Nivolumab and Lenalidomide in Treating Patients With Relapsed or Refractory Non-Hodgkin or Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of the combination of lenalidomide and nivolumab
in patients with relapsed/refractory non-Hodgkin lymphoma (NHL). (Phase I) II. To determine
the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of the combination of
lenalidomide and nivolumab in patients with relapsed/refractory NHL. (Phase I) III. To
evaluate the feasibility and toxicities of the combination of lenalidomide and nivolumab in
patients with relapsed/refractory Hodgkin's disease (HD). (Phase IB) IV. To evaluate the
efficacy of the combination of lenalidomide and nivolumab in terms of overall response rate
in patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell
lymphoma (DLBCL). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of the combination of lenalidomide and nivolumab in patients with
relapsed/refractory NHL in terms of overall response rate (ORR), duration of response (DOR),
progression-free survival (PFS) and overall survival (OS). (Phase I) II. To evaluate the
efficacy of the combination of lenalidomide and nivolumab in patients with
relapsed/refractory HD in terms of complete response rate (CR). (Phase IB) III. To evaluate
the efficacy of the combination of lenalidomide and nivolumab in patients with
relapsed/refractory HD in terms of duration of response (DOR), progression-free survival
(PFS) and overall survival (OS). (Phase IB) IV. To evaluate the efficacy of the combination
of lenalidomide and nivolumab in patients with relapsed/refractory FL and DLBCL in terms of
duration of response (DOR), progression-free survival (PFS) and overall survival (OS). (Phase
II)

TERTIARY OBJECTIVES:

I. To explore the relationship between prognostic parameters including ki-67 staining, PD-1
staining and cell of origin (activated B-cell or ABC versus germinal center B-cell or GCB)
with ORR to the combination of lenalidomide and nivolumab in patients with
relapsed/refractory NHL. (Phase I) II. To evaluate and monitor effects on B-, T-, and natural
killer (NK)-cell function with the combination of lenalidomide and nivolumab in patients with
relapsed/refractory NHL. (Phase I) III. To explore the relationship between prognostic
parameters including ki-67 staining, PD-1 staining and cell of origin (activated B-cell or
ABC versus germinal center B-cell or GCB) with ORR to the combination of lenalidomide and
nivolumab in patients with relapsed/refractory FL and DLBCL. (Phase II) IV. To evaluate and
monitor effects on B-, T-, and NK-cell function with the combination of lenalidomide and
nivolumab in patients with relapsed/refractory FL and DLBCL. (Phase II)

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

Patients receive lenalidomide orally (PO) on days 1-21 and nivolumab intravenously (IV) over
60 minutes on days 1 and 15 of courses 1-4 and on day 1 of courses 5-12. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- PHASE I: Histologically confirmed B-cell NHL with any of the following subtypes:
DLBCL, mantle cell lymphoma (MCL), FL, marginal zone lymphoma (MZL) and
lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia (LL/WM), Burkitt's lymphoma
(BL); patients with histological transformation to DLBCL from indolent lymphoma,
primary mediastinal lymphoma and grey zone lymphoma are eligible

- PHASE I: Histologically confirmed classical or lymphocyte predominant Hodgkin's
disease that is relapsed or refractory after at least one prior chemotherapy

- PHASE I: Patients must have received at least one prior therapy; prior autologous stem
cell transplant is permitted; patients with DLBCL who have not had prior high-dose
therapy (HDT)/autologous stem cell transplant (ASCT) must be ineligible for
transplant; prior lenalidomide is not permitted if patients have progressed on therapy

- PHASE IB DOSE EXPANSION: Histologically confirmed classical or lymphocyte predominant
Hodgkin's disease

- PHASE IB DOSE EXPANSION: Patients must have received at least one prior therapy; prior
autologous stem cell transplant is permitted; patients who have not had prior HDT/ASCT
must be ineligible for transplant; prior lenalidomide is not permitted if patients
have progressed on therapy

- PHASE II: Histologically confirmed B-cell NHL:

- Cohort 1: with only de novo DLBCL,

- Cohort 2: with only FL of grade 1, 2 or 3a

- PHASE II: Patients must have received at least one prior therapy; prior autologous
stem cell transplant is permitted; patients with DLBCL who have not had prior HDT/ASCT
must be ineligible for transplant; prior lenalidomide is not permitted if patients
have progressed on therapy

- Be willing and able to provide written informed consent/assent for the trial

- Have evaluable disease

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

- Absolute neutrophil count (ANC) >= 1,500 /mcL

- Platelets >= 100,000 /mcL in the absence of transfusion support within 7 days of
determining eligibility

- Hemoglobin >= 8 g/dL

- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]) >= 40 mL/min creatinine clearance

- Serum total bilirubin =< 1.5 X ULN OR except subjects with Gilbert syndrome, who can
have total bilirubin < 3.0 mg/dL

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 X
ULN

- Female subject of childbearing potential should have a negative urine or serum
pregnancy at screening and within 24 hours prior to receiving the first dose of study
medication; if the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required

- Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication; subjects should
agree to ongoing pregnancy testing during the course of the study and after the end of
study therapy; female subjects of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > 1 year

- Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy;
males must refrain from donating sperm during study participation and for 120 days
after the last dose of study medication

- Willing and able to receive adequate prophylaxis and/or therapy for thromboembolic
events

- Be willing and able to understand and give written informed consent and comply with
all study related procedures

Exclusion Criteria:

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 3 weeks of the first dose of treatment

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment; subjects may use topical or inhaled corticosteroids or low-dose steroids
(=< 10 mg of prednisone or equivalent per day) as therapy for comorbid conditions;
during study participation, subjects may receive systemic or enteric corticosteroids
as needed for treatment-emergent comorbid conditions

- Has a known history of active TB (bacillus tuberculosis)

- Hypersensitivity to nivolumab or lenalidomide or any of their excipients

- Has had a prior anti-cancer monoclonal antibody (mAb) within 2 weeks prior to study
day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier

- Has had prior chemotherapy or radiation therapy within 2 weeks prior to study day 1 or
who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a
previously administered agent

- Note: subjects with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study

- Note: if subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
therapy; patients must be 4 weeks out from major procedures

- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer

- Has known active central nervous system (CNS) lymphoma

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs); replacement therapy (thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment; conditions expected to not recur in the absence of an
external trigger

- Has an active infection requiring intravenous systemic therapy

- Is unable to swallow capsules or malabsorption syndrome, disease or condition
significantly affecting gastrointestinal function

- Clinically significant cardiovascular disease with uncontrolled arrhythmia, New York
Association class 3 or 4 congestive heart failure, history of myocardial infarction
within 6 months, or prolonged corrected QT (QTc) > 500 msec

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

- Has progressed on prior therapy with lenalidomide

- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)

- Has a history of deep venous thrombosis/embolism, threatening thromboembolism or known
thrombophilia or are at a high risk for a thromboembolic event in the opinion of the
investigator and who are not willing/able to take venous thromboembolic event
prophylaxis during the entire treatment period