Combination of Ibrutinib and Bortezomib to Treat Patients With Mantle Cell Lymphoma
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|ClinicalTrials.gov Identifier: NCT02356458|
Recruitment Status : Recruiting
First Posted : February 5, 2015
Last Update Posted : April 9, 2019
|Condition or disease||Intervention/treatment||Phase|
|Mantle Cell Lymphoma||Drug: Ibrutinib Drug: bortezomib||Phase 1 Phase 2|
Disease background, therapy background and aim
Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma. It represents ~5% of all lymphomas and typically is present in advanced stages, a median age of 60-65 years and a dismal prognosis with a median survival of ~3 years. Currently, it remains incurable, as the patients will relapse after first line treatment and require subsequent therapy. The disease-free survival is progressively shorter with each subsequent relapse.
Currently, there is no standard therapy for relapsed MCL patients. MCL is predominantly a disease of the elderly who are not suitable for aggressive chemotherapy. Allogeneic transplants are preferred in young and fit patients, whereas (preferably single agent) chemotherapy is used to treat older patients, but usually with short duration of responses. Recently, the therapeutic armamentarium has been expanded with the availability of novel agents targeting crucial and deregulated pathways in MCL. These include the Bruton's Kinase (BTK) inhibitor ibrutinib with excellent single agent activities. New therapeutic options in the targeted patient population are clearly needed to prolong remissions especially for elderly patients where aggressive chemotherapy and allogeneic transplants are no suitable treatment options. Recently, a synergistic increase in the proteasomal inhibition of ibrutinib in both bortezomib-sensitive and refractory MCL cells was shown.
This trial is targeting patients with diagnosis of refractory or relapsed MCL disease after pretreatment with ≤2 lines of non-bortezomib-containing chemotherapy. The proposed treatment of ibrutinib in combination with bortezomib might lead to an improvement of the therapy in the targeted relapsed/refractory patient population. Given the absence of a dose-limiting toxicity also when applied long-term, ibrutinib is well suited in this patient population as a maintenance therapy. Therefore, the combination treatment of the trial is followed by a maintenance therapy part for patients that had no disease progression. New treatment options should control the disease as best and long as possible.
Treatment consists of 6 cycles of 21 days each of ibrutinib in combination with bortezomib, followed by a maintenance therapy with ibrutinib monotherapy. In the maintenance therapy courses repeat every 28-days in the absence of disease progression or unacceptable toxicity.
Objectives Phase I The primary object of the trial is to establish the recommended phase II dose (RP2D) of ibrutinib in combination with bortezomib in patients with relapsed or refractory MCL.
The secondary objectives are
- to determine the safety and tolerability of ibrutinib in combination with bortezomib and
- to assess the preliminary antitumor activity of ibrutinib in combination with bortezomib Phase II The main object of the trial is to define the efficacy of the combination treatment of ibrutinib with bortezomib in patients with relapsed or refractory MCL.
The secondary objectives are
- to determine the safety and tolerability of the RP2D and
- to assess the efficacy of ibrutinib in combination with bortezomib in patients with relapsed MCL followed by an ibrutinib maintenance therapy.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||73 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Combination of Ibrutinib and Bortezomib Followed by Ibrutinib Maintenance to Treat Patients With Relapsed and Refractory Mantle Cell Lymphoma; a Multicenter Phase I/II Trial.|
|Actual Study Start Date :||August 31, 2015|
|Estimated Primary Completion Date :||March 2021|
|Estimated Study Completion Date :||March 2022|
Experimental: Ibrutinib & Bortezomib
Combination therapy (trial treatment of ibrutinib in combination with bortezomib) followed by ibrutinib maintenance therapy
Trial treatment of ibrutinib in combination with bortezomib Cycles 1-6 (1 cycle = 21 days) Ibrutinib: p.o daily; Phase I: according to DL; Phase II: RP2D established in phase I
p.o daily: 560 mg
Other Name: Imbruvica
Trial treatment of ibrutinib in combination with bortezomib Cycles 1-6 (1 cycle = 21 days) Injection of Bortezomib (s.c.), dose of 1.3 mg/m2 on day 1, 4, 8, 11
Other Name: Velcade®
- Phase I: Dose limiting toxicity (DLT) observed during the first cycle of trial treatment [ Time Frame: At day 8, 14, 21 during cycle 1 (1 cycle = 21 days) ]DLTs are defined based on adverse events observed in cycle 1 that are possibly, probably or definitively related to ibrutinib and/or bortezomib.
