NCT07507526

A Study of Disitamab Vedotin, Tunlametinib, and PD-1 Antibody for Advanced Gastric Cancer

A Study on the Efficacy and Safety of Disitamab Vedotin Combined With Tunlametinib and PD-1 Antibody in Third-Line and Above Treatment of Patients With HER2-Overexpressing Advanced Gastric Cancer

• Status: Not Yet Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 76 (estimated)
• Sponsor: Sun Yat-sen University · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

The goal of this clinical trial is to learn if the combination of disitamab vedotin, tunlametinib, and a PD-1 antibody works to treat HER2-overexpressing advanced gastric cancer in patients who have already received at least two lines of prior therapy. It will also learn about the safety of this combination therapy. The main questions it aims to answer are: What is the objective response rate (tumor shrinkage) in participants receiving this combination? What medical problems (side effects) do participants have when taking this combination? Researchers will evaluate the efficacy and safety of disitamab vedotin combined with tunlametinib and a PD-1 antibody in patients with HER2-overexpressing advanced gastric cancer who have failed at least two lines of standard treatment. Participants will: Receive disitamab vedotin intravenously every 2 weeks and a PD-1 antibody intravenously once every 6 weeks. Take tunlametinib orally every 12 hours. Continue treatment until disease progression or unacceptable toxicity. Visit the clinic every 2 weeks for checkups, blood tests, and safety monitoring. Undergo tumor imaging assessments every 6 weeks to evaluate treatment response.

Detailed description

This is an open-label, single-arm, phase II clinical trial evaluating the efficacy and safety of disitamab vedotin (RC48) in combination with tunlametinib and a PD-1 antibody (tislelizumab) in patients with HER2-overexpressing advanced gastric cancer who have failed at least two lines of prior systemic therapy. Background HER2-overexpressing gastric cancer accounts for approximately 12-23% of advanced gastric cancer cases. Disitamab vedotin, a novel anti-HER2 antibody-drug conjugate (ADC) conjugated with the microtubule inhibitor MMAE, has demonstrated an objective response rate (ORR) of 24.8% and a median overall survival (OS) of 7.9 months in third-line treatment of HER2-overexpressing advanced gastric cancer (C008 study). However, primary and acquired resistance to ADC monotherapy remains a significant clinical challenge. Preclinical studies by the study team have shown that MAPK-ERK pathway inhibition with MEK inhibitors can upregulate HER2 expression, enhance lysosomal activity, and synergistically augment the antitumor activity of HER2-ADCs both in vitro and in vivo. The combination of a MEK inhibitor with disitamab vedotin and a PD-1 antibody has demonstrated synergistic effects in humanized mouse models. Study Design The study consists of a safety run-in phase followed by an expansion phase. The safety run-in phase will evaluate three dose levels of tunlametinib (6 mg, 9 mg, and 12 mg orally every 12 hours) in combination with fixed doses of disitamab vedotin (2.5 mg/kg intravenously every 2 weeks) and tislelizumab (400 mg intravenously every 6 weeks) to determine the recommended dose for the expansion phase. Following determination of the recommended dose, the expansion phase will enroll additional patients to further evaluate the efficacy and safety of the triplet combination. Treatment Regimen Disitamab vedotin (RC48): 2.5 mg/kg intravenously on Day 1 of each 14-day cycle Tislelizumab: 400 mg intravenously on Day 1 of each 42-day cycle Tunlametinib: Orally every 12 hours at the dose determined during the safety run-in phase Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-specified discontinuation criteria are met. Tumor assessments will be performed every 6 weeks ± 3 days using enhanced CT or MRI according to irRECIST criteria. Study Objectives Primary Objectives: To evaluate the objective response rate (ORR) and safety profile of the combination therapy Secondary Objectives: To evaluate progression-free survival (PFS), overall survival (OS), and quality of life Exploratory Objectives To analyze HER2 protein expression and immune cell infiltration in pre-/post treatment tumor tissue samples To assess changes in serum cytokine levels before and after treatment To characterize gut microbiota composition using 16S and metagenomic sequencing of fecal samples collected at baseline, first efficacy assessment, and disease progression.

Conditions

• Gastric Adenocarcinoma

Interventions

Type	Name	Description
DRUG	Tunlametinib+PD-1 mAb	Disitamab vedotin (RC48): 2.5 mg/kg intravenously on Day 1 of each 14-day cycle Tislelizumab: 400 mg intravenously on Day 1 of each 42-day cycle Tunlametinib: Orally every 12 hours at the dose determined during the safety run-in phase

Timeline

• Start date: 2026-04-01
• Primary completion: 2028-04-30
• Completion: 2028-04-30
• First posted: 2026-04-02
• Last updated: 2026-04-02

Locations

1 site across 1 country: China