Nivolumab in Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders and EBV-Positive Non-HodgkinLymphomas

BACKGROUND:

- Epstein-Barr virus (EBV) is a chronic viral infection associated with a heterogeneous
group of lymphoproliferative disorders (LPD) and non-Hodgkin lymphomas (NHL).

- The shared pathobiology of EBV-positive LPDs and NHLs includes a defect in host
mechanisms of immune tolerance and immunosurveillance.

- Programmed death-1 (PD-1) is a surface protein present on T cells, B cells, and
macrophages that serves a co-inhibitory role to negatively regulate immune responses

- PD-1 and its ligands, PD-L1 and PD-L2, are overexpressed in EBV-positive lymphomas and
are markers of aggressive behavior.

- Blockade of the PD-1 pathway induces T-cell responses against tumor antigens in a
variety of cancers, including Hodgkin lymphoma, that lead to clinical remissions.

- Nivolumab is a fully human IgG4 monoclonal anti-PD-1 receptor antibody with clinical
activity in both indolent and lymphomas.

OBJECTIVE:

-To determine the best overall response rate of nivolumab in subjects with EBV-positive LPD
and EBV-positive NHL

ELIGIBLITY:

- Subjects must have a confirmed diagnosis of an EBV-positive B-cell LPD or an EBV-
positive NHL confirmed by Laboratory of Pathology, NCI

- Cohort 1: LPD subjects may be previously untreated or relapsed from prior therapy

- Cohort 2: EBV-positive B-cell NHL subjects must have relapsed from previous
treatment with an anthracycline and rituximab-based regimen or be considered not
eligible for the same

- Adequate bone marrow function (unless disease-related) defined as:

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

- Hemoglobin greater than 9g/dL (transfusion permitted)

- Platelet count greater than or equal to 50,000/mcL (transfusion not permitted)

- Age greater than or equal to 12 years



DESIGN:

- Phase II study of subjects with EBV-positive LPD and EBV-positive NHL, both relapsed and
untreated.

- Subjects will be treated with nivolumab 480 mg IV every 4 weeks for up to 2 years if
responding disease with clinical improvement and no unacceptable toxicity.

- All responding subjects (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.

- An optimal two-stage phase II trial design will be used to rule out a best overall
response rate of 20% in each cohort. If fewer than 3 of the first 17 subjects respond,
that cohort would accrue no more subjects.

- 37 subjects with EBV-positive LPD and 37 subjects with EBV-positive NHL will be enrolled
on this protocol.

- INCLUSION CRITERIA:

- Subjects must have histologically or cytologically confirmed EBV-positive LPD or an
EBV-positive NHL confirmed by the Laboratory of Pathology, NCI.

- Cohort 1: EBV-positive B-cell LPD. Subjects may be previously untreated or
relapsed from prior therapy.

1. Lymphomatoid granulomatosis (LYG), grades I-II

2. Chronic active EBV disease (CAEBV)

3. EBV-positive post-transplantation lymphoproliferative disorder (PTLD) NOTE:
PTLD after solid organ transplantation is excluded. Patients who, at the
discretion of the investigator, need urgent therapy with standard agents
will not be eligible.

- Cohort 2: EBV-positive B-cell NHL subjects must have relapsed from previous
treatment with an anthracycline and rituximab-based regimen or be considered not
eligible for the same.

1. Lymphomatoid granulomatosis (LYG), grade III

2. EBV-positive immunodeficiency-associated diffuse large B-cell lymphoma
(DLBCL)

3. EBV-positive DLBCL

- Subjects must be at least 2 weeks from prior anti-lymphoma therapy (including
radiation therapy)

- Subjects must be at least 100 days from prior stem cell transplant (autologous or
allogeneic) or Donor Lymphocyte Infusion (DLI)

- Age greater than or equal to 12 years

- Patients greater than or equal to 12 and less than 18 years of age should weigh
at least 40 kilograms (kg); there is no weight requirement for adult subjects.

- NOTE: If a pediatric patient is identified for possible enrollment who weighs
less than 40 kg, the safety of the nivolumab dosing strategy used in this study
must be discussed with the PI and manufacturer to confirm safety, and this
discussion/approval for enrollment documented in the medical record prior to
declaring the pediatric patient eligible.

- Adequate performance status as follows:

- Patients greater than or equal to 16 years must have ECOG Performance Status 0-2
(Karnofsky greater than or equal to 60%)

- Pediatric patients less than 16 years must have Lansky play-performance of
60-100%

- Subjects must have measurable or evaluable disease.

