Obinutuzumab, Venetoclax, and Lenalidomide in Treating Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To determine the dose limiting toxicity (DLT) and the recommended phase 2 dose (RP2D),
which is typically the maximum tolerated dose (MTD), of the combination of obinutuzumab,
venetoclax, and lenalidomide in patients with relapsed or refractory B-cell non-Hodgkin
lymphoma (NHL).

SECONDARY OBJECTIVES:

I. To estimate the overall objective response rate to the combination of obinutuzumab,
venetoclax, and lenalidomide in patients with relapsed or refractory B-cell NHL.

II. To estimate the duration of response and 2 year progression-free survival associated with
obinutuzumab, venetoclax, and lenalidomide treatment in patients with relapsed and refractory
B-cell NHL.

III. To define the qualitative and quantitative toxicities of the combination of
obinutuzumab, venetoclax, and lenalidomide in patients with relapsed or refractory B-cell
NHL.

OUTLINE: This is a dose-escalation study of venetoclax and lenalidomide.

Patients receive lenalidomide orally (PO) on days 1-21 and venetoclax PO on days 1-28.
Patients also receive obinutuzumab intravenously (IV) on days 1, 8, and 15 of course 1 and on
day 1 of courses 2-6. Treatment repeats every 28 days for up to 12 courses in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks, every 3 months for
2 years, then every 6 months.

Inclusion Criteria:

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Prior venetoclax or other BCL-2 family inhibitors or prior lenalidomide is not
permitted

- Creatinine clearance >= 50 ml/min using a 24 hour creatinine clearance or estimated
creatinine clearance using the Cockcroft-Gault equation

- Bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's syndrome

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN

- Absolute neutrophil count (ANC) >= 1000/mm^3

- Platelet >= 75,000/mm^3

- Unless related to bone marrow involvement with disease, in which case platelets
must be >= 50,000/mm^3

- Recovery to =< grade 1 from all toxicities associated with prior therapy except
alopecia

- Histologically confirmed B-cell non-Hodgkin's lymphoma (NHL) of any of the following
subtypes recognized by the World Health Organization (WHO) classification: Burkitt
lymphoma, B-cell lymphoma unclassifiable with features intermediate between diffuse
large B-cell lymphoma and Burkitt lymphoma, diffuse large B-cell lymphoma, marginal
zone lymphoma, or follicular lymphoma; patients with evidence of histological
transformation to diffuse large B-cell lymphoma from indolent NHL are eligible

- At least one prior therapy; prior autologous stem cell transplant is permitted;
patients with aggressive lymphoma who have not received high-dose therapy
(HDT)/autologous stem cell transplantation (ASCT) must be ineligible for HDT/ASCT;
prior allogeneic stem cell transplant is not permitted

- Patients with indolent lymphoma must have an indication for treatment in the opinion
of the investigator

- Radiographically measurable disease by computed tomography (CT) scan, defined as at
least one node > 1.5 cm in size or assessable disease

- All study participants must be registered into the mandatory Revlimid risk evaluation
and mitigation strategy (REMS) program, and be willing and able to comply with the
requirements of the REMS program

- Females of reproductive potential must adhere to the scheduled pregnancy testing as
required in the Revlimid REMS program

- Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients
intolerant to aspirin (ASA) may use low molecular weight heparin or equivalent)

- EXPANSION COHORT

- Cohort A will enroll 10 patients with a diagnosis of diffuse large B-cell lymphoma;
B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell
lymphoma and Burkitt lymphoma (double hit lymphoma), Burkitt lymphoma, and transformed
lymphoma

- Cohort B will enroll 20 patients with a diagnosis of follicular lymphoma, grade 1-2
and 3A; grade 3B is excluded; diagnoses made by a fine needle aspirate or bone marrow
biopsy alone are not permitted

Exclusion Criteria:

- Patients with active central nervous system (CNS) involvement with lymphoma are not
eligible

- Patients with human immunodeficiency virus (HIV) or human T-cell leukemia virus 1
(HTLV-1) are not eligible

- Evidence of active hepatitis B infection, based on positive surface antigen or
hepatitis B deoxyribonucleic acid (DNA) polymerase chain reaction (PCR), or active
hepatitis C infection; patients who are hepatitis B core antibody positive must take
prophylaxis with lamivudine or equivalent and be willing to undergo monthly hepatitis
B DNA PCR testing

- Prior allogeneic stem cell transplant is not permitted

- Unable to swallow capsules or malabsorption syndrome, disease significantly affecting
gastrointestinal function, or resection of the stomach or small bowel or ulcerative
colitis, symptomatic inflammatory bowel disease, or partial or complete bowel
obstruction likely to interfere with the delivery, absorption, or metabolism of
venetoclax or lenalidomide

- Any chemotherapy or radiation therapy within 4 weeks of the first dose of study drug

- Patients may take steroids for disease control up to 24 hours prior to study
enrollment

- Any illness, medical condition or organ system dysfunction which, in the
investigator's opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of venetoclax and lenalidomide, or put the study outcomes at
undue risk

- A cardiovascular disability status of New York Heart Association class >= 2

- History of severe allergic reactions to humanized monoclonal antibodies

- History of other 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 or in situ carcinoma of the
cervix are eligible; patients with a malignancy that has been treated with surgery
alone with curative intent will also be excluded; individuals in documented remission
without treatment for >= 2 years prior to enrollment may be included at the discretion
of the investigator

- Known hypersensitivity to any of the study drugs or analogs

- 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 4 weeks prior study therapy

- Requires the use of warfarin (because of potential drug-drug interactions that may
potentially increase the exposure of warfarin)

- Received the following agents within 7 days prior to the first dose of venetoclax:

- Strong and moderate CYP3A inhibitors

- Strong and moderate 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

- Clinically significant history of liver disease, including viral or other hepatitis,
current alcohol abuse, or cirrhosis

- Receipt of live-virus vaccines within 28 days prior to the initiation of study
treatment or need for live-virus vaccines at any time during study treatment

- Recent major surgery (within 6 weeks prior to the start of study treatment) other than
for diagnosis

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

- Known allergy to both xanthine oxidase inhibitors and rasburicase

- Pregnant or lactating, or intending to become pregnant during the study