PRIMARY OBJECTIVES:
I. To determine the efficacy of epacadostat in combination with pembrolizumab as determined
by the best overall response rate in previously treated patients with advanced pancreatic
adenocarcinoma with homologous recombination repair deficiency (HRD) aberrations.
SECONDARY OBJECTIVES:
I. To further determine the efficacy of epacadostat in combination with pembrolizumab in
previously treated patients with advanced pancreatic adenocarcinoma with HRD aberrations.
II. To assess the safety and tolerability of epacadostat in combination with pembrolizumab in
previously treated patients with advanced pancreatic adenocarcinoma with HRD aberrations.
EXPLORATORY OBJECTIVES:
I. To identify predictive, mechanistic, and/or surrogate biomarkers of clinical efficacy of
epacadostat in combination with pembrolizumab in previously treated patients with advanced
pancreatic adenocarcinoma with HRD aberrations utilizing exploratory studies investigating
the patients tumor and immune system response including: flow cytometry of fresh peripheral
blood mononuclear cell (PBMC), PDL-1.
OUTLINE:
Participants receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and
epacadostat orally (PO) twice daily (BID) on days 1-21. Cycles repeat every 21 days in the
absence of disease progression or unaccepted toxicity.
After completion of study treatment, participants are followed up at 30 days, every 8 weeks
for 3 years, and then every 12 weeks thereafter.
Inclusion Criteria:
- Be willing and able to provide written informed consent/assent for the trial
- Have received at least one prior therapy for metastatic disease
- Patients with HRD identified by one of the following criteria: a) Tested positive for
BRCA 1 or 2 germline deleterious mutation, b) Previously identified genetic
aberrations that are associated with HRD (e.g., somatic BRCA mutation, PALB2, Fanconi
anemia gene or RAD51 mutations), c) Patients with somatic ATM loss as identifiable
with immunohistochemistry or with ATM mutation, d) Pancreatic ductal adenocarcinoma
(PDAC) patients with family history of 2 or more first-degree relatives with
BRCA-associated cancers (stomach, breast, ovary) or 1 or more first-degree relative
with PDAC
- Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
1.1 or at least one site of disease must be uni-dimensionally measurable as per RECIST
1.1. All radiology studies must be performed within 28 days prior to registration
- Patients must have an archival sample of tumor or metastatic site core biopsy to be
eligible
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale
- Within 10 days of treatment initiation: Absolute neutrophil count (ANC) >= 1.5 x 109/L
- Within 10 days of treatment initiation: platelet count >= 100 x 109/L
- Within 10 days of treatment initiation: hemoglobin >= 9 g/dl without transfusion or
erythropoietin (EPO) dependency (within 7 days of assessment)
- Within 10 days of treatment initiation: If serum creatinine concentration >= 1.5 x
upper limit of normal (ULN), then estimated creatinine clearance must be >= 60 mL/min
for subject with creatinine levels > 1.5 x institutional ULN
- Within 10 days of treatment initiation: total bilirubin =< 1.5 x ULN (3 x ULN if a
exists a history of Gilbert syndrome) or direct bilirubin >= ULN for subjects with
total bilirubin levels > 1.5 ULN
- Within 10 days of treatment initiation: alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) =< 2.5 x ULN
- Within 10 days of treatment initiation: albumin >= 3 mg/dL. Creatinine clearance
should be calculated per institutional standard
- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required
- Female subjects of childbearing potential must be willing to use an adequate method of
contraception, for the course of the study through 120 days after the last dose of
study medication. Note: Abstinence is acceptable if this is the usual lifestyle and
preferred contraception for the subject
- Male subjects of childbearing potential must agree to use an adequate method of
contraception. Contraception, starting with the first dose of study therapy through
120 days after the last dose of study therapy. Note: Abstinence is acceptable if this
is the usual lifestyle and preferred contraception for the subject
Exclusion Criteria:
- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment
- For screening electrocardiographs (ECGs), exclude patients with a Fridericia's
corrected QT interval (QTcF) > 480 ms, or JTc > 340 ms for those with an
intraventricular conduction delay. If the screening ECG has a QTcF > 480 ms,
eligibility can be confirmed if the average of 3 ECGs done 5 minutes apart have an
average QTcF < 480 ms
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment
- Has a known history of active TB (Bacillus tuberculosis)
- Hypersensitivity to pembrolizumab or epacadostat or any of their excipients
- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at
baseline) from adverse events due to a previously administered agent. Note: Subjects
with =< grade 2 neuropathy are an exception to this criterion and may qualify for the
study. Note: If subject received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting therapy
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis, which is excluded regardless of clinical stability
- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment
- Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis
- Has an active infection requiring systemic therapy
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment
- Has received prior therapy with an anti-IDO-1 agent
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)
- Has received a live vaccine within 30 days of planned start of study therapy
- Has ascites that requires frequent paracentesis or a pleural effusion that requires
repeated thoracentesis
- Has arterial vascular involvement
- Has received monoamine oxidase inhibitors within 21 days prior to starting study
- Has any history of serotonin syndrome after receiving serotonergic drugs