Phase II, Open-label, Multicenter Study to Evaluate the Efficacy and Safety of HLX43 (an Anti-PD-L1 ADC) in Subjects With Advanced Colorectal Cancer

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 advanced Colorectal Cancer (CRC).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. After approximately 5 subjects are enrolled in each dose group, enrollment will be suspended. As soon as the efficacy signals and safety data are observed, two dose groups were selected for further exploration in Patients with advanced Colorectal Cancer (CRC).

Inclusion criteria

• Have a full understanding of the study content, process, and possible adverse reactions before the study, and sign the informed consent form (ICF); voluntarily participate in the study; be able to complete the study as per protocol requirements;
• Aged ≥ 18 years AND ≤ 75 years at the time of signing the ICF, male or female;
• Histologically or cytologically confirmed advanced Colorectal Cancer
• Locally advanced or metastatic colorectal cancer that has failed or progressed after at least one standard systemic treatment for colorectal cancer in the past, or has experienced intolerable toxicity (CTCAE≥ grade 3), or has contraindications to standard treatment and is not suitable for radical treatment.
• At least one measurable lesion as per RECIST 1.1 within 4 weeks prior to randomization;
• Subjects who agree to provide archived tumor tissue specimens that meets the testing requirements (either from the most recent surgery or biopsy, preferably within 2 years) or agree to undergo a biopsy to collect tumor tissue for PD-L1 expression testing;
• The following conditions must be met in terms of the time of the first administration of the investigational product: at least 3 weeks (or 5 half-lives of the drug, whichever is shorter) from the previous major surgery, medical device treatment, locoregional radiotherapy (except for palliative radiotherapy for bone lesions), cytotoxic chemotherapy, immunotherapy, or biological product therapy; at least 2 weeks from the previous hormone therapy or small molecular targeted therapy; at least 1 week from the administration of the traditional Chinese medicine for anti-cancer indications or minor surgery; and recovery of treatment-induced AEs to Grade ≤ 1 (CTCAE v5.0, except for Grade 2 peripheral neurotoxicity and alopecia);
• ECOG PS score of 0-1 within 1 week prior to randomization;
• Life expectancy > 3 months;
• Adequate organ functions as confirmed by laboratory tests within 1 week prior to randomization (no blood transfusions or treatment with granulocyte colony-stimulating factor is allowed within 14 days prior to the first dose)
• Male and female subjects with child-bearing potential must agree to use at least one highly effective contraception method during the study and within at least 6 months after the last dose of the investigational product; female subjects of childbearing age must be negative for pregnancy test within 7 days prior to enrollment.

Exclusion criteria

• Radical radiation therapy within 3 months prior to the first dose;
• History of any second malignancy within 2 years prior to randomization, except for early-stage malignancies (carcinoma in situ or stage I tumors) that have received radical treatment, such as non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer, ductal carcinoma in situ of the breast, and papillary thyroid carcinoma;
• History of adverse events leading to permanent discontinuation of immunotherapy, or occurrence of ≥ Grade 2 immune-related pneumonitis or myocarditis during prior immunotherapy;
• Presence of uncontrollable pleural effusion, pericardial effusion, or ascites requiring repeated drainage;
• Active gastrointestinal bleeding (grade ≥2 according to the National Cancer Institute's General Terminology Criteria for Adverse Events [CTCAE]5.0).
• Presence of spinal cord compression or clinically active metastases to central nervous system (referring to untreated or symptomatic metastases, or metastases requiring corticosteroids or anticonvulsants to control associated symptoms), carcinomatous meningitis. Subjects who have previously received treatment for brain metastases (such as whole brain radiotherapy or stereotactic brain radiotherapy) may be eligible, provided that they are clinically stable for at least 4 weeks with no imaging evidence of brain metastasis progression;
• Subjects with current or prior history of clinically significant pulmonary impairment due to pulmonary comorbidities, including but not limited to any underlying lung disease (e.g., pulmonary embolism within 3 months prior to the first dose, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, interstitial pneumonia, pneumoconiosis, drug-related pneumonitis, and pleural effusion within 3 months prior to the first dose), any autoimmune, connective tissue, or inflammatory disease that may involve the lungs (i.e., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis), prior pneumonectomy that may interfere with the detection and management of suspected drug-related pulmonary toxicity, or history of with radiation pneumonitis within 6 months;
• Patients with any poorly-controlled cardiovascular and cerebrovascular clinical symptoms or diseases, including but not limited to: (1) NYHA Class II or greater heart failure or left ventricular ejection fraction (LVEF) < 50%; (2) unstable angina pectoris; (3) myocardial infarction or cerebrovascular accident within 6 months (except lacunar infarction, slight cerebral ischemia, or transient ischemic attack); (4) poorly controlled arrhythmia (including QTc intervals ≥ 470 ms) (QTc intervals are calculated by Fridericia's formula); (5) poorly-controlled hypertension (systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg after active treatment);
• Patients with active systemic infectious diseases requiring intravenous antibiotics or with active tuberculosis within 2 weeks prior to randomization;
• Patients who have used moderate or potent CYP2D6 or CYP3A inhibitors or inducers within 2 weeks prior to randomization;
• Patients who have received systemic corticosteroids (prednisone > 10 mg/d or equivalent dose of similar drug) or other immunosuppressants within 2 weeks prior to randomization; Except: patients treated with topical, ocular, intra-articular, intranasal, and inhaled corticosteroids; short-term prophylactic use of corticosteroids for contrast agents, etc.;
• Patients with known active or suspected autoimmune diseases. Patients with autoimmune-related hypothyroidism and receiving thyroid hormone replacement therapy and those with type 1 diabetes mellitus controlled with insulin therapy are eligible to be enrolled;
• Patients who have received live vaccine or live attenuated vaccine within 4 weeks prior to randomization;
• Patients who are known to have anaphylaxis to macromolecular protein preparations/monoclonal antibodies or are allergic to any component in the formulation of the investigational product;
• Patients with a history of immunodeficiency, including human immunodeficiency virus (HIV)-positive or other acquired or congenital immunodeficiencies, or history of organ transplantation;
• Patients with active HBV or HCV infection or HBV/HCV co-infection;
• Pregnant or lactating women;
• Patients who are not suitable for participating in this clinical study due to any clinical or laboratory abnormalities or other reasons as assessed by the investigator.