Joske, David

Abstract Background: Responses to the novel HDAC inhibitor romidepsin were observed in patients (pts) with T-cell lymphoma in a phase 1 NCI trial. Aims: To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced cutaneous T-cell lymphoma (CTCL). As an exploratory endpoint, to examine the molecular effects of romidepsin in both CTCL and peripheral T-cell lymphoma (PTCL). Methods: This Phase 2, open-label, multi-arm, multicenter study enrolled 71 CTCL pts from the NCI and 9 extramural sites. PTCL pts were also enrolled. Clinical results for pts with CTCL and biomarker analyses for both PTCL and CTCL are presented here; clinical results for the PTCL pts are presented elsewhere. This study is now closed to accrual. Pts with recurrent CTCL (Stages IA-IVB) received romidepsin at 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 q 28 days. Responses were assessed using a composite endpoint that evaluated overall changes in skin (modified Physicians Global Assessment), lymph nodes, extranodal visceral lesions and abnormal circulating T-cells. Molecular endpoints evaluated in NCI pts were: histone acetylation in peripheral blood mononuclear cells (PBMCs); MDR-1 gene expression in PBMCs and in biopsy samples; and blood fetal hemoglobin levels. Results: 71 pts (48 men and 23 women) with a mean age of 56 yrs (range 28–84) were enrolled and received romidepsin; 63 pts received ≥2 cycles of therapy. Mean number of prior therapies was 3.4 (range 1–10). Objective disease response rates (ORR) are presented in the table. Overall disease control (CR+PR+SD90) was 62% in all pts and 70% in pts who received ≥2 cycles. Target skin lesions were followed and changes were generally similar to overall skin changes. Median duration of response (DOR) was 11 months (mo) and the maximum DOR as of data cut-off was 5.5+ yrs. The most frequent drug-related AEs (all grades, all cycles) were generally mild, including nausea (82%; 4% ≥grade 3), fatigue (73%; 14% ≥ grade 3), electrocardiogram T-wave amplitude decreased (69%, 0% ≥grade 3); hemoglobin decreased (59%, 9% ≥grade 3), and platelet count decreased (59%; 13% ≥grade 3). Six pts died within 30 days of study drug administration: 2 after salvage chemotherapy, 1 with ARDS due to PD, 2 with infection, and 1 of unknown cause; 2 of these deaths were considered possibly related to treatment. An increase in all biomarkers measured was observed, although not in all pts. Correlation between global histone H3 acetylation (AcH3) at the 24-hr time point and Cmax, AUC, and clearance was observed (r = 0.37, 0.36, and −0.44, respectively, p = 0.03). Pts with major responses were more likely to have higher levels of AcH3 at 24 hr. Conclusions: This study demonstrates tolerability and durable clinical benefit (ORR of 35% and median DOR of 11 mo in all pts) of romidepsin in pts with recurrent CTCL. Significant responses were observed at all stages of disease, including an ORR of 32% in all pts with stage ≥IIB and 20% in all pts with stage IV. Time to response was rapid, within 2 mo in most pts, and responses were durable, >6 mo in most pts. Molecular analyses confirmed that romidepsin inhibits its target deacetylases in pts. Increases were not observed in all pts, perhaps reflecting, in part, variable drug exposure or variable response to HDAC inhibition. Correlation of global acetylation with PK parameters suggests that increased drug exposure results in increased global acetylation. All Pts N=71 Pts ≥ 2 cycles N=63 ORR (CR+PR), n (%) 25 (35%) 25 (40%) PR, n (%) 21 (30%) 21 (33%) CR, n (%) 4 (6%) 4 (6%) SD90, n(%) 19 (27%) 19 (30%) Overall disease control (CR+PR+ SD90) 44 (62%) 44 (70%) DOR 11 (1+ mo, 5.5+ yrs) 11 (1+ mo, 5.5+ yrs) OR for pts with stage ≥ IIB, n (%) 20/62 (32%) 20/55 (36%) SD90= stable disease for ≥90 days

Abstract Background: The histone deacetylase (HDAC) inhibitors are a class of epigenetic agents undergoing clinical testing. HDAC inhibitors modulate expression of genes involved in cell cycle regulation, leading to induction of differentiation or apoptosis. Romidepsin, a novel, HDAC inhibitor, has previously demonstrated activity as a single agent in patients (pts) with T-cell lymphoma in a phase 1 NCI study. Aims: To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced PTCL and as an exploratory endpoint, to examine the molecular effects of romidepsin in both PTCL and cutaneous T-cell lymphoma (CTCL). Methods: This Phase 2, open-label, multi-arm, multicenter study enrolled 43 PTCL pts from the NCI and 9 extramural sites. CTCL pts were also enrolled in this study. The clinical results for pts with PTCL are presented here; the clinical results for the pts with CTCL and the biomarker analyses for both PTCL and CTCL are presented elsewhere. This study is now closed to accrual. Pts with relapsed or refractory PTCL or primary cutaneous anaplastic large cell lymphoma were eligible. Pts received romidepsin 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 every 28 days. Responses were assessed using elements of the IWG criteria and RECIST, as appropriate, for pts with lymph node involvement and extranodal disease. Results: 43 pts (23[53%] men and 20 [47%] women) with a mean age of 58.1 (range: 27 to 84) years were treated with romidepsin. 31 pts received ≥ 2 cycles of therapy. Mean number of prior therapies was 3.9 (range 1 to 12). Objective disease response rates (ORR) are summarized in the table. The mean number of cycles of treatment was 6.8 (range 1–37) and the overall median duration of response was 8.3 months (range 1.6 months to 4.8+ yrs) for all pts. The median duration of response for the 7 pts who achieved CR was 8.5 months (range 4.6 months to 4.8+yrs). The most frequent drug-related AEs (all grades, all cycles) were generally mild and included: nausea (86%; 0% ≥grade 3), fatigue (79%; 0% ≥grade 3), decreased platelets (70%; 7% ≥grade 3), and decreased AGC (63%; 5% ≥grade 3). One death, in a pt with significant cardiovascular disease who had achieved a CR, was considered possibly related to treatment. Conclusions: This study demonstrates tolerability and durable clinical benefit (ORR of 39% and median duration of response of 8.3 months) of romidepsin in pts with recurrent or refractory PTCL. Based on these promising results, a Phase 2B protocol investigating romidepsin in pts with progressive or relapsed PTCL is ongoing at multiple international centers. All Pts N=43 Pts ≥ 2 cycles N=31 ORR (CR+PR), n (%) 17 (39%) 17 (55%) PR, n (%) 10 (23%) 10 (32%) CR, n (%) 7 (16%) 7 (23%)

Purpose Romidepsin (depsipeptide or FK228) is a member of a new class of antineoplastic agents active in T-cell lymphoma, the histone deacetylase inhibitors. On the basis of observed responses in a phase I trial, a phase II trial of romidepsin in patients with T-cell lymphoma was initiated. Patients and Methods The initial cohort was limited to patients with cutaneous T-cell lymphoma (CTCL), or subtypes mycosis fungoides or Sézary syndrome, who had received no more than two prior cytotoxic regimens. There were no limits on other types of therapy. Subsequently, the protocol was expanded to enroll patients who had received more than two prior cytotoxic regimens. Results Twenty-seven patients were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months. Conclusion The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.