Biliary tract cancer is a rare malignant neoplasm including intrahepatic cholangiocarcinoma (IhCCA), extrahepatic cholangiocarcinoma (EhCCA) and Gallbladder cancer (GBC). Survival outcome of advanced BTCs are still poor and heterogeneity of tissue and molecular differences between BTCs limit the clinical studies in BTCs.

Combination therapy of Gemcitabine and Cisplatin has become the standard of care after the ABC-02 trial. This trial demonstrated that the addition of cisplatin to gemcitabine improved survival outcomes compared to that with gemcitabine alone. However, the median overall survival (OS) of Gem/Cis chemotherapy is only about one year.

Anti-Program cell death-1 (anti-PD-1) inhibitor monotherapy including Nivolumab (OPDIVO) had shown efficacy in refractory, advanced BTC. Various ICIs combined with Gem/Cis as the 1st line treatment in BTCs are under the trials. Combination of Nivolumab and Gem/Cis showed improved overall survival (15.4 months) in a small sized study (n=30) with tolerable side effects in advanced BTC patients. Recently reported interim analysis of phase III TOPAZ-1 trial (NCT03875235) showed Durvalumab, anti-PD-L1 agent, combined with Gem/Cis showed improvement of overall survival. Considering other studies currently ongoing, ICIs combined with Gem/Cis are thought to be the future standard of care in 1st line treatment of advanced stage BTCs.

HER2 amplification/overexpression is presented as many as 15% of total BTC patients. Basket trial of administration of pertuzumab and trastuzumab combination in previously treated HER2 positive advanced BTC patients showed promising overall response rate of 23%. Also, multicenter phase II study conducted by Korean investigators (KCSG-HB19-14) showed promising effect of Trastuzumab combined with modified FOLFOX in Gem/Cis refractory HER2 positive BTC patients with ORR of 29.4%. Moreover, preclinical data showed synergistic anti-cancer effect of trastuzumab combined with ICIs in HER2 positive cancers. Similar data are reported in HER2 positive gastric cancer that phase II and phase III clinical data showed 1st-line ICIs combined with trastuzumab and cytotoxic chemotherapy showed promising overall survival outcomes.

In treating HER2-positive advanced BTC, the triple combination of nivolumab, trastuzumab, and cytotoxic chemotherapy (Gem/Cis) may overcome innate resistance and activate an immune response to cancer along with inhibiting oncogenic signal from HER2 pathway, resulting in a synergistic effect with a longer response.

This phase Ib/II study is designed to see whether trastuzumab+nivolumab+gemcitabine+cisplatin is active as palliative 1st line treatment for HER2-positive biliary tract cancer patients.

Inclusion Criteria:

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

2. HER2 positive biliary tract cancer (IHC 3+ or 2+ with ISH + (HER2/CEP17≥2.0) or ERBB2 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 recurrent disease >6 months after curative surgery or adjuvant therapy (allow up to 1 cycle of gemcitabine-based chemotherapy for advanced/unresectable or metastatic cholangiocarcinoma prior to enrollment)

5. Explicit and voluntary consent to participate in the study obtained using a signed and dated informed consent form clearly and fully describing the purpose, potential risks, 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 before enrollment.

   White blood cells ≥2,000/mm3 and neutrophils ≥1,500/mm3 Platelets ≥100,000/mm3 Hemoglobin ≥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 with liver 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 or estimated value using the Cockcroft-Gault equation) >45 mL/min INR ≤1.5-fold or prothrombin time ≤1.5-fold the ULN of the study site aPTT ≤1.5-fold the ULN of the study site

10. Women of childbearing potential (including women with chemical menopause or no menstruation for other medical reasons) #1 must agree to use contraception#2 from the time of informed consent until 5 months or more after the last dose of the investigational product. Also, women must agree not to breastfeed from the time of informed consent until 5 months or more after the last dose of the investigational product.

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

    • 1. Women of childbearing potential are defined as all women after the onset of menstruation who are not postmenopausal and have not been surgically sterilized (e.g., hysterectomy, bilateral tubal ligation, bilateral oophorectomy). Postmenopause is defined as amenorrhea for ≥12 consecutive months without specific reasons. Women using oral contraceptives, intrauterine devices, or mechanical contraception such as contraceptive barriers are regarded as having childbearing potential.
    • 2. The subject must consent to use any of the following methods of contraception: vasectomy or condom for patients who are male or female subject's partner and tubal ligation, contraceptive diaphragm, intrauterine device, spermicide, or oral contraceptive for patients who are female or male subject's partner.

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

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

14. 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 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.