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

 Aggressive B-cell lymphomas can be cured but people with disease that resists treatment or
 that returns after treatment have poor outcomes with standard therapies. Indolent B-cell
 lymphomas are generally incurable with standard therapy and treatment is aimed at controlling
 symptoms and achieving a durable remissions. Researchers want to see if a combination of
 drugs can help patients with both aggressive and indolent B-cell lymphomas.

 Objective:

 To learn if it is safe and effective to give polatuzumab along with venetoclax, ibrutinib,
 prednisone, obinutuzumab, and lenalidomide to people with certain B-cell lymphomas.

 Eligibility:

 Adults ages 18 and older with relapsed and/or refractory B-cell lymphoma who have had at
 least one prior cancer treatment.

 Design:

 Participants will be screened with:

 Medical history

 Physical exam

 Assessment of how they do their daily activities

 Blood and urine tests

 Heart function test

 Tissue biopsy (if needed)

 Body imaging scans (may get a contrast agent through an intravenous (IV) catheter)

 Participants will have a bone marrow aspiration and/or biopsy. A needle will be put into the
 hipbone. Bone marrow will be removed.

 Participants may give blood, tissue, saliva, or cheek swab samples. They may have optional
 biopsies.

 Screening tests will be repeated during the study.

 Treatment will be given for up to 6 cycles. Each cycle lasts 21 days.

 Participants will take venetoclax and prednisone tablets by mouth. They will take ibrutinib
 and lenalidomide capsules by mouth. They will get obinutuzumab and polatuzumab by IV
 infusion. They will keep a medicine diary.

 Participants will visit the clinic 30 days after treatment ends. They will have follow-up
 visits for 5 years. If needed, they can visit their local doctor instead. They may be
 contacted by phone, mail, etc., for the rest of their life.
Background:

 -  Combination chemotherapy with rituximab has been the mainstay of treatment for
 CD20-positive B-cell lymphomas.

 -  Significant advances have been made in curing aggressive B-cell lymphomas with
 chemoimmunotherapy, but indolent lymphomas and relapsed/refractory aggressive lymphomas
 remain mostly incurable with chemotherapy alone.

 -  Targeted therapies, aimed at disrupting key survival pathways in lymphoid malignancies,
 are emerging and showing significant activity in non-Hodgkin lymphoma (NHL) in both the
 relapsed and first-line settings.

 -  Mechanistically based combinations of targeted agents are likely to benefit patients who
 cannot tolerate or who relapse after or are refractory to standard chemoimmunotherapy.

 -  ViPOR-P targets major survival pathways in B-cell lymphomas including BCL-2 (apoptosis);
 BTK (B-cell receptor signaling and NF-kB); Cereblon (NF-kB) and CD20 with additional
 genotoxic stress from the anti-mitotic antibody-drug conjugate targeting CD79b,
 polatuzumab.

 Objectives:

 To determine the maximum tolerated dose (MTD) and the safety and toxicity profile of
 polatuzumab in combination with venetoclax, ibrutinib, prednisone, obinutuzumab and
 Revlimid(SqrRoot) (lenalidomide) (ViPOR-P) in relapsed/refractory B-cell lymphomas

 Eligibility:

 -  Women and men greater than or equal to 18 years of age

 -  ECOG performance status of less than or equal to 2

 -  Histologically or cytologically confirmed relapsed and/or refractory B-cell lymphoma,
 excluding mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic
 lymphoma (CLL/SLL)

 -  Adequate organ function unless dysfunction secondary to lymphoma

 Design:

 -  Open-label, single-center, non-randomized phase 1 study

 -  Standard 3 + 3 design will be used to determine the MTD of polatuzumab in combination
 with venetoclax, ibrutinib, prednisone, obinutuzumab and Revlimid (lenalidomide)
 (ViPOR-P) in relapsed/refractory B-cell lymphomas

 -  A small expansion cohort will be treated at the MTD in a further analysis of safety and
 preliminary activity.

 -  Maximum 6 cycles of combination targeted therapy every 21 days.

 -  To explore all dose levels in the phase 1 study and to allow for the possibility of a
 few screen failures and inevaluable subjects, the accrual ceiling will be set at 32
 patients.
-  INCLUSION CRITERIA:

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

 -  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/or BCL6 rearrangement(s).

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

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

 -  CLL/SLL is excluded given alternative dosing of FDA-approved venetoclax for
 relapsed CLL/SLL and increased risk of TLS with CLL/SLL compared to other
 non-Hodgkin lymphomas.

