Mantle Cell LymphomaPhase 3NCT01776840
A Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Given in Combination With Bendamustine and Rituximab in Patients With Newly Diagnosed Mantle Cell Lymphoma
A Phase 3 study testing Bendamustine, Rituximab and Ibrutinib in people with Mantle Cell Lymphoma, run by Janssen Research & Development, LLC at 201 sites in 28 countries.
Trial summary
The purpose of this study is to evaluate the efficacy and safety of ibrutinib given in combination with bendamustine and rituximab in patients 65 years of age or older with newly diagnosed mantle cell lymphoma. Read more about this study
- Who is it for?
- Ages 65 years and older
- Conditions the study is for
- Mantle Cell Lymphoma
- What is being tested?
- Bendamustine, Rituximab and Ibrutinib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 523 participants
- Where
- 201 sitesin 28 countries
- Study dates
- 16 May 2013to 24 Jun 2024
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 65 years and older
- All sexes
- No healthy volunteers
- Older adult
Who may be able to join
- Diagnosis of mantle cell lymphoma (MCL) reviewed and approved by central laboratory: diagnosis must include morphology and expression of either cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5 and CD5) or evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR)
- Clinical Stage II, III, or IV by Ann Arbor Classification
- At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma
- No prior therapies for MCL
- Eastern Cooperative Oncology Group (ECOG) performance status grade 0 or 1
- Hematology and biochemical laboratory values within protocol-defined limits
- Agrees to protocol-defined use of effective contraception
- Negative blood or urine pregnancy test at screening
Who cannot join
- Major surgery within 4 weeks of random assignment
- Known central nervous system lymphoma
- 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 random assignment; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated cervical carcinoma in situ without evidence of disease
- Patients for whom the goal of therapy is tumor debulking prior to stem cell transplant
- History of stroke or intracranial hemorrhage within 6 months prior to random assignment
- Requires anticoagulation with warfarin or equivalent vitamin K antagonists
Show all 11Show fewer
- 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
- Vaccinated with live, attenuated vaccines within 4 weeks of random assignment
- Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection requiring intravenous antibiotics
- 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
Trial locations and contacts
201 sites in 28 countries.
201 sites in 28 countries
United States44 sites
Study site
Albany, New York
Study site
Albuquerque, New Mexico
Study site
Ann Arbor, Michigan
Study site
Bismarck, North Dakota
Study site
Burbank, California
Study site
Burlington, Vermont
Study site
Chicago, Illinois
Study site
Denver, Colorado
Study site
Detroit, Michigan
Study site
Durham, North Carolina
Study site
Eugene, Oregon
Study site
Fargo, North Dakota
Study site
Goshen, Indiana
Study site
Greenville, North Carolina
Study site
Greenville, South Carolina
Study site
Hackensack, New Jersey
Study site
Hawthorne, New York
Study site
Houston, Texas
Study site
Iowa City, Iowa
Study site
Jefferson City, Missouri
Study site
La Jolla, California
Study site
Lexington, Kentucky
Study site
Lincoln, Nebraska
Study site
Louisville, Kentucky
Study site
Maywood, Illinois
Study site
Metairie, Louisiana
Study site
Nashville, Tennessee
Study site
New Brunswick, New Jersey
Study site
New Haven, Connecticut
Study site
New York, New York
Study site
Niles, Illinois
Study site
Philadelphia, Pennsylvania
Study site
Portland, Oregon
Study site
San Antonio, Texas
Study site
Sioux City, Iowa
Study site
Spokane, Washington
Study site
Springfield, Illinois
Study site
Stamford, Connecticut
Study site
Stanford, California
Study site
