Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib, and Rituximab (TEDDI-R) in Aggressive B-cell Lymphomas With Secondary Involvement of the Central Nervous System (CNS)

Inclusion Criteria

• - INCLUSION CRITERIA: - Participants must have histologically or cytologically confirmed secondary involvement of an aggressive B-cell lymphoma in the CNS (eye, CSF, and/or brain parenchyma). NOTE: B-cell lymphomas that were previously indolent but now involve the CNS (i.e. transformed from previous follicular lymphoma or chronic lymphocytic leukemia and mantle cell lymphoma) are eligible. - Participants must have disease that is relapsed or refractory after initial systemic treatment or participants without prior therapy for systemic DLBCL must have concomitant involvement of the eyes, CSF or brain parenchyma. - Age greater than or equal to18 years. NOTE: Because no dosing or adverse event data are currently available on the use of ibrutinib and TEDDI-R in participants <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials. - ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%) unless due to disease - Participants must have adequate organ function as defined below, independent of growth factor or platelet transfusion support: - Absolute neutrophil count (ANC): greater than or equal to 750 cells/mcL (0.75 (SqrRoot) 10^9/L) - Platelets: greater than or equal to 50,000 cells/mcL (50 (SqrRoot) 10^9/L) - Hemoglobin: greater than or equal to 8 g/dL (transfusions permitted) - Serum total bilirubin: less than or equal to 1.5 X ULN unless Gilbert s syndrome or disease infiltration of the liver is present) - AST (SGOT) and ALT (SGPT): less than or equal to 3.0 (SqrRoot) institutional ULN (less than or equal to 5 x ULN for participants with liver involvement by lymphoma) - Serum creatinine: less than or equal to 1.5 mg/dL OR - Creatinine clearance: greater than or equal to 40 ml/min/1.73m^2 unless lymphoma related - Prothrombin time/INR (PT) and activated partial thromboplastin time (aPTT) must be < 1.5 x the upper limit of the normal range (ULN); except if, in the opinion of the Investigator, the aPTT is prolonged because of a positive Lupus Anticoagulant. - Women of childbearing potential must have a negative pregnancy test upon study entry. This is not required for women who are of non-reproductive potential (i.e., post-menopausal by history - defined as: no menses for greater than or equal to 1 year; OR, history of hysterectomy; OR, history of bilateral tubal ligation; OR, history of bilateral oophorectomy). - The effects of ibrutinib and TEDDI-R on the developing human fetus are unknown. For this reason, women must agree to use highly effective methods of birth control. A "highly effective method of birth control" is defined as a method that has a low failure rate (i.e., less than 1% per year) when used consistently and correctly and includes implants, injectables, birth control pills with two hormones, some intrauterine devices (IUDs). Men who can father children cannot use highly effective methods and are required to use barrier. The specific guidelines are as follows: - Women of childbearing potential (WOCBP) must use a highly effective method of birth control and a barrier method, or sexual abstinence (which is defined as refraining from all aspects of sexual activity), while taking the study treatment, as well as for 12 months after the last dose of rituximab. - Men who can father children must use a barrier method to prevent pregnancy of their partner and should also not donate sperm while taking the study treatment and for 12 months after the last dose of rituximab. - Ability of participant or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document EXCLUSION CRITERIA: - Systemic chemotherapy less than or equal to 14 days prior to ibrutinib window study - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or other agents used in study - Participants who are allergic to isavuconazole or any of its ingredients - Participants who received a strong cytochrome P450 (CYP) 3A inhibitor or inducer within 7 days prior to the first dose of protocol anti-fungal prophylaxis, or participants who require continuous treatment with a strong CYP3A inhibitor/inducer (i.e., with the exception of any medication to be specifically studied in this protocol). NOTE: In addition, because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list; medical reference texts such as the Physicians Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product. - HIV positive participants will be excluded because of their increased susceptibility to fungal infections which outweighs the potential benefit of participation. - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or an infection requiring systemic antibiotics, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Recent infections requiring systemic treatment need to have completed therapy >14 days before the first dose of study drug. - Pregnant and nursing women are excluded from this study. Pregnant women are excluded in this study because ibrutinib is a tyrosine kinase inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ibrutinib, nursing should be discontinued if the mother is treated with ibrutinib. - Presence of transfusion-dependent thrombocytopenia. - History of prior malignancy, with the exception of the following: - Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years prior to screening and felt to be at low risk for recurrence by treating physician - Adequately treated non-melanomatous skin cancer or lentigo malignant melanoma without current evidence of disease - Adequately treated carcinoma in situ without current evidence of disease. - Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction unstable angina, or acute coronary syndrome within 6 months prior to enrollment in the study. - Unable to swallow capsules, or disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, or symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. - Serologic status reflecting active hepatitis B or C infection. Participants that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. Those who are (PCR positive will be excluded.) Those with a negative PCR for hepatitis B will be treated with antivirals designed to prevent hepatitis B reactivation (e.g., entecavir) and have monitoring for hepatitis B reactivation with PCR. - History of stroke or intracranial hemorrhage within 3 months prior to enrollment. - Any life-threatening illness, medical condition, or organ system dysfunction that, in the Investigator s opinion, could compromise the participant s safety, or put the study at undue risk. Participants with suspicious radiologic evidence of aspergillosis infection (i.e., Chest CT and/or Brain MRI) will not be eligible unless confirmatory laboratory testing of Beta-D glucan and aspergillus antigen are negative. - Concomitant use of warfarin or other vitamin K antagonists within the last 7 days. - Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g., cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug. - Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. - Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to grade less than or equal to1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia. - Known bleeding disorders (e.g., von Willebrand s disease) or hemophilia. - Unwilling or unable to participate in all required study evaluations and procedures. - Currently active, clinically significant hepatic impairment (greater than or equal to moderate hepatic impairment according to the NCI/Child Pugh classification