Nivolumab With or Without Ipilimumab in Treating Patients With Persistent or Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

PRIMARY OBJECTIVES:

I. To estimate the proportion of patients who have objective tumor response (complete or
partial) by modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients
with persistent or recurrent epithelial ovarian, fallopian tube, primary peritoneal cancers,
treated with nivolumab or the combination of nivolumab and ipilimumab and to assess the
difference in objective response rate (ORR) between patients treated with nivolumab versus
those treated with the combination of nivolumab and ipilimumab.

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) hazard ratio for patients treated with
nivolumab versus those treated with the combination of nivolumab and ipilimumab.

II. To estimate and compare the duration of overall survival (OS) for patients treated with
nivolumab or the combination of nivolumab and ipilimumab.

III. To determine the frequency and severity of adverse events associated with treatment with
nivolumab or the combination of nivolumab and ipilimumab as assessed by Common Terminology
Criteria for Adverse Events (CTCAE).

IV. To determine whether cellular and molecular laboratory parameters in pre-treatment tissue
and peripheral blood specimens predict overall survival (OS), tumor response by modified
RECIST 1.1, and progression-free survival (PFS): PD-L1 expression in tumor cells and
tumor-infiltrating lymphocytes (TILs) measured by quantitative immunohistochemistry (IHC);
natural anti-tumor immunity in tumor cells and TILs measured using IHC and T cell repertoire
analyses; tumor "immunogenicity" as determined by the neo-epitope landscape using
next-generation whole exome sequencing (NGS); anti-tumor immune response in peripheral blood,
including serologic responses and analysis of T cell receptor (TCR) repertoires by deep
sequencing; and shift in quantitative laboratory peripheral blood parameters after the first
6 and 12 weeks of therapy.

OUTLINE: Patients are randomized to 1 of 2 treatment groups.

GROUP I:

INDUCTION: Patients receive nivolumab intravenously (IV) over 30 minutes every 2 weeks.
Treatment repeats every 4 weeks for 2 cycles in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE: Patients receive nivolumab IV over 30 minutes every 2 weeks. Treatment repeats
every 4 weeks for up to 21 cycles in the absence of disease progression or unacceptable
toxicity.

GROUP II:

INDUCTION: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes.
Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE: Patients receive nivolumab IV over 30 minutes every 2 weeks. Treatment repeats
every 4 weeks for up to 21 cycles in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up for 100 days, every 3 months
for 2 years, and then every 6 months for 3 years.

Inclusion Criteria:

- Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or
primary peritoneal cancer with documented disease progression (disease not amendable
to curative therapy); histologic confirmation of the original primary tumor is
required via the pathology report; NOTE: patients with mucinous histology are NOT
eligible; patients with carcinosarcoma histology are NOT eligible

- All patients 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 effects of recent surgery, radiotherapy or chemotherapy

- Free of active infection requiring antibiotics (with the exception of
uncomplicated urinary tract infection [UTI])

- Any hormonal therapy directed at the malignant tumor must be discontinued at
least one week prior to registration

- Any other prior therapy directed at the malignant tumor including
chemotherapy, targeted agents, immunologic agents, and any investigational
agents, must be discontinued at least 4 weeks prior to registration (6 weeks
for nitrosoureas or mitomycin C)

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

- At least 4 weeks must have elapsed since major surgery

- Patients are allowed to have received up to three prior cytotoxic regimens for
treatment of their epithelial ovarian, fallopian tube, or primary peritoneal cancer;
they must have had one prior platinum-based chemotherapeutic regimen for management of
primary disease, possibly including intra-peritoneal therapy, consolidation,
biologic/targeted (non-cytotoxic) agents or extended therapy
(maintenance/consolidation) administered after surgical or non-surgical assessment;
patients are allowed to have received, but are not required to have received, one to
two cytotoxic regimens for management of recurrent or persistent disease; (for the
purposes of this study poly adenosine diphosphate [ADP] ribose polymerase [PARP]
inhibitors given for recurrent or progressive disease will be considered cytotoxic;
PARP inhibitors given as maintenance therapy in continuation with management of
primary disease will not be considered as a separate cytotoxic regimen); if two
cytotoxic regimens had been received for management of recurrent or persistent
disease, one of these regimens would have had to contain either a platinum or a taxane
agent

- Performance status of 0, 1 or 2 within 28 days prior to registration

- Absolute neutrophil count (ANC) >= 1,500/ul (within 14 days prior to registration)

- Platelets >= 100,000/ul (within 14 days prior to registration)

- Creatinine =< 1.5 x institutional/laboratory upper limit of normal (ULN) (within 14
days prior to registration)

