A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma
Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic
Typ dokumentu klinické zkoušky, fáze II, časopisecké články, multicentrická studie
Grantová podpora
Pharmacyclics LLC, an AbbVie Company
PubMed
31883396
PubMed Central
PMC7216833
DOI
10.1111/ejh.13377
Knihovny.cz E-zdroje
- Klíčová slova
- bortezomib, dexamethasone, ibrutinib, multiple myeloma,
- MeSH
- adenin aplikace a dávkování analogy a deriváty MeSH
- bortezomib aplikace a dávkování MeSH
- chemorezistence MeSH
- dexamethason aplikace a dávkování MeSH
- dospělí MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetný myelom diagnóza farmakoterapie mortalita MeSH
- opakovaná terapie MeSH
- piperidiny aplikace a dávkování MeSH
- prognóza MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky terapeutické užití MeSH
- recidiva MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- staging nádorů MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- Názvy látek
- adenin MeSH
- bortezomib MeSH
- dexamethason MeSH
- ibrutinib MeSH Prohlížeč
- piperidiny MeSH
OBJECTIVE: We evaluated ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, combined with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma who had received 1-3 prior therapies. METHODS: This was a phase 2, single-arm, open-label, multicentre study (NCT02902965). The primary endpoint was progression-free survival (PFS). RESULTS: Seventy-six patients were enrolled; 74 received ≥1 dose of study treatment. After median follow-up of 19.6 months, median PFS was 8.5 months (95% CI: 6.2-10.8); median overall survival was not reached. Overall response rate was 57% (95% CI: 45-68), and median duration of response was 9.5 months (95% CI: 6.9-10.6). Grade 3/4 AEs occurred in 73% of patients and fatal AEs occurred in 15% of patients. Incidence of major haemorrhage was 5%; one patient died from cerebral haemorrhage. After an observed increased incidence of serious (42%) and fatal (11%) infections, enrolment was suspended to implement risk-minimisation measures. The safety profile was otherwise consistent with known safety profiles of the individual drugs. CONCLUSION: Ibrutinib combined with bortezomib and dexamethasone elicited clinical responses. However, efficacy assessments conducted at potential restart of enrolment indicated that the targeted PFS could not be reached with additional patient enrolment, and the study was terminated.
Ankara University School of Medicine Ankara Turkey
Faculty of Medicine University of Ostrava Ostrava Czech Republic
General Hospital of Thessaloniki G Papanikolaou Thessaloniki Greece
Hospital Universitario Virgen del Rocio Sevilla Spain
IRCCS Casa Sollievo della Sofferenza Hospital San Giovanni Rotondo Italy
Pharmacyclics LLC an AbbVie Company Sunnyvale CA USA
Pharmacyclics Switzerland GmbH an AbbVie Company Schaffhausen Switzerland
University Hospital Brno Brno Czech Republic
University Hospital of Ostrava Ostrava Poruba Poruba Czech Republic
Zobrazit více v PubMed
Kumar SK, Rajkumar V, Kyle RA, et al. Multiple myeloma. Nat Rev Dis Primers. 2017;3:17046. PubMed
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7‐30. PubMed
Nijhof IS, van de Donk N, Zweegman S, Lokhorst HM. Current and new therapeutic strategies for relapsed and refractory multiple myeloma: an update. Drugs. 2018;78(1):19‐37. PubMed PMC
Tai Y‐T, Chang BY, Kong S‐Y, et al. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood. 2012;120(9):1877‐1887. PubMed PMC
Yang Y, Shi J, Gu Z, et al. Bruton tyrosine kinase is a therapeutic target in stem‐like cells from multiple myeloma. Cancer Res. 2015;75(3):594‐604. PubMed PMC
Janssen‐Cilag International NV . IMBRUVICA (ibrutinib) Summary of Product Characteristics 2018. Beerse, Belgium.
Pharmacyclics LLC . IMBRUVICA (ibrutinib) prescribing information 2019. Sunnyvale, CA.
Rushworth SA, Bowles KM, Barrera LN, Murray MY, Zaitseva L, MacEwan DJ. BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF‐kappaB. Cell Signal. 2013;25(1):106‐112. PubMed
Richardson PG, Bensinger WI, Huff CA, et al. Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results. Br J Haematol. 2018;180(6):821‐830. PubMed PMC
Chari A, Larson S, Holkova B, et al. Phase 1 trial of ibrutinib and carfilzomib combination therapy for relapsed or relapsed and refractory multiple myeloma. Leuk Lymphoma. 2018;59(11):2588‐2594. PubMed
European Medicines Agency . Velcade: EPAR ‐ Product Information 2019; Amsterdam, The Netherlands. https://www.ema.europa.eu/en/documents/product-information/velcade-epar-product-information_en.pdf. Accessed July 28, 2019.
US Food and Drug Administration . VELCADE (bortezomib) for injection, for subcutaneous or intravenous use 2019. Silver Spring, Maryland, USA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021602s044lbl.pdf. Accessed July 28, 2019.
Rajkumar SV, Harousseau J‐L, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691‐4695. PubMed PMC
Millennium Pharmaceuticals Inc . VELCADE (bortezomib) prescribing information 2019. Cambridge, MA.
Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213‐223. PubMed PMC
Dimopoulos MA, Trotman J, Tedeschi A, et al. Ibrutinib for patients with rituximab‐refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open‐label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2017;18(2):241‐250. PubMed
Wang ML, Blum KA, Martin P, et al. Long‐term follow‐up of MCL patients treated with single‐agent ibrutinib: updated safety and efficacy results. Blood. 2015;126(6):739‐745. PubMed PMC
Gopal AK, Schuster SJ, Fowler NH, et al. Ibrutinib as treatment for patients with relapsed/refractory follicular lymphoma: results from the open‐label, multicenter, phase II DAWN study. J Clin Oncol. 2018;36(23):2405‐2412. PubMed
Chanan‐Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double‐blind, phase 3 study. Lancet Oncol. 2016;17(2):200‐211. PubMed
Shanafelt TD, Wang V, Kay NE, et al. Randomized phase III study of ibrutinib (PCI‐32765)‐based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG‐ACRIN Cancer Research Group (E1912). Blood. 2018;132:LBA‐4.
San‐Miguel JF, Hungria VTM, Yoon S‐S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double‐blind phase 3 trial. Lancet Oncol. 2014;15(11):1195‐1206. PubMed