Ibrutinib With Methotrexate and Temozolomide for Patients With Newly Diagnosed Primary CNS Lymphoma

Inclusion Criteria:

* Men and woman who are 18 to 70 years of age on the day of consenting to the study.
* Histologically documented PCNSL
* ECOG performance status ≤ 2.
* Life expectancy of \> 3 months (in the opinion of the investigator).
* Adequate bone marrow and organ function shown by:

  * Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L
  * Platelets ≥ 75 x 10\^9/L and no platelet transfusion within the past 14 days prior to study registration
  * Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14 days prior to study registration
  * International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal
  * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal
  * Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome
  * Serum creatinine ≤ 2 times the upper limit of normal
  * Lipase ≤ 1.5 x upper limit of normal
* Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for the time period between signing of the informed consent form and 30 days (for WOCBP) and 90 days (for men) after the last administration of study treatment. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy.

  * The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control (failure rate of less than 1%), e.g. intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner and sexual abstinence
  * The use of condoms by male patients is required unless the female partner is permanently sterile. Female subjects of childbearing potential must have a negative plasma pregnancy test upon study entry
* Must be able to tolerate MRI/CT scans
* Must be able to tolerate lumbar puncture and/or Ommaya taps
* Able to submit up to 20 unstained formalin-fixed, paraffin-embedded (FFPE) slides from the initial or most recent tissue diagnosis for correlative studies

Exclusion Criteria:

Patients eligible for this study must NOT MEET ANY of the following criteria:

• Active concurrent malignancy requiring active therapy

Excluded medical conditions:

* Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure (New York Heart Association \> Class 2), unstable angina, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
* Uncontrolled hypertension despite optimal medical management (per investigators assessment)
* Patient has poorly controlled diabetes mellitus with a glycosylated hemoglobin \>8% or poorly controlled steroid-induced diabetes mellitus with a glycosylated hemoglobin of \>8%
* Patient is known to have an uncontrolled active systemic infection (\>CTCAE grade 2) and recent infection requiring intravenous anti-infective treatment that was completed ≤14 days before the first dose of study drug
* Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 3 months before the start of study treatment
* Non-healing wound, ulcer or bone fracture
* Known bleeding diathesis (eg, von Willebrands disease) or hemophilia
* Known history of infection with human immunodeficiency virus (HIV) or active stage of infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests, or any uncontrolled active systemic infection
* Patient underwent major systemic surgery ≤ 2 weeks prior to starting the trial treatment or who has not recovered from the side effects of such surgery, or who plan to have surgery within 2 weeks of the first dose of the study drug
* Unable to swallow capsules or disease significantly affecting gastrointestinal function, such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel obstruction
* Any life-threatening illness, medical condition including uncontrolled diabetes mellitus (DM), uncontrolled hypertension or organ system dysfunction that, in the opinion of the investigator, could compromise the subjects safety or put the study outcomes at undue risk
* Lactating or pregnant

Excluded previous Therapies and medications:

* Concurrent use of warfarin or other vitamin K antagonists (need to be stopped 7 days prior to starting on trial drug)
* Concurrent use of a strong cytochrome P450 (CYP) 3A4/5 inhibitor and inducers (need to be stopped 2 weeks prior to starting on trial drug)
* Enzyme-inducing antiepileptic drugs (EIAED) need to be discontinued and switched to a non-EIAED 2 weeks prior to starting on trial drug)
* Patient requires more than 4 mg of dexamethasone daily or the equivalent
* Patient is using systemic immunosuppressant therapy, including cyclosporine A, tacrolimus, sirolimus, and other such medications, or chronic administration of \> 5 mg/day or prednisone or the equivalent. Participants must be off of immunosuppressant therapy for at least 28 days prior to the first dose of the study drug
* Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration of \> 5 mg/day of prednisone) within 28 days of the first dose of study drug