Epacadostat and Pembrolizumab in Treating Patients with Metastatic or Unresectable Gastroesophageal Junction or Gastric Cancer

Inclusion Criteria

• Be willing and able to provide written informed consent/assent for the study
• Histologically or cytologically confirmed adenocarcinoma of the distal esophagus, gastroesophageal junction or stomach, including patients with HER2+ disease; distal esophagus is defined as within 5 centimeters of the gastroesophageal junction (GEJ)
• Patients must have metastatic or unresectable disease, including those with HER2+ disease
• Must have progressed on at least one line of prior therapy for metastatic disease, or be intolerant to that therapy if they have not progressed, and for HER2+ disease should have received prior trastuzumab
• Life expectancy >= 12 weeks
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Have measurable disease per RECIST v1.1, assessed within 4 weeks prior to study entry
• Tumor deemed amenable to biopsy by core for metastatic site or endoscopic biopsy for primary tumor (for both before and on-treatment biopsies)
• Patient must be willing to undergo two biopsies- before and on-treatment, provided the procedure is not deemed high-risk and is clinically feasible
• Absolute neutrophil count (ANC) >= 1,500/mcL (performed within 7 days of treatment initiation)
• Platelets >= 100,000/mcL (performed within 7 days of treatment initiation)
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (performed within 7 days of treatment initiation)
• Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl) =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (performed within 7 days of treatment initiation)
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 7 days of treatment initiation)
• Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases (performed within 7 days of treatment initiation)
• Albumin >= 2.5 mg/dL (performed within 7 days of treatment initiation)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 7 days of treatment initiation)
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 7 days of treatment initiation)
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 3 days 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 starting with the date of consent 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 starting with the date of consent 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
• Must be able to swallow pills

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 planned dose of treatment
• Has known hypersensitivity to pembrolizumab and/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 to baseline) from adverse events due to agents administered more than 4 weeks earlier; note that denosumab for treatment for bone metastases is allowed
• 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 to 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 surgery prior to starting therapy
• Have been treated on any Merck-sponsored pembrolizumab-containing gastric cancer pivotal trial will require prior authorization by Merck in order to enroll in this study
• Has had prior therapy with indoleamine-pyrrole 2,3-dioxygenase (IDO)-inhibitors
• 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 known history of, or any evidence of active, non-infectious pneumonitis
• Has received a live vaccine within 30 days of planned start of study therapy; NOTE: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
• 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 study 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 study treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability; patients with prior CNS metastases treated w/ prior radiation therapy (RT) will also need all of the following: * 2 months off RT before starting study or 4 weeks following radiation therapy (XRT) if magnetic resonance imaging (MRI) is stable and the patient is off steroids * Baseline MRI with no edema and * Stable for at least 8 weeks
• Has known additional malignancy that has progressed or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Has active infection requiring systemic therapy
• Has a known history of active TB (Bacillus tuberculosis)
• 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] detected)
• 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 study medication
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with pre-screening or screening visit through 120 days after the last dose of study treatment
• Has had monoamine oxidase inhibitors within 21 days before screening
• Has any history of serotonin syndrome after receiving 1 or more serotonergic drugs
• Has presence of a gastrointestinal condition that may affect drug absorption
• Use of systemic corticosteroids
• Has history or presence of an abnormal electrocardiogram (ECG) which, in the investigator's opinion, is clinically significant * Corrected QT Fredericia's formula (QTcF) >= 480 ms or presence of a left bundle branch block (LBBB); if the QRS duration > 120ms, the JTc can be used in place of the QTcF; the JTc must be < 340 ms
• Has history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, 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 study
• Has known allergy or reaction to any component of either study drug or formulation components