Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (TEDDI-R) in Primary CNS Lymphoma

BACKGROUND: * Primary CNS lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma. * The outcome for patients with this diagnosis is significantly worse than for that of systemic DLBCL. Most treatment approaches in the past have included high dose methotrexate and radiation treatment. * Most PCNSLs appear to be of activated B-cell (ABC) origin. * Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and effective for systemic DLBCL of ABC origin. * We propose doing a study in which ibrutinib is combined with a novel chemotherapy platform called dose adjusted temozolomide, etoposide, doxil, dexamethasone, ibrutinib, rituximab (TEDDI-R). OBJECTIVE: \- Identify the maximum tolerated dose (MTD) of ibrutinib or the dose that achieves adequate CSF concentrations, whichever comes first, when ibrutinib is given with TEDDI-R. ELIGIBILITY: * Relapsed/refractory PCNSL. * Age greater than or equal to 18 years. * No pregnant or breast-feeding women. * Adequate organ function (defined in protocol). STUDY DESIGN: * This is a phase 1 study of 40 patients. * The study will have two components. 1. Phase 1: MTD of ibrutinib will be identified or the dose at which ibrutinib achieves a concentration of less than or equal to 100 nM in the CSF, when given in combination with TEDDI-R immuno-chemotherapy, whichever comes first. 2. Expansion cohort: Safety and tolerability of the regimen in relapsed/refractory or previously untreated PCNSL (DLBCL type) will be assessed at the final ibrutinib dose with TEDDI-R in 10 patients. Secondary objectives will be PFS and OS.

* ELIGIBILITY CRITERIA: * Patients must have histologically or cytologically confirmed primary central nervous system diffuse large B-cell lymphoma. Patients with PCNSL that is only extracranial will not be eligible. Patients with relapsed or refractory disease, as well as untreated patients, are eligible. Untreated patients must not have high dose chemotherapy and autologous stem cell transplantation (ASCT) planned as part of frontline therapy to be eligible for the trial. * At least 2 weeks have passed since prior chemotherapy, biological therapy, radiation therapy, other investigational or anti-cancer therapy that is considered disease-directed. * Ibrutinib must be discontinued 7 days before (when possible) until 7 days after major surgery, and 3 days before (when possible) until 3 days after minor surgery. Thus, patients to be enrolled on an ibrutinib trial must have completed major surgery \>= 7 days before initiating treatment, and/or must have completed minor surgery \>= 3 days before initiating treatment. * Recovered from prior toxicities to Grade 0-1 at least 2 weeks prior to investigational therapy. * Age \>=18 years. Because no dosing or adverse event data are currently available on the use of ibrutinib and TEDDI-R in patients \= 750 cells/mcL (0.75 x 10(9)/L) * platelet count \>= 50,000 cells/mcL (50 X 10(9)/L) * Hemoglobin \> 8.0 g/dL * total bilirubin \14 days before the first dose of study drug. * Pregnant and nursing individuals are excluded from this study. Pregnant individuals 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 with a nursing participant ibrutinib, nursing should be discontinued if the mother is treated with ibrutinib. * Uncontrolled Autoimmune Hemolytic Anemia or ITP resulting in (or as evidenced by) declining platelet or Hgb levels within the 4 weeks prior to first dose of study drug. * 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 3 years prior to Screening and felt to be at low risk for recurrence by treating physician * Adequately treated non-melanomatous skin cancer or lentigo maligna 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. Patients 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 6 months prior to enrollment. * Any life-threatening illness, medical condition, or organ system dysfunction that, in the Investigator's opinion, could compromise the patient's safety, or put the study at undue risk. Patients 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 \