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HER2 Positive Advanced/Metastatic/Nonresectable Biliary Tract CancerPhase 1/2NCT05749900

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)

A Phase 1/2 study testing Trastuzumab+Nivolumab+Gemcitabine+Cisplatin in people with HER2 Positive Advanced/Metastatic/Nonresectable Biliary Tract Cancer, run by Yonsei University at 1 site in South Korea.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial summary

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… Read more about this study

Who is it for?
Ages 19 years and older
What is being tested?
Trastuzumab+Nivolumab+Gemcitabine+Cisplatin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
44 participants
Where
1 siteSouth Korea
Study dates
12 May 2023to 28 Feb 2027
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 19 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Subjects with histologically- or cytologically-confirmed biliary tract cancer (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gall bladder cancer)
  • HER2 positive biliary tract cancer (IHC 3+ or 2+ with ISH + (HER2/CEP17≥2.0) or ERBB2 gene copy number ≥ 6.0 by NGS)
  • Age (at the time of informed consent): 20 years and older
  • 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)
  • 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
  • Subject with measurable lesions according to RECIST v. 1.1
Show all 17Show fewer
  • ECOG Performance Status Score 0 or 1
  • Patients with a life expectancy of at least 3 months
  • 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
  • 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.
  • 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.
  • EF ≥ 50% via Transthoracic echocardiography or MUGA scan
  • Subjects willing to provide tumor biopsy tissue or excisional biopsy tissue.
  • Subjects with adequate organ function

Who cannot join

  • 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.
  • If disease recurrence occurs 6 months after the last dose of adjuvant chemotherapy, previous adjuvant chemotherapy is permitted.
  • 1 cycle of Gemcitabine-based anticancer therapy for locally advanced or metastatic cholangiocarcinoma prior to enrollment in this trial is permitted.
  • 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)
  • 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.
  • Patients with current or past history of severe hypersensitivity to any other antibody products
Show all 36Show fewer
  • Patients with concurrent autoimmune disease or history of chronic or recurrent autoimmune disease
  • 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.
  • Patients with concurrent diverticulitis or symptomatic gastrointestinal ulcerative disease
  • 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.
  • Patients with pericardial fluid, pleural effusion, or ascites requiring treatment
  • Patients with uncontrollable, tumor-related pain
  • Patients who have experienced a transient ischemic attack or cerebrovascular accident within 180 days before enrollment
  • Patients with a history of uncontrollable or significant cardiovascular disease meeting any of the following criteria:
  • Myocardial infarction within 180 days before enrollment
  • Uncontrollable angina pectoris within 180 days before enrollment
  • New York Heart Association (NYHA) Class III or IV congestive heart failure
  • Uncontrollable hypertension despite appropriate treatment (e.g., systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥ 90 mmHg lasting 24 hours or more)
  • Arrhythmia requiring treatment
  • Patients with uncontrollable diabetes mellitus
  • Patients with systemic infections requiring treatment (infection controlled by oral antibiotics is permitted)
  • 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
  • Patients who have received antineoplastic drugs (e.g., chemotherapy agents, molecular-targeted therapy agents, or immunotherapy agents) within 28 days before enrollment
  • Patients who have undergone surgical adhesion of the pleura or pericardium within 28 days before enrollment
  • Patients who have undergone surgery under general anesthesia within 28 days before enrollment
  • Patients who have undergone surgery involving local or topical anesthesia within 14 days before enrollment
  • Patients who have received radiotherapy within 28 days before enrollment, or radiotherapy to bone metastases within 14 days before enrollment
  • Patients who have received any radiopharmaceuticals (except for examination or diagnostic use of radiopharmaceuticals) within 56 days before enrollment
  • 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
  • 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.)
  • Women who are pregnant or breastfeeding, or possibly pregnant
  • 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
  • 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
  • Patients judged to be incapable of providing consent for reasons such as concurrent dementia
  • Other patients judged by the investigator or sub-investigator to be inappropriate as subjects of this study
  • Patient with current or past history of hypersensitivity to Nivolumab.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Choong-kun Lee contact

82-2-2228-3122

cklee512@yuhs.ac

South Korea1 site, 1 recruiting

  • Severance Hospital, Yonsei University Health System

    Seoul

    Choong-kun Lee, 82-2-2228-3122, cklee512@yuhs.ac

    Recruiting

Other trials in South Korea

About this study

Official title: First-line Trastuzumab Plus Chemoimmunotherapy for Biliary Tract Cancer (HERBOT Trial)

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.

