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
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ClinicalTrials.gov Identifier: NCT01776840 |
Recruitment Status :
Active, not recruiting
First Posted : January 28, 2013
Results First Posted : July 26, 2022
Last Update Posted : April 25, 2024
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Mantle Cell Lymphoma | Drug: Bendamustine Drug: Rituximab Drug: Ibrutinib Drug: Placebo | Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 523 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Triple (Participant, Care Provider, Investigator) |
Primary Purpose: | Treatment |
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 |
Actual Study Start Date : | May 16, 2013 |
Actual Primary Completion Date : | June 30, 2021 |
Estimated Study Completion Date : | May 15, 2024 |
Arm | Intervention/treatment |
---|---|
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 |
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 |
- Progression-free Survival (PFS) [ Time Frame: Up to 97 months ]Progression-free survival (PFS) is 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 is first reported. Disease assessments were based on the 2007 Revised Response Criteria for Malignant Lymphoma. PD is 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).
- Overall Survival [ Time Frame: Up to 97 months ]Overall survival is defined as the time from the date of randomization to the date of the participant's death.
- Complete Response Rate [ Time Frame: Up to 97 months ]Complete response (CR) rate is 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.
- Time-to-Next Treatment [ Time Frame: Up to 97 months ]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.
- Percentage of Participants With Overall Response [ Time Frame: Up to 97 months ]Percentage of participants with overall response that is participants who achieved CR or PR was reported. 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.
- Minimal Residual Disease (MRD)-Negative Response Rate [ Time Frame: Up to 97 months ]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.
- 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 ]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 is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life.
- Duration of Response (DoR) [ Time Frame: Up to 97 months ]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.
- Duration of Complete Response (DoCR) [ Time Frame: Up to 97 months ]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, for participants who achieved CR.
- Time to Response [ Time Frame: Up to 97 months ]Time to response was defined as the interval between the date of randomization and the date of initial documentation of a response.
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to 97 months ]Number of participants with TEAEs were reported. Treatment-emergent adverse events are 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.
- Oral Plasma Clearance (CL/F) of Ibrutinib [ Time Frame: Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) ]CL/F of Ibrutinib was determined using population pharmacokinetics (PopPK modeling).
- Oral Volume of Distribution at Steady State of Ibrutinib [ Time Frame: Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) ]Oral volume of distribution at steady state of ibrutinib was determined using PopPK modeling.
- Area Under the Concentration Curve of Ibrutinib During 24 Hours After Dosing at Steady State [ Time Frame: Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) ]Area under the concentration curve of ibrutinib during 24 hours after dosing at steady state was determined using PopPK modeling.
- Minimum Observed Plasma Concentration of Ibrutinib [ Time Frame: Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) ]Minimum observed plasma concentration of ibrutinib was determined using PopPK modeling.
- Maximum Observed Plasma Concentration of Ibrutinib [ Time Frame: Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) ]Maximum observed plasma concentration of ibrutinib was determined using PopPK modeling.
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Ages Eligible for Study: | 65 Years and older (Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01776840
Study Director: | Janssen Research & Development, LLC Clinical Trial | Janssen Research & Development, LLC |
Documents provided by Janssen Research & Development, LLC:
Responsible Party: | Janssen Research & Development, LLC |
ClinicalTrials.gov Identifier: | NCT01776840 |
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 ) |
First Posted: | January 28, 2013 Key Record Dates |
Results First Posted: | July 26, 2022 |
Last Update Posted: | April 25, 2024 |
Last Verified: | April 2024 |
Studies a U.S. FDA-regulated Device Product: | No |
Mantle cell lymphoma Ibrutinib Bruton's tyrosine kinase inhibitor Bendamustine hydrochloride Rituximab |
Lymphoma Lymphoma, Mantle-Cell Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Lymphoma, Non-Hodgkin Rituximab Bendamustine Hydrochloride Ibrutinib |
Antineoplastic Agents, Immunological Antineoplastic Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Tyrosine Kinase Inhibitors Protein Kinase Inhibitors Enzyme Inhibitors |