E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012820 |
E.1.2 | Term | Diffuse large B-cell lymphoma NOS |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to evaluate if the addition of ibrutinib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) prolongs event-free survival (EFS) compared with R-CHOP alone in subjects with newly diagnosed non-GCB subtype of DLBCL selected by IHC or in subjects with newly diagnosed ABC subtype of DLBCL identified by GEP or both patient populations. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to: Evaluate PFS Evaluate CR rate Evaluate overall survival Evaluate patient-reported lymphoma symptoms and concerns as measured by the Lym subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Characterize the pharmacokinetics of ibrutinib and to explore the potential relationships between ibrutinib metrics of exposure with relevant clinical or biomarker information Evaluate the safety of ibrutinib when combined with R-CHOP
The exploratory objectives are to: Evaluate patient-reported outcomes (PRO), related to well-being and general health status, utilizing the FACT-Lym and EuroQol questionnaire (EQ-5D-5L) Explore the relationship between relevant biomarkers (eg, GEP, gene mutations) with clinical outcomes and mechanism of resistance |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- No prior treatment for diffuse B-cell lymphoma (DLBCL) - Histologically-confirmed nongerminal center B-cell subtype DLBCL - Stage II (not candidates for local x-ray therapy), III, or IV disease by the Ann Arbor Classification - At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma - Revised International Prognostic Index score of >=1 - Eastern Cooperative Oncology Group performance status grade of 0, 1, or 2 - Hematology and biochemical laboratory values within protocol- defined parameters prior to random assignment and at baseline - Left ventricular ejection fraction within institutional normal limits, as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan - Agrees to protocol-defined use of effective contraception (for women, these restrictions apply for 12 months after the last dose of rituximab or 1 month after the last dose of study drug, whichever is later; for men, these restrictions apply for 12 months after the last dose of rituximab or 3 months after the last dose of study drug, whichever is later) - Men must agree to not donate sperm during and after the study for 12 months after the last dose of rituximab or 3 months after the last dose of study drug, whichever is later - Women of childbearing potential must have a negative serum or urine pregnancy test at screening |
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E.4 | Principal exclusion criteria |
- Major surgery within 4 weeks of random assignment - Known central nervous system or primary mediastinal lymphoma - Prior history of indolent lymphoma - Diagnosed or treated for malignancy other than DLBCL, except: malignancy treated with curative intent and with no known active disease present for >=3 years before random assignment; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated carcinoma in situ without evidence of disease - History of stroke or intracranial hemorrhage within 6 months prior to random assignment - Requires anticoagulation with warfarin or equivalent vitamin K antagonists - Requires treatment with strong CYP3A inhibitors - Prior anthracycline use >=150 mg/m2 - 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 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification - Known history of human immunodeficiency virus or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection requiring intravenous antibiotics - Women who are pregnant or breastfeeding - Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the patient’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to disease progression, relapse from complete response, initiation of subsequent systemic antilymphoma therapy after completion of at least 6 cycles of R-CHOP therapy, or death, whichever occurs first, up to Year 7 |
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E.5.2 | Secondary end point(s) |
- Progression-free survival - Complete response rate - Overall survival - Time to worsening symptoms in the Lym subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) - Oral plasma clearance of ibrutinib - Oral volume of distribution at steady state of ibrutinib - Area under the plasma concentration-time curve of ibrutinib - Minimum observed plasma concentration of ibrutinib - Number of participants affected by an adverse event |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Up to disease progression, relapse from complete response, or death, whichever occurs first, up to Year 7 - Up to the date of the participants death, up to Year 7 - Up to completion of chemotherapy treatment, up to Year 7 - Up to the start date of the worsening of patient symptoms, up to Year 7 - Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 - Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 - Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 - Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 - Up to 30 days after the last dose of study medication |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 85 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Belgium |
Brazil |
Canada |
China |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Hungary |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
Netherlands |
Norway |
Poland |
Russian Federation |
Spain |
Sweden |
Taiwan |
Turkey |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study is defined as when 50% of the randomized subjects have died or 5 years after the last subject is randomized or the sponsor terminates the study, whichever comes first. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |