Cadonilimab (AK104) Plus Lenvatinib in Previously Immunotherapy-Treated Advanced/Metastatic Clear Cell Renal Cell Carcinoma

A Multicenter, Single-Arm, Phase II Study of Cadonilimab (AK104) Plus Lenvatinib in Patients With Advanced/Metastatic Clear Cell Renal Cell Carcinoma Previously Treated With Immunotherapy-Based Combination Therapy

This is a phase II, open-label, multicenter, single-arm study evaluating the efficacy and safety of cadonilimab (AK104) in combination with lenvatinib in patients with unresectable advanced or metastatic clear cell renal cell carcinoma (ccRCC) who experienced disease progression during or after prior first-line immunotherapy-based combination therapy. Patients receive cadonilimab plus lenvatinib until radiographic disease progression, unacceptable toxicity, withdrawal of consent, death, or investigator decision. The primary endpoint is objective response rate (ORR) according to RECIST version 1.1 as assessed by investigators.

Study Overview

• Status: Active, not recruiting
• Conditions: Clear Cell Renal Cell Carcinoma
• Intervention / Treatment: Drug: AK104（anti-PD-1/CTLA-4 bi-specific antibody ，intravenously）,lenvatinib（ targeted VEGFR 1-3、FGFR、PDGFRα， small molecule TKI，orally

Detailed Description

This is a multicenter, open-label, single-arm phase II clinical trial with a planned enrollment of 28 patients with unresectable advanced or metastatic clear cell renal cell carcinoma (ccRCC). Participating centers include Renji Hospital and Ruijin Hospital in Shanghai, China.

Patients receive oral lenvatinib at a starting dose of:

8 mg once daily for body weight <60 kg 12 mg once daily for body weight ≥60 kg Cadonilimab (AK104) is administered intravenously at 10 mg/kg every 3 weeks. Treatment continues until radiographic disease progression, unacceptable toxicity, withdrawal of informed consent, initiation of new anticancer therapy, death, loss to follow-up, or investigator decision.

Tumor assessments are performed at baseline, every 6 weeks (±7 days) during treatment, and at the end-of-treatment visit.

This study uses Simon's optimal two-stage phase II design. In stage 1, 12 evaluable patients are enrolled for futility assessment. If 2 or fewer confirmed objective responses are observed, the study may be terminated early for futility. Otherwise, enrollment proceeds to a total of 28 evaluable patients.

The study is designed to assess whether cadonilimab plus lenvatinib demonstrates sufficient antitumor activity to warrant further clinical investigation in patients with advanced ccRCC previously treated with immunotherapy-based therapy.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200123
      • Shanghai Renji Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Criteria: Inclusion Criteria:

1. Written informed consent provided prior to study procedures.
2. Age ≥18 and ≤80 years at the time of consent.
3. Histologically or cytologically confirmed renal cell carcinoma with clear cell component.
4. Unresectable locally advanced or metastatic disease.
5. Radiographic disease progression during or after prior first-line immunotherapy-based combination therapy for advanced RCC.
6. At least one measurable lesion according to RECIST v1.1.
7. ECOG performance status of 0 or 1.
8. Estimated life expectancy of at least 3 months.
9. Adequate organ function, including hematologic, renal, hepatic, and coagulation parameters, as defined in the protocol.

Exclusion Criteria:

1. History of hypersensitivity to monoclonal antibodies or any component of cadonilimab or lenvatinib.
2. Known additional malignancy that is progressing or has required active treatment. Exceptions include adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ.
3. Prior treatment with dual immune checkpoint blockade, defined as anti-PD-1/PD-L1 combined with anti-CTLA-4 therapy.
4. Uncontrolled clinically significant cardiovascular disease or symptoms.
5. Diagnosis of immunodeficiency or receipt of systemic corticosteroids (>10 mg/day prednisone equivalent) or other immunosuppressive therapy within 14 days prior to first dose.
6. Active autoimmune disease or history of autoimmune disease that may worsen with immunostimulatory therapy. Subjects with type 1 diabetes mellitus, vitiligo, psoriasis, or hypo-/hyperthyroidism not requiring immunosuppressive treatment are eligible.
7. History of non-infectious pneumonitis requiring steroids or current pneumonitis/interstitial lung disease.
8. Active tuberculosis or active syphilitic infection.
9. Known history of human immunodeficiency virus (HIV) infection.
10. Active hepatitis B infection (HBsAg positive with HBV DNA >500 IU/mL) or active hepatitis C infection (detectable HCV RNA).
11. Clinically significant toxicities from prior anticancer therapy not recovered to Grade ≤1 (except alopecia or stable endocrinopathies).
12. Active bleeding disorder or history of clinically significant bleeding episodes.
13. Drug abuse, psychiatric illness, or medical/social conditions that may interfere with study participation or evaluation of results.

14. Pregnant or breastfeeding women, or participants planning conception during the study treatment period.

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AK104 combine with lenvatinib; Patients will receive AK104 (10mg/kg ,Q3W，intravenously) plus lenvatinib(<60kg，8 mg qd；≥60kg，12mg qd, orally.	Drug: AK104（anti-PD-1/CTLA-4 bi-specific antibody ，intravenously）,lenvatinib（ targeted VEGFR 1-3、FGFR、PDGFRα， small molecule TKI，orally; AK104 (10mg/kg ,Q3W，intravenously) plus lenvatinib(<60kg，8 mg qd；≥60kg，12mg qd, orally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Proportion of participants achieving confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by investigators.	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of response (DOR)	Time from first documented objective response to disease progression or death.	Up to 2 years
Disease control rate (DCR)	Proportion of participants achieving complete response (CR), partial response (PR), or stable disease (SD)	Up to 2 years
Time to response（TTR）	Time from treatment initiation to first documented objective response.	Up to 2 years
Progression-free survival (PFS)	Time from treatment initiation to first documented disease progression per RECIST v1.1 or death from any cause, whichever occurs first.	Up to 2 years
Overall survival (OS)	Time from treatment initiation until death from any cause.	Up to 2 years
Adverse event	Incidence, type, and severity of treatment-emergent adverse events graded per CTCAE v5.0.	Up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory biomarker analyses of PD-L1 expression	Exploratory biomarker analyses	Up to 2 years
Exploratory biomarker analyses of circulating tumor DNA (ctDNA)	Exploratory biomarker analyses	Up to 2 years

Collaborators and Investigators

• Sponsor: RenJi Hospital
• Collaborators: Shanghai Zhongshan Hospital; Ruijin Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2023
• Primary Completion (Actual): January 12, 2026
• Study Completion (Estimated): October 31, 2026

Study Registration Dates

• First Submitted: September 6, 2023
• First Submitted That Met QC Criteria: September 12, 2023
• First Posted (Actual): September 13, 2023

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 15, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Tyrosine kinase inhibitor; Clear cell renal cell carcinoma; PD-1/CTLA-4 bispecific antibody; Immunotherapy rechallenge
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Carcinoma; Kidney Neoplasms; Carcinoma, Renal Cell; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Antibodies; Antibodies, Bispecific; Lenvatinib
• Other Study ID Numbers: CLEAR-IT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No