Topeka, Kansas
Study site
Tucson, Arizona
Study site
Vancouver, Washington
Study site
Watertown, South Dakota
Study site
Westwood, Kansas
Russia14 sites
Study site
Chelyabinsk
Study site
Krasnodar
Study site
Moscow
Study site
Nizhny Novgorod
Study site
Novosibirsk
Study site
Petrozavodsk
Study site
Rostov-on-Don
Study site
Ryazan
Study site
Saint Petersburg
Study site
Sochi
Study site
St.Petersurg
Study site
Syktyvkar
Study site
Volgograd
Study site
Yekaterinburg
United Kingdom10 sites
Study site
Canterbury
Study site
Glasgow
Study site
Leeds
Study site
Leicester
Study site
Liverpool
Study site
London
Study site
Manchester
Study site
Plymouth
Study site
Southampton
Study site
Sutton
Israel9 sites
Study site
Afula
Study site
Beersheba
Study site
Haifa
Study site
Jerusalem
Study site
Nahariya
Study site
Petah Tikva
Study site
Ramat Gan
Study site
Tel Aviv
Study site
Tsrifin
Japan9 sites
Study site
Fukuoka
Study site
Hiroshima
Study site
Kyoto
Study site
Nagoya
Study site
Osaka
Study site
Sapporo
Study site
Sendai
Study site
Suita
Study site
Tokyo
Australia8 sites
Study site
Adelaide
Study site
Auchenflower
Study site
Box Hill
Study site
Concord
Study site
Douglas
Study site
Gosford
Study site
Hobart
Study site
Prahran
Germany8 sites
Study site
Berlin
Study site
Heidelberg
Study site
Jena
Study site
Mainz
Study site
München
Study site
TÿBINGEN
Study site
Ulm
Study site
Villingen-Schwenningen
Belgium7 sites
Study site
Antwerp
Study site
Bruges
Study site
Brussels
Study site
Ghent
Study site
Leuven
Study site
Wilrijk
Study site
Yvoir
France7 sites
Study site
Créteil
Study site
F-75 730 Paris Cedex 15
Study site
Grenoble
Study site
Nantes
Study site
Paris
Study site
Pessac
Study site
Tours
Turkey (Türkiye)7 sites
Study site
Adana
Study site
Ankara
Study site
Diyarbakır
Study site
Istanbul
Study site
Izmir
Study site
Kayseri
Study site
Mersin
Brazil6 sites
Study site
Barretos
Study site
Goiânia
Study site
Porto Alegre
Study site
Ribeirão Preto
Study site
Rio de Janeiro
Study site
São Paulo
China6 sites
Study site
Beijing
Study site
Chengdu
Study site
Guangzhou
Study site
Hangzhou
Study site
Shanghai
Study site
Tianjin
Netherlands6 sites
Study site
Amsterdam-Zuidoost
Study site
Dordrecht
Study site
Groningen
Study site
Leiden
Study site
Rotterdam
Study site
Utrecht
Spain6 sites
Study site
Barcelona
Study site
Madrid
Study site
Oviedo
Study site
Palma de Mallorca
Study site
Salamanca
Study site
Santiago de Compostela
Taiwan6 sites
Study site
Changhua
Study site
Kaohsiung County
Study site
Taichung
Study site
Tainan
Study site
Taipei
Study site
Taoyuan
Canada5 sites
Study site
Edmonton, Alberta
Study site
Hamilton, Ontario
Study site
Montreal, Quebec
Study site
Ottawa, Ontario
Study site
Vancouver, British Columbia
Hungary5 sites
Study site
Budapest
Study site
Debrecen
Study site
Kaposvár
Study site
Pécs
Study site
Szeged
Poland5 sites
Study site
Bydgoszcz
Study site
Krakow
Study site
Olsztyn
Study site
Warsaw
Study site
Wroclaw
Slovakia5 sites
Study site
Banská Bystrica
Study site
Bratislava
Study site
Košice
Study site
Martin
Study site
Prešov
Sweden5 sites
Study site
Linköping
Study site
Lund
Study site
Stockholm
Study site
Umeaa
Study site
Uppsala
Ukraine5 sites
Study site
Cherkassy
Study site
Donetsk
Study site
Khmelnitskiy
Study site
Kiev
Study site
Lviv
Argentina4 sites
Study site
Buenos Aires
Study site
Córdoba
Study site
La Capital
Study site
Paraná
Greece3 sites
Study site
Athens
Study site
Athens Attica
Study site
Thessalonikis
South Korea3 sites
Study site
Gyeonggi-do
Study site
Jeollanam-do
Study site
Seoul
About this study
Official title: A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination With Bendamustine and Rituximab (BR) in Subjects With Newly Diagnosed Mantle Cell Lymphoma
The purpose of this study is to evaluate the efficacy and safety of ibrutinib given in combination with bendamustine and rituximab in patients 65 years of age or older with newly diagnosed mantle cell lymphoma.
