Ultrasound-Based Treatment (Histotripsy) with Chemoimmunotherapy for the Treatment of Locally Advanced or Metastatic Biliary Tract Cancer

Inclusion Criteria

• Age >/= 18 at time of screening
• Willing and able to provide informed consent for the trial
• Histologically or cytologically confirmed biliary tract cancer (BTC) including cancers of the intrahepatic bile ducts, extrahepatic bile ducts, and gallbladder
• Locally advanced or metastatic disease not eligible for resection or transplant
• Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 measurable disease
• No prior systemic therapy for the treatment of locally advanced/metastatic disease * Recurrent disease after surgical resection must have occurred ≥ 6 months from completion of adjuvant therapy
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count ≥ 1.5 x 10^9/L
• Platelet count ≥ 100 x 10^9/L
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN)
• Creatinine within normal limits OR measured creatinine clearance (CL) > 50 mL/min OR calculated creatinine clearance (CL) > 50 mL/min as determined by Cockcroft-Gault
• Willing and able to undergo general anesthesia and histotripsy procedure
• A tumor(s) for histotripsy treatment ≤ 3 cm in longest diameter * Note: a maximum of three (3) tumors are allowed to be treated with histotripsy during the index procedure, regardless of how many tumors the subject has
• Subject has an adequate acoustic window to visualize targeted tumor(s) using ultrasound imaging
• COHORT 1: Bilirubin ≤ 1.5 x upper limit of normal (ULN) * Note: patients with Gilbert’s Syndrome may be allowed in consultation with the treating physician and the study principal investigator (PI)
• COHORT 2: Bilirubin > 1.5x ULN due to BTC-related biliary tract obstruction after at least 1 attempt at percutaneous/endoscopic stenting
• COHORT 2: With the exception of hyperbilirubinemia, no contraindication to chemoimmunotherapy

Exclusion Criteria

• Prior exposure to immune-mediated therapy, including, but not limited to, anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-PD-L2 antibodies
• History of allogeneic or solid organ transplant
• Active or prior documented autoimmune disorders. The following are exceptions to this criterion: * Patients with vitiligo or alopecia * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Patients with celiac disease controlled by diet alone * Patients without active disease in the last 5 years may be included but only after consultation with the study PI
• Uncontrolled intercurrent illness, including, but not limited to: * Ongoing or active infection including but not limited to the below. Patients on prophylactic antibiotics may be eligible after discussion with the study PI ** Tuberculosis (tuberculosis testing by local institutional practice is required prior to receipt of chemoimmunotherapy) ** Hepatitis B (HBV) defined as presence of hepatitis B surface antigen (HBsAg) and/or anti-hepatitis B virus core antibody (HBcAb) with detectable hepatitis B virus (HBV) deoxyribonucleic acid (DNA) ≥ 10 IU/mL (testing is required prior to receipt of chemoimmunotherapy) *** Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and the absence of HBsAg) are eligible. ** Hepatitis C (HCV) defined as positive HCV antibody (testing is required prior to receipt of chemoimmunotherapy) *** Patients positive for hepatitis C (HCV) antibody are eligible only if the polymerase chain reaction is negative for HCV ribonucleic acid (RNA) ** Uncontrolled HIV/AIDS. Testing for HIV 1/2 antibodies is required prior to receipt of chemoimmunotherapy. Patients with known HIV are allowed on study provided they have: *** A stable regimen of highly active anti-retroviral therapy (HAART) *** No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infection *** A CD4 count > 250 cells/mcL *** An undetectable HIV viral load on standard polymerase chain reaction (PCR)-based testing
• Symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, myocardial infarction (MI)/transient ischemic attack (TIA)/cerebrovascular accident (CVA) within 3 months prior to study enrollment, uncontrolled cardiac arrhythmia
• Active interstitial lung disease (ILD) or history of immune-mediated pneumonitis
• Active primary immunodeficiency
• Psychiatric illness/social situations that would limit compliance with study requirement, substantially increase the risk of incurring adverse events (AEs), or compromise the ability of the patient to give written informed consent
• Other co-morbid disease or condition that would cause undue risk and/or interfere with the conduct or interpretation of the trial in the opinion of the treating investigator
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessments of the investigational regimen. Patients whose prior or concurrent malignancy natural history and/or treatment does NOT have the potential to impact safety or study assessments are eligible
• Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Grade ≥ 2 from a previous anticancer therapy, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment may be included after consultation with the study PI
• Histotripsy-related criteria: * Targeted tumor(s) treatment volume overlaps a non-targeted tumor visible via imaging * Targeted tumor(s) is not clearly visible with diagnostic ultrasound and computed tomography (CT) or magnetic resonance (MR) imaging * Targeted tumor(s) is located in liver segment 1 * The Planned Treatment Volume intended to cover the targeted tumor includes or encompasses any portion of the main portal vein, common hepatic duct, common bile duct, gallbladder or stomach/bowel
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
• Subject is pregnant or planning to become pregnant or nursing (lactating)
• Subjects of reproductive potential who are not willing to use effective birth control from screening to 180 days after the last dose of GCD/P or 90 days after last dose of D/P monotherapy
• Subject is enrolled in another investigational trial and/or is taking investigational medication and/or has been treated with an investigational device </= 30 days prior to planned procedure date