Clinical trial NCT01776840: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Mantle Cell Lymphoma
Keywords: Mantle cell lymphoma
Ibrutinib
Bruton's tyrosine kinase inhibitor
Bendamustine hydrochloride
Rituximab
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
Collaborators: name: Pharmacyclics LLC.
First posted: 2013-01-28
Enrollment: 523
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Up to 97 months
Secondary outcomes:
measure: Overall Survival
timeFrame: Up to 97 months
measure: Complete Response Rate
timeFrame: Up to 97 months
measure: Time-to-Next Treatment
timeFrame: Up to 97 months
measure: Percentage of Participants With Overall Response
timeFrame: Up to 97 months
measure: Minimal Residual Disease (MRD)-Negative Response Rate
timeFrame: Up to 97 months
measure: Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Questionnaire
timeFrame: Up to 97 months
measure: Duration of Response (DoR)
timeFrame: Up to 97 months
measure: Duration of Complete Response (DoCR)
timeFrame: Up to 97 months
measure: Time to Response
timeFrame: Up to 97 months
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: Up to 97 months
measure: Oral Plasma Clearance (CL/F) of Ibrutinib
timeFrame: Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)
measure: Oral Volume of Distribution at Steady State of Ibrutinib
timeFrame: Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)
measure: Area Under the Concentration Curve of Ibrutinib During 24 Hours After Dosing at Steady State
timeFrame: Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)
measure: Minimum Observed Plasma Concentration of Ibrutinib
timeFrame: Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)
measure: Maximum Observed Plasma Concentration of Ibrutinib
timeFrame: Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days)
Other outcomes:
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city: Athens
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city: Seoul
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city: Dordrecht
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city: Groningen
country: Netherlands
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country: Poland
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country: Poland
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country: Poland
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country: Poland
city: San Juan
country: Puerto Rico
city: Chelyabinsk
country: Russian Federation
city: Ekaterinburg
country: Russian Federation
city: Krasnodar
country: Russian Federation
city: Moscow N/a
country: Russian Federation
city: Moscow
country: Russian Federation
city: Nizhny Novgorod
country: Russian Federation
city: Novosibirsk
country: Russian Federation
city: Petrozavodsk
country: Russian Federation
city: Rostov-Na-Donu
country: Russian Federation
city: Ryazan
country: Russian Federation
city: Sochi
country: Russian Federation
city: St-Petersburg
country: Russian Federation
city: St.Petersurg
country: Russian Federation
city: Syktyvkar
country: Russian Federation
city: Volgograd
country: Russian Federation
city: Banska Bystrica
country: Slovakia
city: Bratislava
country: Slovakia
city: Kosice
country: Slovakia
city: Martin
country: Slovakia
city: Presov 1
country: Slovakia
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Oviedo
country: Spain
city: Palma De Mallorca
country: Spain
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country: Spain
city: Santiago De Compostela
country: Spain
city: Linköping
country: Sweden
city: Lund
country: Sweden
city: Stockholm
country: Sweden
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country: Sweden
city: Uppsala
country: Sweden
city: Changhua
country: Taiwan
city: Kaohsiung County
country: Taiwan
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country: Taiwan
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country: Taiwan
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country: Taiwan
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country: Taiwan
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country: Turkey
city: Ankara
country: Turkey
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country: Turkey
city: Istanbul
country: Turkey
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country: Turkey
city: Kayseri
country: Turkey
city: Mersin
country: Turkey
city: Cherkassy
country: Ukraine
city: Donetsk
country: Ukraine
city: Khmelnitskiy
country: Ukraine
city: Kiev
country: Ukraine
city: Lviv
country: Ukraine
city: Canterbury
country: United Kingdom
city: Glasgow
country: United Kingdom
city: Leeds
country: United Kingdom
city: Leicester
country: United Kingdom
city: Liverpool
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Plymouth
country: United Kingdom
city: Southampton
country: United Kingdom
city: Sutton
country: United Kingdom
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: 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.