Rituximab, Lenalidomide, and Nivolumab in Treating Participants With Relapsed or Refractory Non-Germinal Center Type Diffuse Large B Cell Lymphoma or Primary Central Nervous System Lymphoma

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose and toxicity profile of lenalidomide in combination
with standard doses of rituximab and nivolumab in relapsed/refractory (R/R) diffuse large B
cell lymphoma (DLBCL) (non-germinal center B cell [non-GCB]) and in primary central nervous
system (CNS) lymphoma (PCNSL) (Phase I).

II. Evaluate the efficacy of lenalidomide in combination with standard doses of rituximab and
nivolumab in R/R non-GCB type DLBCL and PCNSL (Phase II).

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of nivolumab when combined with lenalidomide and
rituximab.

II. To determine the time to progression (complete response, partial response or stable
disease), progression free survival (PFS) and overall survival (OS).

III. To evaluate the difference in overall response rate between those with and without
programmed cell death ligand 1 (PD-L1) protein expression in tumor (subgroup analysis).

IV. To evaluate the difference in overall response rate between those with and without MYD88
mutation in tumor (subgroup analysis).

EXPLORATORY OBJECTIVES:

I. To perform PD-L1, PD-1 expression on tumor cells by immunohistochemistry including double
staining for PAX-5 and PD-L1 and CD68 and PD-L1, CD3/CD4/CD8 for T cell infiltration, CD68
for tumor associated macrophages.

II. To assess for presence of MYD88 L265 mutation by allele specific polymerase chain
reaction (PCR) in tumor tissue and /or cerebrospinal fluid (CSF) (where lumbar puncture is
clinically performed).

III. To perform fluorescence in situ hybridization (FISH) for 9p24.1/ PD-L1/PD-L2 locus.

IV. To evaluate MYD88 PCR on CSF (where available). V. To perform gene expression panel for
tumor immune response in tumor samples (prioritizing cases in which a second serial biopsy is
available).

OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II
study.

Participants receive nivolumab intravenously (IV) over 60 minutes on days 1 and 15, rituximab
IV on day 1, and lenalidomide orally (PO) once daily (QD) on days 1-21. Treatment repeats
every 28 days for up to of 8 courses in the absence of disease progression or unacceptable
toxicity. Patients with partial response (PR) or stable disease at the end of 8 cycles will
be offered lenalidomide and nivolumab maintenance for up to 12 courses.

After completion of study treatment, participants are followed up every 3 months for 2 years
and then every 6 months until year 4.

Inclusion Criteria:

- Understand and voluntarily sign an informed consent form.

- Able to adhere to the study visit schedule and other protocol requirements in the
opinion of the investigator

- Patients with histological confirmation of relapsed/refractory non-GCB type (using
Hans algorithm) diffuse large B cell lymphoma (DLBCL) or relapsed/refractory primary
CNS lymphoma (PCNSL) with at least one of the following characteristics:

- Definition of refractory disease: progression of disease based on Cheson criteria
for DLBCL or international primary CNS lymphoma cooperative group for PCNSL
either with nonresponse or progression within 3 months of prior therapy

- Definition of relapsed disease: progression of disease based on Cheson criteria
for DLBCL or International primary CNS lymphoma cooperative group for PCNSL at
least 3 months after prior therapy

- Definition of non-GCB subtype (Hans algorithm): cases will be subclassified based
on immunohistochemical staining with CD10, BCL-6 and MUM-1 as previously
described.

- Patients should have exhausted (or be ineligible for) approved therapies known to
provide clinical benefit for DLBCL or PCNSL (e.g. high dose chemotherapy with
autologous stem cell transplant, chimeric antigen receptor-transduced [CAR-T]
therapy, etc.).

- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 at study entry.

- Absolute neutrophil count >= 1000/mm^3 within 45 days prior to initiation of therapy.
(Patients with documented marrow involvement (with lymphoma) or hypersplenism
secondary to involvement of the spleen by lymphoma at the time of randomization are
not required to meet the parameter).

- Platelet count >= 75K /mm^3 within 45 days prior to initiation of therapy. (Patients
with documented marrow involvement (with lymphoma) or hypersplenism secondary to
involvement of the spleen by lymphoma at the time of randomization are not required to
meet the parameter).

