A Clinical Study of Ivonescimab in Combination With Cadonilimab or Ipilimumab for Advanced Renal Cancer

This is a multiregional, randomized, open-label Phase II clinical study to evaluate the safety and efficacy of Ivonescimab alone or in combination with Cadonilimab or Ipilimumab in the treatment of advanced clear cell renal cell carcinoma (ccRCC). Approximately 100 participants will be randomized across five treatment arms: ivonescimab in combination with cadonilimab, ivonescimab in combination with ipilimumab, ivonescimab monotherapy, or nivolumab in combination with ipilimumab.

• Ivonescimab (dose level 1) combined with Cadonilimab (Drug): Subjects will receive Ivonescimab (dose level 1) combined with Cadonilimab via intravenous infusion (IV) up to 2 years.
• Ivonescimab (dose level 2) combined with Cadonilimab (Drug): Ivonescimab (dose level 2) combined with Cadonilimab via intravenous infusion (IV) up to 2 years.
• Ivonescimab combined with Ipilimumab (Drug): Ivonescimab combined with Ipilimumab via intravenous infusion (IV) up to 4 cycles. Afterward, Ivonescimab for maintenance treatment up to 2 years total.
• Ivonescimab (Drug): Ivonescimab monotherapy via intravenous infusion (IV) up to 2 years.
• Nivolumab combined with Ipilimumab (Drug): Nivolumab combined with Ipilimumab via intravenous infusion (IV) up to 4 cycles. Afterward, Nivolumab will be used for maintenance treatment up to 2 years total.

Primary outcomes

• Objective Response Rate (ORR) [From randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years.]: ORR per RECIST v1.1 by investigator
• Adverse Events (AEs) [At the time of initiation of the first dose through 90 days after the last dose of study treatment.]: Adverse events (AEs) as characterized by type, incidence, severity, seriousness, and relationship to study treatment

Secondary outcomes

• Disease Control Rate (DCR) [From randomization to first occurrence of disease progression, death or study completion, whichever came first, assessed up to 3 years.]: DCR assessed by investigator according to RECIST v1.1.
• Duration of Response (DoR) [From time of first recorded response randomization to progressive disease, or death or study completion, whichever came first, assessed up to 3 years.]: Duration of response (DoR) assessed by investigator according to RECIST v1.1.
• Progression Free Survival (PFS) [From randomization to progressive disease or death, whichever came first, assessed up to 3 years.]: Progression Free Survival (PFS) is defined as the time from randomization to the first documented disease progression (per RECIST v1.1) assessed by investigator or death due to any cause, whichever occurs first.
• Overall Survival (OS) [From randomization to death, assessed up to 4 years.]: Overall Survival (OS) is defined as the time from randomization to death due to any cause.
• Pharmacokinetics (PK) [From first dose of study drug until end of treatment, assessed up to 3 years.]: Serum drug concentration at different time points after administration
• Anti-Drug Antibodies (ADA) [From time of initiation of first dose to 30 days after end of treatment.]: Number of subjects with detectable anti-drug antibodies (ADA).

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Able to understand and voluntarily sign a written informed consent form, which must be signed prior to the performance of the designated study procedures required by the study.
2. Age ≥ 18 years both male and female.
3. Karnofsky Performance Status Score (KPS) ≥ 70%.
4. Expected survival ≥ 6 months.
5. According to RECIST v1.1, there is at least one measurable lesion that is suitable for repeated and accurate measurements.
6. Histologically or cytologically, pathologically confirmed renal cancer with a clear cell carcinoma component (ccRCC).
7. Locally advanced or metastatic RCC not amenable to curative surgery or radiotherapy.
8. Adequate organ function.

Exclusion Criteria:

1. Locally advanced disease that is resectable or suitable for local therapy with curative intent.
2. Histologically or cytologically confirmed renal non-clear cell carcinoma (nccRCC).
3. Presence of active central nervous system (CNS) metastases.
4. Previous anti-tumor therapy toxicity has not been resolved.
5. Have other malignancies within 5 years prior to enrollment.
6. Known presence of active pulmonary tuberculosis and active syphilis infection.
7. Other reasons for ineligibility as evaluated by investigator.