Read the detailed description
This is a randomized (individuals assigned to study treatment by chance), double blind (neither physician nor participant knows the treatment that the participant receives), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial)-controlled study to compare the efficacy and safety of ibrutinib given in combination with bendamustine and rituximab (BR) with BR alone in participants newly diagnosed with mantle cell lymphoma (MCL) who are 65 years of age or older. Approximately 520 participants will be randomly assigned in a 1:1 ratio and stratified by simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) score (low risk [0-3] versus intermediate risk [4-5] versus high risk [6-11]). The treatment phase will extend from randomization until discontinuation of all study treatment or the clinical cutoff for the end of study. A cycle is defined as 28 days. All participants will receive open-label (identity of assigned study drug will be known) BR background therapy for a maximum of 6 cycles; participants with a complete response or partial response will continue to receive open-label background therapy with rituximab maintenance every second cycle for a maximum of 12 additional doses. In addition to the background therapy, all participants will receive blinded study drug (ibrutinib or placebo). Participants randomized to treatment Arm A will receive placebo capsules and participants randomized to treatment Arm B will receive ibrutinib capsules. Study drug will be administered daily and continuously until disease progression, unacceptable toxicity, or study end. Participants with stable disease after initial chemoimmunotherapy (BR+ibrutinib/placebo) should continue treatment with ibrutinib/placebo until disease progression, unacceptable toxicity, or study end. Participants with progressive disease must discontinue all study treatment. For participants who discontinue background therapy and do not have progressive disease, treatment with study drug will continue until disease progression or unacceptable toxicity or the clinical cutoff for the final analysis of progression-free survival (PFS). Participants receiving BR, rituximab, or ibrutinib at the clinical cutoff for the final analysis of PFS will continue open-label treatment until disease progression or unacceptable toxicity. Placebo will be stopped when the study is unblinded for the clinical cutoff for the final analysis of PFS. The posttreatment follow-up phase will begin once a participant discontinues bendamustine and rituximab and study drug. Participants who discontinue for reasons other than disease progression must continue to have disease evaluations as outlined in the protocol. Participants who discontinue due to disease progression will be followed for survival and subsequent anti-MCL therapy. The posttreatment follow-up phase will continue until death, lost to follow up, consent withdrawal, or study end, whichever occurs first. Four clinical cutoffs are planned. The first 3 clinical cutoffs will occur when approximately 134, 180, and 265 PFS events have been observed, respectively. The interim analyses and the final analysis of PFS will take place at these 3 clinical cutoffs, respectively; participant treatment assignment will be unblinded and placebo treatment will be stopped at the clinical cutoff for the final analysis of PFS. Treatment unblinding and stopping of placebo treatment could occur before the planned final analysis of PFS if recommended by the independent Data Monitoring Committee (DMC) after an interim analysis. The last cutoff will occur at the end of study, when 60% of the randomized participants have died or the Sponsor terminates the study, whichever comes first. Efficacy assessments will be conducted in accordance with the Revised Response Criteria for Malignant Lymphoma. Safety will be monitored throughout the study and summarized. Blood samples will be drawn for assessment of pharmacokinetic parameters. Blood and bone marrow will be collected for assessment of minimal residual disease and biomarker studies.