Read more

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.

Read the detailed description

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.

Being tested
Trastuzumab+Nivolumab+Gemcitabine+Cisplatin

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Trastuzumab+Nivolumab+Gemcitabine+CisplatinDrug

    Phase Ib Nivolumab 360mg IV q 3weeks Gemcitabine 1000mg/m2 IV D1, D8 q 3weeks Cisplatin 25mg/m2 IV D1, D8 q 3weeks Trastuzumab 8mg/kg (C1) then 6mg/kg IV q 3weeks Level -1 Nivolumab 360mg IV q 3weeks Gemcitabine 800mg/m2 IV D1, D8 q 3weeks Cisplatin 25mg/m2 IV D1, D8 q 3weeks Trastuzumab 8mg/kg (C1) then 6mg/kg IV q 3weeks

Study groups in NCT05749900
Study groupRoleWhat they receive
Trastuzumab+Nivolumab+Gemcitabine+CisplatinExperimentalTrastuzumab+Nivolumab+Gemcitabine+Cisplatin
Receives: Drug: Trastuzumab+Nivolumab+Gemcitabine+Cisplatin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Phase Ib: Recommended Phase II Dose

    Phase Ib: Recommended Phase II Dose decided during DLT periods

    Measured: up to 4 years

  2. Phase II: Objective response rate, ORR

    Phase II: Objective response rate, ORR: rate of patients with complete remission (CR) or partial remission (PR) based on RESIST1.1.

    Measured: up to 4 years

Secondary outcomes (6)

  1. Progression Free Survival, PFS

    PFS is defined as time interval from cycle 1 day 1 to tumor progression/death/last follow-up

    Measured: up to 4 years

  2. Overall Survival, OS

    OS is defined as time interval from cycle 1 day 1 to tumor death/last follow-up.

    Measured: up to 4 years

  3. Disease Control Rate, DCR

    DCR is rate of patients with CR, PR, or SD per RECIST 1.1.

    Measured: up to 4 years

  4. Duration of Response, DOR

    DOR is defined as time interval from first response per RECIST 1.1 to tumor progression/death/last follow-up

    Measured: up to 4 years

  5. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

    Safety per NCI CTCAE v5.0 ()Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 )

    Measured: up to 4 years

  6. Quality of Life (QoL)

    QoL determined by EORTC QLQ-C30 (QoL determined by EORTC QLQ-C30)

    Measured: up to 4 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Mar 2023
  2. Study start12 May 2023
  3. Primary completion28 Feb 2026 (estimated)
  4. Study completion28 Feb 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
44 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05749900
Sponsor's protocol ID
4-2022-1610
Status last verified
Jan 2025
First submitted
19 Feb 2023
Last updated
5 Feb 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Lee CK, Chung T, Kim IH, Chon HJ, Kim JW, Park SJ, Bae WK, Kang J, Yoo C, Koo DH, Kang S, Kwon M, Kim JW, Kang B, Park S, Hwang W, Ahn CH, Kim CG, Choi HJ. Trastuzumab plus nivolumab with gemcitabine and cisplatin as first-line therapy for HER2-positive unresectable biliary tract cancer: a phase 1b/2 trial. Nat Med. 2026 Sep 22. doi: 10.1038/s41591-026-04679-x. Online ahead of print.

    PubMed 42773210

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Trastuzumab+Nivolumab+Gemcitabine+Cisplatin in people with HER2 Positive Advanced/Metastatic/Nonresectable Biliary Tract Cancer, run by Yonsei University at 1 site in South Korea.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 36 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 5 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Choong-kun Lee (82-2-2228-3122, cklee512@yuhs.ac), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase Ib: Recommended Phase II Dose (time frame: up to 4 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05749900, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Feb 2025.

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