Smart Start: A Phase II Study of Rituximab, Lenalidomide, and Ibrutinib

Inclusion Criteria

• Histopathologically confirmed diagnosis of previously untreated DLBCL of the non-GCB DLBCL subtype
• No prior treatment except a prior limited-field radiotherapy, a short course of glucocorticoids = = 1.5 cm
• Patients with performance status of = 80% unconjugated bilirubin
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) = 1000/mm^3 unless deemed related to lymphoma involvement in the bone marrow and felt potentially reversible by the treating physician
• Platelets > 100, 000/mm^3 unless deemed related to lymphoma involvement in the bone marrow and felt potentially reversible by the treating physician
• Renal function assessed by calculated creatinine clearance:
• Calculated creatinine clearance >=30 ml/min by Cockcroft-Gault formula
• Patients must be willing to receive transfusions of blood products
• All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the REMS program
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) or urine pregnancy test at screening and must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program
• Women of childbearing potential and men who are sexually active with a woman of childbearing potential must be practicing a highly effective method of birth control during and after the study (12 months for women and 3 months for men), consistent with local regulations regarding the use of birth control methods for subjects participating in this clinical study; men must agree to not donate sperm during and for up to 3 months after their conclusion of therapy on study
• Able to take aspirin (81 mg) daily or alternative therapy as prophylactic anticoagulation

Exclusion Criteria

• Any serious medical condition including but not limited to uncontrolled hypertension, uncontrolled congestive heart failure within past 6 months prior to screening (class 3 [moderate] or class 4 [severe] cardiac disease as defined by the New York Heart Association Functional Classification), uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), left ventricular ejection fraction (LVEF) less than 40%, renal failure, active infection, history of invasive fungal infection, moderate to severe hepatic disease (Child Pugh class B or C), active hemorrhage, laboratory abnormality, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form; patients with history of cardiac arrhythmias should have cardiac evaluation and clearance
• Pregnant or lactating females
• Known hypersensitivity to lenalidomide or thalidomide, ibrutinib, rituximab, etoposide, vincristine, doxorubicin, cyclophosphamide, or prednisone
• Known human immunodeficiency virus (HIV) infection; patients with active hepatitis B infection (not including patients with prior hepatitis B vaccination; or positive serum hepatitis B antibody); known hepatitis C infection is allowed as long as there is no active disease and is cleared by gastrointestinal (GI) consultation
• All patients with central nervous system involvement with lymphoma
• Diagnosis of prior malignancy within the past 2 years with the exception of successfully treated basal cell carcinoma, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast; history of other malignancies are allowed if in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated, with a life expectancy > 3 years
• Significant neuropathy (grades 2 or grade 1 with pain) within 14 days prior to enrollment
• Contraindication