Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13)Research in context
Summary: Background: The Bruton's tyrosine kinase inhibitor ibrutinib and the proteasome inhibitor bortezomib have single-agent activity, non-overlapping toxicities, and regulatory approval in mantle cell lymphoma (MCL). In vitro, their combination provides synergistic cytotoxicity. In this in...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | EClinicalMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S258953702300398X |
| _version_ | 1827808689205018624 |
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| author | Urban Novak Martin Fehr Sämi Schär Martin Dreyling Christian Schmidt Enrico Derenzini Thilo Zander Georg Hess Ulrich Mey Simone Ferrero Nicolas Mach Carola Boccomini Sebastian Böttcher Michèle Voegeli Anne Cairoli Vanesa-Sindi Ivanova Thomas Menter Stefan Dirnhofer Bernhard Scheibe Sandra Gadient Katrin Eckhardt Emanuele Zucca Christoph Driessen Christoph Renner |
| author_facet | Urban Novak Martin Fehr Sämi Schär Martin Dreyling Christian Schmidt Enrico Derenzini Thilo Zander Georg Hess Ulrich Mey Simone Ferrero Nicolas Mach Carola Boccomini Sebastian Böttcher Michèle Voegeli Anne Cairoli Vanesa-Sindi Ivanova Thomas Menter Stefan Dirnhofer Bernhard Scheibe Sandra Gadient Katrin Eckhardt Emanuele Zucca Christoph Driessen Christoph Renner |
| author_sort | Urban Novak |
| collection | DOAJ |
| description | Summary: Background: The Bruton's tyrosine kinase inhibitor ibrutinib and the proteasome inhibitor bortezomib have single-agent activity, non-overlapping toxicities, and regulatory approval in mantle cell lymphoma (MCL). In vitro, their combination provides synergistic cytotoxicity. In this investigator-initiated phase 1/2 trial, we established the recommended phase 2 dose of ibrutinib in combination with bortezomib, and assessed its efficacy in patients with relapsed or refractory MCL. Methods: In this phase 1/2 study open in 15 sites in Switzerland, Germany and Italy, patients with relapsed or refractory MCL after ≤2 lines of chemotherapy and both ibrutinib-naïve and bortezomib-naïve received six cycles of ibrutinibb and bortezomib, followed by ibrutinib maintenance. For the phase 1 study, a standard 3 + 3 dose escalation design was used to determine the recommended phase 2 dose of ibrutinib in combination with bortezomib. The primary endpoint in phase 1 was the dose limiting toxicities in cycle 1. The phase 2 study was an open-label, single-arm trial with a Simon's two-stage min–max design, with a primary endpoint of overall response rate (ORR) assessed by CT/MRI. This study was registered with ClinicalTrials.gov, NCT02356458. Findings: Between August 2015 and September 2016, nine patients were treated in the phase 1 study, and 49 patients were treated between November 2016 and March 2020 in the phase 2 of the trial. The ORR was 81.8% (90% CI 71.1, 89.8%, CR(u) 21.8%) which increased with continued ibrutinib (median 10.6 months) to 87.3%, (CR(u) 41.8%). 75.6% of patients had at least one high-risk feature (Ki-67 > 30%, blastoid or pleomorphic variant, p53 overexpression, TP53 mutations and/or deletions). In these patients, ibrutinib and bortezomib were also effective with an ORR of 74%, increasing to 82% during maintenance. With a median follow-up of 25.4 months, the median duration of response was 22.7, and the median PFS was 18.6 months. PFS reached 30.8 and 32.9 months for patients with a CR or Cru, respectively. Interpretation: The combination of ibrutinib and bortezomib shows durable efficacy in patients with relapsed or refractory MCL, also in the presence of high-risk features. Funding: SAKK (Hubacher Fund), Swiss State Secretariat for Education, Research and Innovation, Swiss Cancer Research Foundation, and Janssen. |
| first_indexed | 2024-03-11T22:30:38Z |
| format | Article |
| id | doaj.art-2a646da2dfa940a19c0def3d5335b73c |
| institution | Directory Open Access Journal |
| issn | 2589-5370 |
| language | English |
| last_indexed | 2024-03-11T22:30:38Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EClinicalMedicine |
| spelling | doaj.art-2a646da2dfa940a19c0def3d5335b73c2023-09-23T05:12:01ZengElsevierEClinicalMedicine2589-53702023-10-0164102221Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13)Research in contextUrban Novak0Martin Fehr1Sämi Schär2Martin Dreyling3Christian Schmidt4Enrico Derenzini5Thilo Zander6Georg Hess7Ulrich Mey8Simone Ferrero9Nicolas Mach10Carola Boccomini11Sebastian Böttcher12Michèle Voegeli13Anne Cairoli14Vanesa-Sindi Ivanova15Thomas Menter16Stefan Dirnhofer17Bernhard Scheibe18Sandra Gadient19Katrin Eckhardt20Emanuele Zucca21Christoph Driessen22Christoph Renner23Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland; Corresponding author. Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland.Department of Medical Oncology and Haematology, Kantonsspital Sankt Gallen, SwitzerlandSAKK Competence Centre, Bern, SwitzerlandDepartment of Medicine III, University Hospital, Ludwig Maximilian University, Munich, GermanyDepartment of Medicine III, University Hospital, Ludwig Maximilian University, Munich, GermanyOnco-Haematology Division, IEO European Institute of Oncology IRCCS, Department of Health Sciences, University of Milan, ItalyDivision of Medical Oncology, Luzerner Kantonsspital, SwitzerlandUniversity Medical Centre of the Johannes Gutenberg University Mainz, GermanyDepartment of Oncology and Haematology, Kantonsspital Graubünden, SwitzerlandHaematology Department of Molecular Biotechnologies and Health Sciences, University of Torino, and Haematology 1, AOU “Città della Salute e della Scienza di Torino”, ItalyDepartment of Oncology, University Hospital of Geneva, SwitzerlandAOU “Città della Salute e della Scienza di Torino”, ItalyDepartment of Medicine, Clinic III, Rostock University Medical Centre, GermanyDepartment of Haematology and Oncology, Kantonsspital Baselland, Liestal, SwitzerlandDepartment of Oncology, Lausanne University Hospital and University of Lausanne, SwitzerlandInstitute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, SwitzerlandInstitute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, SwitzerlandInstitute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, SwitzerlandSAKK Competence Centre, Bern, SwitzerlandSAKK Competence Centre, Bern, SwitzerlandSAKK Competence Centre, Bern, SwitzerlandOncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, SwitzerlandDepartment of Medical Oncology and Haematology, Kantonsspital Sankt Gallen, SwitzerlandOnkozentrum Hirslanden & Zürich, SwitzerlandSummary: Background: The Bruton's tyrosine kinase inhibitor ibrutinib and the proteasome inhibitor bortezomib have single-agent activity, non-overlapping toxicities, and regulatory approval in mantle cell lymphoma (MCL). In vitro, their combination provides synergistic cytotoxicity. In this investigator-initiated phase 1/2 trial, we established the recommended phase 2 dose of ibrutinib in combination with bortezomib, and assessed its efficacy in patients with relapsed or refractory MCL. Methods: In this phase 1/2 study open in 15 sites in Switzerland, Germany and Italy, patients with relapsed or refractory MCL after ≤2 lines of chemotherapy and both ibrutinib-naïve and bortezomib-naïve received six cycles of ibrutinibb and bortezomib, followed by ibrutinib maintenance. For the phase 1 study, a standard 3 + 3 dose escalation design was used to determine the recommended phase 2 dose of ibrutinib in combination with bortezomib. The primary endpoint in phase 1 was the dose limiting toxicities in cycle 1. The phase 2 study was an open-label, single-arm trial with a Simon's two-stage min–max design, with a primary endpoint of overall response rate (ORR) assessed by CT/MRI. This study was registered with ClinicalTrials.gov, NCT02356458. Findings: Between August 2015 and September 2016, nine patients were treated in the phase 1 study, and 49 patients were treated between November 2016 and March 2020 in the phase 2 of the trial. The ORR was 81.8% (90% CI 71.1, 89.8%, CR(u) 21.8%) which increased with continued ibrutinib (median 10.6 months) to 87.3%, (CR(u) 41.8%). 75.6% of patients had at least one high-risk feature (Ki-67 > 30%, blastoid or pleomorphic variant, p53 overexpression, TP53 mutations and/or deletions). In these patients, ibrutinib and bortezomib were also effective with an ORR of 74%, increasing to 82% during maintenance. With a median follow-up of 25.4 months, the median duration of response was 22.7, and the median PFS was 18.6 months. PFS reached 30.8 and 32.9 months for patients with a CR or Cru, respectively. Interpretation: The combination of ibrutinib and bortezomib shows durable efficacy in patients with relapsed or refractory MCL, also in the presence of high-risk features. Funding: SAKK (Hubacher Fund), Swiss State Secretariat for Education, Research and Innovation, Swiss Cancer Research Foundation, and Janssen.http://www.sciencedirect.com/science/article/pii/S258953702300398XMantle cell lymphomaHigh risk biologyIbrutinibBortezomib |
| spellingShingle | Urban Novak Martin Fehr Sämi Schär Martin Dreyling Christian Schmidt Enrico Derenzini Thilo Zander Georg Hess Ulrich Mey Simone Ferrero Nicolas Mach Carola Boccomini Sebastian Böttcher Michèle Voegeli Anne Cairoli Vanesa-Sindi Ivanova Thomas Menter Stefan Dirnhofer Bernhard Scheibe Sandra Gadient Katrin Eckhardt Emanuele Zucca Christoph Driessen Christoph Renner Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13)Research in context EClinicalMedicine Mantle cell lymphoma High risk biology Ibrutinib Bortezomib |
| title | Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13)Research in context |
| title_full | Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13)Research in context |
| title_fullStr | Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13)Research in context |
| title_full_unstemmed | Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13)Research in context |
| title_short | Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13)Research in context |
| title_sort | combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high risk features a phase 1 2 trial of the european mcl network sakk 36 13 research in context |
| topic | Mantle cell lymphoma High risk biology Ibrutinib Bortezomib |
| url | http://www.sciencedirect.com/science/article/pii/S258953702300398X |
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