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 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.

Study Overview

• Status: Completed
• Conditions: Mantle Cell Lymphoma
• Intervention / Treatment: Drug: Bendamustine; Drug: Rituximab; Drug: Placebo; Drug: Ibrutinib

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 Type: Interventional
• Enrollment (Actual): 523
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
  • Ciudad Autonoma de Buenos Aires, Argentina
  • Cordoba, Argentina
  • La Capital, Argentina
  • Parana, Argentina
• Australia
  • Adelaide, Australia
  • Auchenflower, Australia
  • Box Hill, Australia
  • Concord, Australia
  • Douglas, Australia
  • Gosford, Australia
  • Hobart, Australia
  • Prahran, Australia
• Belgium
  • Antwerpen, Belgium
  • Brugge, Belgium
  • Brussels, Belgium
  • Gent, Belgium
  • Leuven, Belgium
  • Wilrijk, Belgium
  • Yvoir, Belgium
• Brazil
  • Barretos, Brazil
  • Goiania, Brazil
  • Porto Alegre, Brazil
  • Ribeirao Preto, Brazil
  • Rio de Janeiro, Brazil
  • Sao Paulo, Brazil
• Canada
  • Alberta
    • Edmonton, Alberta, Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
  • Ontario
    • Hamilton, Ontario, Canada
    • Ottawa, Ontario, Canada
  • Quebec
    • Montreal, Quebec, Canada
• China
  • Beijing, China
  • Chengdu, China
  • Guangzhou, China
  • Hangzhou, China
  • Shanghai, China
  • Tianjin, China
• Czechia
  • Brno, Czechia
  • Hradec Kralove, Czechia
  • Praha 10, Czechia
• France
  • Creteil, France
  • F-75 730 Paris Cedex 15, France
  • Grenoble, France
  • Nantes, France
  • Paris, France
  • Pessac, France
  • Tours Cedex 9, France
• Germany
  • Berlin, Germany
  • Heidelberg, Germany
  • Jena, Germany
  • Mainz, Germany
  • München, Germany
  • TÿBINGEN, Germany
  • Ulm, Germany
  • Villingen-Schwenningen, Germany
• Greece
  • Athens, Greece
  • Athens Attica, Greece
  • Thessalonikis, Greece
• Hungary
  • Budapest N/a, Hungary
  • Debrecen, Hungary
  • Kaposvár, Hungary
  • Pecs, Hungary
  • Szeged, Hungary
• Ireland
  • Dublin, Ireland
  • Galway, Ireland
• Israel
  • Afula, Israel
  • Beer-Sheva, Israel
  • Haifa, Israel
  • Jerusalem, Israel
  • Nahariya, Israel
  • Petach Tikva, Israel
  • Ramat-Gan, Israel
  • Tel Aviv, Israel
  • Zerifin, Israel
• Japan
  • Fukuoka, Japan
  • Hiroshima, Japan
  • Kyoto, Japan
  • Nagoya, Japan
  • Osaka, Japan
  • Sapporo, Japan
  • Sendai-shi, Japan
  • Suita, Japan
  • Tokyo, Japan
• Korea, Republic of
  • Gyeonggi-do, Korea, Republic of
  • Jeollanam-do, Korea, Republic of
  • Seoul, Korea, Republic of
• Mexico
  • Monterrey, Mexico
  • Oaxaca, Mexico
• Netherlands
  • Amsterdam Zuidoost, Netherlands
  • Dordrecht, Netherlands
  • Groningen, Netherlands
  • Leiden, Netherlands
  • Rotterdam, Netherlands
  • Utrecht, Netherlands
• Poland
  • Bydgoszcz, Poland
  • Krakow, Poland
  • Olsztyn, Poland
  • Warszawa, Poland
  • Wroclaw, Poland
• Puerto Rico
  • San Juan, Puerto Rico
• Russian Federation
  • Chelyabinsk, Russian Federation
  • Ekaterinburg, Russian Federation
  • Krasnodar, Russian Federation
  • Moscow, Russian Federation
  • Moscow N/a, Russian Federation
  • Nizhny Novgorod, Russian Federation
  • Novosibirsk, Russian Federation
  • Petrozavodsk, Russian Federation
  • Rostov-Na-Donu, Russian Federation
  • Ryazan, Russian Federation
  • Sochi, Russian Federation
  • St-Petersburg, Russian Federation
  • St.Petersurg, Russian Federation
  • Syktyvkar, Russian Federation
  • Volgograd, Russian Federation
• Slovakia
  • Banska Bystrica, Slovakia
  • Bratislava, Slovakia
  • Kosice, Slovakia
  • Martin, Slovakia
  • Presov 1, Slovakia
• Spain
  • Barcelona, Spain
  • Madrid, Spain
  • Oviedo, Spain
  • Palma De Mallorca, Spain
  • Salamanca, Spain
  • Santiago De Compostela, Spain
• Sweden
  • Linköping, Sweden
  • Lund, Sweden
  • Stockholm, Sweden
  • Umeaa, Sweden
  • Uppsala, Sweden
• Taiwan
  • Changhua, Taiwan
  • Kaohsiung County, Taiwan
  • Taichung, Taiwan
  • Tainan, Taiwan
  • Taipei, Taiwan
  • Taoyuan, Taiwan
• Turkey
  • Adana, Turkey
  • Ankara, Turkey
  • Diyarbakir, Turkey
  • Istanbul, Turkey
  • Izmir, Turkey
  • Kayseri, Turkey
  • Mersin, Turkey
• Ukraine
  • Cherkassy, Ukraine
  • Donetsk, Ukraine
  • Khmelnitskiy, Ukraine
  • Kiev, Ukraine
  • Lviv, Ukraine
• United Kingdom
  • Canterbury, United Kingdom
  • Glasgow, United Kingdom
  • Leeds, United Kingdom
  • Leicester, United Kingdom
  • Liverpool, United Kingdom
  • London, United Kingdom
  • Manchester, United Kingdom
  • Plymouth, United Kingdom
  • Southampton, United Kingdom
  • Sutton, United Kingdom
• United States
  • Arizona
