Study of Iparomlimab and Tuvonralimab Plus Chemotherapy in Malignant Mesothelioma

Overview

This clinical trial aims to investigate the effectiveness and safety of a new treatment combination-Iparomlimab and Tuvonralimab (QL1706, a dual-function antibody targeting PD-1 and CTLA-4) combined with chemotherapy-for patients with malignant mesothelioma (MM). MM is a rare and aggressive cancer often linked to asbestos exposure. Current treatments have limited success, and this study seeks to explore a potentially more effective and safer option. Study Design: Phase Ib (Safety Phase): 6 patients will receive the combination therapy to assess safety. If no major safety issues arise, the study will proceed to Phase II. Phase II (Efficacy Phase): 49 patients will be enrolled to evaluate treatment effectiveness. The study includes two groups for first-line treatment and second-line treatment.

Study Rationale Malignant mesothelioma (MM) is a rare and aggressive cancer primarily associated with asbestos exposure. Despite advances in treatment, the prognosis remains poor, with a median overall survival (OS) of approximately 12-18 months for advanced disease. Current standard therapies include platinum-based chemotherapy combined with pemetrexed, immune checkpoint inhibitors (ICIs) such as nivolumab plus ipilimumab, or pembrolizumab with chemotherapy. However, these treatments have limitations, including significant toxicity (e.g., immune-related adverse events, irAEs) and modest survival benefits in certain populations. The iparomlimab and tuvonralimab (QL1706) combination is a novel bispecific antibody therapy targeting PD-1 and CTLA-4, designed to enhance anti-tumor immune responses while minimizing toxicity. Preclinical and early clinical data suggest this dual checkpoint blockade may offer comparable efficacy to existing ICI combinations but with an improved safety profile. Given the unmet need for effective and tolerable therapies in MM, this study evaluates the clinical potential of iparomlimab and tuvonralimab combined with chemotherapy in Chinese patients. Study Design This is a single-arm, multicenter, open-label Ib/II trial with two sequential phases: Phase Ib (Safety Run-In, n=6): Evaluates the safety of iparomlimab and tuvonralimab + chemotherapy in patients with 1-3 prior lines of therapy. Phase II (Expansion, n=49): First-line cohort (n=39): Patients receive iparomlimab and tuvonralimab + pemetrexed/platinum (Simon two-stage design). Second-line cohort (n=10): Fixed-sample evaluation of iparomlimab and tuvonralimab + investigator-selected chemotherapy. Treatment Regimen Induction Phase (4-6 cycles, Q3W): Iparomlimab and tuvonralimab (5 mg/kg IV, Day 1) Chemotherapy backbone: First-line: Pemetrexed (500 mg/m²) + cisplatin (75 mg/m²) or carboplatin (AUC 5). Second-line: Investigator's choice (pemetrexed, gemcitabine, or vinorelbine). Maintenance Phase (up to 2 years, Q3W): Iparomlimab and tuvonralimab monotherapy (5 mg/kg) until progression or unacceptable toxicity.