Pembrolizumab in Relapsed and Refractory Gray-Zone Lymphoma (GZL), Primary Central Nervous System Lymphoma (PCNSL), and Other Extranodal Diffuse Large B-cell Lymphomas

Background:

- Gray-zone lymphomas (GZL) are rare, aggressive lymphomas that share clinical and
biological features of diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma

- Standard upfront therapy for GZL is dose-intensive chemotherapy, though disease is often
resistant; consolidative radiation therapy reserved for patients who are relapsed or
refractory, and patients who fail radiation therapy have a poor prognosis

- Primary central nervous system lymphoma (PCNSL), primary testicular lymphoma (PTL),
primary breast lymphoma (PBL), primary cutaneous DLBCL, leg-type, and intravascular
B-cell lymphoma (IVBCL) are rare, aggressive extranodal subsets of DLBCL that usually
have gene expression signatures of activated B-cell (ABC) DLBCL

- ABC-DLBCL has cure rates below 40% after standard therapy, and is associated with late
recurrences, often involving the CNS where treatment options are limited by chemotherapy
resistance and an inability of many agents to cross the blood-brain barrier

- Molecular biology studies of GZL and extranodal DLBCL have identified potentially
targetable genetic features involving the programmed death-1 (PD-1) signaling pathway

- A high proportion of GZL, PCNSL, and PTL cases have copy number alterations or
chromosomal rearrangements involving the PD-1 ligands, PD-L1 and PD-L2

- Pembrolizumab, a humanized IgG4 monoclonal antibody that targets the PD-1 receptor, is a
rational therapeutic target for patients with relapsed and refractory GZL, PCNSL, PTL,
and other extranodal DLBCL

Objectives:

-To determine the best overall response rate of pembrolizumab in patients with relapsed and
refractory GZL and extranodal DLBCL

Eligibility:

- Confirmed diagnosis of B-cell lymphoma, relapsed from or refractory to prior:

- Cohort 1: B-cell lymphoma, unclassifiable, with features intermediate between
diffuse large B-cell lymphoma and classical Hodgkin lymphoma (i.e., Gray-zone
lymphoma or GZL)

- Cohort 2: Extranodal diffuse large B-cell lymphoma involving one or more of the
specified extranodal sites (i.e., extranodal DLBCL)

- Adequate bone marrow and organ function defined

- Age greater than or equal to 14 years

Design:

- Phase 2 study of patients with relapsed and refractory GZL and extranodal DLBCL

- Patients will be treated with pembrolizumab 200 mg (flat dose) IV every 3 weeks provided
they have clinical benefit and no unacceptable toxicity; patients who achieve a complete
response (CR) will have the option stop after 1 year of therapy.

- All responding patients (CR, PR, or SD with clinical benefit) who subsequently relapse
or progress within 1 year after discontinuation of study drug are eligible for
re-treatment.

- At least 20 evaluable patients each with GZL and DLBCL will be evaluated on this
protocol for the primary endpoint (overall accrual ceiling of 52 patients)

- INCLUSION CRITERIA:

- Patients must have a diagnosis of B-cell lymphoma confirmed by Laboratory of
Pathology, NCI, that is relapsed from or refractory to prior therapy as follows:

- Cohort 1: B-cell lymphoma, unclassifiable, with features intermediate between
diffuse large B-cell lymphoma and classical Hodgkin lymphoma (i.e., Gray-zone
lymphoma or GZL)

- Cohort 2: Extranodal diffuse large B-cell lymphoma involving one or more of the
specified extranodal sites (i.e., extranodal DLBCL). The following subtypes are
included (they do not have to be confirmed as non-GCB subtype for study entry):

- Primary CNS lymphoma (PCNSL)

- Primary testicular lymphoma (PTL)

- Primary breast lymphoma (PBL)

- Primary cutaneous DLBCL, leg-type

- Intravascular large B-cell lymphoma (IVBCL)

- Diffuse large B-cell, NOS, activated B-cell type, involving 1 or more
extranodal site

NOTE: For GZL, diagnosis will be in accordance with the 2016 World Health Organization
classification of lymphoid malignancies. Patients diagnosed with other extranodal DLBCL
subtypes or that are not otherwise specified (NOS) must involved at least 1 extranodal site
and must be considered non-GCB by local immunohistochemistry algorithms. Cases that are
non-GCB by the Hans criteria are considered eligible as well as cases of DLBCL that are
both CD10+ and MUM1+.

- Evaluable disease by clinical exam (i.e., palpable lymphadenopathy, measurable skin
lesions, etc.), laboratory assessment (i.e., lymphoma involvement of bone marrow or
peripheral blood by morphology, cytology or flow cytometry), and/or imaging
(measurable lymph nodes or masses on CT or MRI and/or evaluable FDG-avid lesions on
PET)

- Adequate tumor tissue (archival or fresh) must be available for correlative studies.
NOTE: Tumor tissue may be from any previously collected tissue and adequacy is at the
discretion of the Principal Investigator. If prior tissue is not available, patient
must be willing to undergo baseline tumor biopsy.

