E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory Mantle Cell Lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
Relapsed or refractory Mantle 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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10026801 |
E.1.2 | Term | Mantle cell lymphoma refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to evaluate whether treatment with ibrutinib compared with temsirolimus will result in prolongation of PFS, as determined by blinded independent central review, in subjects with relapsed or refractory MCL who have received at least 1 prior rituximab-containing chemotherapy regimen. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
•To evaluate the overall response rate (CR + PR)
•To evaluate overall survival
•To evaluate the 1-year survival rate
•To evaluate duration of response
•To evaluate time-to-next treatment (TTNT)
•To evaluate the safety of ibrutinib and temsirolimus
•To characterize the pharmacokinetics of ibrutinib
•To evaluate patient-reported outcomes (PRO) utilizing the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and EuroQol (EQ-5D)
•To evaluate medical resource utilization (MRU) information
•To identify biomarkers that alter B-cell receptor (BCR) signaling or activate alternative signaling pathways and to explore their association with response to ibrutinib
•To explore the potential relationships between ibrutinib metrics of exposure with relevant clinical or biomarker information.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Confirmed diagnosis of mantle cell lymphoma (MCL)
- Received at least 1 prior rituximab-containing chemotherapy regimen (separate lines of therapy are defined as single or combination therapies that are either separated by disease progression or by a > 6 month treatment-free interval)
- Documented relapse or disease progression following the last anti-MCL treatment
- At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma
- Eastern Cooperative Oncology Group performance status grade 0 or 1
- Protocol-defined hematology and biochemical laboratory values |
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E.4 | Principal exclusion criteria |
- Prior nitrosoureas within 6 weeks, chemotherapy within 3 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy or other investigational agents within 3 weeks, or major surgery within 4 weeks of randomization
- Prior treatment with temsirolimus, other mTOR inhibitors, ibrutinib, or other Bruton’s tyrosine kinase (BTK) inhibitors
- Known central nervous system lymphoma
- Received an allogeneic or autologous hematopoietic stem cell transplant <=6 months from the date of randomization and on immunosuppressive therapy or have evidence of active graft versus host disease
- Diagnosed or treated for malignancy other than MCL, except: malignancy treated with curative intent and with no known active disease present for >=3 years before randomization, adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, adequately treated cervical carcinoma in situ without evidence of disease
- History of stroke or intracranial hemorrhage within 6 months prior to randomization
- Requires anticoagulation with warfarin or equivalent vitamin K antagonist
- Requires treatment with strong CYP3A inhibitors
- 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 (HIV) or active hepatitis C virus (HCV) or active hepatitis B virus (HBV) infection or any uncontrolled active systemic infection requiring intravenous antibiotics
- Woman who is pregnant or breast-feeding
- 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
clinical cutoff (defined by 178 patients with progression free survival events; up to 3 years after the last patient is randomized)
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E.5.2 | Secondary end point(s) |
- Overall response rate
- Overall survival
- 1-year survival rate
- Duration of response
- Time-to-next treatment
- Number of participants with adverse events
- Mean plasma concentrations of ibrutinib
- Maximum observed plasma concentration of ibrutinib
- Minimum observed plasma concentration of ibrutinib
- Area under the plasma concentration-time curve from time 0 to 24 hours of ibrutinib
- Mean change from baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) scale score
- Mean change from baseline in EuroQol (EQ-5D-5L) index score
- Mean change from baseline in medical resource utilization
- Mean change from baseline in biomarkers that alter B-cell receptor (BCR) signaling or activate alternative signaling pathways
- Mean change from baseline in identified resistance biomarkers from bone marrow |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-up to 3 years after last patient randomized
-up to 3 years after last patient randomized
-Month 12
-up to 3 years after last patient randomized
-up to 3 years after last patient randomized
-up to 30 days after last dose of study medication
-Cycles 1-3: predose on Day 1, Cycles 1-2: postdose at 1, 2, and 4 hours
-Cycles 1-3: predose on Day 1, Cycles 1-2: postdose at 1, 2, and 4 hours
-Cycles 1-3: predose on Day 1, Cycles 1-2: postdose at 1, 2, and 4 hours
-Cycles 1-3: predose on Day 1, Cycles 1-2: postdose at 1, 2, and 4 hours
-up to 3 years after last patient randomized
-up to 3 years after last patient randomized
-up to 30 days from last dose of study medication
-up to 30 days from last dose of study medication
-up to 30 days from 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 | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 77 |
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 |
Belgium |
Brazil |
Canada |
Colombia |
Czech Republic |
France |
Germany |
Hungary |
Ireland |
Italy |
Korea, Republic of |
Mexico |
Netherlands |
Poland |
Portugal |
Russian Federation |
Spain |
Sweden |
Taiwan |
Ukraine |
United Kingdom |
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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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Study end is considered to be completed when 80% of the randomized subjects have died, or 3 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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 26 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
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 | 26 |