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

 B-cell lymphoma is a cancer of white blood cells found in the lymph nodes. It affects the
 system that fights infections and disease. Researchers want to learn how certain drugs work
 together to treat B-cell lymphomas. The drugs are venetoclax, ibrutinib, prednisone,
 obinutuzumab, and lenalidomide (ViPOR).

 Objective:

 To study the safety of ViPOR for people with B-cell lymphoma.

 Eligibility:

 People ages 18 and older with B-cell lymphoma whose cancer has returned or not improved after
 treatment

 Design:

 Participants will be screened with:

 -  Medical history

 -  Physical exam

 -  Blood, urine, and heart tests

 -  Tissue sample from previous procedure

 -  Imaging scans

 -  Registration for counseling on the risks of lenalidomide. They must get counseling at
 least every 28 days.

 Participants will have a bone marrow aspiration before treatment.

 Participants may have tumor samples taken.

 Participants will get ViPOR in 21-day cycles. For up to 6 cycles:

 -  Participants will get one drug by IV on days 1 and 2.

 -  Participants will take the other four drugs by mouth on most days. After their first
 dose of venetoclax, they will stay in the clinic for at least 8 hours and return the
 next day for monitoring. They may be admitted for more drugs or monitoring.

 Participants will keep a drug diary.

 Participants will have a physical exam and blood and urine tests at least once per cycle.
 They will have scans 4 times over 6 cycles.

 Participants will have a visit about 1 month after their last dose of study drug. They will
 then have visits every few months for 3 years, and once a year for years 4 and 5. Visits
 include a physical exam, blood tests, and scans.
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 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 targets major survival pathways in B-cell lymphomas including BCL-2 (apoptosis);
 BTK (B-cell receptor signaling and NFKB); Cereblon (NFKB) and CD20.

 Objectives:

 -  Phase 1b: To determine the maximum tolerated dose (MTD) and the safety and toxicity
 profile of the combination of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab and
 Revlimid (ViPOR) in relapsed/refractory B-cell malignancies

 -  Phase 2: To determine the overall response rate (ORR) and complete response (CR) rate of
 ViPOR in relapsed/refractory B-cell malignancies

 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 CLL/SLL. NOTE: untreated MCL is included in the phase 2 MCL expansion.

 -  Adequate organ function unless dysfunction secondary to lymphoma effect

 Design:

 -  Open-label, single-center, non-randomized phase 1b/2 study

 -  Phase 1b: Standard '3 + 3' design will be used to determine the MTD of dose-escalated
 venetoclax with fixed dose ibrutinib, prednisone, obinutuzumab and Revlimid (ViPOR) in
 relapsed/refractory B-cell malignancies

 -  Phase 2: Expansion cohorts of aggressive and indolent non-MCL patients and MCL patients
 will be treated at the MTD to determine the ORR and CR rate in these subtypes.

 -  Maximum 6 cycles of combination targeted therapy every 21 days

 -  To explore all dose levels in both non-MCL and MCL patient cohorts in the phase 1b
 study, and to assess the ORR and CR rate in aggressive and indolent non-MCL and MCL
 patients in a phase 2 dose expansion at the MTD, the accrual ceiling will be set at 130
 patients.
-  INCLUSION CRITERIA:

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

 Phase1b

 -  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:

 -  CLL/SLL is excluded given alternative dosing of FDA-approved venetoclax for relapsed
 17p CLL and increased risk of TLS with CLL/SLL compared to other non-Hodgkin
 lymphomas.

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

 Phase 2

 -  Relapsed and/or refractory DLBCL and subtypes, including transformed lymphoma as well
 as High grade B-cell lymphoma with MYC and/or BCL2 and/or BCL6 rearrangement(s).

 -  Relapsed and/or refractory Follicular lymphoma (FL)

 -  Untreated Mantle cell lymphoma (MCL)

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

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

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

 -  NOTE: Patients with untreated MCL will be included in the phase 2 MCL expansion.

 -  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 FDGavid
 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 to 18 years

 -  NOTE: Because no dosing or adverse event data are currently available on the use of
 venetoclax in combination with 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 less than or equal to 2

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

 -  absolute neutrophil count* (*RBC transfusions and use of G-CSF will be allowed in
 order to meet eligibility parameters): greater than or equal to 1,000/mcL

 -  hemoglobin* (*RBC transfusions and use of G-CSF will be allowed in order to meet
 eligibility parameters): 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

 -  Total Bilirubin: less than or equal to 1.5 X institutional ULN (or <3 X
 institutional ULN for patients with documented Gilberts syndrome)

 -  AST(SGOT)/ALT(SGPT): less than or equal to 2.5 X institutional ULN

 -  Serum Creatinine: less than or equal to 2.0mg/dL OR

 -  Creatinine Clearance: greater than or equal to 60 mL/min/1.73 m2 for patients
 with creatinine levels above 2 mg/dL

 Cr Cl will be calculated with the use of the 24-hour creatinine clearance or modified
 Cockcroft-Gault equation (eCCR; with the use of ideal body mass [IBM] instead of mass):

 (140 Age) x IBM (kg) x [0.85 if female]/ 72 x serum creatinine (mg/dL)

 *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 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 1% per year as outlined 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 postmenarcheal,
 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
 postovulation 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
 postovulation methods) and withdrawal are not acceptable methods of
 contraception.

 -  Contraception Requirements:

 Pre-Treatment/During Treatment:

 --All Drugs- Women- begins 28 days prior to treatment; Men- Begins on day 1

 Post-Treatment:

 -  Venetoclax- Women- 90 days; Men 90 days

 -  Ibrutinib- Women- 3 months; Men- 3 months

 -  Obinutuzumab- Women- 18 months; Men- 6 months

 -  Revlimid- Women-28 days; Men- 28 days

 -  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 or Legally Authorized Representative (LAR) 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, external beam radiation therapy, or anti-cancer antibodies within 2
 weeks prior to the first dose of study drug

 -  Radio- or toxin-immunoconjugates within 10 weeks prior to the first dose of study drug

 -  Previous treatment with greater than one of the 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 prior to first dose of study drug

 -  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 within 7 days prior to the first dose of
 venetoclax are excluded:

 -  Steroid therapy for anti-neoplastic intent

 -  Strong CYP3A inhibitors

 -  Strong CYP3A inducers

 -  Consumed grapefruit, grapefruit products, Seville oranges (including marmalade
 containing Seville oranges), or star fruit within 3 days prior to the first dose of
 venetoclax

 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 investigator:

 -  Symptomatic congestive heart failure, unstable angina pectoris, 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;

 -  Known infection with human T-cell leukemia virus 1 (HTLV-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. 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 intent to become pregnant during the study, are excluded
 from this study because Revlimid has known teratogenic effects and 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 without treatment for greater
 than or equal to 2 years 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