- Conditions
- Mantle Cell Lymphoma
- Being tested
- Bendamustine, Rituximab, Ibrutinib, Placebo
- Keywords
- Mantle cell lymphoma, Ibrutinib, Bruton's tyrosine kinase inhibitor, Bendamustine hydrochloride, Rituximab
- Medical subject headings
- Lymphoma, Mantle-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BendamustineDrug
90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6
RituximabDrug
375 mg/m2 administered intravenously on Day 1, Cycles 1-6; if complete response or partial response is achieved, 375 mg/m2 is administered on Day 1 of every second cycle for a maximum of 12 additional doses
IbrutinibDrug
560 mg (4 x 140 mg capsules) administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end
PlaceboDrug
4 capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or the final analysis of progression-free survival
| Study group | Role | What they receive |
|---|---|---|
| Treatment Arm A | Placebo comparator | Not described Receives: Drug: Bendamustine; Drug: Rituximab; Drug: Placebo |
| Treatment Arm B | Experimental | Not described Receives: Drug: Bendamustine; Drug: Rituximab; Drug: Ibrutinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression-free Survival (PFS)
Progression-free survival (PFS) was defined as the interval between the date of randomization to the date of disease progression (PD) or relapse from complete response (CR) or death, whichever was first reported. Disease assessments were based on the 2007 Revised Response Criteria for Malignant Lymphoma. PD was defined as any new lesion or increase by 50 percent (%) of previously involved sites from nadir (PD criteria: Appearance of new nodal lesion 1.5 centimeters [cm] in any axis, 50% increase in sum of product of diameters [SPD] of greater than [>] 1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis).
Measured: Up to 97 months
Secondary outcomes (15)
Overall Survival
Overall survival was defined as the time from the date of randomization to the date of the participant's death. Kaplan-Meier estimate was used.
Measured: From randomization (Day -3) up to 121 months
Complete Response Rate
Complete response (CR) rate was defined as the percentage of participants who achieve CR (based on investigator assessment) on or prior to the initiation of subsequent anticancer therapy. Criteria for CR: disappearance of all evidence of disease; mass of any size permitted if positron emission tomography (PET) negative; regression to normal size on computed tomography (CT); spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
Measured: Up to 97 months
Time-to-Next Treatment
Time-to-next treatment was measured from the date of randomization to the start date of any anti-mantle cell lymphoma (anti-MCL) treatment subsequent to the study treatment.
Measured: Up to 97 months
Percentage of Participants With Overall Response
Percentage of participants with overall response was defined as the portion of participants who achieved CR or PR. Criteria for CR: disappearance of all evidence of disease; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy. Criteria for PR: greater than or equal to (>=) 50% decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions.
Measured: Up to 97 months
Minimal Residual Disease (MRD)-Negative Response Rate
Minimal residual disease negative rate was defined as the percentage of participants with a best overall response of CR with MRD-negative disease status (that is, <5 mantle cell lymphoma [MCL] cell per 10,000 leukocytes for detection using the MRD assay), as assessed by flow cytometry of a bone marrow and/or peripheral blood sample.
Measured: Up to 97 months
Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Questionnaire
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 of participant symptoms. Worsening was defined by a 5-point decrease from baseline, death, or a missing assessment due to being "too ill", whichever occurred first. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score was the total of reverse scores, ranged 0 to 60. Higher scores indicated a better quality of life.
Measured: Up to 97 months
Duration of Response (DoR)
Duration of Response (DoR) was defined as the interval between the date of initial documentation of a response including PR and the date of first documented evidence of PD or death
Measured: Up to 97 months
Duration of Complete Response (DoCR)
Duration of complete response (DoCR) was defined as the interval between the date of initial documentation of a CR and the date of first documented evidence of PD or death whichever occurs first.
Measured: Up to 97 months
Time to Response
Time to response was defined as the interval between the date of randomization and the date of initial documentation of a response.
Measured: Up to 97 months
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Number of participants with TEAEs were reported. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. Treatment-emergent adverse events were defined as adverse events with onset or worsening on or after date of first dose of study treatment up to and including 30 days after date of last dose of study medication, or the initiation of subsequent anticancer therapy, whichever is earlier.
Measured: Placebo + BR (Treatment A): From first dose of study treatment (Day 1) up to 100.1 months; Ibrutinib + BR (Treatment B): From first dose of study treatment (Day 1) up to 117.2 months
Oral Plasma Clearance (CL/F) of Ibrutinib
CL/F was defined as apparent total systemic clearance of ibrutinib after extravascular administration. Cl/F of Ibrutinib was determined using population pharmacokinetics (PopPK modeling).
