Gemcitabine, Cisplatin, and Pembrolizumab before and after Surgery for the Treatment of Potentially Resectable Biliary Tract Cancer

Inclusion Criteria

• NEOADJUVANT ELIGIBILITY CRITERIA: Have a newly diagnosed, biopsy-proven biliary tract cancer (BTC) including gallbladder, intrahepatic, extrahepatic, and hilar cholangiocarcinoma
• NEOADJUVANT ELIGIBILITY CRITERIA: Resectable BTC (no extrahepatic spread or distant metastatic disease). Borderline resectable patients will not be excluded
• NEOADJUVANT ELIGIBILITY CRITERIA: Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the investigator
• NEOADJUVANT ELIGIBILITY CRITERIA: Age ≥ 18 years old on the day of consent
• NEOADJUVANT ELIGIBILITY CRITERIA: Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 or Karnofsky ≥ 80
• NEOADJUVANT ELIGIBILITY CRITERIA: Absolute neutrophil count ≥ 1,500/μL
• NEOADJUVANT ELIGIBILITY CRITERIA: Platelets ≥ 100,000/μL
• NEOADJUVANT ELIGIBILITY CRITERIA: Hemoglobin ≥ 9 g/dL. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• NEOADJUVANT ELIGIBILITY CRITERIA: Creatinine serum creatinine ≤ 1.5x upper limit of normal (ULN) OR creatinine clearance ≥ 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• NEOADJUVANT ELIGIBILITY CRITERIA: Lipase ≤ 1.5 x ULN and no radiologic or clinical evidence of pancreatitis
• NEOADJUVANT ELIGIBILITY CRITERIA: ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN
• NEOADJUVANT ELIGIBILITY CRITERIA: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases)
• NEOADJUVANT ELIGIBILITY CRITERIA: Serum albumin ≥ 2.8 g/dL
• NEOADJUVANT ELIGIBILITY CRITERIA: Prothrombin time (PT)/international normalized ratio (INR_ or partial thromboplastin time (PTT) test ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants
• NEOADJUVANT ELIGIBILITY CRITERIA: Participants with controlled hepatitis B are eligible for the study, as long as they meet the following criteria: * Participants with chronic hepatitis B virus (HBV) infection, defined as hepatitis B surface antigen (HBsAg) positive and/or detectable HBV DNA, must be given antiviral therapy for HBV for at least 4 weeks prior to the first dose of study intervention and HBV viral load must be less than 100 IU/mL prior to first dose of study intervention. Participants on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout study intervention. Antiviral therapy after completion of study intervention should follow local guidelines * Participants with clinically resolved HBV infection, defined as HBsAg negative and hepatitis B virus core antibody (anti-HBc) positive, and who have an undetectable HBV viral load at screening should be checked every 6 weeks for HBV viral load and treated for HBV if viral load is over 100 IU/mL. Antiviral therapy after completion of study intervention should follow local guidelines * Do not have a concurrent active hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and hepatitis C virus (defined as hepatitis C virus antibody [anti-HCV Ab] positive and detectable hepatitis C virus [HCV] ribonucleic acid [RNA]) infection
• NEOADJUVANT ELIGIBILITY CRITERIA: Participants with active hepatitis C infection on appropriate antiviral therapy are eligible for the study, except if they have a concurrent active Hepatitis B infection as defined * Note: There is not a defined maximum viral load requirement for study entry
• NEOADJUVANT ELIGIBILITY CRITERIA: Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test. Women with modestly elevated choriogonadotropin beta (bHCG) must obtain a negative transvaginal ultrasound in order to enroll on this protocol
• NEOADJUVANT ELIGIBILITY CRITERIA: A female participant is eligible to participate if she is not pregnant (contraceptive guidance), not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) as defined OR * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment
• NEOADJUVANT ELIGIBILITY CRITERIA: A male participant must agree to use a contraception as detailed during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
• NEOADJUVANT ELIGIBILITY CRITERIA: Ability to understand and the willingness to sign a written informed consent document
• ADJUVANT ELIGIBILITY CRITERIA: Patients must have had surgical resection of primary tumor * Note: Patients who have surgical margin positivity (R1/R2 resection) are eligible. Radiation therapy to address surgical margin positivity is allowed. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention
• ADJUVANT ELIGIBILITY CRITERIA: ECOG performance status 0-1
• ADJUVANT ELIGIBILITY CRITERIA: Absolute neutrophil count ≥ 1,500/μL
• ADJUVANT ELIGIBILITY CRITERIA: Platelets ≥ 100,000/μL
• ADJUVANT ELIGIBILITY CRITERIA: Hemoglobin ≥ 9 g/dL
• ADJUVANT ELIGIBILITY CRITERIA: Creatinine Serum creatinine ≤ 1.5x ULN OR creatinine clearance ≥ 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• ADJUVANT ELIGIBILITY CRITERIA: Total bilirubin ≤ 2 mg/dL. For subjects with known Gilbert’s disease, bilirubin ≤ 3.0 mg/dL
• ADJUVANT ELIGIBILITY CRITERIA: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.5 × ULN
• ADJUVANT ELIGIBILITY CRITERIA: Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test for the patient to be eligible for trial enrollment. Women with modestly elevated bHCG must obtain a negative transvaginal ultrasound in order to enroll on this protocol
• ADJUVANT ELIGIBILITY CRITERIA: A female participant is eligible to participate if she is not pregnant (contraceptive guidance), not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) as defined OR * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment
