A Phase II Clinical Study to Evaluate HLX43 in Patients With Recurrent/Metastatic ESCC Failed or Intolerance to Standard Therapy

This study is an open-label phase II clinical study to explore the reasonable dosage and evaluate the efficacy, safety and tolerability of HLX43 (Anti-PD-L1 ADC) in Patients with Recurrent/Metastatic Esophageal Squamous Cell Carcinomar (ESCC) Failed or Intolerance to Standard First-Line Therapy.

In this study, eligible subjects will be randomized at 1:1:1 ratio, and the patients will be administered with HLX43 at different doses via intravenous infusion.

Inclusion criteria

• Volunteer to participate in clinical research; To fully understand and understand this study and to sign the Informed Consent Form (ICF); Willing to follow and able to complete all test procedures;
• The age of signing ICF is ≥ 18 years old and ≤ 75 years old;
• Esophageal Squamous Cell Carcinoma (ESCC) confirmed by histopathology or cytology;
• Patients with advanced esophageal squamous cell carcinoma who have failed or are intolerant to prior first-line standard therapy (for patients with PD-L1 expression positive [CPS ≥1], first-line standard therapy is defined as platinum-based chemotherapy and immune checkpoint inhibitor [ICI] therapy; for patients with PD-L1 expression negative [CPS <1], first-line standard therapy is defined as platinum-based chemotherapy). Intolerable toxicity refers to the occurrence of CTCAE grade ≥3 adverse events.;
• Within 4 weeks prior to the first administration of the medication, at least one measurable target lesion must be evaluated according to the RECIST v1.1 criteria;
• Tumor tissue should be provided as much as possible for an evaluable PD-L1 expression result at Screening period；
• Before the initial administration of the study drug, there should be at least a 3-week interval or 5 times the half-life of the last cytotoxic chemotherapy, immunotherapy, or biological therapy, whichever is shorter. There should be at least a 2-week interval from the previous small molecule targeted therapy, at least a 1-week interval from traditional Chinese medicine treatment with antitumor indications or minor surgery. Additionally, treatment-related adverse events (AEs) should have recovered to NCI-CTCAE grade ≤ 1 (except for grade 2 peripheral neurotoxicity and alopecia)；
• The ECOG physical performance score of 0-1 in the week prior to randomization；
• Expected survival ≥ 3 monthes；
• Laboratory tests within the previous week confirm adequate organ function (within 14 days prior to the first dose of medication, without receiving interventions such as blood transfusions, granulocyte colony-stimulating factor, or recombinant human thrombopoietin)；
• Male and female subjects of childbearing potential must agree to use at least one highly effective method of contraception during the trial and for at least 6 months after the last dose of the study drug. Female subjects of childbearing potential must have a negative pregnancy test within 7 days prior to enrollment.

Exclusion criteria

• History of any second malignant tumor within the first 2 years prior to randomization;
• BMI <17.5 kg/m2；
• Symptomatic, untreated, or progressively worsening central nervous system (CNS) or leptomeninges metastases;
• After appropriate intervention, uncontrollable pleural effusion, pericardial effusion or ascites still need to be drained frequently;
• A history of ≥ grade 3 radiation pneumonia; A history of (non-infectious) interstitial lung disease (ILD) requiring steroid use, or a current ILD, or suspected ILD cannot be ruled out by imaging at the time of screening; Or there are lung diseases leading to clinical severe respiratory impairment;
• Subjects exhibit poorly controlled cardiovascular clinical symptoms or diseases, including but not limited to: (1) NYHA class II or above heart failure, or left ventricular ejection fraction (LVEF) < 50%; (2) unstable angina; (3) myocardial infarction or cerebrovascular accident within the last 6 months (excluding lacunar infarction, minor ischemic stroke, or transient ischemic attack); (4) uncontrolled arrhythmias (including QTc interval ≥ 450 ms for males, ≥ 470 ms for females) (QTc interval calculated by Fridericia's formula); (5) poorly controlled hypertension (systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg despite active treatment);
• Subjects who are preparing for or have previously received an organ or bone marrow transplant;
• Within the 2 weeks prior to randomization, there is the presence of an active systemic infectious disease requiring intravenous antibiotic treatment;
• Used strong inhibitors or strong inducers of CYP2D6 or CYP3A within 2 weeks prior to randomization;
• Received systemic corticosteroids (prednisone >10 mg/day or an equivalent dose of similar drugs) or other immunosuppressive treatments within 14 days prior to the first dose; with the following exceptions: use of topical, ophthalmic, intra-articular, intranasal, and inhaled corticosteroids; short-term use of corticosteroids for prophylactic treatment during situations such as the use of contrast agents;
• History of adverse events leading to permanent discontinuation of immunotherapy; or a history of grade 2 or higher immune-related pneumonitis or myocarditis;
• Active or suspected autoimmune disease. Patients with autoimmune-related hypothyroidism who are undergoing thyroid hormone replacement therapy are permitted to participate in the study; patients with controlled Type 1 diabetes mellitus receiving insulin therapy are also allowed to participate in the study;
• Live vaccinations or attenuated live vaccinations should not be administered within 4 weeks prior to the initial dosing. Administration of inactivated viral vaccines for seasonal influenza is permitted;
• Known history of severe allergic reactions to macromolecular protein preparations/monoclonal antibodies, or allergy to components of the trial drug formulation；previous treatment with antibody-drug conjugates (ADCs) using a topoisomerase I inhibitor as the payload;
• Active tuberculosis;
• Human immunodeficiency virus (HIV) infection;
• Pregnant or lactating women;
• The researcher deems that the subject has any other factors that make them unsuitable for participation in this trial.