An open-label randomized trial of zanidatamab for advanced HER2positive biliary tract cancer

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• 1. Prior treatment with a HER2-targeted agent, with the exception of participants who completed HER2targeted treatment for breast cancer > 5 years prior to their diagnosis of BTC. 2. Prior treatment with checkpoint inhibitors, other than durvalumab or pembrolizumab as part of the up to 2 cycles of systemic therapy allowed prior to randomization per Inclusion Criterion 3. Exclusionary checkpoint inhibitors include but are not limited to other anti-PD-1, anti-PD-L1, anticytotoxic T lymphocyte-associated antigen (CTLA)-4 antibodies. 3. The following BTC histologic subtypes are excluded: small cell cancer, neuroendocrine tumors, lymphoma, sarcoma, mixed tumor histology, and mucinous cystic neoplasms detected in the biliary tract region. 4. Received radiotherapy within 2 weeks of randomization. 5. Had major surgery within 4 weeks of randomization. 6. Total lifetime load of anthracycline exceeding 360 mg/m2 doxorubicin or equivalent. 7. Use of systemic corticosteroids administered at doses equivalent to > 10 mg per day of prednisone within 2 weeks of randomization. Topical, ocular, intra-articular, intranasal, and/or inhalation corticosteroids are permitted. 8. Brain metastases: Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks of randomization. Stable, treated brain metastases are allowed (defined as participants who are off steroids and anticonvulsants and are neurologically stable with no evidence of radiographic progression for at least 4 weeks at the time of screening). 9. Known history of or ongoing leptomeningeal disease (LMD). Participants will be eligible if LMD has been reported radiographically but is not suspected clinically by the investigator, and the participant does not have neurological symptoms of LMD. 10. Poorly controlled seizures in the judgment of the investigator.
• 11. Grade 2 or greater peripheral neuropathy that is related to prior cancer therapy. 12. Concurrent uncontrolled or active hepatobiliary disorders or untreated or ongoing complications after laparoscopic procedures or stent placement, including but not limited to active cholangitis, unresolved biliary obstruction, infected biloma, or abscess. Any complications must be resolved at least 2 weeks prior to randomization. 13. Prior or concurrent invasive malignancy whose natural history or treatment has, in the opinion of the investigator or medical monitor, the potential to interfere with the safety or efficacy assessment of the investigational regimen. 14. Severe chronic or active infections requiring systemic parenteral antibacterial, antifungal or antiviral therapy; or any other potentially life-threatening viral or bacterial infection (participants on oral antibiotics must complete the planned course of treatment prior to randomization). 15. Active hepatitis, including the following: a. Acute or chronic hepatitis B (Exception: Participants who are hepatitis B surface antigen [HBsAg] positive are eligible if they have hepatitis B virus (HBV) DNA less than 500 IU/mL or 2,500 copies/mL). Note: Participants with detectable HBsAg or detectable HBV DNA should be managed per institutional or local standards. Participants beginning antiviral agents at screening should be treated for > 2 weeks prior to randomization. b. Infection with hepatitis C (Exceptions: [i] Participants who have no history of curative viral treatment and are documented to be viral load negative are eligible; [ii] Participants who have completed curative viral therapy ≥ 12 weeks or on concurrent hepatitis C virus treatment prior to expected date of C1D1, and viral load is negative are eligible.)
• 16. Infection with human immunodeficiency virus (HIV)-1 or HIV-2. (Exception: Participants with wellcontrolled HIV [ie, CD4 > 350/mm3 and undetectable viral load] are eligible.) 17. Active tuberculosis (TB). 18. History of allogeneic organ transplantation. 19. Active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) with the exception of: a. Vitiligo or alopecia b. Endocrine disorders stable on replacement therapy (thyroxine, insuline, etc) c. Chronic skin conditions that do not require systemic therapy d. Celiac disease controlled by diet alone e. Primary sclerosing cholangitis Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment of the autoimmune disease and is allowed. 20. History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in the drug formulation of any of the agents in the trial (cisplatin, gemcitabine, the selected PD1/L1 inhibitor, or zanidatamab). 21. Known hypersensitivity to any components of the combination therapy. 22. Ongoing, clinically significant toxicity (Grade 2 or higher) associated with prior cancer therapies, with the exception of alopecia. 23. Clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic congestive heart failure (CHF). Participants with known myocardial infarction or unstable angina within 6 months (180 days) prior to randomization are also excluded. Previous anticancer therapy-related CHF must have been ≤ Grade 1 at the time of occurrence and must have completely resolved. 24. History of interstitial lung disease or non-infectious pneumonitis. 25. History of active primary immunodeficiency. 26. Participation in another clinical trial with an investigational medicinal product within the last 3 months (90 days). 27. Acute or chronic uncontrolled pancreatitis or Child-Pugh Class C liver disease. 28. Females who are breastfeeding or pregnant, and females and males planning a pregnancy. 29. Any other medical, social, or psychosocial factors (eg, hearing impairment) that, in the opinion of the investigator, could impact safety or compliance with study procedures. 30. Use of prophylactic phenytoin.