NCT05749900

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)

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

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 44 (estimated)
• Sponsor: Yonsei University · Academic / Other
• Sex: All
• Age: 19 Years
• Healthy volunteers: Not accepted

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 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.

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.

Conditions

• HER2 Positive Advanced/Metastatic/Nonresectable Biliary Tract Cancer

Interventions

Type	Name	Description
DRUG	Trastuzumab+Nivolumab+Gemcitabine+Cisplatin	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

Timeline

• Start date: 2023-05-12
• Primary completion: 2026-02-28
• Completion: 2027-02-28
• First posted: 2023-03-01
• Last updated: 2025-02-05

Locations

1 site across 1 country: South Korea