A Trial to Compare Ibrutinib Versus Lenalidomide in Combination With MRE-chemotherapy for Adult Patients With Recurrent/Refractory Primary Central Nervous System Lymphoma (PCNSL)

Inclusion Criteria:

1. Participants must be able to understand and be willing to sign a written informed consent document.
2. Men and woman who are 18-75 years old on the day of consenting to the study.
3. Histologically documented PCNSL and histologically documented systemic diffuse large B-cell lymphoma (DLBCL).
4. Patients must have relapsed/refractory PCNSL or relapsed/refractory SCNSL
5. All patients need to have received at least one prior CNS directed therapy. There is no restriction on the number of recurrences.
6. Patients with parenchymal lesions must have unequivocal evidence of disease progression on imaging (MRI of the brain or head CT) 21 days prior to study registration.
7. Participants must have an ECOG performance status of 0-3.
8. Participants must have adequate bone marrow and organ function shown by:

   1. Absolute neutrophil count (ANC) ≥ 1.0 x 10\^9/L
   2. Platelets ≥ 75 x 10\^9/L and no platelet transfusion within the past 21 days prior to study registration
   3. Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 21 days prior to study registration
   4. International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal
   5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal
   6. 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.
   7. Serum creatinine ≤ 2 times the upper limit of normal
9. Woman of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 30 days after the last dose of the study drug. Men who are sexually active must agree to use highly effective contraception during the period of therapy and for 3 months after the last dose.
10. Patients must be able to tolerate MRI/CT scans.
11. Participants must have recovered to grade 1 toxicity from prior therapy.
12. Participants should be able to submit up to 20 unstained formalin-fixed, paraffinembedded (FFPE) slides from the initial tissue diagnosis prior to study registration for confirmation of diagnosis and correlative studies
13. NOTE: Prior autologous stem cell transplant as well as prior radiation to the CNS does NOT prevent patients from enrollment into the trial.

Exclusion Criteria:

1. Patients with SCNSL actively receiving treatment for extra-CNS disease are excluded.
2. Patient has received chemotherapy, monoclonal antibodies or targeted anticancer therapy ≤ 4 weeks or 5 half-lives, whichever is shorter, or 6 weeks for nitrosourea or mitomycin-C prior to starting the study drug, or the patient has not recovered from the side effects of such therapy.
3. Patient has received external beam radiation therapy to the CNS within 21 days of the first dose of the study drug.
4. Patient requires more than 8 mg of dexamethasone daily or the equivalent
5. Patient has an active concurrent malignancy requiring active therapy
6. The patient has been treated with radio- or toxin-immunoconjugates within 70 days of the first Patient is allergic to components of the study drug.
7. Patient is using warfarin or any other Coumadin-derivative anticoagulant or vitamin K antagonists. Patients must be off warfarin-derivative anticoagulants for at least seven days prior to starting the study drug. Low molecular weight heparin is allowed. Patients with congenital bleeding diathesis are excluded.
8. Patient is taking a drug known to be a moderate and strong inhibitor or inducers of the P450 isoenzyme CYP3A. Participants must be off P450/CYP3A inhibitors and inducers for at least two weeks prior to starting the study drug.
9. 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 immunosuppressant therapy for at least 28 days prior to the first dose of the study drug.
10. Patient has significant abnormalities on screening electrocardiogram (EKG) and active and significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, hypertension, valvular disease, pericarditis, or myocardial infarction within 6 months of screening,
11. Patient has a known bleeding diathesis (e.g. von Willebrand"s disease) or hemophilia.
12. Patient is known to have human immunodeficiency virus (HIV) infection.
13. Patient is known to have a history of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests.
14. Patient is known to have an uncontrolled active systemic infection.
15. Patient underwent major systemic surgery ≤ 4 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.
16. Patient is unable to swallow capsules or has a disease or condition significantly affecting gastrointestinal function, such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel obstruction.
17. Patient has a life-threatening illness, medical condition, or organ system dysfunction that, in the opinion of the investigator, could compromise the subject"s safety or put the study outcomes at undue risk.
18. Women who are pregnant or nursing (lactating), where pregnancy is defined as a state of a female after conception until the termination of gestation, confirmed by a positive serum hCG laboratory test of \> 5 mIU/mL (See section on Pregnancy and Reproduction)
19. Patient has undergone prior allogenic stem cell transplant (autologous stem cell transplant is NOT an exclusion)
20. The patient is unwell or unable to participate in all required study evaluations and procedures
21. Known hypersensitivity to ibrutinib, thalidomide or lenalidomide