Measured: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Oral Volume of Distribution at Steady State of Ibrutinib
Oral volume of distribution at steady state of ibrutinib was determined using PopPK modeling.
Measured: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Area Under the Concentration Curve of Ibrutinib During 24 Hours After Dosing at Steady State
Area under the concentration curve of ibrutinib during 24 hours after dosing at steady state was determined using PopPK modeling.
Measured: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Minimum Observed Plasma Concentration of Ibrutinib
Minimum observed plasma concentration of ibrutinib was determined using PopPK modeling.
Measured: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Maximum Observed Plasma Concentration of Ibrutinib
Maximum observed plasma concentration of ibrutinib was determined using PopPK modeling.
Measured: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jan 2013 (estimated)
- Study start16 May 2013
- Primary completion30 Jun 2021
- Study completion24 Jun 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Mantle Cell LymphomaStudies of the same condition, open and under way.
- More trials run by Janssen Research & Development, LLCThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 523 participants (actual)
Sponsor and investigators
- Lead sponsor
- Janssen Research & Development, LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Pharmacyclics LLC.
- Responsible party
- Sponsor
- Investigators
- Janssen Research & Development, LLC Clinical Trial, Study director, Janssen Research & Development, LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01776840
- Sponsor's protocol ID
- CR100967
- Other IDs
- PCI-32765MCL3002, U1111-1137-0389, 2012-004056-11
- Status last verified
- Jun 2025
- First submitted
- 24 Jan 2013
- Last updated
- 8 Jul 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated device
- No
Publications
Wang ML, Jurczak W, Jerkeman M, Trotman J, Zinzani PL, Belada D, Boccomini C, Flinn IW, Giri P, Goy A, Hamlin PA, Hermine O, Hernandez-Rivas JA, Hong X, Kim SJ, Lewis D, Mishima Y, Ozcan M, Perini GF, Pocock C, Song Y, Spurgeon SE, Storring JM, Walewski J, Zhu J, Qin R, Henninger T, Deshpande S, Howes A, Le Gouill S, Dreyling M; SHINE Investigators. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N Engl J Med. 2022 Jun 30;386(26):2482-2494. doi: 10.1056/NEJMoa2201817. Epub 2022 Jun 3.
PubMed 35657079
Study at a glance
From the registry record, last updated by the sponsor on 8 Jul 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination With Bendamustine and Rituximab (BR) in Subjects With Newly Diagnosed Mantle Cell Lymphoma
- ClinicalTrials.gov ID
- NCT01776840
- Acronym / sponsor ID
- CR100967
- Conditions
- Mantle Cell Lymphoma
- Keywords
- Mantle cell lymphoma, Ibrutinib, Bruton's tyrosine kinase inhibitor, Bendamustine hydrochloride, Rituximab
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 523 participants (actual)
- Lead sponsor
- Janssen Research & Development, LLCIndustry (pharma, biotech, devices)
- Collaborators
- Pharmacyclics LLC.
- Study start
- 16 May 2013 (actual)
- Primary completion
- 30 Jun 2021 (actual)
- Study completion
- 24 Jun 2024 (actual)
- First posted
- 28 Jan 2013 (estimated)
- Results
- Posted 26 Jul 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to evaluate the efficacy and safety of ibrutinib given in combination with bendamustine and rituximab in patients 65 years of age or older with newly diagnosed mantle cell lymphoma.
