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.

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.