A Phase II Clinical Study to Evaluate the Efficacy and Safety of HLX43 (Anti-PD-L1 ADC) in Patients With Advanced Gynecological Malignant Tumors

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 cervical or ovarian cancer 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;
• Cohort 1: Metastatic or recurrent cervical cancer including squamous cell, adenocarcinoma or adenosquamous histology confirmed by histopathology or cytology.

Cohort 2: Histologically confirmed high-grade serous ovarian, fallopian tube, or primary peritoneal cancer.

• Cohort 1: Previous failure or progression of standard systemic therapy for cervical cancer (For patients with PD-L1 expression positive [CPS≥1], the standard therapy is defined as platinum-based chemotherapy in combination with immune checkpoint inhibitor (ICI) therapy; for patients with PD-L1 expression negative [CPS<1], the standard therapy is defined as platinum-based chemotherapy), or intolerability toxicity (CTCAE≥3 adverse events), or contraindications to standard therapy.

Cohort 2: Ovarian cancer patients with platinum-resistant disease: If the patient has previously received only first-line platinum-based chemotherapy, platinum resistance is defined as having received at least 4 cycles of platinum-based chemotherapy, with the tumor showing a response to platinum-based chemotherapy (best tumor assessment being complete remission/partial remission), and the time from the last platinum-based chemotherapy to tumor progression being >3 months and ≤6 months. If the patient has previously received multiple lines of platinum-based chemotherapy, platinum resistance is defined as disease progression occurring during the last line of platinum-based chemotherapy treatment or within 6 months after the last platinum-based chemotherapy.

• 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 months；
• 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 or granulocyte colony-stimulating factor)；
• 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;
• Subjects who are preparing for or have previously received an organ or bone marrow transplant;
• 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;
• Present with grade ≥1 radiation pneumonia as defined by RTOG/EORTC; A history of interstitial lung disease (ILD) or imaging findings during screening that suggest such disease is suspected; 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);
• Previous occurrence of adverse events leading to permanent discontinuation of immunotherapy; or A history of ≥ Grade 2 immune-related pneumonia 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;
• 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;
• Within the 2 weeks prior to randomization, there is the presence of an active systemic infectious disease requiring intravenous antibiotic treatment;
• 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;
• Used strong inhibitors or strong inducers of CYP2D6 or CYP3A within 2 weeks prior to randomization;
• Known history of severe allergic reactions to macromolecular protein preparations/monoclonal antibodies, or allergy to components of the trial drug formulation; Previously received ADC drugs with topoisomerase I inhibitors as toxins.
• Active tuberculosis;
• Human immunodeficiency virus (HIV) infection;
• Active Hepatitis B or Hepatitis C virus (HBV or HCV) infection or HBV/HCV co-infection;
• Pregnant or lactating women;
• The researcher deems that the subject has any other factors that make them unsuitable for participation in this trial.