ALBERT

Description: Background: Romidepsin is a bicyclic peptide that inhibits Class I and II HDACs. Piekarz et al noted responses to romidepsin in CTCL (ASCO, 2004). This pivotal phase II study sought to confirm the activity. Methods: This single arm, open label study enrolled CTCL (Stages 1B–1VA), including MF and Sézary syndrome (SS) patients (pts) from ∼40 sites in Europe, Russia, Ukraine, Georgia and the US. Pts with biopsy-proven CTCL (centrally reviewed) who failed ≥1 prior systemic therapy received romidepsin at 14 mg/m2 as a 4-hour IV infusion on Days 1, 8, and 15 q 28 days for up to 6 cycles but could continue if deriving benefit. Eligibility criteria included adequate organ function and ECOG PS ≤ 1. Exclusions included significant CV abnormality or treatment with QTc-prolonging or CYP3A4-inhibiting drugs. The primary endpoint is response rate measured by a combination of imaging, circulating malignant T-cell counts and a weighted scoring instrument to determine skin involvement (confirmed by photography). Target accrual of 64 evaluable pts (i.e. received 2 courses) has been reached and the study will close. Results: 92 pts were eligible with 68 evaluable for efficacy per protocol. Responses in evaluable pts are 1 CR, 3 CCRs, 20 PRs, 40 SD and 4 PD for an ORR of 35% (duration 2–21 months). Of pts who received ≥1 dose, the ORR is 26% (24/92) but includes 5 too early to be assessed. Median time to response is 8 weeks (range 4 – 20). Responses by stage at entry in evaluable pts, as available: Stage IB-IIA 7/23 (30%); Stage IIB-IVA 15/37 (41%). In pts with pruritus at baseline i.e. score of ≥ 30 mm on a 100 mm visual analogue scale (VAS), relief of ≥ 30 mm from baseline or a VAS score of 0 (no itching) for at least 2 cycles, was seen in 18/38 pts (47%). In those pts with severe pruritus (VAS score ≥70 mm), 14/24 (58%) experienced relief of itching. Adverse event (AE) data are available for 75 pts. AEs were reported in 54/75 (72%) of dosed pts but Grade (G) 3/4 events in only 12/75 (16%). Most frequent AEs are nausea/vomiting (G2) fatigue (G2/3), myelosuppression (G2/3), and asymptomatic ECG changes (transient mild QTc prolongation and nonspecific ST-T wave abnormalities). Thirteen pts withdrew due to AEs but there were no treatment-related deaths although 4 pts died of PD and 1 from right ventricular failure. Serious AEs considered possibly, probably or likely related to treatment were reported in 12 pts. Of these, 8 had ≥G3 events: tumor lysis, cardiac tamponade, sepsis, constipation, oral candidiasis, dermatitis, hyperglycemia/vomiting/nausea and bradyarrhythmia/atrial fibrillation. Conclusions: This study confirms the efficacy of romidepsin in treatment-refractory CTCL including relief of pruritus and an encouraging response rate with 4 CCR (1 pathology-confirmed). The low rate of discontinuation due to AEs and prolonged treatment duration of some patients illustrate that toxicity has been manageable.

Description: Background: Panobinostat is a histone deacetylase inhibitor that has shown promising results in cutaneous T-cell lymphoma (CTCL). Objectives: An open-label, multicenter, Phase II study is being conducted with a primary objective of establishing the efficacy and safety of the pan-deacetylase inhibitor, panobinostat (LBH589), for patients (pts) with relapsed/refractory CTCL with Stage IB–IVA mycosis fungoides (MF) or Sézary syndrome (SS). Methods: Inclusion criteria include adequate organ function, no clinically significant cardiovascular abnormalities (QTcF ≤ 450 ms, ECOG PS ≤2), failure of ≥2 prior systemic therapies, and no prior HDAC inhibitor treatment. Pts were grouped as having bexarotene therapy (Group [Gr] 1) or bexarotene naïve (Gr 2). Panobinostat was administered at a dose of 20 mg orally on Days 1, 3, 5, weekly, every 28 days until progression or unacceptable toxicity. Response was based on a composite score, including skin assessment with the modified Severity-Weighted Assessment Tool (mSWAT) and systemic disease assessed by CT scan. Results: To date, 95 pts (Gr 1=62; Gr 2=33) have enrolled with median age of 58 yrs [range 25–88]: 58 male, 37 female; 70 MF, 25 SS. Median prior treatment regimens are 4 and 3 for Gr 1 and 2, respectively. Most pts were ≥Stage IIB at study entry (Gr 1=42; Gr 2=26) and received 1–17+ (median=3) treatment cycles of panobinostat. In Gr 1, 11/62 pts have had confirmed skin responses by SWAT, including 2 complete skin responses. Confirmatory CT scans are pending for 2 patients. In Gr 2, 4/33 pts had confirmed skin and CT scan responses. Common AEs (〉20%; all grades, regardless of causality) included diarrhea, thrombocytopenia, nausea, pruritus, fatigue, and asthenia, and Grade 3/4 AEs (〉2%, regardless of causality) included thrombocytopenia, neutropenia, pruritus, diarrhea, and hypophosphatemia. Of 4,542 ECGs analyzed, 2 pts have had QTcF 〉480 ms; 4 had QTcF 〉60 ms increase from baseline. Conclusions: Panobinostat continues to demonstrate encouraging clinical activity with a manageable safety profile in pts with CTCL. Per predefined criteria, Group 2 enrollment to Stage 2 is open. Updated efficacy and safety data will be presented.

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

Description: B-cell lymphoma 2 (Bcl-2) is a pivotal regulator of apoptotic cell death and it is overexpressed in many cancers. Consequently, the Bcl-2 protein is an attractive target for drug design, and Bcl-2–specific antisense oligonucleotides or small-molecule Bcl-2 inhibitors have shown broad anticancer activities in preclinical models and are currently in several clinical trials. The clinical application of immunotherapy against cancer is rapidly moving forward in multiple areas, including the adoptive transfer of anti–tumor-reactive T cells and the use of “therapeutic” vaccines. The overexpression of Bcl-2 in cancer and the fact that immune escape by down-regulation or loss of expression of this protein would impair sustained tumor growth makes Bcl-2 a very attractive target for anticancer immunotherapy. Herein, we describe spontaneous T-cell reactivity against Bcl-2 in peripheral blood from patients suffering from unrelated tumor types (ie, pancreatic cancer, breast cancer, acute myeloid leukemia [AML], and chronic lymphocytic leukemia [CLL]). Additionally, we show that these Bcl-2–reactive T cells are indeed peptide-specific, cytotoxic effector cells. Thus, Bcl-2 may serve as an important and widely applicable target for anticancer immunotherapeutic strategies (eg, in the combination with conventional radiotherapy and chemotherapy).