SKB500 Combinations in Patients With Esophageal Squamous Cell Carcinoma

This is a Phase II, multicenter, open-label study to evaluate the safety, tolerability and preliminary antitumor activity of SKB500 combinations in patients with Esophageal Squamous Cell Carcinoma. The study is divided into three parts: the safety run-in phase, randomized enrollment phase and cohort expansion phase.

Inclusion criteria

• Age ≥18 years and ≤75 years
• Histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC), who are ineligible for curative-intent therapies:

• Safety run-in phase (Cohort 1, 2 and 3): received no more than 1 prior line of systemic therapy for locally advanced or metastatic ESCC.
• Safety run-in phase (Cohort 4), randomized enrollment phase and cohort expansion phase: no prior systemic therapy for locally advanced or metastatic ESCC.
• Participants are required to provide tumor tissue samples for biomarker analysis.
• Has at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy ≥ 12 weeks.

Exclusion criteria

• Histology or cytology confirms the presence of concurrent adenocarcinoma components.
• Leptomeningeal, brainstem, spinal, spinal cord compression, or active CNS metastases.
• Risk of esophagotracheal/esophagopleural fistula, or symptomatic invasion/compression of vital organs/major blood vessels.
• Active autoimmune disease requiring systemic therapy within past 2 years.
• Weight loss ≥10% within 4 weeks prior to the first dose, or Nutritional Risk Index (NRI) < 83.5.
• Severe infection within 4 weeks or active infection requiring systemic treatment within 2 weeks pre-dose.
• Uncontrolled comorbidities (e.g., decompensated liver cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, Grade ≥2 peripheral neuropathy).
• Cardiovascular/cerebrovascular events within 6 months pre-dose (e.g., Myocardial Infarction, unstable angina, acute/persistent ischemia, Grade 3/4 Heart Failure, symptomatic/uncontrolled arrhythmia, Cerebrovascular Accident, Transient Ischemic Attack).
• Uncontrolled hypertension, diabetes, or recurrent pleural/pericardial/abdominal effusion requiring drainage.
• History of interstitial lung disease (ILD) or noninfectious pneumonitis that require steroid treatment, or currently has ILD/noninfectious pneumonitis.
• Unresolved to grade ≤ 1 of prior anti-cancer treatment toxicities criteria per CTCAE v6.0.
• Previously received B7-H3-targeted agents, including antibody, antibodydrug conjugate (ADC), and other agents.
• Previously received treatment with an ADC that consists of a topoisomerase l inhibitor.
• Pregnant or lactating women.