Nivolumab in Treating Patients With Recurrent and/or Metastatic Nasopharyngeal Cancer

PRIMARY OBJECTIVES:

I. Objective tumor response to nivolumab in patients with previously treated recurrent and/or
metastatic nasopharyngeal carcinoma (NPC) based on Response Evaluation Criteria in Solid
Tumors (RECIST) criteria version 1.1.

SECONDARY OBJECTIVES:

I. Tumor response to nivolumab based on immune-related response criteria (IRC). II. Duration
of response. III. Progression-free survival and overall survival. IV. Safety and
tolerability.

TERTIARY OBJECTIVES:

I. To investigate the effect of nivolumab on tumor burden by analyzing the clearance of
plasma Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) during the first 4-6 weeks of
treatment.

II. To investigate the association between treatment outcome and immunological markers: a)
Intratumoral expression of programmed cell death 1 (PD-1) and programmed cell death-ligand
(PD-L1) in archived NPC tissues (mandatory); b) Serum absolute lymphocyte count at baseline
and post-treatment (mandatory); and c) Plasma cytokine levels at baseline and serially during
the first 8 weeks of treatment; d) Expression of PD-1 in cluster of differentiation (CD)8+ T
cells in tumor infiltrating lymphocytes (TIL) at baseline (optional).

III. To investigate functional magnetic resonance imaging (MRI) sequences as an early
predictor of response to nivolumab (optional only at Chinese University of Hong Kong [CUHK]).

OUTLINE:

Patients receive nivolumab intravenously (IV) over approximately 60 minutes on days 1 and 15.
Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 years.

Inclusion Criteria:

- Ability to understand and the willingness to sign a written informed consent document

- Histologically or cytologically confirmed non-keratinizing nasopharyngeal carcinoma
(NPC) that has recurred at locoregional and/or distant sites; NOTE: patients with
local recurrence at the bony skull-base as the only site of index disease are
excluded; patients with locoregional recurrence without distant metastases must have
undergone radical radiotherapy previously

- Measurable disease according to the RECIST criteria (version 1.1), for the evaluation
of measurable disease

- Received one or more lines of chemotherapy, which must include prior treatment with a
platinum agent and must not be amenable to potentially curative radiotherapy or
surgery

- Archived or fresh tumor sample available; willingness to donate blood and tissue for
mandatory correlative research studies

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

- Absolute neutrophil count >= 1.5 x 10^9/L

- Platelet count >= 100 x 10^9/L

- Hemoglobin >= 8.0 g/dL

- Serum alanine aminotransferase ([ALT]; serum glutamate-pyruvate transferase [SGPT]),
or serum aspartate aminotransferase [AST] where available at the center) < 2.5 x upper
limit of normal (ULN), OR < 5 x ULN in the presence of liver metastases

- Serum total bilirubin < 2 x ULN (except patients with Gilbert syndrome, who can have
total bilirubin < 3.0 mg/dL)

- Serum creatinine < 1.5 x ULN

Exclusion Criteria:

- Any of the following:

- Chemotherapy =< 4 weeks prior to registration

- Radiotherapy =< 4 weeks prior to registration

- Nitrosoureas =< 6 weeks prior to registration or

- Mitomycin C =< 6 weeks prior to registration

- Those who have not recovered from adverse events (to grade =< 1 in severity) due
to agents administered more than 4 weeks earlier; prior palliative radiotherapy
to bone metastases =< 2 weeks prior to registration (i.e. prior palliative
radiotherapy to bone metastases is allowed if it is performed > 2 weeks prior to
registration)

- Prior investigational agents =< 4 weeks prior to registration

- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-cytotoxic T-lymphocyte
antigen 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting
T-cell co-stimulation or immune checkpoint pathways

- Known brain metastases or leptomeningeal metastases; NOTE: symptomatic, and/or if they
require immunosuppressive doses of corticosteroids (e.g. > 10 mg/day prednisone or
equivalents) for at least 2 weeks prior to study drug administration; patients with
treated brain metastases who are deemed clinically stable and without radiological
progression on positron emission tomography (PET), MRI or computed tomography (CT)
scan performed =< 8 weeks of study entry, are not excluded; NOTE: primary
nasopharyngeal cancers that directly invade the skull base and extend into the
infratemporal fossa (e) are not regarded as brain metastases and are not excluded

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

- History of severe hypersensitivity reaction to any monoclonal antibody

- Uncontrolled intercurrent illness including, 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

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception NOTE: breastfeeding should be discontinued if the mother is treated
with nivolumab; women of childbearing potential and men must use two forms of
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation; they must adhere to
contraception for a period of 31 weeks after the last dose of nivolumab

- For patients with unknown human immunodeficiency virus (HIV) status at the time of
enrollment, HIV serology must be tested during screening; patients who are tested
positive for HIV could be included if there is an adequate cluster of differentiation
4 (CD4) count (> 350/ul) on a stable regimen of highly active anti-retroviral therapy
(HAART) with no detectable or minimal viral burden, and no active infections

- For patients with unknown hepatitis B virus surface antigen (HbsAg) status, must be
tested during study screening; patients who are tested positive test for HBsAg are
excluded if they have inadequately controlled hepatitis B and/or Child-Pugh Class B or
C cirrhosis; however, patients with adequately controlled hepatitis are not excluded
from the study if they satisfy all of the following criteria: (i) must be receiving a
nucleoside analog anti-viral drug for 3 or more months; and (ii) have a serum
hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level of less than 100 IU/ml via
polymerase chain reaction quantification assays prior to enrollment

- For patients with unknown hepatitis C virus ribonucleic acid (HCV antibody) status,
must be tested during study screening; patients who are tested positive for HCV
antibody are excluded from the study if they have inadequately controlled hepatitis C
and/or Child-Pugh Class B or C cirrhosis; patients with adequately controlled
hepatitis are not excluded from the study as defined by having undetectable level of
serum HCV antibody level prior to enrollment; patients who are currently on interferon
or other anti-HCV therapy will be excluded from study

- Active autoimmune disease or history of autoimmune disease that might recur, which may
affect vital organ function or require immune suppressive treatment including systemic
corticosteroids; NOTE: these include but are not limited to patients with a history of
immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating)
neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease
such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma,
inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients
with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or
phospholipid syndrome should be excluded; patients with vitiligo, endocrine
deficiencies including thyroiditis managed with replacement hormones including
physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other
arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and
patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid
antibodies should be evaluated for the presence of target organ involvement and
potential need for systemic treatment but should otherwise be eligible

- Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger (precipitating event)

- Condition requiring systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalents) or other immunosuppressive medications within 14 days of study
drug administration; inhaled or topical steroids and adrenal replacement doses =< 10
mg daily prednisone equivalents are permitted in the absence of active autoimmune
disease; patients are permitted to use topical, ocular, intra-articular, intranasal,
and inhalational corticosteroids (with minimal systemic absorption); physiologic
replacement doses of systemic corticosteroids are permitted, even if =< 10 mg/day
prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g.,
contrast dye allergy) or for treatment of non-autoimmune conditions (e.g.,
delayed-type hypersensitivity reaction caused by contact allergen) is permitted

- Evidence of active or acute (i.e. current, or recent within 4 weeks prior to
registration) diverticulitis, intra-abdominal abscess, gastrointestinal (GI)
obstruction and abdominal carcinomatosis which are known risk factors for bowel
perforation; patients with abdominal carcinomatosis, a history of non-recent
intra-abdominal abscess, or a history of non-recent GI obstruction should be evaluated
for the potential need for additional treatment before coming on study