A Study of AK104 Plus Axitinib in Advanced/Metastatic Special Pathological Subtypes of Renal Cell Carcinoma

Efficacy and Safety of First-Line Cadonilimab Plus Axitinib in Patients With Advanced Special Pathological Type Renal Cell Carcinoma: A Prospective, Multi-center, Phase Ib/II Trial

This is a Phase Ib/II, open-label, single arm trial to evaluate the efficacy and safety of AK104 in combination with axitinib as a first-line treatment for advanced/metastatic special pathological subtypes of renal cell carcinoma (ssRCC). Subjects will receive AK104 plus axitinib until disease progression, development of unacceptable toxic effects, death, a decision by the physician or patient to withdraw from the trial.

Primary objective:

Phase Ib: To evaluate the safety and tolerability of different doses of cadonilimab combined with axitinib as first-line therapy in subjects with advanced RCC with special pathological types to determine the recommended phase II dose (RP2D).

Phase II: To evaluate the objective response rate (ORR) of cadonilumab combined with axitinib as first-line therapy in subjects with advanced RCC with special pathological types according to the RECIST 1.1 criteria.

Study Overview

• Status: Active, not recruiting
• Conditions: Renal Cell Carcinoma; Sarcomatoid Renal Cell Carcinoma; First-line Treatment; Non Clear Cell Renal Cell Carcinoma
• Intervention / Treatment: Drug: Axitinib; Drug: AK104

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients aged ≥18 years and ≤75 years, with no restriction on gender;
2. Diagnosis of RCC with histopathological evidence, with non-clear cell carcinoma confirmed by pathology or genetic testing including pRCC, chRCC, TFE3-rearranged RCC, FH-dRCC, CDC, medullary carcinoma, and unclassified RCC, etc.;
3. Patients must be diagnosed with mRCC or unresectable RCC or TNM stage IV (based on the 2017 TNM staging system). Metastasis is evidenced by imaging or pathology, and for patients including in phase II, there must be at least one measurable tumor lesion (based on RECIST v1.1 criteria);
4. P atients who had not received any prior systemic therapy, including cytokines, targeted agents, ICIs, or other investigational drugs, or those who had received monotherapy with a targeted agent (limited to first-line targeted agents recommended by NCCN 2022 for renal cell carcinoma) for less than 1 month without disease progression and who had completed the washout period;
5. Expected survival of more than 3 months;
6. Have signed an informed consent form and be able to comply with the visit and related procedures specified in the protocol;
7. Agree to collect tumor tissue and blood samples required for the study and apply them to related research;
8. Important organ and bone marrow function meet the following requirements: Absolute neutrophil count (ANC) ≥1.5×109/L, platelets (PLT) ≥100×109/L, hemoglobin (HGB) ≥90g/L; liver function: serum total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤2.5×ULN, serum albumin (ALB) ≥20 g/L; renal function: serum creatinine (Cr) ≤1.5×ULN or creatinine clearance rate (CrCI) ≥50mL/min;
9. ECOG performance score ≤2.

Exclusion Criteria:

1. Patients with pathological diagnosis only of clear cell renal cell carcinoma (ccRCC);
2. Patients who have previously received anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways;
3. Active brain metastases;
4. Patients with a personal history of other malignant tumors different from or histologically different from the primary site of the tumor being evaluated in this study within 3 years, except for patients with papillary thyroid cancer, basal cell carcinoma of the skin, squamous cell carcinoma, or in situ cervical cancer in a well-controlled state;
5. Patients who have undergone major surgery or suffered severe trauma within 4 weeks prior to enrollment;
6. Patients with diseases requiring systemic glucocorticoid (more than 10mg/day prednisone equivalent dose) or other immunosuppressive drug treatment within 14 days before the first administration of the study drug. Patients without active immune diseases are allowed to receive local, ophthalmic, intra-articular, intranasal, inhaled corticosteroids, and adrenal replacement corticosteroids (more than 10mg/day prednisone dose or equivalent) treatment;
7. Known or suspected active autoimmune diseases (congenital or acquired), such as interstitial pneumonia, uveitis, colitis, hepatitis, pituitaryitis, vasculitis, nephritis, thyroiditis, etc. Patients with type 1 diabetes, hypothyroidism requiring only hormone replacement therapy, skin diseases (such as vitiligo, psoriasis, or alopecia) that do not require systemic treatment, or conditions that are not expected to recur in the absence of external triggering factors are allowed to participate in this study. Known allogeneic organ transplantation (excluding corneal transplantation) or allogeneic hematopoietic stem cell transplantation;
8. Allergic to any component of monoclonal antibodies;

