Back to resultsStudy of Ibrutinib (a Bruton's Tyrosine Kinase Inhibitor), Versus Temsirolimus in Patients With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy
Primary Purpose
Mantle Cell Lymphoma
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Ibrutinib
Temsirolimus
Sponsored by
About this trial
This is an interventional treatment trial for Mantle Cell Lymphoma focused on measuring Mantle cell lymphoma, Relapsed mantle cell lymphoma, Refractory mantle cell lymphoma, Ibrutinib, Bruton's tyrosine kinase inhibitor, Temsirolimus
Eligibility Criteria
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 biochemistry laboratory values
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 inhibitor
- 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 patient's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Ibrutinib
Temsirolimus
Arm Description
Outcomes
Primary Outcome Measures
Progression Free Survival (PFS)
PFS is defined as the duration in months from the date of randomization to the date of progression disease (PD) or relapse from complete response (CR) or death whichever was reported first and was assessed based on the investigator assessment. Revised Response Criteria for Malignant Lymphoma categorizes the response of the treatment of a patient's tumour to CR (the disappearance of all evidence of disease), Relapsed Disease or PD (Any new lesion or increase by greater than or equal to [>=] 50 percent [%] of previously involved sites from nadir).
Secondary Outcome Measures
Overall Response Rate (ORR)
ORR is defined as the percentage of participants who achieved either CR or PR as best overall response based on the investigator assessment. CR is Disappearance of all target lesions while PR is greater than or equal to 30 % decrease in the sum of the longest diameter of target lesions and Overall Response (OR) is sum of CR and PR.
Overall Survival (OS)
Overall survival (OS) was defined as the interval between the date of randomization and the date of death from any cause.
Duration of Response
Duration of response (CR or PR), defined as the duration in days from the date of initial response to the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death. The analysis was based on the investigator assessment.
Time-to-Next Treatment
Time to next treatment was measured from the date of randomization to the start date of any anti-neoplastic treatment subsequent to study treatment.
Progression-Free Survival 2
Progression-free survival 2 defined as the time interval between the date of randomization and date of event, defined as progressive disease as assessed by investigator that started after the next line of subsequent anti-neoplastic therapy (including cross-over to ibrutinib), death from any cause, or the start of the second subsequent anti-neoplastic therapy if no progressive disease was recorded after the first subsequent anti-neoplastic therapy.
Time to Worsening in the Lymphoma Sub Scale of Functional Assessment of Cancer Therapy- Lymphoma (FACT-Lym)
Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as the interval from the date of randomization to the start date of worsening. Worsening was defined by a 5-point decrease from baseline. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life.
Number of Participants Affected With Treatment-emergent Adverse Events
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Full Information
NCT ID
NCT01646021
First Posted
July 18, 2012
Last Updated
December 15, 2017
Sponsor
Janssen Research & Development, LLC
Collaborators
Pharmacyclics LLC.
1. Study Identification
Unique Protocol Identification Number
NCT01646021
Brief Title
Study of Ibrutinib (a Bruton's Tyrosine Kinase Inhibitor), Versus Temsirolimus in Patients With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy
Official Title
A Randomized, Controlled, Open-Label, Multicenter Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, Versus Temsirolimus in Subjects With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy
Study Type
Interventional
2. Study Status
Record Verification Date
December 2017
Overall Recruitment Status
Completed
Study Start Date
December 10, 2012 (Actual)
Primary Completion Date
June 5, 2015 (Actual)
Study Completion Date
December 15, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Janssen Research & Development, LLC
Collaborators
Pharmacyclics LLC.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to evaluate the efficacy and safety of ibrutinib versus temsirolimus in patients with relapsed or refractory mantle cell lymphoma who received at least 1 prior chemotherapy regimen.
