A Study of IBR854 Combined With Pazopanib Versus Pazopanib in Advanced Renal Cell Carcinoma

This is a multicenter, randomized, open-label, active-controlled study. Eligible patients with Advanced Renal Cell Carcinoma who meet all inclusion criteria and none of the exclusion criteria will be randomly assigned in a 2:1 ratio to either the experimental arm or the control arm.

• Experimental arm: IBR854 in combination with Pazopanib
• Control arm: Pazopanib The primary endpoint is PFS per RECIST 1.1. Efficacy and safety datas will be continuously collected until criteria for discontinuation are met.

Inclusion criteria

• Male or female, age ≥ 18 years old
• Advanced clear cell renal cell carcinoma confirmed by histology or cytology and not amenable to curative surgery.
• Has not received any previous systemic anti-tumor treatment for advanced renal cell carcinoma.
• Expected survival period is at least 3 months.
• ECOG performance status of 0 or 1, or KPS score of at least 70.
• Has measurable disease per RECIST 1.1.
• Organ function should meet the following criteria:

• Absolute neutrophil count (ANC) ≥ 1.5×10^9/L; Platelet (PLT) ≥90×10^9/L; Hemoglobin (Hb) ≥ 90 g/L (no blood transfusion or hematopoietic stimulator treatment within 7 days).
• Albumin ≥ 30 g/L; Total bilirubin ≤1.5×ULN (for subjects with Gilbert's syndrome, it can be ≤3×ULN); ALT and AST ≤1.5×ULN (If liver metastasis is combined, ALT and AST≤3×ULN).
• Creatinine (Cr) ≤1.5 × ULN; Creatinine clearance (Ccr) (to be calculated only when Cr > 1.5× ULN) > 50 ml/min (Cockcroft-Gault formula).
• Activated partial thrombin time (APTT) ≤1.5×ULN, International normalized ratio (INR) ≤1.5×ULN.
• Voluntarily sign the informed consent form, understand the study and be willing to follow the protocol and complete all experimental procedures.

Exclusion criteria

• Documented central nervous system metastases.
• Received prior antineoplastic therapy (including chemotherapy, biologic therapy, immunotherapy, or Chinese traditional medicines with antitumor indications) before the first dose of study treatment.
• Has received major surgery (grade 3 or 4 as defined in the Measures for the Administration of Clinical Application of Medical Technology) within 28 days before the first dose of study treatment and has not yet recovered from which; or any planned curative surgery for renal cell carcinoma during the study.
• History of another malignancy within 5 years before the first dose of study treatment, except for Lung carcinoma in situ, low-risk early-stage prostate cancer, or cured basal-cell carcinoma, squamous-cell carcinoma of the skin, cervical carcinoma in situ, or papillary thyroid carcinoma.
• Clinically significant gastrointestinal abnormalities such as malabsorption syndrome, major gastric or small-bowel resection that may affect drug absorption, active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other conditions increasing the risk of perforation; or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days before the first dose of study treatment.
• Systemic corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive agents required within 2 weeks before the first dose or anticipated during study treatment, except for:

• Topical, intranasal, or inhaled corticosteroids.
• Corticosteroids as premedication for infusion-related or hypersensitivity reactions (e.g., premedication for CT imaging).
• Replacement therapy such as levothyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency.
• Low-dose corticosteroids for orthostatic hypotension.
• Clinically significant cardiovascular or cerebrovascular disease documented by any of the following:

• Ischemic stroke (excluding silent lacunar infarction) or severe thromboembolic event within 6 months before the first dose of study treatment.
• Myocardial infarction, unstable angina, congestive heart failure, or clinically significant arrhythmia within 6 months before the first dose of study treatment.
• New York Heart Association (NYHA) class ≥ II heart failure before the first dose of study treatment.
• QTcF interval >450 ms (men) or >470 ms (women) before the first dose of study treatment.
• Left-ventricular ejection fraction (LVEF) ≤50 % before the first dose of study treatment.
• Prior organ transplant, except corneal transplant; prior allogeneic stem-cell transplant.
• Hepatitis B surface antigen (HBsAg) positive with HBV DNA >500 IU/mL or >2,500 copies/mL, or hepatitis C antibody positive with detectable HCV RNA, or known HIV infection, or active tuberculosis.
• Interstitial lung disease or non-infectious pneumonitis that is currently symptomatic or has previously required systemic corticosteroids, in the opinion of the investigator likely to interfere with toxicity assessment or management.
• Any severe, progressive, or uncontrolled medical condition that, in the investigator's judgment, makes the subject unsuitable for the study, including but not limited to:

• Infection requiring systemic therapy.
• Symptomatic pleural, pericardial, or ascitic fluid requiring or having undergone drainage within 2 weeks before the first dose (minimal asymptomatic effusion, third-spacing due to hypoalbuminaemia, or cases where benefit outweighs risk may be allowed).
• History of coagulopathy (e.g., deep-vein thrombosis) or severe bleeding diathesis; clinically significant bleeding event (e.g., gastrointestinal bleeding) within 1 month before the first dose.
• History of severe psychiatric disorder.
• Any other condition that, in the investigator's opinion, renders study participation riskier than beneficial.
• Prior grade 3-4 immune-related adverse events that, in the investigator's judgment, should be excluded.
• Severe allergic or hypersensitivity disorders, significant drug allergies (including to investigational agents), or known hypersensitivity to any component of the study drug, including severe reactions to monoclonal antibodies.
• Participation in another clinical trial and receipt of an investigational agent within 28 days before the first dose of study treatment.
• Clinically significant organ dysfunction or comorbidity likely to interfere with protocol adherence.
• Live vaccine received within 30 days before the first dose, or planned during the study or within 1 month after the last dose.
• Pregnant or breast-feeding women (women who agree to discontinue breast-feeding before signing informed consent may be enrolled).
• Any other condition or circumstance that, in the investigator's opinion, unsuitable for participation.