Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid in Combination With Polatuzumab (ViPOR-P) in Relapsed/Refractory B-cell Lymphoma

• INCLUSION CRITERIA:

• Patients must have histologically or cytologically confirmed B-cell lymphomaconfirmed by the Laboratory of Pathology, NCI, as follows:

Cohorts 1 and 2:

• Aggressive B-cell lymphoma: includes DLBCL and subtypes, transformed lymphoma,Burkitt lymphoma, as well as high-grade B-cell lymphoma with MYC and/or BCL2 and/orBCL6 rearrangement(s).

• Indolent B-cell lymphoma: with the following exceptions:

• MCL is excluded given increased risk of tumor lysis syndrome (TLS) withvenetoclax compared to other non-Hodgkin lymphomas and need for venetoclaxramp-up, dose-escalation.

• CLL/SLL is excluded given alternative dosing of FDA-approved venetoclax forrelapsed CLL/SLL and increased risk of TLS with CLL/SLL compared to othernon-Hodgkin lymphomas.

Cohort 3:

-Non-GCB DLBCL: includes DLBCL NOS and subtypes, transformed lymphoma, THRLBCL, as well as high-grade B-cell lymphoma with MYC and/or BCL6 rearrangement(s).

NOTE: Patients with known active CNS lymphoma are not eligible.

• Relapsed and/or refractory disease after at least 1 prior treatment regimen, asfollows:

• Aggressive B-cell lymphoma: relapsed after and/or refractory to at least 1prior anthracycline-containing regimen

• Indolent B-cell lymphoma: relapsed after and/or refractory to at least 1 prioranti- CD20 antibody-containing regimen.

• Patients must have evaluable disease by clinical exam (i.e., palpablelymphadenopathy, measurable skin lesions, etc.), laboratory assessment (i.e.,lymphoma involvement of bone marrow or peripheral blood by morphology, cytology orflow cytometry), and/or imaging (measurable lymph nodes or masses on CT or MRIand/or evaluable FDG-avid lesions on PET).

NOTE: Lesions that have been irradiated cannot be included in the tumor assessment unless unequivocal tumor progression has been documented in these lesions after radiation therapy.

-Age >=18 years

NOTE: Because no dosing or adverse event data are currently available on the use of polatuzumab in combination with venetoclax, ibrutinib, obinutuzumab, prednisone and Revlimid(R) in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.

• ECOG performance status <=2.

• Adequate organ and marrow function as defined below unless dysfunction is secondaryto lymphoma:

• absolute neutrophil count* >=1,000/mcL

• hemoglobin* >=8 g/dL

• Platelets >=75,000/mcL

• INR <=1.5 X institutional upper limit of normal (ULN) for patients notreceiving therapeutic anticoagulation

• PTT/aPTT <=1.5 X institutional ULN normal except if, in the opinion of theinvestigator, the aPTT is elevated because of a positive Lupus Anticoagulant,or a significant bleeding risk has been ruled out in the absence of a positiveLupus Anticoagulant

• total bilirubin <=1.5 X institutional ULN (or <=3 X institutional ULN forpatients with documented Gilberts syndrome identified by an isolatedunconjugated hyperbilirubinemia in the absence of other signs of liverdysfunction and/or UGT1A1 mutational testing)

• AST(SGOT)/ALT(SGPT) <=3 X institutional ULN

• Serum creatinine <=2.0 mg/dL OR

• Creatinine clearance >=30 mL/min/1.73 m2 for patients with creatinine levelsabove 2 mg/dL

NOTE: Cr Cl will be calculated with the use of the 24-hour creatinine clearance or eGRF in the clinical lab

• RBC transfusions and use of G-CSF will be allowed in order to meet eligibilityparameters.

• Immune-modulating drugs (IMiDs) including Revlimid(R) are known to beteratogenic and potential embryo-fetal harm can be seen with use ofpolatuzumab, venetoclax and ibrutinib. The effects of obinutuzumab on thedeveloping human fetus is unknown. For these reasons, individuals ofchild-bearing potential and individuals able to father a child must agree touse adequate contraception as described below.

• For individuals of childbearing potential:

• Agreement to remain abstinent (refrain from heterosexual intercourse)or use a contraceptive method with a failure rate of < 1% per year asoutlined below.

• Agreement to refrain from donating eggs during timelines specifiedbelow.

• Individuals of childbearing potential (ICBP) must have a negativeserum or urine pregnancy test with a sensitivity of at least 25mIU/mL within 10-14 days and again within 24 hours prior toprescribing Revlimid(R) for Cycle 1 (prescriptions must be filledwithin 7 days as required by Revlimid REMSTM) and must either committo continued abstinence from heterosexual intercourse or begin TWOacceptable methods of birth control, one highly effective method andone additional effective method AT THE SAME TIME, at least 28 daysbefore she starts taking Revlimid(R) ICBP must also agree to ongoingpregnancy testing.

• An individual is considered to be of childbearing potential if thatperson is post-menarcheal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause otherthan menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).

• Examples of contraceptive methods with a failure rate of < 1% peryear include bilateral tubal ligation, male sterilization, hormonalcontraceptives that inhibit ovulation, hormone-releasing intrauterinedevices, and copper intrauterine devices.

• The reliability of sexual abstinence should be evaluated in relationto the duration of the clinical trial and the preferred and usuallifestyle of the patient. Periodic abstinence (e.g., calendar,ovulation, symptothermal, or post-ovulation methods) and withdrawalare not acceptable methods of contraception.

• For individuals able to father a child:

• Agreement to remain abstinent (refrain from heterosexual intercourse)or use contraceptive measures, and agreement to refrain from donatingsperm, as defined below:

• With partners of childbearing potential, individuals able to father achild must remain abstinent or use a condom plus an additionalcontraceptive method that together result in a failure rate of < 1%per year as noted below. Individuals must refrain from donating spermduring this same period.

