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

NCT ID: NCT01776840

Last Updated: 2025-07-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 523 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-05-16
• Study Completion Date: 2024-06-24

Brief 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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Treatment Arm A

Group Type: PLACEBO_COMPARATOR

Bendamustine

Intervention Type: DRUG

90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6

Rituximab

Intervention Type: DRUG

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

Placebo

Intervention Type: DRUG

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

Treatment Arm B

Group Type: EXPERIMENTAL

Bendamustine

Intervention Type: DRUG

90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6

Rituximab

Intervention Type: DRUG

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

Ibrutinib

Intervention Type: DRUG

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

Interventions

Bendamustine

90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6

Intervention Type: 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

Intervention Type: 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

Intervention Type: 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

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pharmacyclics LLC.

INDUSTRY

Sponsor Role: collaborator

Janssen Research & Development, LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Janssen Research & Development, LLC Clinical Trial

Role: STUDY_DIRECTOR

Janssen Research & Development, LLC

Locations

Tucson, Arizona, United States

Burbank, California, United States

La Jolla, California, United States

Stanford, California, United States

Denver, Colorado, United States

New Haven, Connecticut, United States

Stamford, Connecticut, United States

Chicago, Illinois, United States

Maywood, Illinois, United States

Niles, Illinois, United States

Springfield, Illinois, United States

Goshen, Indiana, United States

Iowa City, Iowa, United States

Sioux City, Iowa, United States

Topeka, Kansas, United States

Westwood, Kansas, United States

Lexington, Kentucky, United States

Louisville, Kentucky, United States

Metairie, Louisiana, United States

Ann Arbor, Michigan, United States

Detroit, Michigan, United States

Jefferson City, Missouri, United States

Lincoln, Nebraska, United States

Hackensack, New Jersey, United States

New Brunswick, New Jersey, United States

Albuquerque, New Mexico, United States

Albany, New York, United States

Hawthorne, New York, United States

New York, New York, United States

Durham, North Carolina, United States

Greenville, North Carolina, United States

Bismarck, North Dakota, United States

Fargo, North Dakota, United States

Eugene, Oregon, United States

Portland, Oregon, United States

Philadelphia, Pennsylvania, United States

Greenville, South Carolina, United States

Watertown, South Dakota, United States

Nashville, Tennessee, United States

Houston, Texas, United States

San Antonio, Texas, United States

Burlington, Vermont, United States

Spokane, Washington, United States

Vancouver, Washington, United States

Buenos Aires, , Argentina

Córdoba, , Argentina

La Capital, , Argentina

Paraná, , Argentina

Adelaide, , Australia

Auchenflower, , Australia

Box Hill, , Australia

Concord, , Australia

Douglas, , Australia

Gosford, , Australia

Hobart, , Australia

Prahran, , Australia

Antwerp, , Belgium

Bruges, , Belgium

Brussels, , Belgium

Ghent, , Belgium

Leuven, , Belgium

Wilrijk, , Belgium

Yvoir, , Belgium

Barretos, , Brazil

Goiânia, , Brazil

Porto Alegre, , Brazil

Ribeirão Preto, , Brazil

Rio de Janeiro, , Brazil

São Paulo, , Brazil

Edmonton, Alberta, Canada

Vancouver, British Columbia, Canada

Hamilton, Ontario, Canada

Ottawa, Ontario, Canada

Montreal, Quebec, Canada

Beijing, , China

Chengdu, , China

Guangzhou, , China

Hangzhou, , China

Shanghai, , China

Tianjin, , China

Brno, , Czechia

Hradec Králové, , Czechia

Prague, , Czechia

Créteil, , France

F-75 730 Paris Cedex 15, , France

Grenoble, , France

Nantes, , France

Paris, , France

Pessac, , France

Tours, , France

Berlin, , Germany

Heidelberg, , Germany

Jena, , Germany

Mainz, , Germany

München, , Germany

TÿBINGEN, , Germany

Ulm, , Germany

Villingen-Schwenningen, , Germany

Athens, , Greece

Athens Attica, , Greece

Thessalonikis, , Greece

Budapest, , Hungary

Debrecen, , Hungary

Kaposvár, , Hungary

Pécs, , Hungary

Szeged, , Hungary

Dublin, , Ireland

Galway, , Ireland

Afula, , Israel

Beersheba, , Israel

Haifa, , Israel

Jerusalem, , Israel

Nahariya, , Israel

Petah Tikva, , Israel

Ramat Gan, , Israel

Tel Aviv, , Israel

Ẕerifin, , Israel

Fukuoka, , Japan

Hiroshima, , Japan

Kyoto, , Japan

Nagoya, , Japan

Osaka, , Japan

Sapporo, , Japan

Sendai, , Japan

Suita, , Japan

Tokyo, , Japan

Monterrey, , Mexico

Oaxaca City, , Mexico

Amsterdam-Zuidoost, , Netherlands

Dordrecht, , Netherlands

Groningen, , Netherlands

Leiden, , Netherlands

Rotterdam, , Netherlands

Utrecht, , Netherlands

Bydgoszcz, , Poland

Krakow, , Poland

Olsztyn, , Poland

Warsaw, , Poland

Wroclaw, , Poland

San Juan, , Puerto Rico

Chelyabinsk, , Russia

Krasnodar, , Russia

Moscow, , Russia

Nizhny Novgorod, , Russia

Novosibirsk, , Russia

Petrozavodsk, , Russia

Rostov-on-Don, , Russia

Ryazan, , Russia

Saint Petersburg, , Russia

Sochi, , Russia

St.Petersurg, , Russia

Syktyvkar, , Russia

Volgograd, , Russia

Yekaterinburg, , Russia

Banská Bystrica, , Slovakia

Bratislava, , Slovakia

Košice, , Slovakia

Martin, , Slovakia

Prešov, , Slovakia

Gyeonggi-do, , South Korea

Jeollanam-do, , South Korea

Seoul, , South Korea

Barcelona, , Spain

Madrid, , Spain

Oviedo, , Spain

Palma de Mallorca, , Spain

Salamanca, , Spain

Santiago de Compostela, , Spain

Linköping, , Sweden

Lund, , Sweden

Stockholm, , Sweden

Umeaa, , Sweden

Uppsala, , Sweden

Changhua, , Taiwan

Kaohsiung County, , Taiwan

Taichung, , Taiwan

Tainan City, , Taiwan

Taipei, , Taiwan

Taoyuan District, , Taiwan

Adana, , Turkey (Türkiye)

Ankara, , Turkey (Türkiye)

Diyarbakır, , Turkey (Türkiye)

Istanbul, , Turkey (Türkiye)

Izmir, , Turkey (Türkiye)

Kayseri, , Turkey (Türkiye)

Mersin, , Turkey (Türkiye)

Cherkassy, , Ukraine

Donetsk, , Ukraine

Khmelnitskiy, , Ukraine

Kiev, , Ukraine

Lviv, , Ukraine

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

Countries

United States; Argentina; Australia; Belgium; Brazil; Canada; China; Czechia; France; Germany; Greece; Hungary; Ireland; Israel; Japan; Mexico; Netherlands; Poland; Puerto Rico; Russia; Slovakia; South Korea; Spain; Sweden; Taiwan; Turkey (Türkiye); Ukraine; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 35657079 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

PCI-32765MCL3002

Identifier Type: OTHER

Identifier Source: secondary_id

U1111-1137-0389

Identifier Type: OTHER

Identifier Source: secondary_id

2012-004056-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CR100967

Identifier Type: -

Identifier Source: org_study_id