title: Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study.
abstract: BACKGROUND
  Romidepsin is a histone deacetylase inhibitor approved in the USA for patients with recurrent or refractory peripheral T-cell lymphoma and has shown activity in this setting with mainly haematological and gastrointestinal toxicity. Although it has limited efficacy, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used for treatment of de-novo peripheral T-cell lymphoma. We aimed to assess the safety, tolerability, and activity of romidepsin combined with CHOP in patients with previously untreated disease.
  
  
  METHODS
  We enrolled patients aged 18-80 years with histologically proven, previously untreated, peripheral T-cell lymphoma (Eastern Cooperative Oncology Group performance status ≤2) into a dose-escalation (phase 1b) and expansion (phase 2) study at nine Lymphoma Study Association centres in France. In the dose-escalation phase, we allocated consecutive blocks of three participants to receive eight 3 week cycles of CHOP (intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) [maximum 2 mg] on day 1 and oral prednisone 40 mg/m(2) on days 1-5) in association with varying doses of romidepsin. The starting dose was 10 mg/m(2) intravenously on days 1 and 8 of each cycle, and we used a 3 + 3 design. We assessed dose-limiting toxicities only during the first two cycles. The primary endpoint was to determine the recommended dose for the combination. For the phase 2 study, we aimed to increase the cohort of patients receiving the recommended dose to a total of 25 patients. Patients were assessed for safety outcomes at least twice per cycle according to the Common Terminology Criteria for Adverse Events, version 4.0. Safety analyses included all patients who received at least one dose of romidepsin and CHOP. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-020962-91 and ClinicalTrials.gov, number NCT01280526.
  
  
  RESULTS
  Between Jan 13, 2011, and May 21, 2013, we enrolled 37 patients (18 treated in phase 1b and 19 patients in phase 2). Three of six patients initially treated at 10 mg/m(2) had a dose-limiting toxicity. The dose-escalation committee decided to modify the study protocol to redefine dose-limiting toxicities with regard to haematological toxicity. Three patients were treated with 8 mg/m(2) of romidepsin, an additional three at 10 mg/m(2) (one dose-limiting toxicity), and six patients at 12 mg/m(2) (three dose-limiting toxicities). We chose romidepsin 12 mg/m(2) as the recommended dose for phase 2. Of the 37 patients treated, three had early cardiac events (two myocardial infarctions and one acute cardiac failure). No deaths were attributable to toxicity. 25 (68%) of 37 patients had at least one serious adverse event. Overall, the most frequent serious adverse events were febrile neutropenia (five [14%] of 37 patients), physical health deterioration (five [14%]), lung infection (four [11%]), and vomiting (three [8%]). 33 (89%) of patients had grade 3-4 neutropenia, and 29 (78%) had grade 3-4 thrombocytopenia.
  
  
  CONCLUSIONS
  Romidepsin can be combined with CHOP but this combination should now be tested in comparison to CHOP alone in a randomised trial.
  
  
  BACKGROUND
  Celgene.
authors.affiliation: Lymphoid Malignancies Unit, Henri Mondor University Hospital, Créteil, France.
authors.forename: Jehan
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: Department of Hematology, GRITA Unit, Claude Huriez University Hospital, Lille, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Morschhauser
authors.affiliation: Department of Hematology, Léon Bérard Cancer Center, Lyon, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Ghesquières
authors.affiliation: Department of Hematology, Henri Becquerel Cancer Center, Rouen, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tilly
authors.affiliation: Department of Hematology, Le Bocage Hospital, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Casasnovas
authors.affiliation: Department of Hematology-Oncology, Saint Louis Hospital, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Thieblemont
authors.affiliation: Department of Hematology, Gustave Roussy Cancer Center, Villejuif, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
authors.affiliation: Department of Pathology, Hôtel Dieu University Hospital, Nantes, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Bossard
authors.affiliation: Lymphoid Malignancies Unit, Henri Mondor University Hospital, Créteil, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Le Bras
authors.affiliation: Department of Hematology, Hospices Civils de Lyon and University Lyon 1, Lyon, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bachy
authors.affiliation: Department of Hematology, GRITA Unit, Claude Huriez University Hospital, Lille, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Hivert
authors.affiliation: Department of Hematology, Léon Bérard Cancer Center, Lyon, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Nicolas-Virelizier
authors.affiliation: Department of Hematology, Henri Becquerel Cancer Center, Rouen, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jardin
authors.affiliation: Department of Hematology, Le Bocage Hospital, Dijon, France.
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Bastie
authors.affiliation: Department of Hematology-Oncology, Saint Louis Hospital, Paris, France.
authors.forename: Sandy
authors.initials: S
authors.lastname: Amorim
authors.affiliation: Department of Hematology, Gustave Roussy Cancer Center, Villejuif, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Lazarovici
authors.affiliation: Department of Pathology, Avicenne University Hospital, Bobigny, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Martin
authors.affiliation: Department of Hematology, Hospices Civils de Lyon and University Lyon 1, Lyon, France. Electronic address: bertrand.coiffier@chu-lyon.fr.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coiffier
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000627:therapeutic use; D047630:Depsipeptides / Q000627:therapeutic use*; D004317:Doxorubicin / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D005602:France; D006801:Humans; D016411:Lymphoma, T-Cell, Peripheral / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use; D016896:Treatment Outcome; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D047630:Depsipeptides; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; C087123:romidepsin; D011241:Prednisone