A Phase I/II Dose Escalation and Expansion Trial to Evaluate Safety and Preliminary Efficacy of BNT141 in Patients with Claudin-18.2-positive Solid Tumors.

TPS2670 Background: Claudin-18.2 (CLDN18.2), whose expression is normally restricted to short-lived gastric epithelial cells, is ectopically expressed in tumors with unmet needs such as gastric, gastroesophageal junction (GEJ), pancreatic, ovarian, and biliary tract tumors. CLDN18.2 has thus emerged as a promising target for therapeutic antibody development. BNT141 is a novel RNA-based therapeutic that comprises two pseudouridine-modified mRNAs encapsulated in lipid nanoparticles. Upon intravenous injection, BNT141 is preferentially taken up by the liver where RNAs are translated and released into the circulation as fully assembled anti-CLDN18.2 antibodies. The resulting antibody is sequence identical to IMAB362, a CLDN18.2-targeted antibody that provided clinical benefit as an add-on to chemotherapy in the Phase III SPOTLIGHT trial (Shitara et al. J Clin Oncol. 2023). RNA-encoded antibodies can be developed more rapidly compared with recombinant antibodies and have the potential for favorable PK/PD properties and improved tolerability. Methods: This is a Phase I/II, open-label, multisite, dose escalation and expansion trial to examine safety, efficacy, and PK/PD of BNT141 in patients with CLDN18.2+ tumors (NCT04683939). The trial comprises 3 parts: dose escalation with BNT141 as monotherapy, dose escalation with BNT141 in combination with nab-paclitaxel and gemcitabine, and dose expansion. For monotherapy dose escalation, patients with CLDN18.2+ gastric, GEJ, pancreatic, mucinous ovarian, and biliary tract cancers who have exhausted or are ineligible for the current standard of care are eligible. CLDN18.2 positivity is defined as intermediate/strong staining intensity in ≥50% of tumor cells evaluated using a validated immunohistochemistry assay. Doses of BNT141 are escalated in up to 8 planned dose levels (DLs) until the maximum tolerated dose (MTD) is reached. For combination dose escalation, patients with advanced CLDN18.2+ pancreatic adenocarcinoma or cholangiocarcinoma who are eligible for treatment with nab-paclitaxel/gemcitabine will be included. Combination therapy will start at the first safe DL where the target antibody concentration is reached during monotherapy. Combination dose escalation will continue in parallel with the monotherapy part and will define the recommended Phase II dose (RP2D). For both parts, up to 10 additional patients may be enrolled at the MTD level to collect further safety and PK/PD data. For dose expansion, 2 cohorts of patients with CLDN18.2+ pancreatic adenocarcinoma or cholangiocarcinoma will receive combination therapy (nab-paclitaxel/gemcitabine) together with BNT141 at the defined RP2D. The study was initiated in January 2022 and recruitment is ongoing in the USA and Canada. Sites in Spain, Portugal, Germany, Denmark, Netherlands and the UK will be opened in 2023. Clinical trial information: NCT04683939 .