ALBERT

Description: 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.

Description: Abstract 2683 Poster Board II-659 Background: Responses to romidepsin, a novel pan-HDAC inhibitor, have been observed in patients (pts) with cutaneous T-cell lymphoma (CTCL) in 2 phase 2 studies. One of these studies, the pivotal study was a phase 2, single-arm, open-label study that enrolled 96 pts with CTCL (Stages IB–IVA) at 33 European and US sites. The objective response rate (ORR) was 34% including 6 complete clinical responses (CCR) in all treated pts. Responses (including CCRs) were seen across all stages of disease with a 42% ORR in stage ≥IIB. The median duration of response (DOR) was 14.9 months (mo). The safety profile was characterized principally by mild (grade 1 and 2) gastrointestinal disturbances, hematologic toxicities, clinical chemistry abnormalities and asthenic conditions [Kim, et al. Blood (ASH Abstracts), Nov 2008; 112: 263]. This report summarizes the analysis of 37 pts in the study with blood involvement (Sézary cells 〉5% circulating lymphocytes at baseline). Methods: Pts who failed ≥1 prior systemic therapy, had adequate organ function, and ECOG PS 0 or 1 were eligible. Exclusions included significant cardiovascular abnormality or treatment with QTc-prolonging or CYP3A4-inhibiting drugs. Pts received romidepsin 14 mg/m2 as a 4-hr IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles (extended for stable disease [SD] or response). Response was measured with a quantitative composite which included skin involvement [severity-weighted assessment tool (SWAT) or erythroderma scale], lymph node involvement (CT or MRI scans), and blood involvement (circulating Sézary cells assessed by flow cytometry). Pruritus was assessed by visual analog scale (VAS). Pts with baseline VAS ≥30mm were included in pruritus analysis. Results: Of the 37 pts with 〉5% circulating Sézary cells, 27 (73%) met the definition of evaluable (received ≥2 cycles of romidepsin) for efficacy. 8 of these 27 pts with blood involvement had a greater blood tumor burden (Sézary cell counts 〉1000 cells/mm3 and/or Sézary cells 〉20% of lymphocytes). Mean age was 57±13 yrs and median number of prior systemic therapies was 6 (range 1–14) for all pts. 17 (46%) pts received prior bexarotene and 5 (14%) received prior denileukin diftitox. Response (by composite assessment) and pruritus relief data for the evaluable pts are included in the table. Pts who achieved a response had a rapid, dramatic and durable reduction in Sézary cell counts. ORR was 32% by composite assessment in all pts including 2 CCRs. 5 pts who responded had received bexarotene (including 1 CCR) and 2 had received both denileukin diftitox and bexarotene. The median DOR (for pts with a response by composite assessment) has not been reached; the maximum DOR was 19.8 months. 12 of 27 evaluable pts had erythroderma; 5 of these pts had ≥50% response in skin (4=partial response [PR], 1=SD by composite assessment). 16 of the 37 as-treated pts had erythroderma; 6 of these pts had '50% response in skin (4=PR, 2=SD by composite assessment). The safety profile in this subset of 37 pts is similar to the overall safety profile of romidepsin in this study and the overall safety profile of romidepsin. No unusual drug-related adverse events were observed. Conclusions: This study shows clinical benefit associated with romidepsin treatment in a heavily pre-treated group of pts with CTCL with blood involvement. Additional treatment options are needed for these pts. The ORR (32%) in all pts in this group was comparable with the ORR in the entire study (34%). Toxicities associated with romidepsin were tolerable and manageable. The new drug application for the use of romidepsin in CTCL is under review at the FDA. Disclosures: Robak: F Hoffmann-La Roche: Honoraria. McCulloch:Gloucester Pharmaceuticals: Consultancy. Whittaker:Gloucester Pharmaceuticals: Research Funding.

Description: Background: Responses to romidepsin, a novel pan-HDAC inhibitor, have been observed in patients (pts) with cutaneous T-cell Lymphoma (CTCL). This Phase 2B, singlearm, open-label registration study enrolled pts with CTCL (Stages IB–IVA) at 33 European and US sites. Pts with histologically confirmed CTCL who failed ≥1 prior systemic therapy, had adequate organ function, and ECOG PS 0 or 1 were eligible. Exclusions included significant cardiovascular abnormality or treatment with QTc-prolonging or CYP3A4-inhibiting drugs. Pts received romidepsin 14 mg/m2 as a 4-hr IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles (extended for stable disease or response). Aim: The primary endpoint was the response rate among evaluable pts, measured by a combination of a weighted scoring instrument to determine skin involvement (SWAT), imaging, and circulating Sézary cells (as applicable). Results: 96 pts were enrolled and received romidepsin (as-treated); 72 (75%) were evaluable (≥2 cycles) for efficacy. Enrollment is complete, 4 pts with confirmed PR continue to receive romidepsin on extended treatment, 5 pts off-treatment are being followed. Mean age of all pts was 57±12 yrs, and median time since diagnosis was 3 yrs (range 500 msec. Conclusions: This study shows clinical benefit associated with romidepsin use in treatment-refractory CTCL, with pts achieving durable response and relief from pruritus. Toxicities associated with romidepsin were tolerable and manageable. Evaluable Pts N=72 As-treated Pts N=96 a stable disease for ≥90 days b relief = ≥ 30mm decrease on 100mm VAS or score of 0 for 2 consecutive cycles Confirmed ORR 42% 34% PR, n (%) 24 (33%) 27 (28%) CCR, n (%) 6 (8%) 6 (6%) SD90a, n (%) 26 (36%) 28 (29%) Overall disease control (CCR+PR+SD90) 56 (78%) 61 (64%) Median time (mo) to response (range) 1.9 (0.9–4.8) 1.9 (0.9–4.8) Median time (mo) to disease progression (range) 9.0 (2.7–21.7) 8.3 (0–21.7) Confirmed OR in stage ≥ IIB, n (%) 23/48 (48%) 26/68 (38%) Relief of pruritusb, n (%) 25/52 (48%) NA Relief of severe pruritus, n (%) 16/29 (55%) NA