Detailed description
This is a randomized (individuals assigned to study treatment by chance), double blind (neither physician nor participant knows the treatment that the participant receives), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial)-controlled study to compare the efficacy and safety of ibrutinib given in combination with bendamustine and rituximab (BR) with BR alone in participants newly diagnosed with mantle cell lymphoma (MCL) who are 65 years of age or older. Approximately 520 participants will be randomly assigned in a 1:1 ratio and stratified by simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) score (low risk [0-3] versus intermediate risk [4-5] versus high risk [6-11]). The treatment phase will extend from randomization until discontinuation of all study treatment or the clinical cutoff for the end of study. A cycle is defined as 28 days. All participants will receive open-label (identity of assigned study drug will be known) BR background therapy for a maximum of 6 cycles; participants with a complete response or partial response will continue to receive open-label background therapy with rituximab maintenance every second cycle for a maximum of 12 additional doses. In addition to the background therapy, all participants will receive blinded study drug (ibrutinib or placebo). Participants randomized to treatment Arm A will receive placebo capsules and participants randomized to treatment Arm B will receive ibrutinib capsules. Study drug will be administered daily and continuously until disease progression, unacceptable toxicity, or study end. Participants with stable disease after initial chemoimmunotherapy (BR+ibrutinib/placebo) should continue treatment with ibrutinib/placebo until disease progression, unacceptable toxicity, or study end. Participants with progressive disease must discontinue all study treatment. For participants who discontinue background therapy and do not have progressive disease, treatment with study drug will continue until disease progression or unacceptable toxicity or the clinical cutoff for the final analysis of progression-free survival (PFS). Participants receiving BR, rituximab, or ibrutinib at the clinical cutoff for the final analysis of PFS will continue open-label treatment until disease progression or unacceptable toxicity. Placebo will be stopped when the study is unblinded for the clinical cutoff for the final analysis of PFS. The posttreatment follow-up phase will begin once a participant discontinues bendamustine and rituximab and study drug. Participants who discontinue for reasons other than disease progression must continue to have disease evaluations as outlined in the protocol. Participants who discontinue due to disease progression will be followed for survival and subsequent anti-MCL therapy. The posttreatment follow-up phase will continue until death, lost to follow up, consent withdrawal, or study end, whichever occurs first. Four clinical cutoffs are planned. The first 3 clinical cutoffs will occur when approximately 134, 180, and 265 PFS events have been observed, respectively. The interim analyses and the final analysis of PFS will take place at these 3 clinical cutoffs, respectively; participant treatment assignment will be unblinded and placebo treatment will be stopped at the clinical cutoff for the final analysis of PFS. Treatment unblinding and stopping of placebo treatment could occur before the planned final analysis of PFS if recommended by the independent Data Monitoring Committee (DMC) after an interim analysis. The last cutoff will occur at the end of study, when 60% of the randomized participants have died or the Sponsor terminates the study, whichever comes first. Efficacy assessments will be conducted in accordance with the Revised Response Criteria for Malignant Lymphoma. Safety will be monitored throughout the study and summarized. Blood samples will be drawn for assessment of pharmacokinetic parameters. Blood and bone marrow will be collected for assessment of minimal residual disease and biomarker studies.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment Arm A | Placebo comparator | Drug: Bendamustine, Drug: Rituximab, Drug: Placebo |
| Treatment Arm B | Experimental | Drug: Bendamustine, Drug: Rituximab, Drug: Ibrutinib |
Who may qualify
- Ages
- 65 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Older adult
Key inclusion criteria (8 listed)
- Diagnosis of mantle cell lymphoma (MCL) reviewed and approved by central laboratory: diagnosis must include morphology and expression of either cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5 and CD5) or evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR)
- Clinical Stage II, III, or IV by Ann Arbor Classification
- At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma
- No prior therapies for MCL
- Eastern Cooperative Oncology Group (ECOG) performance status grade 0 or 1
Key exclusion criteria (11 listed)
- Major surgery within 4 weeks of random assignment
- Known central nervous system lymphoma
- 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 random assignment; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated cervical carcinoma in situ without evidence of disease
- Patients for whom the goal of therapy is tumor debulking prior to stem cell transplant
- History of stroke or intracranial hemorrhage within 6 months prior to random assignment
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Bendamustine90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6 | Drug | Treatment Arm A, Treatment Arm B |
| Rituximab375 mg/m2 administered intravenously on Day 1, Cycles 1-6; if complete response or partial response is achieved, 375 mg/m2 is administered on Day 1 of every second cycle for a maximum of 12 additional doses | Drug | Treatment Arm A, Treatment Arm B |
| Ibrutinib560 mg (4 x 140 mg capsules) administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end | Drug | Treatment Arm B |
| Placebo4 capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or the final analysis of progression-free survival | Drug | Treatment Arm A |
Primary outcome
Progression-free Survival (PFS)
Time frame: Up to 97 months
Progression-free survival (PFS) was defined as the interval between the date of randomization to the date of disease progression (PD) or relapse from complete response (CR) or death, whichever was first reported. Disease assessments were based on the 2007 Revised Response Criteria for Malignant Lymphoma. PD was defined as any new lesion or increase by 50 percent (%) of previously involved sites from nadir (PD criteria: Appearance of new nodal lesion 1.5 centimeters [cm] in any axis, 50% increase in sum of product of diameters [SPD] of greater than [>] 1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis).
