. Romidepsin is a potent, bicyclic class 1 selective HDAC inhibitor approved by the US Food Drug Administration for treatment of patients with CTCL who had received ≥ 1 prior systemic therapy as well as patients with peripheral T-cell lymphoma who have received ≥ 1 prior therapy. In the pivotal phase 2 study for the treatment of relapsed/refractory CTCL (GPI-04-0001), romidepsin resulted in rapid and durable responses, with an objective response rate (ORR) of 34% (33/96), including 6% (6/96) with complete response (CR), and median duration of response (DOR) of 15 months. Reduction in pruritus (a common and often debilitating symptom of CTCL) with romidepsin treatment was seen in both clinical responders and nonresponders. Here, we present data for patients with prior systemic chemotherapy from GPI-04-0001.
Methods: Adult patients with stage IB-IVA CTCL, including mycosis fungoides and Sézary syndrome, in whom ≥ 1 prior systemic therapy had failed received romidepsin 14 mg/m2as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for patients with stable disease or response. The primary endpoint was ORR (CR + partial response) using a rigorous composite endpoint based on the sum of changes in the skin, lymph nodes, and blood. DOR was a key secondary endpoint, and reduction in pruritus (by patient-assessed 100-mm visual analog scale [VAS]) was analyzed as an additional indicator of clinical benefit. Concomitant use of antipruritic medications (eg steroids, antihistamines) was not allowed. Responses were assessed at patient screening, on day 1 of each treatment cycle, at end-of-study visit, and every 2 months thereafter for patients off study without disease progression (PD). In this analysis, efficacy and safety of romidepsin in patients with CTCL and prior systemic chemotherapy is assessed.
Results: Patients (N = 96) had received a median of 2 (range, 1-8) prior systemic therapies, and 73 of 96 patients (76%) had been previously treated with systemic chemotherapy. The most common prior single-agent chemotherapy and multiagent regimens were methotrexate, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and COP (CHOP without doxorubicin). Patients with all stages of CTCL (IB-IVA) had been previously treated with chemotherapy, including 10 of 15 patients with stage IB disease and 21 of 25 patients with skin disease only. The ORR in patients with prior chemotherapy was 34% (25/73), including all 6 patients who achieved CR (8%). The median time to response was 57 days, and the median DOR was 15 months, with the longest response ongoing at 19 months. Response rates to romidepsin for patients with 1, 2, 3, or > 3 total prior systemic therapies were 32% (8/25), 43% (6/14), 27% (4/15), and 37% (7/19), respectively. The mean best change in pruritus VAS for the 50 patients with prior chemotherapy and moderate to severe pruritus at baseline was −39 mm; 24 of 50 patients (48%) experienced clinically meaningful pruritus reduction, defined as a reduction of ≥ 30 mm for ≥ 2 consecutive treatment cycles. The most common (≥ 10%) treatment-emergent adverse events in patients with prior chemotherapy were nausea (52%), asthenic conditions (51%), anorexia (26%), vomiting (26%), pyrexia (22%), anemia (19%), thrombocytopenia (19%), diarrhea (15%) and headache (15%), and most events were grade 1/2.
Conclusions: Patients in the pivotal study of romidepsin for the treatment of relapsed/refractory CTCL were heavily pretreated, and the majority—even those with early-stage disease—had received prior systemic chemotherapy. Romidepsin resulted in durable responses with manageable toxicity in patients with prior chemotherapy, supporting the use of romidepsin irrespective of the number of prior therapies.

Disclosures
Duvic: Celgene: Consultancy, Research Funding. Kim:Celgene : Advisory Board Other. Robak:Celgene: Research Funding; Gloucester Pharmaceuticals: Research Funding. McCulloch:Celgene, Inc. : Consultancy, Equity Ownership. Waksman:Brightech International, LLC: Consultancy. Whittaker:Millennium Pharmaceuticals: Advisory Board, Advisory Board Other, Consultancy, Honoraria, Research Funding; Actelion: Advisory Board Other, Consultancy.