Ibrutinib and Standard Immuno-Chemotherapy in Younger, High-Risk Patients With Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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This study will investigate if treatment results obtained with R-CHOEP in young high-risk patients with diffuse large B-cell lymphoma can be further improved by the addition of ibrutinib to this regimen.

Detailed Description
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Encouraging results have been achieved in younger high-risk patients with newly diagnosed diffuse large B-cell lymphoma treated with R-CHOEP. However, more than one fourth of patients still relapse or show primary progressive disease. The outcome of such patients is poor, in particular if first-line therapy contained rituximab. In order to avoid such detrimental situations, we seek to further improve progression-free survival and overall survival by combining R-CHOEP with ibrutinib. Ibrutinib is a first-in-class, orally administered, potent, small-molecule inhibitor of Bruton's tyrosine kinase, a mediator of critical B-cell signaling pathways implicated in the pathogenesis of B-cell cancers.

Official Title
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Ibrutinib and Standard Immuno-Chemotherapy (R-CHOEP-14) in Younger, High-Risk Patients With Diffuse Large B-Cell Lymphoma

Conditions
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Diffuse Large B Cell Lymphoma

Intervention / Treatment
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* Drug: Ibrutinib Oral Capsule [Imbruvica]
* Drug: R-CHOEP chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study. Age between 18-60 years Risk score 2 or 3 according to age-adjusted International Prognostic Index Histology: Primary diagnosis of diffuse large B-cell lymphoma Performance status: ECOG (toxicity and response criteria of the eastern cooperative oncology group) 0-3 Stage: all stages according Ann Arbor Absolute neutrophil count: > 1000 cells/microliter (independent of growth factor support) Platelet count ≥ 100.000/mm³ or ≥ 50.000/mm³ if bone marrow involvement independent of transfusion support in either situation. Alanine-aminotransferase and Aspartate-aminotransferase: < 3 x Upper limit of normal value Total Bilirubin: < 1.5 x Upper limit of normal value Serum Creatinine: < 2 x Upper limit of normal value or estimated Glomerular filtration rate (Glomerular filtration rate [Cockcroft-Gault]) ≥ 40 ml/min Women of childbearing potential and men who are sexually active must be practising a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For male subjects, these restrictions apply for 6 months after last dose of study drug. For female subjects, they apply for 12 months after last dose of study drug. Women of childbearing potential must have negative serum or urine beta-human chorionic gonadotropin pregnancy test at screening. Women who are pregnant or breast-feeding are ineligible for this study. Willing/ able to adhere to the prohibitions and restrictions specified in this protocol. Exclusion Criteria: Vaccinated with live, attenuated vaccines within 4 weeks of inclusion. Major surgery within 4 weeks of inclusion. Any prior lymphoma-directed therapy (except pre-phase treatment). Known central nervous system involvement. Diagnosed or treated for malignancy other than diffuse large B-cell lymphoma, in particular any other (indolent) lymphoma. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional classification. Bone marrow involvement > 25% History of stroke or intracranial hemorrhage within six months of inclusion. Requires anticoagulation with warfarin or equivalent vitamin K antagonist. Known history of human immunodeficiency virus or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection requiring IV antibiotics. Requires treatment with strong CYP3A inhibitors. Use of preparations containing St. John's Wort. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk. Concurrent treatment with other investigational agent or X-ray therapy. Previous chemo- or radiotherapy for any other malignancy, in particular indolent lymphoma. Any psychological, cognitive, familial, sociological or geographical condition that, in the investigator's opinion, compromises the patient's ability to understand the patient information, to give informed consent or to comply with the study protocol. Participation in another interventional clinical trial during this trial. There may be exceptions at the discretion of the coordinating investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibrutinib and R-CHOEP chemotherapy<br>All patients will receive 8 cycles of R-CHOEP immunochemotherapy every two weeks with the following doses per cycle: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m² (dose capped at 2 mg), etoposide 300 mg/m², prednisolone 500 mg. In addition, ibrutinib capsules will be administered orally once daily at a dose of 560 mg (4 x 140 mg hard capsules) for 112 days. | Drug: Ibrutinib Oral Capsule [Imbruvica]<br>* Imbruvica 140 mg hard capsules (Active substance: Ibrutinib)<br>Drug: R-CHOEP chemotherapy<br>* Immunochemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year progression-free survival | Length of time that a patient lives without disease progression or relapse. | From the day of inclusion into the study until one of the following events occurs, whichever is first: disease progression, relapse, death due to any other cause (assessed up to 4 years). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The percentage of patients in this study who are still alive. | From the day of inclusion into the study to death due to any cause (assessed up to 4 years). | 
| Event-free survival | Length of time that a patient remains free of certain events (disease progression, start of additional, unplanned anti-tumor therapy, relapse, death due to any other cause). | From the day of inclusion into the study until one of the following events occurs, whichever comes first: disease progression, start of additional, unplanned anti-tumor therapy, relapse, death due to any other cause (assessed up to 4 years). | 
| Rate of complete remission | Rate of complete remission measured as number of complete remissions divided by the number of patients included. | From the day of inclusion into the study until date of complete remission (assessed up to 6 months). | 
| Rate of partial remission | Rate of partial remission measured as number of partial remissions divided by the number of patients included. | From the day of inclusion into the study until date of partial remission (assessed up to 6 months). | 
| Overall response rate | Overall response rate measured as number of complete and partial remissions divided by the number of patients included. | From the day of inclusion into the study until date of complete or partial remission (assessed up to 6 months). | 
| Progression rate | Progression rate measured as number of progressions divided by the number of patients included. | From the day of inclusion into the study until date of progression during therapy or within 2 months after last treatment course (assessed up to 6 months). | 
| Relapse rate | Relapse rate measured as number of relapses divided by the number of patients included. | From the day of inclusion into the study until date of relapse during therapy or within 2 months after last treatment course (assessed up to 6 months). | 
| Duration of response | The time between the initial response to therapy and subsequent disease progression or relapse. | From documentation of tumor response to disease progression or relapse (assessed up to 6 months). | 
| Adverse events and serious adverse events | Frequency of adverse events and serious adverse events | The documentation of adverse events, including serious adverse events, starts with first study treatment after patient inclusion and ends 100 days after the last application of ibrutinib or any component of R-CHOEP (whichever is applied last). | 
| Rate of treatment-related deaths | The number of deaths during therapy or up to 2 months after the end of therapy divided by the number of patients who started study treatment. | From the start of therapy up to 2 months after the end of therapy. | 
| Therapy cycles (number) | Number of therapy cycles | From the start of therapy until the end of therapy (assessed up to 4 months). | 
| Therapy cycles (duration) | Duration of therapy cycles | From the start of therapy until the end of therapy (assessed up to 4 months). | 
| Used drugs | Cumulative doses of R-CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, rituximab) and ibrutinib. | From the start of therapy until the end of therapy (assessed up to 4 months). | 
| Outcome according to lymphoma biology | Lymphoma tissue from all patients will be characterized. | From the start of study until the end of study (assessed up to 4 years). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ibrutinib