- Bilirubin =< 1.5 x ULN; for patients with Gilbert's syndrome, bilirubin =< 3.0 mg/dL
is acceptable (within 14 days prior to registration)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (within
14 days prior to registration)

- Albumin >= 2.8 g/dL (within 14 days prior to registration)

- Adequate thyroid function within 28 days prior to registration defined as serum
thyroid-stimulating hormone (TSH) in normal range

- The patient or a legally authorized representative must provide study-specific
informed consent prior to study entry

- Platinum-free interval (PFI) - patients must have progressed < 12 months after
completion of their last platinum-based chemotherapy; the date (platinum free
interval) should be calculated from the last administered dose of platinum therapy to
documentation of progression

- Adequate oxygen saturation via pulse oximeter within 28 days prior to registration
(i.e., patient can NOT have CTCAE hypoxia grade 2 or greater)

- Left ventricular ejection fraction (LVEF) >= 50% (measured within 28 days of study
entry)

Exclusion Criteria:

- Patients who have had prior therapy with nivolumab or with an anti-programmed cell
death (PD)-1, anti-PD-ligand (L)1, anti-PD-L2, anti-cytotoxic T-lymphocyte-antigen
(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

- Patients with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer and other specific malignancies are excluded if there is any
evidence of other malignancy being present within the last three years (2 years for
breast cancer); patients are also excluded if their previous cancer treatment
contraindicates this protocol therapy

- Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER
THAN for the treatment of ovarian, fallopian tube, or primary peritoneal cancer within
the last three years are excluded; patients may have received prior adjuvant
chemotherapy and radiotherapy for localized breast cancer, provided that it was
completed more than 2 years prior to registration, and the patient remains free of
recurrent or metastatic disease and hormonal therapy has been discontinued; patients
who have received prior radiotherapy to any portion of the abdominal cavity or pelvis
or thoracic cavity within the last three years are excluded; prior radiation for
localized cancer of the head and neck or skin is permitted, provided that it was
completed more than three years prior to registration, and the patient remains free of
recurrent or metastatic disease

- Patients with uncontrolled illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure and unstable angina pectoris

- Patients with history of organ transplant

- 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 or nivolumab + ipilimumab;
women must not be breastfeeding; women who are not of childbearing potential (i.e.,
who are postmenopausal or surgically sterile) 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 and/or 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; if, following
initiation of the investigational product(s), it is subsequently discovered that a
study subject is pregnant or may have been pregnant at the time of investigational
product exposure, including during at least 6 half-lives after product administration,
the investigational product will be permanently discontinued in an appropriate manner
(e.g., dose tapering if necessary for subject safety); the investigator must report
this event and any outcomes by amendment through Cancer Therapy Evaluation Program
(CTEP)-Adverse Event Reporting System (AERS); protocol-required procedures for study
discontinuation and follow-up must be performed on the subject unless contraindicated
by pregnancy (e.g., X-ray studies); other appropriate pregnancy follow-up procedures
should be considered if indicated; in addition, the investigator must report and
follow-up on information regarding the course of the pregnancy, including perinatal
and neonatal outcome; infants should be followed for a minimum of 8 weeks

- History or evidence upon physical examination of central nervous system (CNS) disease,
including primary brain tumor, seizures which are not controlled with non-enzyme
inducing anticonvulsants, any brain metastases and/or epidural disease, or history of
cerebrovascular accident (cerebrovascular accident [CVA], stroke), transient ischemic
attack (TIA) or subarachnoid hemorrhage within six months prior to the first date of
study treatment

- In order for patients with known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) to be
eligible, they must be on a stable highly active antiretroviral therapy (HAART)
regimen, have cluster of differentiation (CD)4 counts > 350, with no detectable viral
load on quantitative polymerase chain reaction (PCR)

- Patients with treated hepatitis virus infections (hepatitis B or hepatitis C) are
eligible if they have been definitively treated for 6 months, have no detectable viral
load on quantitative PCR, and liver function tests (LFTs) meet eligibility
requirements

- 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, 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

- Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
residual hypothyroidism due to autoimmune condition only requiring hormone replacement
(such as Hashimoto's thyroiditis), 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); 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

- Any of the following within 2 months of registration: active peptic ulcer disease,
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, malabsorption
syndrome; any of the following within 6 months of registration: intra-abdominal
abscess, gastrointestinal obstruction requiring parenteral hydration and/or nutrition,
gastrointestinal perforation; Note: complete resolution of an intra-abdominal abscess
must be confirmed prior to registration even if the abscess occurred more than 6
months prior to registration

- No planned concomitant, non-protocol directed anti-cancer therapy

- Grade >= 2 peripheral neuropathy