- Phase II: Overall response (OR) (combination therapy) [ Time Frame: 4 1/2 months after registration. ]OR is defined as the proportion of patients whose best overall response, is either complete response (CR), complete response unconfirmed (CRu) or partial response (PR) according to the International Working group criteria for NHL. The primary endpoint of phase II is OR observed during the combination therapy.
- Phase I and II: Adverse events (AE) until 30 days after end of trial therapy [ Time Frame: Until 30 days after up to 2 years of trial therapy ]All AEs will be assessed according to NCI CTCAE v4.0
- Phase I: OR (combination therapy) [ Time Frame: 4 1/2 months after inclusion of each patient ]OR observed during the combination therapy.
- Phase I: OR based on best response observed during treatment (combination and maintenance therapy) [ Time Frame: Estimated at 1 1/2 years after patient registration. ]OR observed during the combination therapy and OR observed during trial treatment.
- Phase II: OR based on best response observed during treatment (combination and maintenance therapy [ Time Frame: Estimated at 1 1/2 years after patient registration. ]OR observed during the combination therapy and OR observed during trial treatment.
- Phase II: Progression-free survival (PFS) [ Time Frame: Time from patient registration to progression free survival (estimated 2 years) ]Time from registration until progression of disease or death as a result of any cause.
- Phase II: Time to treatment failure (TTF) [ Time Frame: Time from patient registration to treatment failure (estimated 2 years) ]Time from registration until treatment failure (due to unacceptable toxicity, progression, patient refusal, death, start of subsequent anti-MCL therapy or any other event that determines the termination of the trial treatment will be considered as treatment failure).
- Phase II: Duration of objective response [ Time Frame: Time from patient registration to progression/relapse (estimated 2 years). ]
Time from first observation of CR or PR until documentation of progression, or relapse thereafter.
Only patients with CR or a PR will be included in this analysis.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02356458
|Contact: Simon Schäfer||+41 31 389 91 firstname.lastname@example.org|
|Mainz, Germany, 55131|
|Contact: Georg Hess, Prof +49 6131 17 50 40 email@example.com|
|Principal Investigator: Georg Hess, Prof|
|Klinikum der Universität München||Recruiting|
|München, Germany, 81377|
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|Rostock, Germany, 18057|
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|Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo||Recruiting|
|Alessandria, Italy, 15100|
|Contact: Marco Ladetto, MD +39 131206 262 firstname.lastname@example.org|
|Principal Investigator: Marco Ladetto, MD|
|European Institute of Oncology||Recruiting|
|Milano, Italy, 20141|
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|Università di Torino||Recruiting|
|Torino, Italy, 10126|
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|Principal Investigator: Simone Ferrero, MD|
|Aarau, Switzerland, CH-5001|
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|Principal Investigator: Mario Bargetzi, Prof|
|Baden, Switzerland, 5404|
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|Principal Investigator: Clemens Caspar, MD|
|Bern, Switzerland, CH-3010|
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|Principal Investigator: Urban Novak, MD|
|Chur, Switzerland, 7000|
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|Principal Investigator: Ulrich Mey, MD|
|Hopitaux Universitaires de Geneve||Recruiting|
|Genève 14, Switzerland, 1211|
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|Centre Pluridisciplinaire d`Oncologie CHUV||Recruiting|
|Lausanne, Switzerland, 1011|
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|Liestal, Switzerland, 4410|
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|Principal Investigator: Michèle Voegeli, MD|
|Istituto Oncologico della Svizzera Italiana||Recruiting|
|Lugano, Switzerland, CH-6900|
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|Principal Investigator: Emanuele Zucca, Prof|
|Luzerne, Switzerland, CH-6000|
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|Kantonsspital - St. Gallen||Recruiting|
|St. Gallen, Switzerland, CH-9007|
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|Zurich, Switzerland, CH-8032|
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|Onkozentrum - Klinik Im Park||Recruiting|
|Zürich, Switzerland, 8038|
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|Principal Investigator: Christoph Renner, Prof|
|Zürich, Switzerland, 8091|
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|Principal Investigator: Thorsten Zenz, Prof|
|Study Chair:||Urban Novak, PD Dr. med.||University Hospital Bern - Inselspital|