This is a global, multi-center, open-label, Phase I/II first-in-human study of XNW27011 monotherapy as an investigational product (IP) in patients with locally advanced and/or metastatic solid tumors who have failed or are intolerant to standard therapies. XNW27011 is an antibody-drug conjugate (ADC) targeting Claudin 18.2 (CLDN18.2), a transmembrane protein important to tight junctions. The study consists of 2 parts: Part 1 is the dose-escalation phase (Phase I), and Part 2 is the does-expansion phase (Phase II). In phase I part of the study, approximately 42 patients with locally advanced and/or metastatic solid tumors will be enrolled, irrespective of CLDN18.2 expression. However, the most recently available tumor tissue specimen will be collected (if available) for a retrospective CLDN18.2 expression confirmation. In phase II part of the study, only patients with confirmed CLDN18.2 expression by IHC in the central laboratory will be enrolled.The phase II part of the study will consist of the following four groups，Up to three dose cohorts for each patient group are planned currently. Each dose cohort will include approximately 20 patients. Approximately 240 patients evaluable will be enrolled in Phase Ⅱ part of the study.
Phase I (Dose Escalation)：
Patients are willing and able to provide written informed consent or where consent is provided by legally authorized representatives.
Age ≥18 years old when signing the informed consent form.
Patients with a histologically or cytologically-confirmed, locally advanced or metastatic solid tumor, which has failed on standard therapy or is intolerable to available standard therapy, or there is no available standard therapy for the tumor. The advanced solid tumors include but are not limited to gastric and gastroesophageal junction adenocarcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, lung cancer, colorectal cancer, andbiliary tract cancer.
PHASE I (DOSE ESCALATION)：
Prior severe allergic reaction or intolerance to a monoclonal antibody, including humanized or chimeric antibodies.
Prior severe allergic reaction or intolerance to the Topoisomerase I Inhibitor or Topoisomerase Inhibitor-Based ADC (e.g: Fam-trastuzumab deruxtecan-nxki, Sacituzumab govitecan-hziy, Irinotecan, Topotecan) or any excipient in the XNW27011 formulation.
Acquired or congenital immunodeficiency diseases or organ transplantation.
Parallel
XNW27011
DrugEligible patient(s) in each dose cohort will receive the assigned XNW27011 dose administration every 3 weeks (Q3W, cycle) until intolerable toxicity, progression of the disease without clinical benefit, or withdrawal of informed consent. An accelerated titration scheme will be used for the first two dose levels (0.6 mg/kg and 1.2 mg/kg) starting from 0.6 mg/kg dose as follows: The first patient will be enrolled for 0.6 mg/kg dose. If the subject shows no significant toxicity in cycle 1 (DLT observation period), the second patient will be enrolled for 1.2 mg/kg. 3 + 3 dose escalation:3 patients will be enrolled to the dose cohort first，If 1 of 3 patients experiences a DLT, up to 3 more patients will be enrolled in the same dose cohort.. If none of the additional 3 patients experiences a DLT, dose escalation will continue to the next dose.Dose escalation will be stopped when 2 or more patients out of 3 to 6 patients at the same dose level experience a DLT.
XNW27011
DrugGroup A: Gastric/gastroesophageal junction adenocarcinoma with CLDN18.2 expression, tentatively expand with 3.6, 3.0, 2.4 mg/kg. Group B: Pancreatic adenocarcinoma with CLDN18.2 expression, tentatively expand with 3.6, 3.0, 2.4 mg/kg. Group C: Ovarian cancer with CLDN18.2 expression, tentatively expand with 3.6, 3.0, 2.4 mg/kg. Group D: Other tumors with CLDN18.2 expression, including but not limited to esophagus adenocarcinoma, lung cancer, colorectal cancer, and biliary tract cancer,tentatively expand with 3.6, 3.0, 2.4 mg/kg.
Phase I (Dose Escalation):To determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of XNW27011
In the dose escalation phase, if there are ≥ 2 cases of DLT among 3-6 subjects at a dose level during the DLT observation period (Cycle 1, 21days), the previous dose or intermediate dose (the midway dose between the previous dose group and the intolerant dose group) may be defined as MTD.
Phase Ⅱ (Dose Expansion):To evaluate the objective response rate (ORR) of XNW27011 by cohorts at RP2D. The objective response includes the complete response (CR) and the partial response (PR).
To evaluate the objective response rate (ORR) of XNW27011 by cohorts at RP2D. The objective response includes the complete response (CR) and the partial response (PR).
Phase I (Dose Escalation):To assess the dose limiting toxicities (DLTs) of XNW27011 when administered intravenously (IV) as a monotherapy during the first cycle (3 weeks [21 days]) to patients with locally advanced and/or metastatic solid tumors.
To assess the dose limiting toxicities (DLTs) of XNW27011 when administered intravenously (IV) as a monotherapy during the first cycle (3 weeks \[21 days\]) to patients with locally advanced and/or metastatic solid tumors.
Phase I (Dose Escalation)：To assess the overall safety of XNW27011 when administered IV as a monotherapy every cycle (3 weeks [Q3W]) to patients with locally advanced and/or metastatic solid tumors.
The incidence and severity of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
Phase I (Dose Escalation)：To assess the pharmacokinetic (PK) profiles of XNW27011, total antibody (XNW27011-TAb, including conjugated and unconjugated), the topoisomerase I inhibitor YL0010014 (payload/toxin) and the major metabolites.
To assess the pharmacokinetic (PK) profiles of XNW27011, total antibody (XNW27011-TAb, including conjugated and unconjugated), the topoisomerase I inhibitor YL0010014 (payload/toxin) and the major metabolites.
Phase I (Dose Escalation)：To evaluate the preliminary efficacy of XNW27011 as a monotherapy.
According to RECIST 1.1, the proportion of subjects' ORR was evaluated by researchers.
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