- Serum creatinine =< 2.0 mg/dL or creatinine clearance of > 40 ml/min within 45 days
prior to initiation of therapy. (Patients with documented marrow involvement (with
lymphoma) or hypersplenism secondary to involvement of the spleen by lymphoma at the
time of randomization are not required to meet the parameter).

- Total bilirubin =< 1.5 mg/dL within 45 days prior to initiation of therapy. (Patients
with documented marrow involvement (with lymphoma) or hypersplenism secondary to
involvement of the spleen by lymphoma at the time of randomization are not required to
meet the parameter).

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x
upper limit of normal (ULN) within 45 days prior to initiation of therapy. (Patients
with documented marrow involvement (with lymphoma) or hypersplenism secondary to
involvement of the spleen by lymphoma at the time of randomization are not required to
meet the parameter).

- Disease free of prior malignancies for >= 3 years with exception of currently treated
basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the
cervix or breast.

- All study participants must be registered into the mandatory Revlimid Risk Evaluation
and Mitigation Strategies (REMS) program, and be willing and able to comply with the
requirements of the Revlimid REMS program. program, and be willing and able to comply
with the requirements of the Revlimid REMS program.

* Females of childbearing potential (FCBP) must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days and again
within 24 hours prior to prescribing lenalidomide for cycle 1 (prescriptions must be
filled within 7 days as required by the Revlimid REMS program) 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 lenalidomide. FCBP must also
agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual
contact with a FCBP even if they have had a successful vasectomy.

** A female of childbearing potential is a sexually mature female who: 1) has not
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in
the preceding 24 consecutive months).

- Able to take aspirin (81 or 325 mg) daily or for thromboprophylaxis with lenalidomide.

Exclusion Criteria:

- Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from signing the informed consent.

- Pregnant or breast feeding females (lactating females must agree not to breast feed
while taking lenalidomide).

- Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study.

- Use of any other experimental drug or therapy within 28 days of baseline.

- Known hypersensitivity to thalidomide.

- Known prior development of erythema nodosum if characterized by a desquamating rash
while taking thalidomide or similar drugs.

- Concurrent use of other anti-cancer agents or treatments.

- Patients with a prior history of pulmonary toxicity due to medications (Ex: history of
carmustine [BCNU] toxicity).

- Active human immunodeficiency virus (HIV) infection or infectious hepatitis, type B or
C.

- Patients with a past or resolved hepatitis B virus (HBV) infection (defined as
the presence of hepatitis B core antibody [anti-HBc] and absence of hepatitis B
surface antigen [HBsAg]) may be included if HBV deoxyribonucleic acid (DNA) is
undetectable. If enrolled, patients must be willing to undergo monthly HBV DNA
testing.

- HIV positive patients may enroll if they meet all of the below criteria:

- HIV is sensitive to antiretroviral therapy.

- Must be willing to take effective antiretroviral therapy if indicated.

- No history of CD4 prior to or at the time of lymphoma diagnosis < 300
cells/mm^3.

- No history of acquired immunodeficiency syndrome (AIDS)-defining conditions.

- If on antiretroviral therapy, must not be taking zidovudine or stavudine.

- Must be willing to take prophylaxis for pneumocystis jiroveci pneumonia
(PCP) during therapy and until at least 2 months following the completion of
therapy or until the CD4 cells recover to over 250 cells/mm^3, whichever
occurs later.

- A diagnosis of deep vein thromboses in the preceding four weeks of study enrollment.

- Subjects with active interstitial pneumonitis.

- Patient with active, uncontrolled infections (patients must be afebrile for > 48 hours
off antibiotics).

- Patient with clinically significant history of liver disease, including viral or other
hepatitis, current alcohol abuse, or cirrhosis.

- Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo,
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted
to enroll.

- Evidence of significant, uncontrolled concomitant diseases that could affect
compliance with the protocol or interpretation of results or that could increase risk
to the patient, including renal disease that would preclude chemotherapy
administration or pulmonary disease (including obstructive pulmonary disease and
history of bronchospasm).

- Major surgery within 4 weeks prior to cycle 1, other than for diagnosis.

- Malabsorption syndrome or other condition that precludes oral route of administration
of lenalidomide.

- Vaccinations with a live vaccine within 28 days prior to start of treatment or need
for live vaccine at any time during study treatment.

- Patient must not have serious medical or psychiatric illness likely to interfere with
participation in this clinical study in the opinion of the investigator.

- Inability to swallow oral medications.

- Subjects with New York Heart Association (NYHA) class III or IV heart failure.