Mantle Cell Lymphoma

Primary:  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) (Cheson 2014; Error! Reference source not found.) — hereafter referred to as Lugano Classification for NHL — in subjects with previously untreated mantle cell lymphoma (MCL) Secondary: To evaluate acalabrutinib in combination with BR compared with placebo plus BR in terms of:  Investigator-assessed PFS per the Lugano Classification for NHL  Investigator-assessed overall response rate (ORR; complete response [CR] + partial response [PR]) per the Lugano Classification for NHL  IRC-assessed ORR (CR + PR) per the Lugano Classification for NHL  Overall survival (OS)  IRC-assessed duration of response (DOR) per the Lugano Classification for NHL  IRC-assessed time to response (TTR) per the Lugano Classification for NHL

Acalabrutinib (ACP-196)

Silicified microcrystalline cellulose, which is composed of microcrystalline cellulose and colloidal

Capsule

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Primary Endpoint:
The primary endpoint of the study is PFS as assessed by IRC per the Lugano Classification for
NHL. The primary analysis is a comparison of PFS between Arm 1 (acalabrutinib plus BR) and
Arm 2 (placebo plus BR).
Secondary Endpoints:
 Investigator-assessed PFS per the Lugano Classification for NHL
 Investigator-assessed ORR (CR + PR) per the Lugano Classification for NHL
 IRC-assessed ORR (CR + PR) per the Lugano Classification for NHL
 OS
 IRC-assessed DOR per the Lugano Classification for NHL
 IRC-assessed TTR per the Lugano Classification for NHL
Safety:
 Frequency, severity, seriousness, and relatedness of AEs
 Frequency of AEs requiring treatment discontinuation or modification

Inclusion criteria:
1. Men and women, ≥ 65 years of age.
2. Pathologically confirmed MCL, with documentation of monoclonal CD20+
B cells that have a
chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1.
3. MCL requiring treatment and for which no prior systemic anticancer therapies have been
received.
4. Presence of radiologically measurable lymphadenopathy or extranodal lymphoid malignancy (as
defined by Lugano Classification for NHL).
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
6. Men who are sexually active and can beget children must agree to use highly effective forms of
contraception during the study and for 90 days after the last dose of acalabrutinib, 6 months
after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is
longest. Highly effective forms of contraception are defined in Section Error! Reference source
not found..
7. Men must agree to refrain from sperm donation during the study and for 90 days after the last
dose of acalabrutinib, 6 months after the last dose of bendamustine, or 12 months after the last
dose of rituximab, whichever is longest.
8. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
9. Ability to understand the purpose and risks of the study and provide signed and dated informed
consent and authorization to use protected health information (in accordance with national
and local patient privacy regulations).

Exclusion criteria:
1. History of prior malignancy except for the following:
a. Malignancy treated with curative intent and with no evidence of active disease present for
more than 2 years before screening and felt to be at low risk for recurrence by treating
physician. Note: Provided they meet other eligibility criteria, subjects who are receiving
hormonal therapy alone are allowed to enroll on study.
b. Adequately treated lentigo maligna melanoma without current evidence of disease or
adequately controlled nonmelanomatous skin cancer.
c. Adequately treated carcinoma in situ without current evidence of disease
2. Subjects for whom the goal of therapy is tumor debulking before stem cell transplant.
3. Any history of central nervous system (CNS) lymphoma or leptomeningeal disease.
4. Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura
(ITP).
5. Major surgical procedure within 28 days before first dose of study drug. Note: If a subject had
major surgery, they must have recovered adequately from any toxicity and/or complications
from the intervention before the first dose of study drug.
6. 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.
7. Absolute neutrophil count (ANC) < 1.0 x 109
/L or platelet count < 75 x 109
/L; for subjects with
disease involvement in the bone marrow, ANC < 0.75 x 109
/L or platelet count < 50 x 109
/L.
Subjects will only be considered eligible if peripheral blood counts can be maintained
independent of growth factors or transfusions during the screening period.
8. Total bilirubin > 1.5 x upper limit of normal (ULN); or aspartate aminotransferase (AST) or
alanine aminotransferase (ALT) > 2.5 x ULN.
9. Estimated creatinine clearance of < 50 mL/min, calculated using the formula of Cockcroft and
Gault [(140-Age) • Mass (kg)/(72 • creatinine mg/dL) • multiply by 0.85 if female].
10. Prothrombin time/international normalized ratio (INR) or activated partial thromboplastin time
(aPTT; in the absence of a Lupus anticoagulant) > 2.0 x ULN. Exception: Subjects receiving
warfarin are excluded; however, those receiving other anticoagulant therapy who have a higher
INR/aPTT may be permitted to enroll to this study after discussion with the medical monitor.
11. 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.
12. 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.
13. Known history of infection with human immunodeficiency virus (HIV).
14. Ongoing immunosuppressive therapy, including systemic (eg, IV or oral) corticosteroids within 2
weeks before the first dose of study drug. Note: Subjects may use topical or inhaled
corticosteroids or low-dose steroids as therapy for comorbid conditions. During study
participation, subjects may also receive systemic (eg, IV or oral) corticosteroids as needed for
treatment-emergent comorbid conditions.
15. Known history of anaphylaxis or hypersensitivity to bendamustine, rituximab, or any of their
components.
16. Serologic status reflecting active hepatitis B or C infection.
a. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen
negative will need to have a negative polymerase chain reaction (PCR) result before
randomization. Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B
PCR positive will be excluded.
b. Subjects who are hepatitis C antibody positive will need to have a negative PCR result
before randomization. Those who are hepatitis C PCR positive will be excluded.
17. Received a live virus vaccination within 28 days of first dose of study drug.
18. History of stroke or intracranial hemorrhage within 6 months of first dose of study drug.
19. History of bleeding diathesis (eg, hemophilia or von Willebrand disease).
20. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before first dose
of study drug.
21. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg,
phenprocoumon) within 7 days of first dose of study drug.
22. Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor/inducer.
23. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole,
dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who
switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
24. Concurrent participation in another therapeutic clinical trial.