Detailed Description
This is a randomized (individuals assigned to study treatment by chance), open-label (identity of assigned study drug will be known), study to evaluate the efficacy and safety of ibrutinib when compared with temsirolimus in patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 1 prior rituximab-containing chemotherapy regimen. Approximately 280 eligible patients will be randomly assigned in a 1:1 ratio and stratified (grouped) by the number of prior lines of therapy (1 or 2 versus >=3) and simplified MCL International Prognostic Index criteria to receive either ibrutinib by mouth (Treatment Arm A) or temsirolimus intravenous infusion (Treatment Arm B). The study will consist of screening, treatment, and posttreatment phases. Data will be collected on disease response to the treatment, progression-free survival, overall survival, subsequent anti-MCL therapies, patient reported outcomes, and medical resource utilization. Tumor samples, blood collected at multiple time points, and a bone marrow aspirate will be evaluated to identify markers predictive of response or resistance to ibrutinib. Serial pharmacokinetic (study of what the body does to a drug) samples will be collected as detailed in the protocol. Safety will be monitored throughout the study. Disease evaluations will be performed every 9 weeks for up to 15 months from the start of study drug, and every 24 weeks thereafter, until disease progression, death, or the clinical cutoff, whichever comes first. Patients who receive treatment with temsirolimus and have disease progression (confirmed by an Independent Review Committee) may be eligible to crossover and receive treatment with ibrutinib 560 mg orally, daily, on a 21-day cycle until disease progression, unacceptable toxicity, or study end. Data will be analyzed up to 3 years after the last patient is enrolled for the final follow-up.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mantle Cell Lymphoma
Keywords
Mantle cell lymphoma, Relapsed mantle cell lymphoma, Refractory mantle cell lymphoma, Ibrutinib, Bruton's tyrosine kinase inhibitor, Temsirolimus
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
280 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Ibrutinib
Arm Type
Experimental
Arm Title
Temsirolimus
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Ibrutinib
Intervention Description
560 mg once daily continuous (without interruption) by mouth for 21-day cycles
Intervention Type
Drug
Intervention Name(s)
Temsirolimus
Intervention Description
175 mg once daily intravenous infusion on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each 21-day cycle
Primary Outcome Measure Information:
Title
Progression Free Survival (PFS)
Description
PFS is defined as the duration in months from the date of randomization to the date of progression disease (PD) or relapse from complete response (CR) or death whichever was reported first and was assessed based on the investigator assessment. Revised Response Criteria for Malignant Lymphoma categorizes the response of the treatment of a patient's tumour to CR (the disappearance of all evidence of disease), Relapsed Disease or PD (Any new lesion or increase by greater than or equal to [>=] 50 percent [%] of previously involved sites from nadir).
Time Frame
Time from the date of randomization until the date of first documented evidence of progressive disease (or relapse for subjects who experience CR during the study) or death, whichever occurred first (approximately 48 months)
Secondary Outcome Measure Information:
Title
Overall Response Rate (ORR)
Description
ORR is defined as the percentage of participants who achieved either CR or PR as best overall response based on the investigator assessment. CR is Disappearance of all target lesions while PR is greater than or equal to 30 % decrease in the sum of the longest diameter of target lesions and Overall Response (OR) is sum of CR and PR.
Time Frame
Approximately up to 48 months
Title
Overall Survival (OS)
Description
Overall survival (OS) was defined as the interval between the date of randomization and the date of death from any cause.
Time Frame
Approximately up to 48 months
Title
Duration of Response
Description
Duration of response (CR or PR), defined as the duration in days from the date of initial response to the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death. The analysis was based on the investigator assessment.
Time Frame
Approximately up to 48 months
Title
Time-to-Next Treatment
Description
Time to next treatment was measured from the date of randomization to the start date of any anti-neoplastic treatment subsequent to study treatment.
Time Frame
Approximately up to 48 months
Title
Progression-Free Survival 2
Description
Progression-free survival 2 defined as the time interval between the date of randomization and date of event, defined as progressive disease as assessed by investigator that started after the next line of subsequent anti-neoplastic therapy (including cross-over to ibrutinib), death from any cause, or the start of the second subsequent anti-neoplastic therapy if no progressive disease was recorded after the first subsequent anti-neoplastic therapy.