- Be 14 years of age or older on day of signing informed consent

- Adequate performance status (PS) as follows:

- Patients greater than or equal to 16 years must have ECOG 0-1 (and Karnofsky
greater than or equal to 60%)

- Pediatric patients < 16 years must have Lansky play-performance of equal to or
less than 60.

NOTE: Patients greater than or equal to 16 years with an ECOG PS of 2 and Karnofsky greater
than or equal to 60 will be considered eligible at the discretion of the Principal
Investigator if decreased ECOG performance status is felt to be related to residual
neurologic deficits caused by CNS disease involvement that are not progressive or
anticipated to cause clinical managemnt problems during study participation.

- Adequate organ function as evidenced by the following laboratory parameters (unless
related to lymphoma infiltration at the discretion of the investigator):

- Absolute neutrophil count (ANC) greater than or equal to 750 /mcL

- Platelets greater than or equal to 50,000 / mcL (transfusions not permitted)

- Hemoglobin greater than or equal to 9 g/dL (transfusions permitted)

- Serum creatinine: Adults: less than or equal to 1.5 times upper limit of normal (ULN).
Children: age greater than or equal to 14: less than or equal to 1.5 mg/dL OR Measured
or calculated creatinine clearance (GFR can also be used in place of creatinine or
CrCl):

Greater than or equal to 30 mL/min/1.73 m(2) for subject with creatinine levels > 1.5 times
institutional ULN (CrCl should be calculated per institutional standard)

--Serum total bilirubin less than or equal to 1.5 times ULN

OR

Direct bilirubin less than or equal to ULN for patients with total bilirubin levels > 1.5
ULN

- AST (SGOT) and ALT (SGPT) less than or equal to 3 times ULN (less than or equal to 5 X
ULN if liver involvement)

- The effects of pembrolizumab on the developing human fetus are unknown. For this
reason, the following measures apply:

- Women of childbearing potential must have a negative serum or urine pregnancy test
within 72 hours prior to the first dose of pembrolizumab.

- Men and women of childbearing potential (WOCBP) who are sexually active must agree to
adequate contraception (hormonal or barrier method of birth control; abstinence) prior
to study entry, for the duration of study participation, and for at least 120 days
after the last dose of pembrolizumab. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately.

- Participants must not be planning to conceive or father children within the projected
duration of the trial, starting with the pre-screening/screening visit through 120
days after the last dose of pembrolizumab.

- WOCBP is defined as any female who has experienced menarche and who has not undergone
successful surgical sterilization or who is not postmenopausal.

- Ability of patient or Legally Authorized Representative (LAR) to understand and
the willingness to sign a written informed consent document

EXCLUSION CRITERIA:

- Patients with DLBCL who best fit the criteria of EBV+ DLBCL, NOS are not eligible

- Current or prior anti-cancer treatment prior to the first dose of pembrolizumab as
defined below:

- Chemotherapy, targeted small molecule therapy, or other anti-cancer treatment not
otherwise specified below within 2 weeks

- Radiation therapy within 2 weeks

- Anti-cancer monoclonal antibody (mAb) treatment within 4 weeks

- Use of an investigational agent (e.g., biologic, drug, or other) within 4 weeks

- Allogeneic stem cell transplant within 100 days

- Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent at any time

- No current use of systemic corticosteroids at physiologic doses > 10 mg/day of
dexamethasone or equivalent are permitted. Patients receiving current systemic
steroids must be on a stable steroid dose (i.e., less than or equal to 10 mg/day of
dexamethasone or equivalent at the same dose for at least 7 days). Patients who
recently discontinued systemic steroids must have completed them at least 7 days prior
to entry.

- Uncontrolled intercurrent illness including, but not limited to the following that may
limit interpretation of results or that could increase risk to the patient at the
discretion of the investigator:

- 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). NOTE: 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.

- History of (non-infectious) pneumonitis that required steroids, evidence of
interstitial lung disease or active, non-infectious pneumonitis.

- Clinically significant history of liver disease, including viral or other hepatitis,
current alcohol abuse, or cirrhosis; as well as active infection with HBV or HCV:

---Patients with occult or prior HBV infection (defined as positive total hepatitis B
core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable.

- Uncontrolled and/or symptomatic thyroid disease

- Active graft-vs-host disease (GVHD) requiring treatment or any history of greater
than or equal to grade II acute GVHD

- Seizure activity within the past 4 weeks

- Known mental or physical illness that would interfere with cooperation with the
requirements of the trial or confound the results or interpretation of the
results of the trial and, in the opinion of the treating investigator, would make
the patient inappropriate for entry into the study.

- Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with pembrolizumab, breastfeeding must be
discontinued if the mother is treated with pembrolizumab

- 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.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to pembrolizumab unless felt to be in the best interests of the patient in
the opinion of the investigator

- Known additional malignancy that requires active systemic treatment