Cholangiocarcinoma is reported to have a higher incidence in Asian races than Westerners. The prognosis of cholangiocarcinoma has not been improved much since; 1)a lack of understanding of the molecular pathogenesis and 2)the cause of the early screening method have not been established. The median survival of recurrent cholangiocarcinoma is very poor, about 12 months. The primary chemotherapy for cholangiocarcinoma is Gemcitabine/Cisplatin, which is the standard treatment based on the results of the 2010 clinical trials of ABC, but 8 months of progression free survival and 11.7 months of overall survival. And there is no further development of chemotherapy that further improves survival. In addition, a second-line treatment such as 5-FU or capecitabine has been tried, but there are no treatments that have been proven to improve survival. However, a recent NGS study found druggable gene alterations in about 50% of patients with cholangiocarcinoma, and some cholangiocarcinomas responded to anti-PD-1/PD-L1 immune checkpoint inhibitors. To sum up, cholangiocarcinoma is a carcinoma that is absolutely lacking in treatment compared to high incidence and mortality, and recently, as early and early clinical results have been announced, it is becoming an important cancer type in clinical trials where new target and anticancer drugs are currently being tested. In addition, Korea has a much higher incidence of bile duct cancer than Western countries, and is considered an area that can lead bile duct cancer research and clinical trials. HER2(ERBB2) is a representative oncogenic receptor tyrosine kinase, and overexpression/gene amplification has been reported in breast cancer(20-30%), gastric cancer(10-20%), and colon cancer, and monoclonal antibodies such as trastuzumab and pertuzumab and lapantinib are targeted. The same small-molecule inhibitor is known to be effective. In particular, overexpression of HER2 was found in 10-20% of patients with cholangiocarcinoma, and also genetic alterations such as TP53, NOTCH1, KRAS, KMT2C, BAP1, and ERBB2 alterations were found in the patients with cholangiocarcinoma from Yonsei Cancer Center. Especially, amplification of HER2(ERBB2) was much found in patients(12.9%, 7/54). Importantly, previous retrospective studies have reported high rates of response to HER2-targeted monoclonal antibodies(trastuzumab, pertuzumab) alone or in combination with anticancer drugs in patients with HER2-positive cholangiocarcinoma. However, prospective clinical studies of HER2-targeted antibodies against HER2 overexpression/amplified cholangiocarcinoma have been very limited, and their clinical effects have not been prospectively proven. In a subgroup analysis of the MyPathway study, trastuzumab + pertuzumab has been reported to be effective in HER2-amplified cholangiocarcinoma. (Response rate 37.5%) Four patients were enrolled in the trastuzumab monotherapy conducted by NCI, and two of them reported a response. (NCT00478140) However, to date, no clinical trials have been conducted with significant levels of patients who can be analyzed, and the results of the combined treatment of HER2 antibodies with cytotoxic anticancer agents have not been reported prospectively. According to this background, we will conduct a multicenter phase II trial to investigate the clinical efficacy and safety of combined systemic chemotherapy of FOLFOX and trastuzumab-pkrb(Herzuma) for HER2 positive cholangiocarcinoma patients. Trastuzumab-pkrb(Herzuma) is a biosimilar anticancer agent that has been shown to have the same anti-tumor effect and systemic toxicity as trastuzumab in HER2-positive breast cancer. The treatment of trastuzumab 4mg/kg every two weeks used in this study reported the same low cardiotoxicity as the three-week regimen. In addition, FOLFOX chemotherapy showed a 15-20% response rate in patients with cholangiocarcinoma who failed primary gemcitabine+cisplatin anticancer drugs in a prospective phase2 clinical trial.

Treatment

Herzuma : 6mg/kg (1st), 4mg/kg (from 2nd) every 2 week, IV infusion on Day 1
Oxaliplatin : 85 mg/m2, every 2 week, Days 1-14, per oral
5-FU : 400mg/m2, every 2 week, IV on Day 1
5-FU : 2400mg/m2, every 2 week, IV infusion on Day 1-2, for 46 hrs
Leucovorin : 400mg/m2, every 2 week, IV on Day 1

Arm Label

Target Number of Participant

Arm Type

Arm Description

Herzuma : 6mg/kg (1st), 4mg/kg (from 2nd) every 2 week, IV infusion on Day 1
Oxaliplatin : 85 mg/m2, every 2 week, Days 1-14, per oral
5-FU : 400mg/m2, every 2 week, IV on Day 1
5-FU : 2400mg/m2, every 2 week, IV infusion on Day 1-2, for 46 hrs
Leucovorin : 400mg/m2, every 2 week, IV on Day 1