15 secondary outcomes
Overall Survival
Time frame: From randomization (Day -3) up to 121 months
Complete Response Rate
Time frame: Up to 97 months
Time-to-Next Treatment
Time frame: Up to 97 months
Percentage of Participants With Overall Response
Time frame: Up to 97 months
Minimal Residual Disease (MRD)-Negative Response Rate
Time frame: Up to 97 months
Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Questionnaire
Time frame: Up to 97 months
Duration of Response (DoR)
Time frame: Up to 97 months
Duration of Complete Response (DoCR)
Time frame: Up to 97 months
Time to Response
Time frame: Up to 97 months
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Time frame: Placebo + BR (Treatment A): From first dose of study treatment (Day 1) up to 100.1 months; Ibrutinib + BR (Treatment B): From first dose of study treatment (Day 1) up to 117.2 months
Oral Plasma Clearance (CL/F) of Ibrutinib
Time frame: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Oral Volume of Distribution at Steady State of Ibrutinib
Time frame: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Area Under the Concentration Curve of Ibrutinib During 24 Hours After Dosing at Steady State
Time frame: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Minimum Observed Plasma Concentration of Ibrutinib
Time frame: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Maximum Observed Plasma Concentration of Ibrutinib
Time frame: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Jul 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 35657079Wang ML, Jurczak W, Jerkeman M, Trotman J, Zinzani PL, Belada D, Boccomini C, Flinn IW, Giri P, Goy A, Hamlin PA, Hermine O, Hernandez-Rivas JA, Hong X, Kim SJ, Lewis D, Mishima Y, Ozcan M, Perini GF, Pocock C, Song Y, Spurgeon SE, Storring JM, Walewski J, Zhu J, Qin R, Henninger T, Deshpande S, Howes A, Le Gouill S, Dreyling M; SHINE Investigators. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N Engl J Med. 2022 Jun 30;386(26):2482-2494. doi: 10.1056/NEJMoa2201817. Epub 2022 Jun 3.
Related trials for Mantle Cell Lymphoma
Not yet recruitingPhase 1
Testing the Addition of an Anti-Cancer Drug, Glofitamab, to the Usual Chemotherapy Treatment (Alternating R-CHOP/R-DHAP) for Previously Untreated Mantle Cell Lymphoma
Ann Arbor Stage II Mantle Cell Lymphoma, Ann Arbor Stage III Mantle Cell Lymphoma
RecruitingPhase 3
A Study to Evaluate Glofitamab as a Single Agent vs. Investigator's Choice in Participants With Relapsed/Refractory Mantle Cell Lymphoma
Lymphoma
RecruitingPhase 1
A Study of LY4152199 in Participants With Previously Treated B-cell Malignancies (BAF_FRontier-1 )
Lymphoma, Non-Hodgkin, B-cell Lymphoma
RecruitingPhase 2
Auto Stem Cell Transplant for Lymphoma Patients
Non-Hodgkin Lymphoma, Hodgkin Lymphoma
Active, not recruitingPhase 1
Study to Evaluate Adverse Events, Change in Disease Activity, and How Oral ABBV-101 Moves Through the Body in Adult Participants With B-Cell Malignancies
Hematologic Cancer
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Janssen Research & Development, LLC Clinical Trial study director
Janssen Research & Development, LLC
201 sites in 28 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Bendamustine, Rituximab and Ibrutinib in people with Mantle Cell Lymphoma, run by Janssen Research & Development, LLC at 201 sites in 28 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 201 sites in United States, Russia, United Kingdom, Israel, Japan and 23 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Jul 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression-free Survival (PFS) (time frame: Up to 97 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01776840, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jul 2025.