    • Tucson, Arizona, United States
  • California
    • Burbank, California, United States
    • La Jolla, California, United States
    • Stanford, California, United States
  • Colorado
    • Denver, Colorado, United States
  • Connecticut
    • New Haven, Connecticut, United States
    • Stamford, Connecticut, United States
  • Illinois
    • Chicago, Illinois, United States
    • Maywood, Illinois, United States
    • Niles, Illinois, United States
    • Springfield, Illinois, United States
  • Indiana
    • Goshen, Indiana, United States
  • Iowa
    • Iowa City, Iowa, United States
    • Sioux City, Iowa, United States
  • Kansas
    • Topeka, Kansas, United States
    • Westwood, Kansas, United States
  • Kentucky
    • Lexington, Kentucky, United States
    • Louisville, Kentucky, United States
  • Louisiana
    • Metairie, Louisiana, United States
  • Michigan
    • Ann Arbor, Michigan, United States
    • Detroit, Michigan, United States
  • Missouri
    • Jefferson City, Missouri, United States
  • Nebraska
    • Lincoln, Nebraska, United States
  • New Jersey
    • Hackensack, New Jersey, United States
    • New Brunswick, New Jersey, United States
  • New Mexico
    • Albuquerque, New Mexico, United States
  • New York
    • Albany, New York, United States
    • Hawthorne, New York, United States
    • New York, New York, United States
  • North Carolina
    • Durham, North Carolina, United States
    • Greenville, North Carolina, United States
  • North Dakota
    • Bismarck, North Dakota, United States
    • Fargo, North Dakota, United States
  • Oregon
    • Eugene, Oregon, United States
    • Portland, Oregon, United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
  • South Carolina
    • Greenville, South Carolina, United States
  • South Dakota
    • Watertown, South Dakota, United States
  • Tennessee
    • Nashville, Tennessee, United States
  • Texas
    • Houston, Texas, United States
    • San Antonio, Texas, United States
  • Vermont
    • Burlington, Vermont, United States
  • Washington
    • Spokane, Washington, United States
    • Vancouver, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm B	Drug: Bendamustine; 90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6; Drug: Rituximab; 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; Drug: Ibrutinib; 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
Placebo Comparator: Treatment Arm A	Drug: Bendamustine; 90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6; Drug: Rituximab; 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; Drug: Placebo; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Up to 97 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	Up to 97 months
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.	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.	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.	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.	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	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.	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.	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).	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.	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.	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.	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.	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

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC
• Collaborators: Pharmacyclics LLC.
• Investigators: Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2013
• Primary Completion (Actual): June 30, 2021
• Study Completion (Actual): June 24, 2024

Study Registration Dates

• First Submitted: January 24, 2013
• First Submitted That Met QC Criteria: January 24, 2013
• First Posted (Estimated): January 28, 2013

Study Record Updates

• Last Update Posted (Actual): July 8, 2025
• Last Update Submitted That Met QC Criteria: June 18, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Rituximab; Ibrutinib; Mantle cell lymphoma; Bruton's tyrosine kinase inhibitor; Bendamustine hydrochloride
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Mantle-Cell; Antineoplastic Agents, Immunological; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Protein Kinase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Bendamustine Hydrochloride; Rituximab; Ibrutinib
• Other Study ID Numbers: CR100967; PCI-32765MCL3002 (Other Identifier: Janssen Research & Development, LLC); U1111-1137-0389 (Other Identifier: Universal Trial Number); 2012-004056-11 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No