Epacadostat and Pembrolizumab in Patients With GIST

While targeted therapy with imatinib has significantly improved survival for patients with
inoperable and metastatic gastrointestinal stromal tumors (GIST), the majority will
eventually progress after a median of 20-26 months. Standard second-line treatment with
sunitinib has a response rate of 7%, and third-line treatment with regorafenib has a response
rate of only 5%. More effective treatments for imatinib-refractory GIST are needed.

This study aims to assess the efficacy of combined IDO and PD-1 inhibition with epacadostat
(IDO inhibitor) and pembrolizumab (anti-PD-1 antibody) in patients with imatinib-refractory
GIST.

Inclusion Criteria:

- Histologically confirmed diagnosis of GIST.

- Unresectable or metastatic GIST

- Allowable prior therapies:

1. Subjects must have had clinical or radiographic progression on imatinib. Those
who were taken off of imatinib for intolerance must have progressed on at least
one other tyrosine kinase inhibitor (TKI).

2. Subjects must have received ≥ 1 prior systemic therapy (including imatinib). A
maximum of 4 prior therapies for metastatic disease are allowed.

- Male or female subjects, age 18 years or older.

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

- Life expectance of ≥ 3 months.

- Laboratory and medical history parameters within the following Protocol-defined range.

All screening laboratory tests should be performed within 28 days of treatment initiation
and must be independent of hematopoietic growth factor support.

- Absolute neutrophil count ≥ 1.5 x 109/L.

- Platelets ≥ 100 x 109/L.

- Hemoglobin ≥ 9 g/dL (transfusion is acceptable to meet this criteria)

- Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN) OR calculated
creatinine clearance ≥ 50 mL/min for subjects with creatinine levels > 1.5 x
institutional ULN.

- Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase ≤ 2.5 x
ULN, or ≤ 5 x ULN in subjects with liver metastases.

- Total bilirubin ≤ 1.5 x ULN

o Note: patients with hyperbilirubinemia clinically consistent with an inherited
disorder of bilirubin metabolism (eg, Gilbert syndrome) will be eligible at the
discretion of the principal investigator.

- International normalized ratio (INR) or prothrombin time (PT) < 1.5x ULN unless
subject is receiving anticoagulation therapy as long as PT or INR is within
therapeutic range of intended use of anticoagulant.

- Activated partial thromboplastin time (aPTT) < 1.5 x ULN unless subject is receiving
anticoagulant therapy, as long as PTT is within therapeutic range of intended use of
anticoagulants.

- Presence of baseline measureable disease by RECIST v1.1 for solid tumors, defined
as at least one lesion that can be accurately measured in at least one dimension
(longest diameter to be recorded for non-nodal lesions and short axis for nodal
lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT
scan, MRI, or calipers by clinical exam. (See Section 15.4 for the evaluation of
measurable disease).

- The effects of pembrolizumab and epacadostat on the developing human fetus are
unknown, and thus female subjects of childbearing potential (defined as women who
have not undergone surgical sterilization with a hysterectomy and/or bilateral
oophorectomy, and are not postmenopausal (defined as ≥ 12 months of amenorrhea))
must have a negative pregnancy test at screening and must agree to use adequate
contraception (complete abstinence, or two methods of birth control (Appendix B))
prior to study entry and until at least 4 months after the last dose of study
treatment. Should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this study, she should inform her treating
physician immediately.

- Fertile men must also agree to use adequate contraception (2 barrier methods or
abstinence) during the study and for up to 4 months after the last dose of study
drug.

- All subjects must agree to pre- and on-treatment tumor biopsies. Subjects in whom
biopsy is technically not feasible or in whom would result in unacceptable risk,
in the opinion of the investigator, may be exempted from the biopsy requirement
with discussion with the principal investigator. Use of outside archived tumor
tissue for a baseline biopsy is not permitted.

- Willingness and ability to provide written informed consent prior to any
study-related procedures and to comply with all study requirements.

