Martin Dreyling1, Wojciech Jurczak2, Mats Jerkeman3, Rodrigo Santucci Silva4, Chiara Rusconi5, Marek Trneny6, Fritz Offner7, Dolores Caballero8, Cristina Joao9, Mathias Witzens-Harig10, Georg Hess11, Isabelle Bence-Bruckler12, Seok-Goo Cho13, John Bothos14, Jenna D Goldberg14, Christopher Enny14, Shana Traina14, Sriram Balasubramanian15, Nibedita Bandyopadhyay14, Steven Sun14, Jessica Vermeulen16, Aleksandra Rizo14, Simon Rule17. 1. Department of Medicine III, Klinikum der Universität München, Campus Grosshadern, Munich, Germany. Electronic address: Martin.Dreyling@med.uni-muenchen.de. 2. Department of Hematology, Jagiellonian University, Krakow, Poland. 3. Skånes Universitetssjukhus, Lund, Lund, Sweden. 4. Instituto De Ensino E Pesquisa São Lucas, São Paulo, Brazil. 5. Hematology Division, Hematology and Oncology Department, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy. 6. Vseobecna fakultni nemocnice, Interni Klinika-Klinika Hematologie, Urologicka klinika, Prague, Czech Republic. 7. UZ Gent-Departement Oncologie, Gent, Belgium. 8. Instituto Biosanitario de Salamanca, Hospital Clinico Universitario Salamanca, Salamanca, Spain. 9. Champalimaud Centre for the Unknown, Hematology Department, Lisbon, Portugal; Instituto Português de Oncologia, Lisbon, Portugal. 10. Klinikum der Ruprechts-Karls-Universität Heidelberg-Med. Klinik u. Poliklinik V, Heidelberg, Germany. 11. University Medical School of the Johannes Gutenberg-University, Department of Hematology, Oncology and Pneumology, Mainz, Germany. 12. The Ottawa Hospital-General Campus, Ottawa-Hospital General Campus, Ottawa, Canada. 13. Seoul St Mary's Hospital, Seocho-gu, Seoul, South Korea. 14. Janssen Research & Development, LLC, Raritan, NJ, USA. 15. Janssen Research & Development, LLC, Spring House, PA, USA. 16. Janssen Research & Development, LLC, Leiden, The Netherlands. 17. Derriford Hospital, Plymouth, Devon, UK.
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). FINDINGS: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%]). INTERPRETATION: 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. FUNDING: Janssen Research & Development, LLC.
RCT Entities:
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). FINDINGS: 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%]). INTERPRETATION: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. FUNDING: Janssen Research & Development, LLC.
Authors: Stephen E Spurgeon; Brian G Till; Peter Martin; Andre H Goy; Martin P Dreyling; Ajay K Gopal; Michael LeBlanc; John P Leonard; Jonathan W Friedberg; Lawrence Baizer; Richard F Little; Brad S Kahl; Mitchell R Smith Journal: J Natl Cancer Inst Date: 2016-12-31 Impact factor: 13.506
Authors: Benjamin L Lampson; Lijian Yu; Robert J Glynn; Jacqueline C Barrientos; Eric D Jacobsen; Versha Banerji; Jeffrey A Jones; Renata Walewska; Kerry J Savage; Gregory F Michaud; Javid J Moslehi; Jennifer R Brown Journal: Blood Date: 2017-02-21 Impact factor: 22.113