Pidilizumab in Treating Patients With Stage III-IV Diffuse Large B-Cell Lymphoma Following First Remission

PRIMARY OBJECTIVES:

I. To estimate the rate of response, whereby either cluster of differentiation
(CD)4+CD25+programmed death 1 ligand 1 (PD-L1)+ T lymphocytes or CD4+CD62L+CD127+ T
lymphocytes has an "increase" following administration of pidilizumab in patients with
diffuse large B-cell lymphoma (DLBCL) that have completed induction chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the toxicity and tolerability of pidilizumab therapy following induction
chemotherapy.

II. To estimate the progression free survival (PFS) at 2 years. III. To estimate the overall
survival (OS) at 2 years. IV. To estimate time to second line chemotherapy (TSLC) at 2 years.

TERTIARY OBJECTIVES:

I. To characterize programmed death 1 (PD-1) pathway specific expression markers from the
diagnostic biopsy specimens.

II. To characterize serum biomarkers of immune and inflammatory response during treatment
with pidilizumab.

III. To characterize levels of soluble PD-L1 related to treatment with pidilizumab.

OUTLINE:

Patients receive pidilizumab intravenously (IV) over approximately 5 hours on day 1.
Treatment repeats every 42 days for 3 courses in the absence of disease progression or
unacceptable toxicity.

After completion of treatment, patients are followed up at 30 days and then every 3 months
for 2 years.

Inclusion Criteria:

- Histologically confirmed de novo DLBCL by the 4th edition of the World Health
Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues
published in 2008; patients with transform lymphoma are excluded; patients with known
primary mediastinal large B-cell lymphoma (PMLBCL) are excluded; patients with known
c-v-myc avian myelocytomatosis viral oncogene homolog (c-myc) translocation (by
fluorescence in situ hybridization) positive DLBCL are eligible for enrollment; c-myc
testing prior to study enrollment is not required; availability of diagnostic biopsy
samples in encouraged for the exploratory analysis but not required for enrollment;
patients with "double-hit" or "triple-hit" lymphoma are eligible for enrollment

- Previously completed anthracycline-based induction chemotherapy with standard regimens
including rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate,
and prednisone (R-CHOP), dose adjusted (DA)-etoposide, prednisone, vincristine
sulfate, doxorubicin hydrochloride, cyclophosphamide (EPOCH), and rituximab (R), and
R-hyper cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride,
dexamethasone, methotrexate, and cytarabine (CVAD); patients need a minimum of 6
cycles of treatment; initial treatment with pidilizumab must be administered between
30-90 days from last dose of induction chemotherapy

- Complete remission (CR) according to the Revised Response Criteria for Malignant
Lymphoma after first-line treatment

- Diagnostic CT scans with contrast of chest, abdomen, and pelvis must have been
performed within 8 weeks from the first day of the last cycle of R-chemotherapy;
a neck CT will be required if the patient had involvement of the neck region at
initial diagnosis

- A negative fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/CT scan
performed within 8 weeks from the first day of the last cycle of R-chemotherapy
and confirming CR, with negative defined as a score of 1-3 on the Deauville
5-point scale used to quantify radionucleotide density in PET scans as determined
locally; PET positive/indeterminate lesions which are confirmed on biopsy to
harbor no active lymphoma will be considered negative for determination of CR
status

- If positive bone marrow involvement at initial diagnosis the patient must have a
negative bone marrow biopsy following R-chemotherapy to confirm the CR

- Stage III/IV disease by Ann Arbor Staging

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Any National Comprehensive Cancer Network (NCCN)-International Prognostic Index (IPI)
score; a calculated score required for enrollment

- Absolute neutrophil count (ANC) >= 1000

- Platelet count >= 50,000

- Total bilirubin =< 2 x upper limit of normal (ULN) or if total bilirubin is > 2 x ULN,
the direct bilirubin must be normal

- Alkaline (Alk.) phosphatase =< 3 x ULN

- Aspartate aminotransferase (AST) =< 3 x ULN

- Creatinine =< 2 x ULN or creatinine clearance (CrCl) > 30 ml/min

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test at enrollment; FCBP must either commit to abstinence from heterosexual
intercourse or commit to the use of 2 acceptable methods of birth control; a FCBP is
any woman, regardless of sexual orientation or whether they have undergone tubal
ligation, who meets the following criteria: 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)

- Men must agree to use a latex condom during sexual contact with a FCBP even if they
have had a successful vasectomy

- All subjects must have given signed, informed consent prior to registration on study

Exclusion Criteria:

- Active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy;
exceptions to this are as follows: localized nonmelanotic skin cancer and any cancer
that in the judgment of the investigator has been treated with curative intent and
will not interfere with the study treatment plan and response assessment

- Known central nervous system (CNS) involvement

- Prior stem cell transplantation (autologous or allogeneic)

- Persistent diarrhea or malabsorption > National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) grade 2, despite medical management

- Subjects with known immunodeficiency, known autoimmune disease, or concurrent use of
immunomodulatory agents

- Any cancer directed therapies between completion of induction chemotherapy and
treatment on protocol

- Known hypersensitivity to murine or chimeric antibodies or proteins

- Presence of co-morbid systemic illnesses or other severe concurrent disease which, in
the judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens; this includes, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements

- Subjects with known human immunodeficiency virus (HIV) infection

- Subjects with known active hepatitis B virus (HBV) and hepatitis C virus (HCV)
infection

- Women must not be pregnant or breast-feeding

- Unwillingness or inability to comply with the protocol