Pembrolizumab and Sargramostim in Treating Patients with Advanced Bile Duct Cancer

Inclusion Criteria

• Histologically- or cytologically-diagnosed advanced or locally-advanced biliary cancer not eligible for resection or other curative therapies, including: * Intrahepatic (peripheral) cholangiocarcinoma; * Extrahepatic cholangiocarcinoma including hilar/perihilar (Klatskin), middle, and distal locations; * Gallbladder carcinoma (GBC); * Mixed/combined hepatocellular-cholangiocarcinoma; * Ampullary carcinoma and pancreas ductal adenocarcinoma are NOT eligible.
• Clinical and/or radiographic progression on >= 1 prior systemic treatment regimen with cytotoxic chemotherapy, targeted therapy, and/or investigational therapy for advanced biliary cancer. Cumulative toxicity or intolerability (such as progressive cytopenias, neuropathy, or asthenia on a 1st line regimen of gemcitabine plus cisplatin) requiring treatment discontinuation of >= 1 prior systemic treatment regimen is also sufficient for eligibility. There is no maximum eligible prior number of lines of therapy provided all eligibility criteria are met. Adjuvant chemotherapy including gemcitabine and/or fluoropyrimidine after prior surgical resection of cholangiocarcinoma cholangiocarcinoma (CCA) or GBC will be considered as 1 line of prior therapy if relapse/recurrence with incurable disease occurred within =< 6 months of last dose.
• Be willing and able to provide written informed consent for the trial
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Absolute neutrophil count (ANC) >= 1,000/mcL (performed within 28 days of treatment initiation)
• Platelets >= 60,000/mcL (>= 75,000/mcL in expansion cohort) (performed within 28 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 28 days of treatment initiation)
• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (performed within 28 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 28 days of treatment initiation)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X ULN (performed within 28 days of treatment initiation)
• Albumin >= 2.5 mg/dL (performed within 28 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 prothrombin time (PT) or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 28 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 28 days of treatment initiation)
• Patients with known hepatitis B or C virus (hepatitis B virus [HBV] or hepatitis C virus [HCV]) infection are eligible provided liver function parameters meet laboratory eligibility criteria * Patients with active HBV infection must have monitoring of viral load and demonstrate adequate treatment with appropriate antiviral therapy according to institutional practice * Patients with active HCV infection must have monitoring of liver function tests and viral load if indicated according to institutional practice
• 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 should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
• ADDITIONAL EXPANSION COHORT SUBJECT INCLUSION CRITERIA
• Presence of >= 1 target lesion measurable by RECIST 1.1 not planned for biopsy.
• Presence of >= 1 tumor lesion accessible for paired on-treatment minimally-invasive percutaneous biopsies (computed tomography [CT], ultrasound or punch), as assessed by investigator and/or radiologist; this lesion may be included as a target or non-target lesion for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Platelet count >= 75,000/mcL
• No contraindication to tumor biopsy at time of study enrollment
• Consent for on-treatment paired biopsies

Exclusion Criteria

• Is currently participating and receiving study therapy or has participated and received study therapy in a study of an investigational agent, or used an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy for purposes of immunosuppression 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)
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has untreated active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive)
• Has an active infection requiring systemic antibiotic therapy at time of enrollment * Treatment with antibiotic prophylaxis for indwelling biliary stent(s) or peri-procedural antibiotics for uncomplicated biliary stent exchanges is allowed and not an exclusion
• Hypersensitivity to pembrolizumab or any of its excipients
• Has received treatment with an anticancer 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 received treatment with chemotherapy, targeted small molecule therapy, or radiation therapy to non-liver sites 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 administered more than 2 weeks earlier * Subjects with =< grade 2 neuropathy or alopecia are an exception to this criterion and may qualify for the study * If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Has had prior chemoembolization, bland embolization, radioembolization, local ablative therapies, radiation to liver tumors, or major surgery such as liver resection within 4 weeks prior to study enrollment or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to intervention more than 4 weeks earlier
• 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 known history of or any evidence of active, noninfectious pneumonitis
• Has had prior organ or stem cell transplantation
• 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 prescreening or screening visit through 120 days after the last dose of trial treatment
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent * This criterion does not apply to eligibility for second course treatment
• Has received a live vaccine within 30 days of planned start of study therapy * Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines, and are not allowed