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)

Inclusion Criteria:

1. Subjects with histologically- or cytologically-confirmed biliary tract cancer (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, andgall bladder cancer)

2. HER2 positive biliary tract cancer (IHC 3+ or 2+ with ISH + (HER2/CEP17≥2.0) orERBB2 gene copy number ≥ 6.0 by NGS)

3. Age (at the time of informed consent): 20 years and older

4. Previously untreated if unresectable/metastatic at initial diagnosis; or recurrentdisease >6 months after curative surgery or adjuvant therapy (allow up to 1 cycle ofgemcitabine-based chemotherapy for advanced/unresectable or metastaticcholangiocarcinoma prior to enrollment)

5. Explicit and voluntary consent to participate in the study obtained using a signedand dated informed consent form clearly and fully describing the purpose, potentialrisks, and any other critical issues regarding the study

6. Subject with measurable lesions according to RECIST v. 1.1

7. ECOG Performance Status Score 0 or 1

8. Patients with a life expectancy of at least 3 months

9. Patients whose latest laboratory data meet the below criteria within 14 days beforeenrollment. White blood cells ≥2,000/mm3 and neutrophils ≥1,500/mm3 Platelets ≥100,000/mm3Hemoglobin ≥9.0 g/dL AST (GOT) and ALT (GPT) ≤3.0-fold the upper limit of normal (ULN) of the study site (or ≤5.0-fold the ULN of the study site in patients withliver metastases) Total bilirubin ≤1.5-fold the ULN of the study site Creatinine ≤1.5-fold the ULN of the study site or creatinine clearance (either the measured orestimated value using the Cockcroft-Gault equation) >45 mL/min INR ≤1.5-fold orprothrombin time ≤1.5-fold the ULN of the study site aPTT ≤1.5-fold the ULN of thestudy site

10. Women of childbearing potential (including women with chemical menopause or nomenstruation for other medical reasons) #1 must agree to use contraception#2 fromthe time of informed consent until 5 months or more after the last dose of theinvestigational product. Also, women must agree not to breastfeed from the time ofinformed consent until 5 months or more after the last dose of the investigationalproduct.

11. Men must agree to use contraception#2 from the start of study treatment until 7months or more after the last dose of the investigational product.

1. Women of childbearing potential are defined as all women after the onsetof menstruation who are not postmenopausal and have not been surgicallysterilized (e.g., hysterectomy, bilateral tubal ligation, bilateraloophorectomy). Postmenopause is defined as amenorrhea for ≥12 consecutivemonths without specific reasons. Women using oral contraceptives,intrauterine devices, or mechanical contraception such as contraceptivebarriers are regarded as having childbearing potential.

2. The subject must consent to use any of the following methods ofcontraception: vasectomy or condom for patients who are male or femalesubject's partner and tubal ligation, contraceptive diaphragm,intrauterine device, spermicide, or oral contraceptive for patients whoare female or male subject's partner.

3. EF ≥ 50% via Transthoracic echocardiography or MUGA scan

4. Subjects willing to provide tumor biopsy tissue or excisional biopsy tissue.

5. Subjects with adequate organ function

Exclusion Criteria:

1. Patients treated with systemic chemotherapy, biologic therapy, immunotherapy,hormone therapy, or clinical trials for unresectable, locally advanced or metastaticbiliary tract cancer. However, the following are excluded.

2. If disease recurrence occurs 6 months after the last dose of adjuvantchemotherapy, previous adjuvant chemotherapy is permitted.

3. 1 cycle of Gemcitabine-based anticancer therapy for locally advanced ormetastatic cholangiocarcinoma prior to enrollment in this trial is permitted.

4. Patients with multiple primary cancers (with the exception of completely resectedbasal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ,intramucosal carcinoma, or superficial bladder cancer, or any other cancer that hasnot recurred for at least 5 years)

5. Patients with residual adverse effects of prior therapy or effects of surgery thatwould affect the safety evaluation of the investigational product in the opinion ofthe investigator or sub-investigator.

6. Patients with current or past history of severe hypersensitivity to any otherantibody products

7. Patients with concurrent autoimmune disease or history of chronic or recurrentautoimmune disease

8. Patients with a current or past history of interstitial lung disease or pulmonaryfibrosis diagnosed based on imaging or clinical findings. Patients with radiationpneumonitis may be enrolled if the radiation pneumonitis has been confirmed asstable (beyond acute phase) without any concerns about recurrence.

9. Patients with concurrent diverticulitis or symptomatic gastrointestinal ulcerativedisease

10. Patients with any metastasis in the brain or meninx that is symptomatic or requirestreatment. Patients may be enrolled if the metastasis is asymptomatic and requiresno treatment.

11. Patients with pericardial fluid, pleural effusion, or ascites requiring treatment

12. Patients with uncontrollable, tumor-related pain

13. Patients who have experienced a transient ischemic attack or cerebrovascularaccident within 180 days before enrollment

14. Patients with a history of uncontrollable or significant cardiovascular diseasemeeting any of the following criteria:

15. Myocardial infarction within 180 days before enrollment

16. Uncontrollable angina pectoris within 180 days before enrollment

17. New York Heart Association (NYHA) Class III or IV congestive heart failure

18. Uncontrollable hypertension despite appropriate treatment (e.g., systolic bloodpressure ≥150 mmHg or diastolic blood pressure ≥ 90 mmHg lasting 24 hours ormore)

19. Arrhythmia requiring treatment

20. Patients with uncontrollable diabetes mellitus

21. Patients with systemic infections requiring treatment (infection controlled by oralantibiotics is permitted)

22. Patients who have received systemic corticosteroids (prednisolone or equivalent > 10mg/day) (except for temporary use, e.g., for examination or prophylaxis ofallergic reactions) or immunosuppressants within 28 days before enrollment

23. Patients who have received antineoplastic drugs (e.g., chemotherapy agents,molecular-targeted therapy agents, or immunotherapy agents) within 28 days beforeenrollment

24. Patients who have undergone surgical adhesion of the pleura or pericardium within 28days before enrollment

25. Patients who have undergone surgery under general anesthesia within 28 days beforeenrollment

26. Patients who have undergone surgery involving local or topical anesthesia within 14days before enrollment

27. Patients who have received radiotherapy within 28 days before enrollment, orradiotherapy to bone metastases within 14 days before enrollment

28. Patients who have received any radiopharmaceuticals (except for examination ordiagnostic use of radiopharmaceuticals) within 56 days before enrollment

29. Patients with a positive test result for any of the following: HIV-1 antibody, HIV-2antibody, HTLV-1 antibody, HBs antigen, or HCV antibody

30. Patients with active hepatitis B or C virus (Hepatitis patients can enrolled if HBVDNA and HCV RNA are controlled to less than 500 and are receiving stable antiviraltreatment.)

31. Women who are pregnant or breastfeeding, or possibly pregnant

32. Patients who have received any other unapproved drug (e.g., investigational use ofdrugs, unapproved combined formulations, or unapproved dosage forms) within 28 daysbefore enrollment

33. Patients who have previously received Nivolumab, anti-PD-1 antibody, anti-PD-L1antibody, anti-PD-L2 antibody, anti-CD137 antibody, anti-CTLA-4 antibody or othertherapeutic antibodies or pharmacotherapies for regulation of T-cells

34. Patients judged to be incapable of providing consent for reasons such as concurrentdementia

35. Other patients judged by the investigator or sub-investigator to be inappropriate assubjects of this study

36. Patient with current or past history of hypersensitivity to Nivolumab.