Gender

Age

Description

1. Patients with reccurent, metastatic or unresectable biliary tract cancer who are diagnosed by histological examination. (include intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, Ampula of vater cancer)
2. HER2-positive cholangiocarcinoma confirmed by histological examination. HER2 positive is defined as 3+ or 2+ immunohistochemical staining and positive for HER2 gene amplification on in situ hybridization (ISH), or ERBB2 gene amplification (≥6 copies) on tumor tissue NGS.
3. Patients who have received at least one systemic chemotherapy including gemcitabine + cisplatin for recurrent / metastatic / unresectable cholangiocarcinoma, and subsequently progressed radiologically. The number of previous chemotherapy for recurrent / metastatic / unresectable cholangiocarcinoma should be no more than two, and immunotherapy monotherapy (e.g., anti-PD-1 or anti-PD-L1 immune chemotherapy) is not counted as previous chemotherapy. 
4. Patients who are willing and able to complete a written informed consent form for this study.
5. Patients 19 years of age or older at the time of signing the informed consent form.
6. Patients with measurable lesions according to RECIST 1.1.
7. ECOG performance score 0 or 1.
8. Patients exhibiting proper organ function.
Bone marrow function
 Hemoglobin level: ≥ 9.0 g / dl
 absolute neutrophil count: ≥ 1,500 / µl
 Platelet count: ≥ 10 × 10⁴/ µl
-Kidney function
Creatinine: ≤ 1.5 x upper limit of normal (UNL) or
 Creatinine clearance (Ccr) ≥ 50 ml / min by Cockroft formula
-Liver function
 Total Bilirubin: ≤ 2.0 × UNL
AST / ALT: ≤ 2.5 × UNL (for patients with liver metastasis: ≤ 5.0 × UNL)
 PT / aPTT
≤1.5 X ULN, unless the patient is receiving anticoagulant therapy and PT or PTT is within the therapeutic range of intended anticoagulant use.
9. Patients with 50% or more of LVEF and no severe valve or arrhythmia
10. Women of childbearing potential must have a negative pregnancy or urine test in the urinalysis or serology.
• A female patient of childbearing potential who has a negative urine or serum pregnancy test within 72 hours prior to the first dose of study drug. If the results of a urine test are not positive or negative, a serum pregnancy test should be performed.
• Women of childbearing potential must agree to use two appropriate contraceptive methods, surgical infertility, or stop intersexual sex during clinical trials and until 120 days after the last dose of study drug. A woman of childbearing potential refers to a woman who is not surgically infertile or who has not had menstruation for more than one year.
• Male patients should agree to continue using the appropriate contraceptive method from the first dose of the study to 120 days after the last dose.

1. Patients previously treated with chemotherapy including oxaliplatin or monoclonal antibodies or small molecule inhibitors (trastuzumab, neratinib, lapatinib, etc.) targeting HER2
2. Adverse events due to chemotherapy, targeted small-molecule preparations, or drugs previously administered or administered within 2 weeks prior to Day 1 of this trial have not yet recovered (below Grade 2 or baseline levels). patient.
3. Patients with known other malignancies requiring active treatment within the last three years. The exception is cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma and thyroid or cervical carcinoma treated for cure.
4. Patients known to have active central nervous system (CNS) metastases and / or carcinoma meningitis. Patients previously treated for brain metastases are clinically stable (no imaging evidence for disease progression and all neurological symptoms return to baseline levels on at least 4 weeks prior to the first dose of this drug), If there is no evidence of new or advanced brain metastasis and the steroid has not been used for at least 7 days prior to administration of the test drug, you can participate in this study. However, this exception does not apply to carcinoma meningitis, regardless of clinical stability.
5. History of the disease, treatment, or laboratory abnormalities that, in the opinion of the investigator, cause confusion in the clinical trial results, impede the patient's full participation in the trial, or involvement in the clinical trial itself is not best for the patient.
6. Cardiac dysfunction or clinically significant heart disease, including:
• Clinically significant or uncontrolled heart disease (eg congestive heart failure [NYHA class 2 or higher] requiring treatment, uncontrolled hypertension or clinically significant arrhythmias)
• QTcF> 470 msec or congenital QT prolongation syndrome on screening ECG
• Acute myocardial infarction or unstable angina within 3 months prior to enrollment in the trial
7. Patients with known psychiatric disorders or substance abuse disorders that may interfere with compliance with clinical trial requirements.
8. Patients who are pregnant or lactating, or plan to be 2 years old during the planned clinical trial period from the screening visit to 120 days after the last dose of study drug.
9. Patients with known history of human immunodeficiency virus (HIV) (HIV-1 / 2 antibody).
10. Patients with active hepatitis B (positive HBsAg response and HBV DNA 100 ≧ copies / ml or hepatitis C Anti-HCV antibody positive and HCV RNA [qualitatively detected]).
11. Patients who received live vaccine within 30 days before the first scheduled dose of the test drug.
12. Active infectious diseases of the system that are not resolved.
13. Patients with a history of hypersensitivity or serious side effects to 5-FU, leucovorin, oxaliplatin or trastuzumab.

objective response rate, ORR

during follow up period

Progression-free survival, PFS

during follow up period

disease control rate, DCR at 6 months

during follow up period

Overall survival, OS

during follow up period

Drug toxicity by CTCAE 5.0

during follow up period

Quality of life by patient reported outcome: EQ-5D, EORTC-QLQ-CIPN20 questionnaires

during follow up period

Choong-kun Lee MD et al.. Trastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin: a multi-institutional phase 2 trial of the korean cancer study gropu (KCSG-HB-19-14). Lancet gastroenterology and hepatology. SCI. 2022-07-08 ,
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														https://doi.org/10.1016/S2468-1253(22)00335-1
														

34 participants were enrolled between June 26, 2020, and Sept 1, 2021. At the time of data cutoff on May 1, 2022, median follow-up was 13·0 months (IQR 11·0–16·9), with three participants remaining on treatment. Ten patients had a partial response and 17 had stable disease; the overall response rate was 29·4% (95% CI 16·7–46·3) and the disease control rate was 79·4% (95% CI 62·9–89·9). Median progression-free survival was 5·1 months (95% CI 3·6–6·7); median overall survival was 10·7 (95%CI 7·9–not reached). The most common treatment-related grade 3 or 4 adverse events were neutropenia (ten [29%] participants with grade 3 and nine [26%] with grade 4), grade 3 anaemia (five [15%] participants), and grade 3 peripheral sensory neuropathy (four [12%] participants). There were no treatment-related cardiac toxic effects or deaths. The overall health assessment (EuroQoL-VAS) score did not change significantly throughout the treatment. Sensory and motor neuropathy symptoms as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy twenty-item scale questionnaire did not change significantly over time.