Pembrolizumab and Combination Chemotherapy in Treating Patients With Previously Untreated Diffuse Large B-cell Lymphoma or Grade 3b Follicular Lymphoma

PRIMARY OBJECTIVES:

I. To measure the toxicity profile of pembrolizumab (MK-3475) when co-administered with
full-course RCHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine
sulfate, and prednisone) in subjects with previously untreated diffuse large B-cell lymphoma
(DLBCL).

SECONDARY OBJECTIVES:

I. To assess clinical outcomes including response rate, event-free survival, and overall
survival after MK-3475 + RCHOP induction for subjects with previously untreated DLBCL.

TERTIARY OBJECTIVES:

I. To measure baseline expression of proteins in the programmed death-1 (PD-1) family on
tumor cells and coexisting immune infiltrates, using archival tissue when available.

II. To measure peripheral blood T cell subsets before and after treatment using flow
cytometry, and to measure baseline vitamin D (25-hydroxy, total).

III. To explore relationships with these parameters and likelihood of response to therapy and
outcomes.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and prednisone
orally (PO) on days 1-5. Patients also receive rituximab IV, cyclophosphamide IV, doxorubicin
hydrochloride IV, and vincristine sulfate IV on day 2 of course 1 and on day 1 of subsequent
courses. Treatment repeats every 21 days for 6 courses in the absence of disease progression
or unacceptable toxicity.

After completion of the study treatment, patients are followed up to 5 years.

Inclusion Criteria:

- Previously untreated diffuse large B-cell lymphoma or grade 3B follicular lymphoma (of
any stage); subjects must be planned to receive full course (6 cycles) of RCHOP
chemoimmunotherapy as per clinical standard of care; patients may have de novo DLBCL,
and /or any of the following:

- Composite lymphomas, which include both diffuse DLBCL and another histology (most
commonly follicular lymphoma) in the same lymph node

- Transformed lymphoma with DLBCL histology, as long as the patient has not
received prior therapy for lymphoma

- Discordant presentations, such as DLBCL in a lymph node and low-grade lymphoma
such as follicular lymphoma in the bone marrow

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

- Have measurable nodal disease, including at least 1 disease site measuring 1.5 cm in
longest dimension on computed tomography (CT) or fludeoxyglucose (FDG)-positron
emission tomography (PET)

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

- Absolute neutrophil count (ANC) >= 1,500/mcL except in cases of marrow infiltration by
lymphoma

- Platelets >= 100,000/mcL except in cases of marrow infiltration by lymphoma

- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L except in cases of marrow infiltration by
lymphoma

- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
creatinine clearance >= 60 ml/min for subject with creatinine levels > 1.5 X
institutional ULN (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl])

- 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])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X ULN or =< 5 X ULN for subjects with liver metastases

- 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, or subject is shown to have an antiphospholipid antibody on
workup

- 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 barrier 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 drug or using an investigation 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 additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment

- No active autoimmune disease that has required systemic treatment in 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 history of non-infectious pneumonitis that required steroids or current
pneumonitis

- Has an active infection requiring intravenous antibiotic 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-programmed cell death ligand 1
(PD-L1), anti-programmed cell death ligand 2 (PD-L2), anti-tumor necrosis factor
receptor superfamily, member 9 (CD137), or anti-cytotoxic T-lymphocyte-associated
antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug
specifically targeting T-cell co-stimulation or checkpoint pathways)

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

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

- Has received a live vaccine within 30 days prior to the first dose of trial treatment