Nivolumab in Treating Patients With Persistent, Recurrent, or Metastatic Cervical Cancer

PRIMARY OBJECTIVES:

I. To assess the antitumor activity (proportion of objective response by Response Evaluation
Criteria in Solid Tumors [RECIST] 1.1 criteria) of nivolumab with objective tumor response in
patients with persistent, recurrent or metastatic carcinoma of the cervix.

II. To determine the nature and degree of toxicity of nivolumab as assessed by Common
Terminology Criteria for Adverse Events (CTCAE) in patients with persistent, recurrent or
metastatic carcinoma of the cervix.

SECONDARY OBJECTIVES:

I. To estimate the duration of progression-free survival (PFS) and overall survival (OS).

TERTIARY OBJECTIVES:

I. To systematically evaluate programmed cell death (PD)-1 and B7 homolog 1 (B7-H1) (i.e.,
PD-1 ligand) expression in tumor infiltrating lymphocytes (TILs) and cervical cancer cells
and explore their correlations with objective response, PFS, and OS in nivolumab-treated
patients with PD-1 and B7-H1 scoring results.

II. To explore the composition of immune infiltrates in tumor specimens/biopsies from primary
and/or metastatic/recurrent sites with selected markers including (but not limited) to
cluster of differentiation (CD)4+, CD8+, forkhead box P3 (FoxP3), CD25, lymphocyte activation
gene-3 (LAG-3), T cell immunoglobulin mucin-3 (TIM-3), and inducible T-cell co-stimulator
(ICOS) and their correlations to objective response, PFS and OS in nivolumab-treated
patients.

III. To evaluate human papillomavirus (HPV) status and to explore the changes of pre- and
post-immune therapy responses to HPV16/18/31/35/45 E7 antigens in patients peripheral blood
lymphocytes (PBL) and serum using proliferative and interferon (IFN)-gamma enzyme-linked
immunospot (ELISPOT) (cellular immunity) and serological (enzyme-linked immunosorbent assay
[ELISA]) assays.

IV. To explore the levels of circulating tumor cells (CTCs) pre-treatment and at 8 and 12
weeks and their association with patient outcome.

OUTLINE:

Patients receive nivolumab intravenously (IV) over approximately 60 minutes every 2 weeks for
a maximum of 46 doses over 92 weeks in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- Patients must have persistent, recurrent or metastatic squamous cell carcinoma,
adenosquamous carcinoma or adenocarcinoma of the cervix with documented disease
progression (disease not amendable to curative therapy); NOTE: the following cervical
tumors are not eligible: minimal deviation/adenoma malignum, gastric type
adenocarcinoma, clear cell carcinoma and mesonephric carcinoma; histologic
confirmation of the original primary tumor is required via the pathology report

- All patents must have measurable disease as defined by RECIST 1.1; measurable disease
is defined as at least one lesion that can be accurately measured in at least one
dimension (longest diameter to be recorded); each lesion must be >= 10 mm when
measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper
measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes
must be >= 15 mm in short axis when measured by CT or MRI

- Patients must have at least one "target" lesion" to be used to assess response on this
protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be
designated as "non-target" lesions unless progression is documented or a biopsy is
obtained to confirm persistence at least 90 days following completion of radiation
therapy

- Appropriate for study entry based on the following diagnostic workup:

- History/physical examination within 28 days prior to registration

- Imaging of target lesion(s) within 28 days prior to registration

- Further protocol-specific assessments:

- Recovery from adverse effects of recent surgery, radiotherapy or
chemotherapy

- Any other prior therapy directed at the malignant tumor including
chemotherapy, biologic/targeted agents and immunologic agents must be
discontinued at least three weeks prior to registration

- Investigation agents must be discontinued for at least 30 days prior to
registration

- Any prior radiation therapy must be completed at least 4 weeks prior to
registration

- At least 4 weeks must have elapsed since any major surgery prior to
registration

- Patients must have had one prior systemic chemotherapeutic regimen for management of
persistent, recurrent or metastatic carcinoma of the cervix (e.g.;
paclitaxel/cisplatin, paclitaxel/cisplatin/bevacizumab); chemotherapy administered
concurrent with primary radiation (e.g.; weekly cisplatin) is not counted as a
systemic chemotherapy regimen; adjuvant chemotherapy given following the completion of
radiation therapy (or concurrent chemotherapy and radiation therapy) is not counted as
a systemic chemotherapy regimen (e.g.; paclitaxel and carboplatin for up to 4 cycles);
NOTE: patients who have received more than one prior regimen are NOT eligible

- Performance status of 0 or 1

- Absolute neutrophil count (ANC) >= 1,500/ul

- Platelets >= 100,000/ul

- Creatinine =< 1.5 x institutional upper limit of normal (ULN) or creatinine clearance
(CrCl) >= 40 mL/min using Cockcroft-Gault formula

- Bilirubin =< 1.5 x ULN

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN

- Normal thyroid function testing (thyroid stimulating hormone [TSH]) within 14 days
prior to registration

- The patient or a legally authorized representative must provide study-specific
informed consent authorization permitting release of personal health information prior
to study entry

Exclusion Criteria:

- Patients who have had prior therapy with nivolumab or with an anti-PD-1,
anti-PD-ligand (L)1, anti-PD-L2, anti-cytotoxic T-lymphocyte-associated protein 4
(CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell
co-stimulation or immune check point pathways

- History of severe hypersensitivity reaction to any monoclonal antibody

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years

- Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
or active infection, symptomatic congestive heart failure and unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements

- Patients who are pregnant or nursing; women of child-bearing potential (WOCBP) must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation; WOCBP
should use an adequate method to avoid pregnancy for 23 weeks after the last dose of
investigational drug; WOCBP must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IV/L or equivalent units of human chorionic gonadotropin
[HCG]) within 24 hours prior to the start of nivolumab; women must not be
breastfeeding

- Women who are not of childbearing potential (i.e., who are postmenopausal or
surgically sterile or have undergone definitive radiation) do not require
contraception

- Women of childbearing potential (WOCBP) is defined as any female who has
experienced menarche and who has not undergone surgical sterilization
(hysterectomy of bilateral oophorectomy) or who is not postmenopausal; menopause
is defined clinically as 12 month amenorrhea in a woman over 45 in the absence of
other biological or physiological causes; in addition, women under the age of 55
must have a documented serum follicle stimulating hormone (FSH) level greater
than 40 mIU/mL

- WOCBP receiving nivolumab will be instructed to adhere to contraception for a
period of 23 weeks after the last dose of investigational product

- Should a woman become pregnant or suspect she is pregnant while she is
participating in this study, she should inform the treating physician immediately

- Patients with known brain metastases or leptomeningeal metastases are excluded unless
the following conditions are met:

- Metastases have been treated and there is no magnetic resonance imaging (MRI)
evidence of progression for at least 4 weeks after treatment is complete (must be
confirmed within 28 days prior to the first dose of nivolumab administration)

- There must also be no requirement for immunosuppressive doses of systemic
corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior
to study drug administration

- Patients should be excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

- Patients should be excluded if they have a positive test for hepatitis B virus
surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody)
indicating acute or chronic infection

- Patients with 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, should be excluded; 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 (IRB), Crohn's,
ulcerative colitis, hepatitis; and patients with a history of toxic epidermal
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
excluded; patient 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

- NOTE: 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)

- Patients should be excluded if they have a 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

- Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, abdominal/pelvic fistula, gastrointestinal perforation, gastrointestinal (GI)
obstruction and/or who require parenteral hydration and/or nutrition