Article

Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy

Hematology, Centre Hospitalier Lyon-Sud, 69310 Pierre-Benite, France.
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2012; 30(6):631-6. DOI: 10.1200/JCO.2011.37.4223
Source: PubMed

ABSTRACT

Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee.
Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%).
Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.

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Available from: Henry Miles Prince, Nov 22, 2015
    • "In this study we adopted a " piggyback " approach (Nwaka and Hudson, 2006) to extend these findings, focussing on four HDAC inhibitors (Fig. 1) that are clinically approved for cancer. Vorinostat (SAHA; Sigma Aldrich, USA), romidepsin (FK228; Selleck Chemicals, USA), and belinostat (Beleodaq; Spectrum Pharmaceuticals , Inc., USA) have been approved for the clinical treatment of cutaneous or peripheral T-cell lymphoma (Grant et al., 2007; Prince and Dickinson, 2012; Thompson, 2014) and are undergoing clinical trials for various other cancers, including prostate and epithelial ovarian cancers (Garcia-Manero et al., 2008; Modesitt et al., 2008; Molife et al., 2010; Coiffier et al., 2012). Vorinostat and belinostat are hydroxamate-based pan-inhibitors of class I and II mammalian HDACs (Grant et al., 2007; Steele et al., 2011), while romidepsin is a cyclic tetrapeptide pro-drug (Sandor et al., 2002; Byrd et al., 2005) and has some HDAC isoenzyme-selectivity for class I mammalian HDACs (Prince and Dickinson, 2012 ). "
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    ABSTRACT: Histone deacetylase (HDAC) enzymes work together with histone acetyltransferases (HATs) to reversibly acetylate both histone and non-histone proteins. As a result, these enzymes are involved in regulating chromatin structure and gene expression as well as other important cellular processes. HDACs are validated drug targets for some types of cancer, with three HDAC inhibitors clinically approved. However, they are also showing promise as novel drug targets for other indications, including malaria and other parasitic diseases. In this study the in vitro activity of four anti-cancer HDAC inhibitors was examined against parasites that cause malaria and trypanosomiasis. Three of these inhibitors, suberoylanilide hydroxamic acid (SAHA; vorinostat®), romidepsin (Istodax®) and belinostat (Beleodaq®), are clinically approved for the treatment of T-cell lymphoma, while the fourth, panobinostat, has recently been approved for combination therapy use in certain patients with multiple myeloma. All HDAC inhibitors were found to inhibit the growth of asexual-stage Plasmodium falciparum malaria parasites in the nanomolar range (IC50 10–200 nM), while only romidepsin was active at sub-μM concentrations against bloodstream form Trypanosoma brucei brucei parasites (IC50 35 nM). The compounds were found to have some selectivity for malaria parasites compared with mammalian cells, but were not selective for trypanosome parasites versus mammalian cells. All compounds caused hyperacetylation of histone and non-histone proteins in P. falciparum asexual stage parasites and inhibited deacetylase activity in P. falciparum nuclear extracts in addition to recombinant PfHDAC1 activity. P. falciparum histone hyperacetylation data indicate that HDAC inhibitors may differentially affect the acetylation profiles of histone H3 and H4.
    No preview · Article · Jun 2015 · International Journal for Parasitology: Drugs and Drug Resistance
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    • "Analog kwasu foliowego 111 29% 11% 10 miesięcy Romidepsin [32] Inhibitor deacetylazy histonowej 130 25% 15% 17 miesięcy Alisertib [33] "
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    ABSTRACT: Peripheral T-cell lymphoma (PTCL) is relatively uncommon disorder representing only 8–15% of all non-Hodgkin lymphoma. The nodal types of PTCL, which include PTCL not otherwise specified, anaplastic large cell lymphomas (ALCLs), and angioimmunoblastic T cell lymphoma, are a heterogenous group of diseases that are challenging to treat. Although the outcome of patients with PTCL, with the exception of ALK-positive ALCL, is worse than that of patients with B cell lymphomas, they are treated similarly with the CHOP or CHOP-like regimens. The best treatment option for patients who responded to conventional chemotherapy remains undefined. Several prospective phase II studies support autologous hematopoietic stem cell transplantation as consolidation of first response for PTCL. Allogeneic transplant is usually reserved for relapsed disease. In addition, a variety of new drugs were registered in relapsed disease and are being studied in the upfront setting. This review summarizes the standard of care and new treatment options for the most common aggressive PTCL.
    Full-text · Article · Mar 2015 · Acta haematologica Polonica
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    • "Other HDAC inhibitors, romidepsin and vorinostat, have also demonstrated activity in patients with T-cell lymphoma. Romidepsin, a selective Class 1 HDAC inhibitor, is a bicyclic peptide that received accelerated approval in the US and is indicated for the treatment of both PTCL (ORR 25%) and CTCL (ORR 34%) (Whittaker et al, 2010;Coiffier et al, 2012). The most common toxicities associated with romidepsin were nausea (59%), asthenia/fatigue (55%) and thrombocytopenia (41%); associated ECG changes, including QTc prolongation, were also observed in the pivotal clinical trial. "
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    ABSTRACT: Belinostat is a pan-histone deacetylase inhibitor with antitumour and anti-angiogenic properties. An open label, multicentre study was conducted in patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥1 prior systemic therapy and were treated with belinostat (1000 mg/m2 intravenously ×5 d of a 21-d cycle). The primary endpoint was objective response rate (ORR). Patients with PTCL (n = 24) had received a median of three prior systemic therapies (range 1–9) and 40% had stage IV disease. Patients with CTCL (n = 29) had received a median of one prior skin-directed therapy (range 0–4) and four prior systemic therapies (range 1–9); 55% had stage IV disease. The ORRs were 25% (PTCL) and 14% (CTCL). Treatment-related adverse events occurred in 77% of patients; nausea (43%), vomiting (21%), infusion site pain (13%) and dizziness (11%) had the highest incidence. Treatment-related serious adverse events were Grade 5 ventricular fibrillation; Grade 4 thrombocytopenia; Grade 3 peripheral oedema, apraxia, paralytic ileus and pneumonitis; and Grade 2 jugular vein thrombosis. Belinostat monotherapy was well tolerated and efficacious in patients with recurrent/refractory PTCL and CTCL. This trial was registered at www.clinicaltrials.gov as NCT00274651.
    Full-text · Article · Nov 2014 · British Journal of Haematology
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