Pembrolizumab in Untreated B-Cell Non-Hodgkin Lymphoproliferative Diseases

PRIMARY OBJECTIVES:

I. To gain a preliminary assessment of the efficacy of pembrolizumab as monotherapy for
patients with untreated indolent B-cell non-Hodgkin lymphoproliferative diseases (iBCL) based
on overall response rate (ORR) measured at the end of a 6-cycle treatment period.

SECONDARY OBJECTIVES:

I. To assess the safety and toxicity profile of pembrolizumab in patients with untreated
iBCL.

II. To measure the efficacy of pembrolizumab used as monotherapy for patients with untreated
iBCL by assessing clinical outcomes including complete response rate (CR), time to next
therapy (TNT), progression-free survival (PFS), and the duration of response (DOR).

OUTLINE:

Participants receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment
repeats every 3 weeks for up to 18 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, participants are followed up for 30 days and then up to
5 years.

Inclusion Criteria:

- Untreated indolent lymphoma including the following histologies: follicular lymphoma,
marginal zone lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, small
lymphocytic lymphoma, Waldenstrom's macroglobulinemia, lymphoplasmacytic lymphoma

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

- Must have measurable disease defined by at least one of the following criteria:

- Lesions greater than 1.5 cm that can be accurately measured in two dimensions by
computed tomography (CT) (preferred), or magnetic resonance imaging (MRI)

- Must have indication for treatment (adapted from National Comprehensive Cancer Network
[NCCN] 2015 guidelines)

- Any of the following constitute an indication for treatment:

- Significant symptoms due to any iBCL: Which may include pain/discomfort,
limitation of function, fatigue/malaise/constitutional symptoms, B-symptoms
(fever, weight loss, night sweats), pruritus

- Threatened end-organ function due to any iBCL

- Progressive cytopenia secondary to any iBCL

- Steady progression of follicular lymphoma (FL) and marginal zone lymphoma
(MZL)

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale

- Absolute neutrophil count (ANC) ≥ 1,000/mcL OR ≥ 750/mcL if neutropenia due to iBCL

- Platelets ≥ 75,000/mcL OR ≥ 50.000 if thrombocytopenia due to iBCL

- Hemoglobin ≥ 9 g/dL OR ≥ 8 g/dL if anemia due to iBCL, without transfusion or
erythropoietin (EPO) dependency (within 7 days of assessment)

- 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]) ≥ 60 mL/min for subject with creatinine
levels > 1.5 X institutional ULN

- Serum total bilirubin ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for subjects with total
bilirubin levels > 1.5 ULN

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 X
ULN OR ≤ 5 X ULN for subjects with liver metastases

- Albumin ≥ 2.5 mg/dL

- International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants

- Activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants

- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 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 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

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 4 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

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

- Hypersensitivity to pembrolizumab or any of its excipients

- Has had prior anti-neoplastic therapies such as chemotherapy, radiation therapy, or
immunotherapy for the diagnosis of iBCL

- 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) metastases and/or carcinomatous
meningitis

- 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 (e.g. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment

- Has known history of, or any evidence of active, non-infectious pneumonitis

- Has an active infection requiring systemic therapy

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

- 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 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)

- Be in urgent need of therapy for lymphoma related complications (such as
hyperviscosity syndrome) and those with bulky disease

- Has received a live vaccine within 30 days of planned start of study therapy

- Note: seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
are live attenuated vaccines, and are not allowed