Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid (VIPOR) for Diffuse Large B-cell Lymphoma Involving the Central Nervous System

• INCLUSION CRITERIA:

• Participants must have histologically or cytologically confirmed primary diffuselarge B-cell lymphoma of the central nervous system (CNS) primary central nervoussystem lymphoma (PCNSL) or non-germinal center B-cell-like (GCB) diffuse largeB-cell lymphoma with secondary involvement of the CNS (SCNSL). NOTE: Participantswith B-cell lymphomas that were previously indolent but now involve the CNS (i.e.,transformed from previous follicular lymphoma, chronic lymphocytic leukemia,marginal zone lymphoma, and mantle cell lymphoma) are eligible.

• Participants must have a disease that is relapsed or refractory after initialsystemic treatment or be considered ineligible for standard frontline therapy withhigh-dose methotrexate due to one of the following criteria:

• Age>= 70 years

• Estimated glomerular filtration rate < 60 ml/min/1.73m^2

• Presence of ascites or pleural effusion

• Participants must have evaluable disease by clinical exam (i.e., palpablelymphadenopathy, measurable skin lesions, etc.) and/or imaging (measurable lymphnodes or masses on computed tomography (CT) or magnetic resonance imaging (MRI)and/or evaluable fluorodeoxyglucose (FDG)-avid lesions on positron emissiontomography (PET).

• Participants with second malignancies not requiring active systemic therapy orpremalignant conditions such as monoclonal B-cell lymphocytosis (MBL) or monoclonalgammopathy of undetermined significance (MGUS) are eligible.

• Participants that are positive for hepatitis B core antibody (HBcAb), hepatitis Bsurface antigen (HBsAg), or hepatitis C antibody must have a negative hepatitis Band/or C viral load by polymerase chain reaction (PCR).

• Age >=18 years

• Eastern Cooperative Oncology Group (ECOG) performance status <=2. NOTE: Inparticipants with neurologic deficits caused by CNS lymphoma any ECOG status isacceptable to be eligible.

• Participants must have adequate organ and marrow function as defined below:

• absolute neutrophil count >= 1000 cells/mcL (1 X 10^9/L)

• platelet count >= 50,000 cells/mcL (50 X 10^9/L)

• hemoglobin > 8.0 g/dL (transfusions permitted)

• total bilirubin <= 1.5 X upper limit of normal (ULN) (unless Gilbert's syndromeor disease infiltration of the liver is present)

• Aspartate Aminotransferase or serum glutamic oxaloacetic transaminase/ AlanineAminotransferase or serum glutamic pyruvic transaminase AST(SGOT)/ALT(SGPT) <= 3.0 X institutional ULN for those without lymphoma involvement OR <= 5.0 Xinstitutional ULN for those with lymphoma involvement

• Serum Creatinine OR creatinine clearance (Cr Cl) <= 1.5 mg/dL OR > 40ml/min/1.73m^2

NOTE: Cr Cl will be calculated with the use of the 24-hour creatinine clearance or estimated glomerular filtration rate (eGRF) in the clinical lab

Laboratory assessments to determine eligibility may be performed at Clinical Laboratory Improvement Amendments (CLIA) (or equivalent) certified laboratories outside the National Institutes of Health (NIH) and results forwarded to the study team for review and management. Given that the methodologies utilized are similar across all laboratories, no significant variability is expected and there is no anticipation that study data will be affected. However, as different laboratories use slightly different kinds of equipment, each laboratory must determine/validate its own reference ranges. Therefore, on this protocol, normal ranges from each lab will be used in reference to terms such as upper limit of normal (ULN), except in cases where absolute values are appropriate and are specified as such

• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be < 1.5x the ULN; except if, the aPTT is prolonged because of a positive LupusAnticoagulant.

• Male and female participants must agree to use certain methods of birth control. Ahighly effective method of birth control for female participants is defined as amethod that has a low failure rate (i.e., less than 1% per year) when usedconsistently and correctly and includes implants, injectables, birth control pillswith two hormones, some intrauterine devices (IUDs). Male participant cannot usehighly effective methods and are required to use barrier. The specific guidelinesare as follows:

• Women: Females of childbearing potential (FOCBP), defined as a sexually maturefemale who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or

2. has not been naturally postmenopausal (amenorrhea following cancer therapydoes not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months), musteither commit to continued abstinence from heterosexual intercourse or beginTWO acceptable methods of birth control, one highly effective method and oneadditional effective method AT THE SAME TIME, at least 28 days before shestarts taking Revlimid (R), as well as for the duration after the last dose ofstudy drug as listed below.

• Men: Men must agree to remain abstinent (refrain from heterosexual intercourse)or use contraceptive measures to prevent pregnancy of their partner and shouldalso agree to not donate sperm while taking the study treatment and for thedurations as listed below.

• Contraception Requirements

• Time frame/Study Drug/Women/Men

• Pre-Treatment/During Treatment: Time frame prior to/during dosing:

• All drugs: Begins 28 days prior to treatment/Begins on day 1

• Post-Treatment: Time frame after the last dose:

• Venetoclax: 90 days/90 days

• Ibrutinib: 3 months/3 months

• Obinutuzumab: 18 months/6 months

• Revlimid (R): 28 days/28 days

• All study participants must be registered into the mandatory Revlimid RiskEvaluation and Mitigation Strategy (REMS)(TM) program and be willing and able tocomply with the requirements of Revlimid REMS(TM).

• Breastfeeding participants must be willing to discontinue breastfeeding from studytreatment initiation through designated time points after study drugsdiscontinuation (as required for women contraception in the table above)

EXCLUSION CRITERIA:

• Participants with plasmablastic lymphoma and B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma (DLBCL) and classicalHodgkin lymphoma are not eligible.

• Chemotherapy (excluding corticosteroids), radiation therapy, and/or monoclonalantibody <=7 days prior to first administration of study treatment. Rationale for ashort 7-day window is that participants with relapsed CNS lymphomas often haveexisting neurologic conditions that mandate urgent therapy.

• Previous treatment with more than one of the following classes of medications: (1)Bruton's tyrosine kinase (BTK) inhibitors, (2) B-cell lymphoma 2 (Bcl-2) inhibitors, (3) immunomodulatory imide drugs (IMIDs) (including lenalidomide and pomalidomide).

• Participants who require continuous treatment with a strong cytochrome P450 family 3, subfamily A (CYP3A) inhibitor/inducer (i.e., with the exception of any medicationto be specifically studied in this protocol).

--NOTE: A comprehensive list of inhibitors, inducers, and substrates may be foundat: https://drug-interactions.medicine.iu.edu/MainTable.aspx

• Human immunodeficiency virus (HIV)-positive participants

• Pregnant women- a pregnancy test (urine or serum) with a sensitivity of 25 mIU/mLmust be done at screening.

• Participants with second malignancies requiring active systemic therapy areexcluded.

• Class 3 or 4 congestive heart failure as defined by the New York Heart AssociationFunctional Classification

• History of any ventricular arrhythmia

• Unable to swallow capsules, or disease significantly affecting gastrointestinalfunction, or resection of the stomach or small bowel, or symptomatic inflammatorybowel disease or ulcerative colitis, or partial or complete bowel obstruction.

• Uncontrolled ongoing or active infection

• Concomitant use of warfarin or other vitamin K antagonists

• Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia.

• Currently active, clinically significant hepatic impairment (>= moderate hepaticimpairment according to the National Cancer Institute (NCI)/Child Pughclassification)

• Uncontrolled intercurrent illness or psychiatric illness/social situations thatwould limit compliance with study requirements.