• With pregnant partners, individuals must remain abstinent or use acondom as noted below to avoid exposing the embryo.

• The reliability of sexual abstinence should be evaluated in relationto the duration of the clinical trial and the preferred and usuallifestyle of the patient. Periodic abstinence (e.g., calendar,ovulation, symptothermal, or post-ovulation methods) and withdrawalare not acceptable methods of contraception.

• Contraception Requirements

• Time frame/Study Drug (Pre-Treatment/During Treatment) - Individuals ofchildbearing potential (Time frame prior to/during dosing) / Individualsable to father a child (Time frame prior to/during dosing): ---All drugs; Begins 28 days prior to treatment; Begins on day 1

• Time frame/Study Drug (Post-Treatment) - Individuals of childbearingpotential (Time frame after the last dose) / Individuals able to father achild (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

• Polatuzumab - 3 months / 5 months

• All study participants must be registered into the mandatory Revlimid REMSTMprogram and be willing and able to comply with the requirements of RevlimidREMSTM. NOTE: Individuals of reproductive potential must adhere to thescheduled pregnancy testing as required in the Revlimid REMSTM program.

• Ability of subject to understand and the willingness to sign a written informedconsent document.

EXCLUSION CRITERIA:

• The following restrictions apply to current or prior anti-cancer treatment, prior tothe first dose of study drug:

• Patients who are actively receiving any other investigational agents.

• Any chemotherapy or anti-cancer antibodies within 2 weeks. NOTE: Short coursesof corticosteroids or palliative XRT prior to enrollment are permitted withinthe 2- week washout period.

• Radio- or toxin-immunoconjugates within 10 weeks.

• Previous treatment with more than one of the study agents (i.e., polatuzumab,venetoclax, ibrutinib, or Revlimid(R)), excluding prior prednisone or anti-CD20antibody treatment.

• Prior allogeneic stem cell (or other organ) transplant within 6 months or anyevidence of active graft-versus-host disease or requirement forimmunosuppressants within 28 days.

• Not recovered (i.e., <= Grade 1 or baseline) from adverse events due topreviously administered anti-cancer treatment, surgery, or procedure. NOTE:Exceptions to this include events not considered to place the subject atunacceptable risk of participation in the opinion of the PI (e.g., alopecia).

• Patients requiring the use of warfarin are excluded because of potential drug-druginteractions that may potentially increase the exposure of warfarin.

• Patients requiring the following agents to the first dose of venetoclax or ibrutinibare excluded, as noted:

• Strong CYP3A inhibitors within 7 days

• Strong CYP3A inducers within 7 days

NOTE: Moderate CYP3A inhibitors and inducers should be used with caution and an alternative medication used, whenever possible.

• Uncontrolled intercurrent illness including, but not limited to the following thatmay limit interpretation of results or that could increase risk to the patient atthe discretion of the investigator:

• Symptomatic congestive heart failure, unstable angina pectoris, or uncontrolledcardiac arrhythmia

• Uncontrolled and/or symptomatic thyroid disease

• Known active bacterial, viral, fungal, mycobacterial, parasitic, or otherinfection (excluding fungal infections of nail beds) at study enrollment, orany major episode of infection requiring treatment with IV antibiotics orhospitalization (relating to the completion of the course of antibiotics)within 2 weeks prior to Cycle 1, Day 1;

• Clinically significant history of liver disease, including viral or otherhepatitis, current alcohol abuse, or cirrhosis; as well as active infectionwith HBV or HCV:

• Patients who are positive for HCV antibody must be negative for HCV bypolymerase chain reaction (PCR) to be eligible for study participation

• Patients with occult or prior HBV infection (defined as positive hepatitisB surface antigen (HBsAg) or positive hepatitis B core antibody (HBcAb)and with negative HBsAg) may be included if HBV DNA is undetectable (i.e.,none detected in copies/mL or IU/mL). These patients must be willing toundergo HBV DNA testing during treatment and in surveillance for at least 12 months after completion of study therapy.

• Malabsorption syndrome or other condition that precludes enteral route ofadministration

• Psychiatric illness/social situations that would limit compliance with studyrequirements

• Pregnant individuals, or individuals who intend to become pregnant during the study,are excluded from this study because Revlimid(R) has known teratogenic effects andpolatuzumab, venetoclax, ibrutinib and obinutuzumab are agents with the potentialfor teratogenic or abortifacient effects. Because there is an unknown but potentialrisk for adverse events in nursing infants secondary to treatment of the mother withthese agents, nursing should be discontinued if the individual is treated on study.

• HIV-positive patients are ineligible because of the potential for pharmacokineticinteractions with venetoclax, ibrutinib and Revlimid(R) and combinationantiretroviral therapy. In addition, these patients are at increased risk of lethalinfections when treated with marrow-suppressive therapy. Appropriate studies will beundertaken in patients receiving combination antiretroviral therapy when indicated.

• Evidence of active tumor lysis syndrome based on laboratory assessment

• History of recent major surgery within 6 weeks prior to the start of Cycle 1, Day 1other than for diagnosis

• History of other active malignancy that could affect compliance with the protocol orinterpretation of results

• Patients with a history of curatively treated basal or squamous cell carcinomaor stage 1 melanoma of the skin as well as any in situ carcinoma are eligible.

• Patients with a malignancy that has been treated with curative intent will alsobe eligible. Individuals in documented remission who are not receiving activetreatment prior to enrollment may be included at the discretion of theinvestigator.

• Known allergy to both xanthine oxidase inhibitors and rasburicase; or, knownhypersensitivity to any of the study drugs