First-line Trastuzumab, Gemcitabine, Cisplatin and Nivolumab in Advanced HER2- Positive Biliary Tract Cancer: a Multicenter, Open-label, Single-arm Phase Ib/II Trial (HERBOT)

Exclusion Criteria

• •1. Patients treated with systemic chemotherapy, biologic therapy, immunotherapy, hormone therapy, or clinical trials for unresectable, locally advanced or metastatic biliary tract cancer. However, the following are excluded.
• •1. If disease recurrence occurs 6 months after the last dose of adjuvant chemotherapy, previous adjuvant chemotherapy is permitted.
• •2. 1 cycle of Gemcitabine-based anticancer therapy for locally advanced or metastatic cholangiocarcinoma prior to enrollment in this trial is permitted.
• •2. Patients with multiple primary cancers (with the exception of completely resected basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, or superficial bladder cancer, or any other cancer that has not recurred for at least 5 years)
• •3. Patients with residual adverse effects of prior therapy or effects of surgery that would affect the safety evaluation of the investigational product in the opinion of the investigator or sub-investigator.
• •4. Patients with current or past history of severe hypersensitivity to any other antibody products
• •5. Patients with concurrent autoimmune disease or history of chronic or recurrent autoimmune disease
• •6. Patients with a current or past history of interstitial lung disease or pulmonary fibrosis diagnosed based on imaging or clinical findings. Patients with radiation pneumonitis may be enrolled if the radiation pneumonitis has been confirmed as stable (beyond acute phase) without any concerns about recurrence.
• •7. Patients with concurrent diverticulitis or symptomatic gastrointestinal ulcerative disease
• •8. Patients with any metastasis in the brain or meninx that is symptomatic or requires treatment. Patients may be enrolled if the metastasis is asymptomatic and requires no treatment.
• •9. Patients with pericardial fluid, pleural effusion, or ascites requiring treatment
• •10. Patients with uncontrollable, tumor-related pain
• •11. Patients who have experienced a transient ischemic attack or cerebrovascular accident within 180 days before enrollment
• •12. Patients with a history of uncontrollable or significant cardiovascular disease meeting any of the following criteria:
• •1. Myocardial infarction within 180 days before enrollment
• •2. Uncontrollable angina pectoris within 180 days before enrollment
• •3. New York Heart Association (NYHA) Class III or IV congestive heart failure
• •4. Uncontrollable hypertension despite appropriate treatment (e.g., systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥ 90 mmHg lasting 24 hours or more)
• •5. Arrhythmia requiring treatment
• •13. Patients with uncontrollable diabetes mellitus
• •14. Patients with systemic infections requiring treatment (infection controlled by oral antibiotics is permitted)
• •15. Patients who have received systemic corticosteroids (prednisolone or equivalent \> 10mg/day) (except for temporary use, e.g., for examination or prophylaxis of allergic reactions) or immunosuppressants within 28 days before enrollment
• •16. Patients who have received antineoplastic drugs (e.g., chemotherapy agents, molecular-targeted therapy agents, or immunotherapy agents) within 28 days before enrollment
• •17. Patients who have undergone surgical adhesion of the pleura or pericardium within 28 days before enrollment
• •18. Patients who have undergone surgery under general anesthesia within 28 days before enrollment
• •19. Patients who have undergone surgery involving local or topical anesthesia within 14 days before enrollment
• •20. Patients who have received radiotherapy within 28 days before enrollment, or radiotherapy to bone metastases within 14 days before enrollment
• •21. Patients who have received any radiopharmaceuticals (except for examination or diagnostic use of radiopharmaceuticals) within 56 days before enrollment
• •22. Patients with a positive test result for any of the following: HIV-1 antibody, HIV-2 antibody, HTLV-1 antibody, HBs antigen, or HCV antibody
• •23. Patients with active hepatitis B or C virus (Hepatitis patients can enrolled if HBV DNA and HCV RNA are controlled to less than 500 and are receiving stable antiviral treatment.)
• •24. Women who are pregnant or breastfeeding, or possibly pregnant
• •25. Patients who have received any other unapproved drug (e.g., investigational use of drugs, unapproved combined formulations, or unapproved dosage forms) within 28 days before enrollment
• •26. Patients who have previously received Nivolumab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody, anti-CTLA-4 antibody or other therapeutic antibodies or pharmacotherapies for regulation of T-cells
• •27. Patients judged to be incapable of providing consent for reasons such as concurrent dementia
• •28. Other patients judged by the investigator or sub-investigator to be inappropriate as subjects of this study
• •29. Patient with current or past history of hypersensitivity to Nivolumab.