Pembrolizumab and Epacadostat in Treating Patients With Recurrent, Persistent, or Progressive Ovarian Clear Cell Carcinoma

PRIMARY OBJECTIVES:

I. To assess the objective tumor response (proportion of objective response by Response
Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria) of the combination of
pembrolizumab (MK-3475 [pembrolizumab]) and epacadostat in patients with recurrent or
persistent clear cell carcinoma of the ovary.

SECONDARY OBJECTIVES:

I. To determine the nature and degree of toxicity of MK-3475 (pembrolizumab) + epacadostat as
assessed by Common Terminology Criteria for Adverse Events (CTCAE) in patients with recurrent
or persistent clear cell carcinoma of the ovary.

II. To estimate the progression-free survival (PFS) and overall survival (OS) in patients
treated with combination of MK-3475 (pembrolizumab) and epacadostat.

EXPLORATORY TRANSLATIONAL OBJECTIVES:

I. Determine whether the ratio of plasma tryptophan to kynurenine (T:K) correlates with
response to MK-3475 (pembrolizumab) + epacadostat, by evaluating plasma T:K pre-treatment,
during treatment, and at disease progression.

II. Determine whether the presence of PD-L1, IDO-1, tumor-infiltrating regulatory T cells
(Tregs), CD8 tumor-infiltrating lymphocytes (TILs), and human leukocyte antigen (HLA) class I
in the tumor microenvironment at baseline correlates with objective response to MK-3475
(pembrolizumab) + epacadostat.

III. Determine whether soluble PD-L1 (sPD-L1) levels in plasma are correlated with response
to MK-3475 (pembrolizumab) + epacadostat, by evaluating sPD-L1 concentrations pre-treatment,
during treatment, and at disease progression.

OUTLINE:

Patients receive epacadostat orally (PO) twice daily (BID) and pembrolizumab intravenously
(IV) over 30 minutes once every 3 weeks (Q3W). Cycles repeat every 21 days in the absence of
disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- Primary tumors must be at least 50% clear cell histomorphology in order to be eligible
or have a histologically documented recurrence with at least 50% clear cell
histomorphology. Recurrence should be biopsy proven as per standard of care unless the
tumor is located in an area deemed unsafe to biopsy. Histologic confirmation of the
original primary tumor is required via the pathology report. The percentage of clear
cell histomorphology must be documented in the pathology report or in an addendum to
the original report. If slides of the primary tumor are not available for review due
to disposal of slides by the histology laboratory (typically 10 years after
diagnosis), a biopsy of the recurrent or persistent tumor is required to confirm at
least 50% clear cell histomorphology, as long as tumor is located in an area deemed
safe to biopsy. The percentage of clear cell involvement must be documented in the
pathology report or in an addendum to the original report

- All patents must have measurable disease, and at least one "target lesion" to be used
to assess response 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

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

- History/physical examination within 28 days prior to registration

- Imaging of target lesions 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, and biologic/targeted agents must be discontinued at least 4
weeks prior to registration. Any hormonal therapy directed at the malignant
tumor must be discontinued at least 2 weeks prior to registration

- Any prior radiation therapy must be completed at least 4 weeks prior to
registration, and progression must be outside the radiation field

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

- The trial is open only to women with recurrent or progressive clear cell carcinoma of
the ovary

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 or 1 within 28 days prior to registration

- Patients must have had one prior platinum-based chemotherapy for management of primary
disease. Patients are allowed to receive, but are not required to receive, up to two
additional cytotoxic regimens for management of recurrent or persistent disease

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

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

- Hemoglobin (Hgb) >= 8.0 g/dL within 14 days prior to registration (Note: the use of
transfusion of other intervention to achieve a Hgb >= 8.0 g/dL is acceptable)

- Creatinine =< 1.5 x institutional upper limit of normal (ULN) or creatinine clearance
(CrCl) >= 60 mL/min using Cockcroft-Gault formula (within 14 days prior to
registration)

- Bilirubin =< 2.5 x ULN (within 14 days prior to registration)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
(within 14 days prior to registration)

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

- Negative pregnancy test in women of childbearing potential

- Women of childbearing potential who are sexually active should be willing and able to
use medically acceptable forms of contraception for the course of the study through
120 days after the last dose of MK-3475 (pembrolizumab). Women who are not of
childbearing potential (i.e., who are postmenopausal or surgically sterile, who have
had a hysterectomy and/or bilateral oophorectomy) do not require contraception

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

Exclusion Criteria:

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

- Patients who have had prior therapy with MK-3475 (pembrolizumab) or epacadostat or
with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-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 active auto-immune 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 because of the risk of recurrence or exacerbation of disease. 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 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 with 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, and/or epidural disease, or history of
cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or
subarachnoid hemorrhage within six months prior to the first date of study treatment.
Those with brain metastases are permitted as long as they have been treated with brain
radiation therapy and have been documented stability 4 weeks following completion of
brain radiation therapy

- In order for patients with 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 with no drug-drug interaction with
UGT1A9, have CD4+ counts > 350, with no detectable viral load on quantitative
polymerase chain reaction (PCR), and no opportunistic infection

- Patients with treated hepatitis viral infections (hepatitis B and C) are eligible if
they have completed definitive treatment at least 6 months prior, have no detectable
viral load on quantitative PCR, and liver function tests (LFTs) meet eligibility
requirements

- Patients with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration

- Therapy with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake
inhibitor (SSRIs) within the last 4 weeks or history of serotonin syndrome.
Concomitant use of monoamine oxidase inhibitors with epacadostat (INCB024360) is
prohibited

- 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

- Epacadostat (INCB024360) is a substrate of CYP3A4, CYP1A2, CYP2C19, UGT1A9, P-gp, and
BCRP. Use caution when administered with strong inhibitors/inducers of these
isoenzymes and transporter proteins. Because the lists of these agents are constantly
changing, it is important to regularly consult a frequently-updated medical reference

- History or presence of an abnormal electrocardiography (ECG) that, in the
investigator's opinion, is clinically meaningful. Screening QTc interval > 480
milliseconds is excluded (corrected by Fridericia). In the event that a single QTc is
> 480 milliseconds, the subject may enroll if the average QTc for the 3 ECGs is < 480
milliseconds. For subjects with an intraventricular conduction delay (QRS interval >
120 msec), the JTc interval may be used in place of the QTc with sponsor approval. The
JTc must be < 340 milliseconds if JTc is used in place of QTc. Subjects with left
bundle branch block are excluded

- Patients who are pregnant or nursing