Trastuzumab Plus Chemotherapy vs Chemotherapy Alone in First-line HER2 Positive Advanced Biliary Tract Cancer Patients

Overview

This is a randomized, open-label, two-arm, Phase III clinical trial evaluating the efficacy and safety of trastuzumab plus chemotherapy versus chemotherapy alone as first-line treatment in patients with HER2-positive advanced or metastatic biliary tract cancers (BTC). HER2-positive BTCs represent a molecular subset of these rare cancers, associated with poor prognosis and limited treatment options. Eligible patients with histologically confirmed HER2-positive (IHC 3+ or IHC 2+ with FISH amplification) unresectable or metastatic biliary tract adenocarcinoma-including gallbladder cancer, intrahepatic, and perihilar cholangiocarcinoma-will be randomized in a 1:1 ratio. Participants in the intervention arm (Arm A) will receive either gemcitabine and cisplatin with or without nab-paclitaxel plus trastuzumab, while those in the control arm (Arm B) will receive chemotherapy alone (gemcitabine + cisplatin with or without nab-paclitaxel). Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint is 6-month progression-free survival (PFS). Secondary endpoints include overall survival (OS), response rate (RR), quality of life (QOL), and adverse event (AE) profiles. The study aims to enroll 196 patients across a single center in India over a period of 5 years, with an additional 6-month follow-up. This trial builds on earlier Phase II findings suggesting improved outcomes with trastuzumab in HER2-positive BTC and aims to provide the first randomized evidence for the benefit of HER2-targeted therapy in this setting.

Title of study- Trastuzumab plus chemotherapy vs Chemotherapy alone in first-line HER2 positive advanced biliary tract cancer patients - a randomized non-blinded two-arm Phase III prospective clinical trial (TAB - 2 study) Indication- HER2-positive advanced/metastatic biliary tract cancers fit for first-line chemotherapy with gemcitabine-based combination Type of Study- Two arm open-label prospective Phase III parallel design randomized superiority clinical trial Biliary tract cancers (BTC), including gallbladder cancer and cholangiocarcinomas, are uncommon but aggressive tumors with poor prognosis in the advanced or metastatic setting. The current standard first-line treatment is gemcitabine combined with a platinum agent, which offers limited benefit. Emerging molecular profiling has identified HER2 overexpression or amplification in a subset of BTCs, particularly in gallbladder cancer, and has opened new avenues for targeted therapy. Trastuzumab, a monoclonal antibody targeting the HER2 receptor, has shown clinical activity in HER2-positive BTCs in early-phase studies. Preliminary evidence from a single-arm Phase II study (TAB trial) suggests that combining trastuzumab with chemotherapy may significantly improve progression-free survival in treatment-naïve HER2-positive patients. The TAB-2 study is a prospective, randomized, open-label Phase III trial designed to evaluate whether adding trastuzumab to first-line chemotherapy improves clinical outcomes in patients with HER2-positive advanced BTC. Patients will be randomized to receive chemotherapy with or without trastuzumab. Chemotherapy regimens may include gemcitabine and cisplatin, with or without nab-paclitaxel, based on physician discretion. Trastuzumab will be administered every three weeks along with chemotherapy until disease progression, unacceptable toxicity, or withdrawal of consent. The study will be conducted at a single academic center in India, with a planned enrollment of 196 participants over 5 years. This trial aims to provide definitive randomized evidence regarding the benefit of incorporating HER2-targeted therapy into the first-line treatment of advanced BTC and to inform future clinical practice for this rare molecular subtype. Primary endpoint- To evaluate the difference in progression-free survival (PFS) at 6 months between Trastuzumab - chemotherapy combination and chemotherapy alone. Treatment scheme 1. Arm A (Trastuzumab plus chemotherapy)-Gemcitabine plus Trastuzumab OR Gemcitabine Plus Cisplatin Plus Nab-paclitaxel on D1 and D8 Plus Trastuzumab D1 Start of next cycle on D 22 2. Arm B (Chemotherapy alone)- Gemcitabine Plus Cisplatin D1 and D8 q 21 days OR Gemcitabine Plus Cisplatin Plus Nab-paclitaxel D1 and D8) Start of next cycle on D 22 Treatment in both arms will be continued till unacceptable toxicity, death, or consent withdrawal. In both arms Immunotherapy is allowed as per the discretion of the treating physician Sample Size calculation- Based published phase 2 single-arm TAB trial, the median PFS in HER2 positive biliary tract cancer with Trastuzumab plus chemotherapy was approximately 8 months (6-month PFS was approximately 75 - 80%), while the median PFS with chemotherapy alone ranges from 5-6 months (6-month PFS approximately 55%-65%). Assuming the Trastuzumab combination will increase the 6-month PFS to 75% in comparison to 55% with chemotherapy alone, with a power of 80% and alpha of 0.05 and margin of risk difference of 3 %, a Phase III randomized study will require a total of 196 patients (98 per arm), assuming an attrition rate of 5 % per arm with a study accrual period of 5 years. Follow up the duration of the study will be 6 months post-accrual of the last patient.