Time Frame
Approximately up to 48 months
Title
Time to Worsening in the Lymphoma Sub Scale of Functional Assessment of Cancer Therapy- Lymphoma (FACT-Lym)
Description
Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as the interval from the date of randomization to the start date of worsening. Worsening was defined by a 5-point decrease from baseline. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life.
Time Frame
Approximately up to 48 months
Title
Number of Participants Affected With Treatment-emergent Adverse Events
Description
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time Frame
Time from first dose of study drug until the last dose date + 30 days or the start of a subsequent anti-neoplastic therapy, whichever occur earlier (Approximately up to 4 years)
Other Pre-specified Outcome Measures:
Title
Time to Response
Description
Time to response for participants with CR/PR, defined as the interval between the date of randomization and date of initial documentation of response.
Time Frame
Approximately up to 2.8 years
Title
Extent of Exposure of Time
Description
Extent of exposure is defined as the duration of the treatment administered during the study. Duration of exposure is calculated as the number of months between the start and end of treatment.
Time Frame
Approximately up to 46.8 months
Title
One Year Survival Rate
Description
One -year survival rate, defined as the proportion of participants who were alive 1 year after randomization.
Time Frame
Month 12
Title
Area Under the Plasma Concentration of Ibrutinib During Steady State (AUC-ss)
Description
The AUC-ss is the area under the plasma concentration time curve observed during steady state.
Time Frame
Cycle 1 and 2 (Day 1): Predose, 1, 2, 4 hr. postdose; Cycle 3 (day 1): Predose (Each cycle is of 21 days)
Title
Number of Participants With Biomarkers That Alter B-cell Receptor (BCR) Signaling or Activate Alternative Signaling Pathways and to Explore Their Association With Response or Resistance to Ibrutinib
Description
Biomarker evaluations to identify markers altering BCR signaling or activate alternative signaling pathways and explore their association with response or resistance to ibrutinib. Next-generation sequencing at baseline identifies possible primary resistance mutations and those found only at progression are acquired mutations on therapy.
Time Frame
Approximately up to 28.2 months
Title
Number of Hospitalizations Reported Related Medical Resource Utilization Information (MRUI)
Description
Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study.
Time Frame
Approximately up to 28.2 months
Title
Number of Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI)
Description
Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study.
Time Frame
Approximately up to 28.2 months
Title
Days of Hospitalization and Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI)
Description
Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study.
Time Frame
Approximately up to 28.2 months
Title
The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment
Description
The EQ-5D is a participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression, using 5 levels (1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and possible total score range -0.594 to 1; higher score indicates a better health state.
Time Frame
Baseline, Cycle 2, 3, 4, 5, 6, 7, 8, 11, 14, 17, 20, 28, 36 and End of treatment (approximately up to 23 months)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 biochemistry laboratory values
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 inhibitor
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 patient's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Janssen Research & Development, LLC Clinical Trial
Organizational Affiliation
Janssen Research & Development, LLC
Official's Role
Study Director
Facility Information:
City
Antwerpen
Country
Belgium
City
Brugge
Country
Belgium
City
Brussels
Country
Belgium
City
Edegem
Country
Belgium
City
Gent
Country
Belgium
City
Leuven
Country
Belgium
City
Wilrijk
Country
Belgium
City
Goiânia
Country
Brazil