Exclusion Criteria:

- Treatment with chemotherapy (not including Tyrosine Kinase Inhibitors) or radiotherapy
within 4 weeks (6 weeks from nitrosoureas or mitomycin C), or treatment with
monoclonal antibody therapy within 4 weeks prior to start of study treatment. Note: No
minimum washout period is required for tyrosine kinase inhibitor therapy (eg, imatinib
or sunitinib).

- Patients must have recovered from adverse events (greater than grade 1) due to prior
anticancer therapy, except for stable chronic toxicities such as alopecia.

- Participation in any other clinical study with investigational drug received within 28
days or 5 half lives (whichever is longer) before first dose.

- Subjects who have received prior anti-PD-1 or anti-PD-L1 antibody, or an IDO
inhibitor.

- Subjects who have received experimental vaccines or other immune therapies should be
discussed with the principal investigator to confirm eligibility.

- Any prior ≥ Grade 3 immune-related adverse event (irAE) while receiving immunotherapy,
or any unresolved irAE > grade 1.

- Subjects receiving immunologically based treatment for any reason, including chronic
steroids or prednisone (at dose >10 mg/day of prednisone) within 14 day prior to first
study treatment. Inhaled or topical steroids or systemic steroids (at dose ≤10 mg/day
of prednisone) is permitted.

- Subjects with any active or inactive autoimmune process (eg, rheumatoid arthritis,
moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) or who
are receiving systemic therapy for an autoimmune disease. Exceptions include vitiligo,
hypothyroidism controlled on hormone replacement, type I diabetes, Grave's disease,
adrenal insufficiency on stable replacement doses of steroids (prednisone ≤10 mg/day
or equivalent), or with principal investigator approval.

- No prior organ allograft or allogenic bone marrow transplantation.

- History of (noninfectious) pneumonitis that require steroids or current pneumonitis.

- A diagnosis of another active malignancy with the following exceptions: basal or
squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, isolated
elevation of prostate-specific antigen, indolent secondary malignancies not requiring
active therapy, or with the approval of the principal investigator. Subjects with a
completely treated prior malignancy and no evidence of disease for ≥ 2 years are
eligible.

- Subjects with known active hepatitis B (HBV) or hepatitis C (HCV) infection as defined
by the following (Hepatitis screening studies are required:

- Positive test for hepatitis B surface antigen

- Positive test for hepatitis C antibody and/ or hepatitis C quantitative viral
load (Note: Subjects with a positive hepatitis C antibody and negative
quantitative hepatitis C polymerase chain reaction (PCR) viral load are eligible)

- Subjects with a known history of HIV, including patients with controlled disease on
antiretroviral therapy. HIV testing is not required as part of screening for this
study.

- Subjects receiving monoamine oxidase (MAO) inhibitors within 21 days of study
enrollment (epacadostat increases serotonin levels, theoretically increasing the risk
of serotonin syndrome, although this has not been reported in any ongoing clinical
studies to date).

- Any history of serotonin syndrome (SS) after receiving 1 or more serotonergic drugs.

- Current pregnancy or breast feeding. Pregnant women are excluded from this study
because the teratogenicity of epacadostat and pembrolizumab are unknown. Because there
is an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with pembrolizumab and/or epacadostat, breastfeeding should be
discontinued in all female subjects.

- Receipt of live attenuated vaccines (including, but not limited to: intranasal
influenza vaccine (FluMist), measles, mumps, rubella, chicken pox, yellow fever,
rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine) within 30 days before the
first dose of study treatment.

- Concurrent use of any medication that is an inhibitor of UGT1A9 during the screening
or treatment period.

- Major surgical procedure or significant traumatic injury within 14 days of initiating
study drug or anticipation of the need for major surgery during the study.

- Inability to swallow capsules, or refractory nausea and vomiting, malabsorption, an
external biliary shunt, or significant bowel resection that would preclude adequate
absorption.

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

- History of current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the study, or interfere with the subject's participation
for the full duration of the study.

- Known allergy or reaction to any component of either study drug formulation.