CLARITY-PanTumor01: A phase 2 trial of the claudin 18.2-specific antibody-drug conjugate AZD0901 (CMG901) in patients with CLDN18.2-expressing advanced solid tumors.

TPS3163 Background: Gastric/gastroesophageal junction (G/GEJ) and pancreatic cancer are associated with poor outcomes and high unmet need. Claudin 18.2 (CLDN18.2) is highly expressed in gastric, esophageal, and pancreatic ductal adenocarcinoma (PDAC), and is a clinically validated target. AZD0901 is a potential first-in-class antibody-drug conjugate (ADC) comprising a humanized anti-CLDN18.2 IgG1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE), a cytotoxic microtubule-disrupting agent. Interim results from the ongoing, first-in-human, Phase 1 trial of AZD0901 monotherapy in patients with G/GEJ cancer (NCT04805307) who were refractory to and/or intolerant of standard therapies demonstrated promising efficacy and a manageable safety profile. Here we describe an ongoing, Phase 2 study of AZD0901 in patients with CLDN18.2-expressing advanced solid tumors, including G/GEJ cancer and PDAC. Methods: This open-label, multicenter study (NCT06219941) comprises multiple substudies. Substudy 1 is recruiting patients with human epidermal growth factor receptor 2 (HER2)-negative, CLDN18.2-expressing G/GEJ cancer with ≤2 prior lines of therapy for unresectable or metastatic disease, who are randomized 1:1 to receive AZD0901 1.8 or 2.2 mg/kg intravenous (IV) every 3 weeks (Q3W). Substudy 2 is recruiting patients with previously untreated CLDN18.2-expressing metastatic PDAC to receive AZD0901 (up to 2.2 mg/kg IV Q3W) and either a combination of 5-fluorouracil 2400 mg/m 2 IV on Days 1 and 2 Q2W, leucovorin 400 mg/m 2 or l-leucovorin 200 mg/m 2 IV on Days 1 and 2 Q2W, and irinotecan 150 or 180 mg/m 2 or nanoliposomal irinotecan 50 mg/m 2 IV on Day 1 Q2W (Arm 1), or gemcitabine 1000 mg/m 2 IV on Days 1 and 8 Q3W (Arm 2), per investigator’s choice. Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent. Eligible patients are aged ≥18 years with histologically confirmed, unresectable or metastatic disease, ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, and Eastern Cooperative Oncology Group performance status 0–1. Key exclusion criteria include unstable and/or active peptic ulcer disease or digestive tract bleeding, ascites requiring drainage, central nervous system metastases, and prior exposure to an MMAE-based ADC or CLDN-18.2-targeted agents other than an anti-CLDN18.2 targeted monoclonal antibody. Primary endpoints include safety, tolerability, and objective response rate per RECIST v1.1. Secondary endpoints include overall survival, progression-free survival, duration of response, disease control rate, best change in target lesion size, pharmacokinetics, immunogenicity, and pharmacodynamics. Recruitment began in December 2023, and sites across Australia, Asia, Europe, and North America will enroll patients. Clinical trial information: NCT06219941 .