A Study of BR Alone Versus in Combination With Acalabrutinib in Subjects With Previously Untreated MCL

Study Overview
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Brief Summary
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This study is evaluating the efficacy of acalabrutinib in combination with bendamustine and rituximab (BR) compared with placebo plus BR in subjects with previously untreated mantle cell lymphoma.

Detailed Description
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To evaluate the efficacy of acalabrutinib in combination with bendamustine and rituximab (BR) compared with placebo plus BR based on Independent Review Committee (IRC) assessment of progression-free survival (PFS) per the Lugano Classification for Non-Hodgkin Lymphoma (NHL) in subjects with previously untreated mantle cell lymphoma (MCL).

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter Study of Bendamustine and Rituximab (BR) Alone Versus in Combination With Acalabrutinib (ACP-196) in Subjects With Previously Untreated Mantle Cell Lymphoma

Conditions
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Lymphoma, Mantle Cell

Intervention / Treatment
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* Drug: Acalabrutinib
* Drug: Bendamustine
* Drug: Rituximab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, ≥ 65 years of age. Pathologically confirmed MCL, with documentation of a chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1 in association with other relevant markers (eg, CD5, CD19, CD20, PAX5) . MCL requiring treatment and for which no prior systemic anticancer therapies have been received. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Agreement to use highly effective forms of contraception during the study and 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longest . Exclusion Criteria: Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of first dose of study drug, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec (calculated using Friderica's formula: QT/RR0.33) at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti infective treatment within 2 weeks before first dose of study drug. Concurrent participation in another therapeutic clinical trial.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acalabrutinib in combination with bendamustine and rituximab<br>Acalabrutinib administered twice per day (BID) orally (PO) plus bendamustine on Days 1 and 2 and rituximab on Day 1; cycles are repeated every 28 days. | Drug: Acalabrutinib<br>* Administered orally (PO)<br>* Other names: Calquence;Drug: Bendamustine<br>* Administered intravenously (IV)<br>* Other names: Bendeka;Drug: Rituximab<br>* Administered intravenously (IV)<br>* Other names: Rituxan Hycela;|
| Placebo Comparator: Placebo in combination with bendamustine and rituximab<br>Matching placebo administered BID PO plus bendamustine on Days 1 and 2 and rituximab on Day 1; cycles are repeated every 28 days. | Drug: Bendamustine<br>* Administered intravenously (IV)<br>* Other names: Bendeka;Drug: Rituximab<br>* Administered intravenously (IV)<br>* Other names: Rituxan Hycela;Drug: Placebo<br>* Placebo comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival per the Lugano Classification for NHL in Arm 1 compared to Arm 2 | Defined as the time from the date of randomization until disease progression (assessed by the IRC per the Lugano Classification for NHL) or death from any cause, whichever occurs first. | Up to 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-assessed progression-free survival per the Lugano Classification for NHL in Arm 1 compared to Arm 2 | Defined as the time from the date of randomization until disease progression (assessed by the investigator per the Lugano Classification for NHL) or death from any cause, whichever occurs first. | Up to 6 years | 
| Investigator-assessed overall response rate per the Lugano Classification for NHL in Arm 1 compared to Arm 2 | Defined as the proportion of subjects who achieve either partial response (PR) or complete response (CR) as best overall response according to the Lugano Classification for NHL as assessed by investigator. | Up to 6 years | 
| IRC-assessed overall response rate per the Lugano Classification for NHL in Arm 1 compared to Arm 2 | Defined as the proportion of subjects who achieve either PR or CR as best overall response according to the Lugano Classification for NHL as assessed by IRC. | Up to 6 years | 
| Overall survival in Arm 1 compared to Arm 2 | Defined as the time from randomization until the date of death from any cause. | Up to 6 years | 
| IRC-assessed duration of response per the Lugano Classification for NHL in Arm 1 compared to Arm 2 | Defined as the time from the first documentation of CR or PR to disease progression per the Lugano Classification for NHL or death from any cause, whichever occurs first. | Up to 6 years | 
| IRC assessed time to response per the Lugano Classification for NHL in Arm 1 compared to Arm 2 | Defined as the time from randomization to the first CR or PR per the Lugano Classification for NHL. | Up to 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bruton tyrosine kinase inhibitor, Acalabrutinib, Mantle Cell Lymphoma, ACE-LY-308, Treatment naive, non-Hodgkins Lymphoma, Bendomustine, Rituximab