- Subjects must have adequate organ and bone marrow reserve (unless disease-related) as
defined below:

- absolute neutrophil count - greater than or equal to 750/mcL; greater than or
equal to 500/mcL if impairment is due to LPD/NHL

- platelets - greater than or equal to 50,000/mcL; greater than or equal to
25,000/mcL if impairment is due to LPD/NHL; (transfusions not permitted)

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

- total bilirubin - < 3.0g/dl OR < 5.0g/dl if Gilbert s syndrome or disease
infiltration of the liver is present

- AST(SGOT)/ALT(SGPT) - less than or equal to 3 X institutional upper limit of
normal

- serum creatinine OR creatinine clearance - Adults: less than or equal to 1.5
mg/dL; Minors: serum Cr less than or equal to age-adjusted normal OR greater than
or equal to 40 ml/min/1.73m^2

- A formalin fixed tissue block or at least 15 slides of tumor sample (archival or
fresh) must be available for performance of correlative studies. NOTE: Patient must be
willing to have a pre-treatment tumor biopsy if adequate archival tissue is not
available.

- The toxicity profile of nivolumab in patients with disease involvement of the central
nervous system (CNS) is unknown. For this reason, we will introduce early stopping
rules.

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

- Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) during
screening and within 48 hours prior to the first dose of nivolumab.

- WOCBP and men who are sexually active with WOCBP must use adequate contraception
(e.g., hormonal or 2 barrier methods with a failure rate of less than 1% per year
or abstinence) prior to study entry and throughout study drug administration.
WOCBP receiving nivolumab will be instructed to adhere to contraception for a
period of 23 weeks after the last dose of investigational product. Men receiving
nivolumab and who are sexually active with WOCBP will be instructed to adhere to
contraception for a period of 31 weeks after the last dose of investigational
product.

- Women who are not of childbearing potential (i.e., who are postmenopausal or
surgically sterile as well as azoospermic men do not require contraception.

- WOCBP is defined as any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal
ligation, or bilateral ophorectomy), and who is not postmenopausal. Post
menopause is defined as:

1. Amenorrhea greater than or equal to 12 consecutive months without another
cause, and a documented serum follicle stimulating hormone (FSH) level > 35
mIU/mL or

2. Women with irregular menstrual periods and a documented serum follicle
stimulating hormone (FSH) level > 35 mIU/mL or NOTE: FSH level testing is
not required for women greater than or equal to 62 years old with amenorrhea
of greater than or equal to 1 year

3. Women on hormone replacement therapy (HRT)

- Pregnant women are excluded from this study because nivolumab is an IgG monoclonal
antibody with the potential for teratogenic or abortifacient effects.

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

- Ability of subject or Legally Authorized Representative (LAR) to understand and sign
the written informed consent document.

EXCLUSION CRITERIA:

- Subjects who are receiving any other investigational agents.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab.

- Subjects with second malignancies requiring active systemic therapy are excluded.
Subjects with second malignancies not requiring active systemic therapy or
premalignant conditions such as monoclonal B-cell lymphocytosis (MBL) or monoclonal
gammopathy of undetermined significance (MGUS) may be eligible.

- Subjects with any condition or autoimmune disease that requires systemic
corticosteroids (> 10 mg daily prednisone equivalents) or immunosuppressive
medications within 14 days of study drug administration. Inhaled or topical steroids
are permitted.

- Subjects with active graft-vs-host disease (GVHD) requiring steroids or other
immunosuppressive agents; history of greater than or equal to grade II acute GVHD or
extensive chronic GVHD.

- Subjects who have had solid organ transplant.

- Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti CTLA-4
antibody.

- Non-oncology vaccine therapies for prevention of infectious disease within 4 weeks of
study drug administration.

- A serious uncontrolled medical condition requiring therapy.

- Seizures disorder not controlled by anti-seizure medications.

- Subjects with CNS involvement may be included on the study as long as they have not
had any seizure activity in past 4 weeks.

- Hepatitis B virus surface antigen positive.

- Active Hepatitis C infection with a positive PCR; subjects who are Hepatitis C
antibody positive and PCR negative may be eligible. In these cases the subjects will
be monitored via HCV PCR throughout the study.

- History of anaphylactic reaction to monoclonal antibody therapy.

- HIV positive subjects are excluded because the function of their T-cell immune
responses is impaired.