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 CNS (PCNSL) or non-GCB diffuse large B-cell lymphomawith secondary involvement of the CNS (SCNSL). NOTE: Participants with B-celllymphomas that were previously indolent but now involve the CNS (i.e., transformedfrom previous follicular lymphoma, chronic lymphocytic leukemia, marginal zonelymphoma, 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 CT or MRI and/or evaluable FDG-avid lesions on 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

• ECOG performance status <=2. NOTE: In participants with neurologic deficits causedby CNS lymphoma any ECOG status is acceptable 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 glutamicoxaloacetic 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 eGRF in the clinical lab

Laboratory assessments to determine eligibility may be performed at CLIA (or equivalent) certified laboratories outside the 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 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 REMS(TM)program and be willing and able to comply with the requirements of RevlimidREMS(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 DLBCL and classical Hodgkin 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)BTK inhibitors, (2) BCL2 inhibitors, (3) immunomodulatory imide drugs (IMIDs) (including lenalidomide and pomalidomide).

• Participants who require continuous treatment with a strong CYP3A inhibitor/inducer (i.e., with the exception of any medication to be specifically studied in thisprotocol).

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

• 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 NCI/Child Pugh classification)

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