title: Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study.
abstract: BACKGROUND
  Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma.
  
  
  METHODS
  This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74).
  
  
  RESULTS
  Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]).
  
  
  CONCLUSIONS
  Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma.
  
  
  BACKGROUND
  Janssen Research & Development, LLC.
authors.affiliation: Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany. Electronic address: Martin.Dreyling@med.uni-muenchen.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Dreyling
authors.affiliation: Department of Hematology, Jagiellonian University, Krakow, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Jurczak
authors.affiliation: Skånes Universitetssjukhus, Lund, Lund, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Jerkeman
authors.affiliation: Instituto De Ensino E Pesquisa São Lucas, São Paulo, Brazil.
authors.forename: Rodrigo Santucci
authors.initials: RS
authors.lastname: Silva
authors.affiliation: Hematology Division, Hematology and Oncology Department, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Rusconi
authors.affiliation: Vseobecna fakultni nemocnice, Interni Klinika-Klinika Hematologie, Urologicka klinika, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Trneny
authors.affiliation: UZ Gent-Departement Oncologie, Gent, Belgium.
authors.forename: Fritz
authors.initials: F
authors.lastname: Offner
authors.affiliation: Instituto Biosanitario de Salamanca, Hospital Clinico Universitario Salamanca, Salamanca, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Caballero
authors.affiliation: Champalimaud Centre for the Unknown, Hematology Department, Lisbon, Portugal; Instituto Português de Oncologia, Lisbon, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Joao
authors.affiliation: Klinikum der Ruprechts-Karls-Universität Heidelberg-Med. Klinik u. Poliklinik V, Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Witzens-Harig
authors.affiliation: University Medical School of the Johannes Gutenberg-University, Department of Hematology, Oncology and Pneumology, Mainz, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Hess
authors.affiliation: The Ottawa Hospital-General Campus, Ottawa-Hospital General Campus, Ottawa, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bence-Bruckler
authors.affiliation: Seoul St Mary's Hospital, Seocho-gu, Seoul, South Korea.
authors.forename: Seok-Goo
authors.initials: SG
authors.lastname: Cho
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: John
authors.initials: J
authors.lastname: Bothos
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Jenna D
authors.initials: JD
authors.lastname: Goldberg
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Enny
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Shana
authors.initials: S
authors.lastname: Traina
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Nibedita
authors.initials: N
authors.lastname: Bandyopadhyay
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Sun
authors.affiliation: Janssen Research & Development, LLC, Leiden, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: Vermeulen
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Rizo
authors.affiliation: Derriford Hospital, Plymouth, Devon, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Rule
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010880:Piperidines; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; C401859:temsirolimus; D000225:Adenine; D020123:Sirolimus