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

 -  Relapsed and/or refractory disease after at least 1 prior treatment regimen, as
 follows:

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

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

 -  Patients must have evaluable disease by clinical exam (i.e., palpable lymphadenopathy,
 measurable skin lesions, etc.), laboratory assessment (i.e., lymphoma involvement of
 bone marrow or peripheral blood by morphology, cytology or flow cytometry), and/or
 imaging (measurable lymph nodes or masses on CT or MRI and/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 greater than or equal to18 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 in patients <18 years of age, children are excluded from this study, but will be
 eligible for future pediatric trials.

 -  ECOG performance status less than or equal to 2.

 -  Adequate organ and marrow function as defined below unless dysfunction is secondary to
 lymphoma:

 -  absolute neutrophil count* greater than or equal to 1,000/mcL

 -  hemoglobin* greater than or equal to 8 g/dL

 -  Platelets greater than or equal to 75,000/mcL

 -  INR less than or equal to 1.5 X institutional upper limit of normal (ULN) for
 patients not receiving therapeutic anticoagulation

 -  PTT/aPTT less than or equal to 1.5 X institutional ULN normal except if, in the
 opinion of the investigator, the aPTT is elevated because of a positive Lupus
 Anticoagulant, or a significant bleeding risk has been ruled out in the absence
 of a positive Lupus Anticoagulant

 -  total bilirubin less than or equal to 1.5 X institutional ULN (or less than or
 equal to 3 X institutional ULN for patients with documented Gilberts syndrome
 identified by an isolated unconjugated hyperbilirubinemia in the absence of other
 signs of liver dysfunction and/or UGT1A1 mutational testing)

 -  AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional ULN

 -  Serum creatinine less than or equal to 2.0 mg/dL; OR

 -  Creatinine clearance greater than or equal to 30 mL/min/1.73 m2 for patients with
 creatinine levels above 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 eligibility
 parameters.

 -  Immune-modulating drugs (IMiDs) including Revlimid are known to be teratogenic
 and potential embryo-fetal harm can be seen with use of polatuzumab, venetoclax
 and ibrutinib. The effects of obinutuzumab on the developing human fetus is
 unknown. For these reasons, women of child-bearing potential and men must agree
 to use adequate contraception as described below. Should a woman become pregnant
 or suspect she is pregnant while she or her partner is participating in this
 study, she should inform her treating physician immediately.

 -  For women of childbearing potential:

 -  Agreement to remain abstinent (refrain from heterosexual intercourse)
 or use a contraceptive method with a failure rate of less than 1% per
 year as outlined below.

 -  Agreement to refrain from donating eggs during timelines specified
 below.

 -  Female subjects of childbearing potential (FCBP) must have a negative
 serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL
 within 10-14 days and again within 24 hours prior to prescribing
 Revlimid for Cycle 1 (prescriptions must be filled within 7 days as
 required by Revlimid REMSTM) and must either commit to continued
 abstinence from heterosexual intercourse or begin TWO acceptable
 methods of birth control, one highly effective method and one
 additional effective method AT THE SAME TIME, at least 28 days before
 she starts taking Revlimid FCBP must also agree to ongoing pregnancy
 testing.

 -  A woman is considered to be of childbearing potential if she is
 post-menarcheal, has not reached a postmenopausal state (greater than
 or equal to 12 continuous months of amenorrhea with no identified cause
 other than menopause), and has not undergone surgical sterilization
 (removal of ovaries and/or uterus).

 -  Examples of contraceptive methods with a failure rate of less than 1%
 per year include bilateral tubal ligation, male sterilization, hormonal
 contraceptives that inhibit ovulation, hormone-releasing intrauterine
 devices, and copper intrauterine devices.

 -  The reliability of sexual abstinence should be evaluated in relation to
 the duration of the clinical trial and the preferred and usual
 lifestyle of the patient. Periodic abstinence (e.g., calendar,
 ovulation, symptothermal, or post-ovulation methods) and withdrawal are
 not acceptable methods of contraception.

 -  For men:

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

 -  With female partners of childbearing potential, men must remain
 abstinent or use a condom plus an additional contraceptive method that
 together result in a failure rate of less than 1% per year as noted
 below. Men must refrain from donating sperm during this same period.

 -  With pregnant female partners, men must remain abstinent or use a
 condom as noted below to avoid exposing the embryo.

 -  The reliability of sexual abstinence should be evaluated in relation to
 the duration of the clinical trial and the preferred and usual
 lifestyle of the patient. Periodic abstinence (e.g., calendar,
 ovulation, symptothermal, or post-ovulation methods) and withdrawal are
 not acceptable methods of contraception.

 -  Contraception Requirements

 -  Time frame/Study Drug (Pre-Treatment/During Treatment) - Women/Men (Time
 frame prior to/during dosing):

 --- Pre-Treatment/During Treatment/All drugs; Women - Begins 28 days prior
 to treatment; Men - Begins on day 1

 -  Time frame/Study Drug (Post-Treatment) - Women/Men (Time frame after the
 last dose):

 -  Post-Treatment/Venetoclax; Women - 90 days; Men - 90 days

 -  Post-Treatment/Ibrutinib; Women - 3 months; Men - 3 months

 -  Post-Treatment/Obinutuzumab; Women - 18 months; Men - 6 months

 -  Post-Treatment/Revlimid; Women - 28 days; Men - 28 days

 -  Post-Treatment/Polatuzumab; Women - 3 months; Men - 5 months

 -  All study participants must be registered into the mandatory Revlimid REMSTM
 program and be willing and able to comply with the requirements of Revlimid
 REMSTM. NOTE: Females of reproductive potential must adhere to the scheduled
 pregnancy testing as required in the Revlimid REMSTM program.

 -  Ability of subject to understand and the willingness to sign a written informed
 consent document.

 EXCLUSION CRITERIA:

 -  The following restrictions apply to current or prior anti-cancer treatment, prior to
 the 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 courses of
 corticosteroids or palliative XRT prior to enrollment are permitted within the 2-
 week washout period.

 -  Radio- or toxin-immunoconjugates within 10 weeks.

 -  Previous treatment with polatuzumab or more than one of the other study agents
 (i.e., venetoclax, ibrutinib, or Revlimid ), excluding prior prednisone or
 anti-CD20 antibody treatment.

 -  Prior allogeneic stem cell (or other organ) transplant within 6 months or any
 evidence of active graft-versus-host disease or requirement for
 immunosuppressants within 28 days.

 -  Not recovered (i.e., less than or equal to Grade 1 or baseline) from adverse
 events due to previously administered anti-cancer treatment, surgery, or
 procedure. NOTE: Exceptions to this include events not considered to place the
 subject at unacceptable risk of participation in the opinion of the PI (e.g.,
 alopecia).

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

 -  Patients requiring the following agents to the first dose of venetoclax or ibrutinib
 are excluded, as noted:

 -  Strong CYP3A inhibitors within 7 days

 -  Strong CYP3A inducers within 7 days

 -  Consumed grapefruit, grapefruit products, Seville oranges (including marmalade
 containing Seville oranges), or star fruit within 3 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 that may
 limit interpretation of results or that could increase risk to the patient at the
 discretion of the inves0tigator:

 -  Symptomatic congestive heart failure, unstable angina pectoris, or uncontrolled
 cardiac arrhythmia

 -  Uncontrolled and/or symptomatic thyroid disease

 -  Known active bacterial, viral, fungal, mycobacterial, parasitic, or other
 infection (excluding fungal infections of nail beds) at study enrollment, or any
 major episode of infection requiring treatment with IV antibiotics or
 hospitalization (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 other
 hepatitis, current alcohol abuse, or cirrhosis; as well as active infection with
 HBV or HCV:

 -  Patients who are positive for HCV antibody must be negative for HCV by
 polymerase chain reaction (PCR) to be eligible for study participation

 -  Patients with occult or prior HBV infection (defined as positive total
 hepatitis B core antibody [HBcAb] and 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 to undergo monthly DNA testing during treatment and
 for at least 12 months after completion of study therapy.

 -  Malabsorption syndrome or other condition that precludes enteral route of
 administration

 -  Psychiatric illness/social situations that would limit compliance with study
 requirements

 -  Pregnant women, or women who intend to become pregnant during the study, are excluded
 from this study because Revlimid has known teratogenic effects and polatuzumab,
 venetoclax, ibrutinib and obinutuzumab are agents with the potential for teratogenic
 or abortifacient effects. Because there is an unknown but potential risk for adverse
 events in nursing infants secondary to treatment of the mother with these agents,
 breastfeeding should be discontinued if the mother is treated on study.

 -  HIV-positive patients are ineligible because of the potential for pharmacokinetic
 interactions with venetoclax, ibrutinib and Revlimid and combination antiretroviral
 therapy. In addition, these patients are at increased risk of lethal infections when
 treated with marrow-suppressive therapy. Appropriate studies will be undertaken 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 1
 other than for diagnosis

 -  Receipt of live-virus vaccines within 28 days prior to the initiation of study
 treatment

 -  History of other active malignancy that could affect compliance with the protocol or
 interpretation of results

 -  Patients with a history of curatively treated basal or squamous cell carcinoma or
 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 also
 be eligible. Individuals in documented remission who are not receiving active
 treatment prior to enrollment may be included at the discretion of the
 investigator.

 -  Known allergy to both xanthine oxidase inhibitors and rasburicase; or, known
 hypersensitivity to any of the study drugs