A study to evaluate acalabrutinib, in combination with the R-CHOP standard of care, for previously untreated mantle cell lymphoma in Spain.

Prior treatment

• Subjects for whom the goal of therapy is tumor debulking before stem cell transplant
• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before first dose of study drug.
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.
• Requires treatment with a strong CYP3A inhibitor/inducer
• Concurrent participation in another therapeutic clinical trial.
• 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.
• 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.
• Ongoing immunosuppressive therapy, including systemic (e.g., 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 (≤20 mg prednisone equivalent/day for ≤2 weeks) as a therapy for comorbid conditions and/or pre-phase treatment up to 100 mg/day or equivalent (for a maximum of 10 days prior to beginning study treatment) in participants with bulky disease, systemic symptoms, compressive disease, impaired liver function or cytopenias due to lymphoma, or rapidly progressing adenopathies. During study participation, subjects will receive corticosteroids as part of the R-CHOP regimen according to institution standards. Subjects may also receive systemic (e.g., IV or oral) corticosteroids as needed for treatment-emergent comorbid conditions.
• Received a live virus vaccination within 28 days of first dose of study drug.

Other illness

• 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.
• History of stroke or intracranial hemorrhage within 6 months of first dose of study drug.
• History of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
• Active cytomegalovirus (CMV) infection (active viremia as evidenced by positive PCR result for CMV DNA).
• History of confirmed progressive multifocal leukoencephalopathy (PML).
• Any history of central nervous system (CNS) lymphoma or leptomeningeal disease
• Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP).
• Significant cardiovascular disease such as uncontrolled or untreated 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 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.
• Known history of infection with human immunodeficiency virus (HIV).
• Known history of anaphylaxis or hypersensitivity to any study drug, or any of their components.
• Serologic status reflecting active hepatitis B or C infection. a. Subjects who are anti-HBc positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) result before the first dose of study drug. Those who are 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 the first dose of study drug. Those who are hepatitis C PCR positive will be excluded.

Lab values

• 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 a vitamin K antagonist 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
• 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.
• Total bilirubin >1.5 x upper limit normal (ULN) unless other reason known (e.g. Gilbert Syndrome, or due to lymphoma involvement); or aspartate aminotransferase (AST) or alanine transaminase (ALT) >2.5 x ULN.
• Estimated creatinine clearance of <30 mL/min, calculated using the formula of Cockcroft and Gault [(140-age) • mass (kg)/(72 • creatinine mg/dL) • multiply by 0.85 if female].

Other

• Subjects who are deemed by the treating physician to be unfit to tolerate the R-CHOP regimen.
• Pregnant or breastfeeding women.

• Adult (aged ≥18 years) men or women.
• Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing tablets without difficulty
• 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).
• Unsuitable for autologous stem cell transplantation
• WOCBP who are sexually active must use highly effective methods of contraception during the study treatment and for 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib, whichever is the longerst. NOTE: Female participants should be stable on the chosen method of contraception for a minimum of 3 months before entering a trial.
• Male patients should use barrier contraception (ie, condoms) from the time of screening until 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib , whichever is longest. Male patients wishing to father children in the future should be advised to arrange for the freezing of sperm prior to the start of study treatment. NOTE: Female partners should be advised to use accepted contraception during their partner’s study treatment and for 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib, whichever is longest.
• Pathologically confirmed MCL, with documentation of chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1 in association with other relevant markers
• MCL requiring treatment and for which no prior systemic anticancer therapies have been received
• Presence of radiologically measurable lymphadenopathy, splenomegaly and/or extranodal lymphoid malignancy
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
• Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study treatment and for 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib, whichever is longest.
• Men must agree to refrain from sperm donation during the study treatment and for 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib, whichever is longest