9. Patients with other uncontrolled severe diseases, including but not limited to:

   1. Severe infections in active stage or with poor clinical control;
   2. HIV-infected (HIV antibody positive);
   3. Acute or chronic active hepatitis B (HBsAg positive and HBV DNA > 1*103/ml) or acute or chronic active hepatitis C (HCV antibody positive and HCV RNA > 15 IU/ml);
   4. Active pulmonary tuberculosis, etc.;
10. III-IV grade congestive heart failure (New York Heart Association classification), persistent symptomatic arrhythmias, uncontrolled atrial fibrillation; multiple echocardiographic assessments of left ventricular ejection fraction (LVEF) below the lower limit of normal values.
11. Uncontrolled arterial hypertension (systolic blood pressure ≥160mmHg or diastolic blood pressure ≥100mmHg);
12. Any arterial thrombosis, embolism, or ischemia occurred within 6 months before enrollment treatment, such as myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, etc.;
13. Diseases requiring warfarin (coumarin) anticoagulation therapy;
14. Uncontrolled hypercalcemia (greater than 1.5 mmol/L calcium ion or calcium greater than 12 mg/dL or corrected serum calcium greater than ULN), or symptomatic hypercalcemia requiring continued bisphosphonate therapy;
15. Uncontrolled adrenal insufficiency;
16. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
17. Severe, non-healing wounds or ulcers.
18. Gastrointestinal diseases affecting gastrointestinal function (such as malabsorption, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or small bowel resection).
19. Other acute or chronic diseases, mental illnesses, or abnormal laboratory test values that may lead to the following outcomes: increased risk associated with study participation or administration of study drugs, or interference with the interpretation of study results, and the patient is considered ineligible for the study based on the researcher's judgment;
20. Pregnant or lactating women.

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: Combination treatment group; Subjects in this group will receive AK104 (RP2D, administered intravenously) plus Axitinib 5 mg bid, administered orally.	Drug: Axitinib; An oral, small molecule, TKI selective for VEGFRs; 5mg bid orally; Drug: AK104; Anti-PD-1/CTLA-4 bi-specific antibody drug; Phase 1b: 10mg/kg or 15mg/kg; Phase 2: RP2D intravenously (IV)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase Ib Safety Assessment	Incidence and severity of adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0., dose-limiting toxicity (DLT) during the first treatment cycle, clinically significant abnormal laboratory tests, vital signs, and electrocardiogram (ECG); maximum tolerated dose (MTD), or the maximum administered dose (MAD) when MTD is not reached, as well as the recommended Phase II dose (RP2D).	3 years
Phase II Efficacy Assessment: ORR	ORR assessed by the investigator according to RECIST 1.1 criteria. objective response = complete response (CR) + partial response (PR).	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase Ib Efficacy Assessment	ORR, disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) assessed by the investigator according to RECIST 1.1 criteria. DCR: The proportion of participants achieving CR, PR, or stable disease (SD); DOR: Time from the first occurrence of treatment response (CR or PR) to disease progression or death, whichever occurs first; PFS: Time from the first dose of the treatment drug to disease progression or death due to any cause, whichever occurs first; OS: Time from the first dose of treatment drug to death due to any cause.	3 years
Phase II Safety Assessment	Incidence and severity of AEs, clinically significant abnormal laboratory tests, vital signs, and ECG abnormalities.	3 years
Phase II Efficacy Assessment	DCR, DOR, PFS, and OS assessed by the investigator according to the RECIST 1.1 criteria. DCR: The proportion of participants achieving CR, PR, or stable disease (SD); DOR: Time from the first occurrence of treatment response (CR or PR) to disease progression or death, whichever occurs first; PFS: Time from the first dose of the treatment drug to disease progression or death due to any cause, whichever occurs first; OS: Time from the first dose of treatment drug to death due to any cause.	3 years
Life quality Questionnaire composite	Evaluate life quality using FKSI-19 and EQ-5D-5L	3 years
Pain score	Evaluate pain using visual analogue scale (VAS)	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase Ib: To evaluate the pharmacokinetics of cadolinimab	serum drug concentration at different time points after administration for each subject, maximum concentration (Cmax), area under the plasma concentration-time curve (AUC), clearance (CL), and half-life (t1/2).	1 year

Collaborators and Investigators

• Sponsor: Hao Zeng
• Investigators: Principal Investigator: Hao Zeng, Professor, West China Hospital

Publications and helpful links

General Publications

• Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthelemy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21.
• Ljungberg B, Albiges L, Abu-Ghanem Y, Bedke J, Capitanio U, Dabestani S, Fernandez-Pello S, Giles RH, Hofmann F, Hora M, Klatte T, Kuusk T, Lam TB, Marconi L, Powles T, Tahbaz R, Volpe A, Bex A. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2022 Update. Eur Urol. 2022 Oct;82(4):399-410. doi: 10.1016/j.eururo.2022.03.006. Epub 2022 Mar 26.
• Diaz-Montero CM, Rini BI, Finke JH. The immunology of renal cell carcinoma. Nat Rev Nephrol. 2020 Dec;16(12):721-735. doi: 10.1038/s41581-020-0316-3. Epub 2020 Jul 30.
• 2022 ASCO # Oral abstract 106.

Study record dates

Study Major Dates

• Study Start (Actual): November 17, 2023
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: March 23, 2023
• First Submitted That Met QC Criteria: April 10, 2023
• First Posted (Actual): April 11, 2023

Study Record Updates

• Last Update Posted (Actual): April 7, 2026
• Last Update Submitted That Met QC Criteria: March 31, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• 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; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Azoles; Hydrocarbons; Hydrocarbons, Cyclic; Carboxylic Acids; Hydrocarbons, Aromatic; Amides; Benzene Derivatives; Acids, Carbocyclic; Benzoates; Benzamides; Indazoles; Pyrazoles; Axitinib
• Other Study ID Numbers: AK104AXI-ssRCC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: There is a plan to make IPD and related data dictionaries available
• IPD Sharing Time Frame: Data would be available starting from the time when summary data are published or otherwise made available, for 3 years.
• IPD Sharing Access Criteria: Other researchers access the data by sending an email to our PI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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