• ADJUVANT ELIGIBILITY CRITERIA: A male participant must agree to use a contraception as detailed during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
• ADJUVANT ELIGIBILITY CRITERIA: Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• NEOADJUVANT EXCLUSION CRITERIA: Receiving, or previously received, any systemic chemotherapy, or investigational agent for BTC * Note: Prior surgical resection and perioperative chemotherapy would not exclude trial participation but must have been performed at least 3 years prior to enrollment and there must be an area of viable recurrent tumor on scans
• NEOADJUVANT EXCLUSION CRITERIA: Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
• NEOADJUVANT EXCLUSION CRITERIA: Patients with a history of prior treatment with anti-programmed cell death protein 1 (PD-1) and anti-PD-L1
• NEOADJUVANT EXCLUSION CRITERIA: Have been diagnosed with another cancer or myeloproliferative disorder whose natural history or treatment has the potential to interfere with safety or efficacy assessment of this study’s investigational drugs. The following are examples of exceptions but not a comprehensive list: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤ 6, and prostate specific antigen [PSA] < 10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded
• NEOADJUVANT EXCLUSION CRITERIA: HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease * Note: No HIV testing is required * NOTE: For inclusion on study, HIV-infected participants without history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease can be enrolled in the study if they have well-controlled HIV on antiretroviral therapy (ART), defined as: ** Participants on ART must have a CD4+ T-cell count ≥ 350 cells/mm^3 at the time of screening ** Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the lower limit of quantification (LLOQ) (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening ** It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months ** Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (day 1) and agree to continue ART throughout the study * Participants should be comanaged by a HIV specialist and the investigator during the study, including monitoring of HIV viral load, CD4+ T-cell count, and additional supportive care measures
• NEOADJUVANT EXCLUSION CRITERIA: Has active co-infection with HBV and hepatitis D virus (HDV)
• NEOADJUVANT EXCLUSION CRITERIA: Has a diagnosis of immunodeficiency
• NEOADJUVANT EXCLUSION CRITERIA: 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
• NEOADJUVANT EXCLUSION CRITERIA: Systemic or topical corticosteroids at immunosuppressive doses (> 10 mg/day of prednisone or equivalent). Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• NEOADJUVANT EXCLUSION CRITERIA: Prior tissue or organ allograft or allogeneic bone marrow transplantation, including corneal transplants. Exceptions can be approved by the principal investigator (PI) if loss of the graft is not a clinical concern
• NEOADJUVANT EXCLUSION CRITERIA: Uncontrolled intercurrent active medical and/or psychiatric illness/social psychosocial problems that that would limit compliance with study requirements
• NEOADJUVANT EXCLUSION CRITERIA: Uncontrolled or significant cardiovascular disease (i.e. cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion), including, but not limited to any of the following: * Myocardial infarction (MI) or stroke/transient ischemic attack within the 6 months prior to consent * Uncontrolled angina within the 3 months prior to consent * Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) * Corrected QT interval (QTc) prolongation > 480 msec * Cardiovascular disease-related requirement for daily supplemental oxygen * History of two or more MIs OR two or more coronary revascularization procedures
• NEOADJUVANT EXCLUSION CRITERIA: Evidence of clinical ascites. Trace or small amounts of radiographic ascites may be approved by the protocol chair
• NEOADJUVANT EXCLUSION CRITERIA: Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• NEOADJUVANT EXCLUSION CRITERIA: Previously identified allergy or hypersensitivity to monoclonal antibodies or any component of the study treatment formulations
• NEOADJUVANT EXCLUSION CRITERIA: Pregnant or lactating females
• NEOADJUVANT EXCLUSION CRITERIA: WOCBP and men with female partners (WOCBP) who are not willing to use contraception
• NEOADJUVANT EXCLUSION CRITERIA: Subjects unable to undergo venipuncture and/or tolerate venous access
• NEOADJUVANT EXCLUSION CRITERIA: Patient is at the time of signing informed consent a regular user (including “recreational use”) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol)
• ADJUVANT EXCLUSION CRITERIA: More than 90 days have elapsed since surgery
• ADJUVANT EXCLUSION CRITERIA: Patient was found to have unresectable or metastatic disease intraoperatively
• ADJUVANT EXCLUSION CRITERIA: Patients who develop local recurrence or disease progression at any point in the study
• ADJUVANT EXCLUSION CRITERIA: The patient has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of adjuvant study drug
• ADJUVANT EXCLUSION CRITERIA: 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
• ADJUVANT EXCLUSION CRITERIA: Previously identified allergy or hypersensitivity to monoclonal antibodies or any component of the study treatment formulations