Entinostat and Nivolumab in Treating Patients with Unresectable or Metastatic Cholangiocarcinoma or Pancreatic Adenocarcinoma

Inclusion Criteria

• Patients must have histologically or cytologically confirmed cholangiocarcinoma or pancreatic adenocarcinoma that is metastatic or unresectable and has progressed despite standard therapy or is intolerant of therapy; 1 or 2 prior chemotherapy regimens in the metastatic setting or progression < 6 months from the completion of adjuvant chemotherapy
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >= 70%)
• Life expectancy of greater than 12 weeks
• Hemoglobin (HgB) >= 9.0 g/dL
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); an exception to this may be allowed for participants with Gilbert’s syndrome with documented approval by the Protocol Chair
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
• Creatinine within normal institutional limits or
• Creatinine clearance >= 60 mL/min using the modified Cockcroft-Gault
• Negative (serum or urine) pregnancy test, for women of childbearing potential * NOTE: If a patient has a positive or indeterminate serum or urine pregnancy test, then an ultrasound must be done to rule out pregnancy to enroll on trial. A serum beta-human chorionic gonadotropin (B-HCG) value of < 25 is considered a negative pregnancy test
• Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Patient must have an accessible non-bone tumor lesion from which serial core biopsy specimens can be obtained * NOTE: Patients with bone only disease are not eligible due to difficulties in obtaining serial bone biopsies for correlative analyses
• Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and during all the period of study participation for at least 5 months following the last dose of nivolumab. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at baseline. Women must not be breastfeeding. Women who are not of childbearing potential (e.g., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception. NOTE: If a patient has a positive or indeterminate serum or urine pregnancy test, then an ultrasound must be done to rule out pregnancy to enroll on trial. A serum B-HCG value of < 25 is considered a negative pregnancy test.
• Willingness to provide tissue and blood samples for mandatory translational research
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Patients who have had chemotherapy or other systemic therapy or radiotherapy, or those who have not recovered from adverse events due to prior administered agents as follows: * Chemotherapy < 3 weeks prior to registration * Targeted therapy (other than below) < 2 weeks prior to registration * Radiotherapy < 3 weeks prior to registration (NOTE: A previously irradiated lesion may not be used as a target lesion unless there is evidence of post-radiation progression) * Surgery < 3 weeks prior to registration * Other approved or investigational agents < 3 weeks prior to registration unless otherwise noted by the Protocol Chair * Patients who have received prior epigenetic therapy (e.g. histone deacetylase [HDAC] inhibitors such as entinostat, panobinostat, vorinostat, romidepsin or demethylating agents such as 5-azacitidine or decitabine) * Those who have not recovered from acute adverse events to grade < 2 or baseline due to agents administered, with exception of alopecia or stable neuropathy, unless approved by the Protocol Chair
• Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 antibodies or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Known sensitivity to or history of allergic reactions attributed to compounds of similar chemical or biologic composition of entinostat and/or nivolumab. History of severe hypersensitivity reaction to any monoclonal antibody
• 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 (IBD), Crohn’s, ulcerative colitis, autoimmune 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 * NOTE: Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event)
• Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• Patient has a pulse oximetry of < 92% on room air or is on supplemental home oxygen
• Patients with active or untreated brain metastases or leptomeningeal metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events * NOTE: Patients with previously treated brain metastases must have stable neurologic status and imaging following local therapy (surgery or radiation) for at least 4 weeks, with no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration (stable low dose dexamethasone allowed at discretion of Investigational New Drug [IND] Sponsor)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that in the judgment of the investigator would limit compliance with study requirements
• Pregnant women are excluded from this study because the agents have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued
• Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible. Patients who have a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C antibody (HCV Ab)/ribonucleic acid (RNA) (HCV RNA) indicating acute or chronic infection are also ineligible (baseline testing required)
• 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). Physiologic replacement doses of systemic corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents. 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
• Patients requiring concurrent administration of valproic acid are also excluded
• Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, or gastrointestinal (GI) obstruction which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study
• Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption
• Another active malignancy =< 3 years prior to registration with the exception of non-melanotic skin cancer or carcinoma-in-situ of any type. NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer. Any malignancy considered to be indolent and that has never required therapy may allowed at the discretion of the IND Sponsor
• Patient is unwilling or unable to follow the study schedule for any reason
• Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or other substance abuse (including alcohol) that could potentially interfere with adherence to study procedures or requirements
• Evidence of clinical or radiographic ascites. Trace or small amounts of radiographic ascites without prior concern for malignant ascites or not associated with peritoneal carcinomatosis may be approved by the Protocol Chair. NOTE: 3-dimensional (D) computed tomography (CT) scans and RECIST reads will not be used to determine eligibility at baseline