City
Porto Alegre
Country
Brazil
City
Ribeirão Preto
Country
Brazil
City
Rio De Janeiro
Country
Brazil
City
Sao Paulo
Country
Brazil
City
Edmonton
State/Province
Alberta
Country
Canada
City
Ottawa
State/Province
Ontario
Country
Canada
City
Montreal
State/Province
Quebec
Country
Canada
City
Temuco
Country
Chile
City
Bogota
Country
Colombia
City
Medellin
Country
Colombia
City
Brno
Country
Czechia
City
Praha 10
Country
Czechia
City
Praha 2
Country
Czechia
City
Mulhouse
Country
France
City
Paris Cedex 15
Country
France
City
Paris
Country
France
City
Pessac
Country
France
City
Villejuif
Country
France
City
Berlin
Country
Germany
City
Essen
Country
Germany
City
Heidelberg
Country
Germany
City
Homburg
Country
Germany
City
Kiel
Country
Germany
City
Koln
Country
Germany
City
Mainz
Country
Germany
City
Munchen
Country
Germany
City
Ulm
Country
Germany
City
Budapest
Country
Hungary
City
Debrecen
Country
Hungary
City
Pécs N/A
Country
Hungary
City
Szeged
Country
Hungary
City
Dublin
Country
Ireland
City
Goyang-Si
Country
Korea, Republic of
City
Seoul
Country
Korea, Republic of
City
Monterrey
Country
Mexico
City
Oaxaca
Country
Mexico
City
Queretaro
Country
Mexico
City
Amsterdam
Country
Netherlands
City
Rotterdam
Country
Netherlands
City
Brzozow
Country
Poland
City
Chorzow
Country
Poland
City
Gdansk
Country
Poland
City
Krakow
Country
Poland
City
Opole
Country
Poland
City
Slupsk
Country
Poland
City
Wroclaw
Country
Poland
City
Coimbra
Country
Portugal
City
Lisboa
Country
Portugal
City
Lisbon
Country
Portugal
City
Porto
Country
Portugal
City
Chelyabinsk
Country
Russian Federation
City
Ekaterinburg
Country
Russian Federation
City
Krasnodar
Country
Russian Federation
City
Moscow N/A
Country
Russian Federation
City
Moscow
Country
Russian Federation
City
Nizhny Novgorod
Country
Russian Federation
City
Obninsk
Country
Russian Federation
City
Rostov-Na-Donu
Country
Russian Federation
City
Saint Petersburg
Country
Russian Federation
City
Sochi
Country
Russian Federation
City
St-Petersburg
Country
Russian Federation
City
St. Petersburg
Country
Russian Federation
City
Syktyvkar
Country
Russian Federation
City
Barcelona
Country
Spain
City
Madrid
Country
Spain
City
Palma De Mallorca
Country
Spain
City
Salamanca
Country
Spain
City
Valencia
Country
Spain
City
Göteborg
Country
Sweden
City
Lund
Country
Sweden
City
Stockholm
Country
Sweden
City
Umeå
Country
Sweden
City
Uppsala
Country
Sweden
City
Tainan
Country
Taiwan
City
Taipei
Country
Taiwan
City
Taoyuan
Country
Taiwan
City
Cherkassy
Country
Ukraine
City
Dnepropetrovsk
Country
Ukraine
City
Donetsk
Country
Ukraine
City
Khmelnitskiy
Country
Ukraine
City
Kiev
Country
Ukraine
City
Lviv
Country
Ukraine
City
Birmingham
Country
United Kingdom
City
Harrow
Country
United Kingdom
City
Leeds
Country
United Kingdom
City
Liverpool
Country
United Kingdom
City
London
Country
United Kingdom
City
Manchester
Country
United Kingdom
City
Plymouth
Country
United Kingdom
City
Southampton
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
28751558
Citation
Brown JR, Moslehi J, O'Brien S, Ghia P, Hillmen P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Kipps TJ, Coutre S, Dilhuydy MS, Cramer P, Tedeschi A, Jaeger U, Dreyling M, Byrd JC, Howes A, Todd M, Vermeulen J, James DF, Clow F, Styles L, Valentino R, Wildgust M, Mahler M, Burger JA. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017 Oct;102(10):1796-1805. doi: 10.3324/haematol.2017.171041. Epub 2017 Jul 27.
Results Reference
derived
PubMed Identifier
26673811
Citation
Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Bothos J, Goldberg JD, Enny C, Traina S, Balasubramanian S, Bandyopadhyay N, Sun S, Vermeulen J, Rizo A, Rule S. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016 Feb 20;387(10020):770-8. doi: 10.1016/S0140-6736(15)00667-4. Epub 2015 Dec 7. Erratum In: Lancet. 2016 Feb 20;387(10020):750.
Results Reference
derived
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Study of Ibrutinib (a Bruton's Tyrosine Kinase Inhibitor), Versus Temsirolimus in Patients With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy
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