PTC-Guided Atorvastatin Plus Axitinib and Toripalimab in Advanced RCC

A Study on the Safety and Efficacy of Atorvastatin in Combination With Axitinib and Toripalimab for Advanced Renal Cell Carcinoma Guided by Drug Sensitivity Testing Using Patient-Derived Tumor Cell Models

Given the significant challenge of drug resistance in patients with advanced renal cell carcinoma (RCC) despite standard treatment, this study aims to translate preclinical findings into clinical practice, preliminarily evaluating the safety, tolerability, and preliminary efficacy of atorvastatin calcium combined with targeted and immunotherapy in patients with advanced RCC. We hypothesize that for some patients with advanced RCC who do not respond well to targeted + immunotherapy, identifying potential beneficiaries based on their PTC susceptibility testing and combining atorvastatin with these treatments in real-world settings could be an effective susceptibility enhancement strategy, thereby further improving patient survival. This prospective clinical study aims to validate the safety and efficacy of this "organoid-guided precision combination therapy model."

1. Study Objectives

1.1 Primary Objective: To evaluate the effectiveness of personalized treatment strategies guided by patient-derived tumor cell cluster (PTC) susceptibility testing in patients with advanced/metastatic renal cell carcinoma. The primary endpoint is objective response rate (ORR). Specifically, this study compares the in vitro drug sensitivity differences between two treatment regimens: "targeted therapy + immunotherapy" and "targeted therapy + immunotherapy + atorvastatin calcium tablets," by performing PTC culture and susceptibility testing on tumor tissue obtained from patient biopsies. This will guide subsequent clinical treatment decisions regarding the addition of oral atorvastatin calcium tablets to standard targeted therapy combined with immunotherapy.

1.2 Secondary Objectives:

1. To evaluate the disease control rate, progression-free survival, overall survival, 12-month progression-free survival rate, and 12- and 24-month overall survival rates of atorvastatin combined with targeted and immunotherapy regimens in patients with advanced/metastatic renal cell carcinoma.
2. Safety: Incidence of adverse events and serious adverse reactions.
3. To evaluate health-related quality of life (HRQoL).

2. Study Design

2.1 Overall Design This is a single-center, prospective, non-randomized controlled, two-arm clinical trial of superiority. The study plans to enroll 20-40 patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC). All subjects will receive targeted therapy plus immunotherapy. The addition of oral atorvastatin will be determined based on the drug sensitivity results of the patient-derived tumor cell cluster (PTC) model. Treatment will continue until any of the following occurs: disease progression, intolerable toxicity, the subject voluntarily requests to discontinue treatment or withdraw from the study, or other reasons determined by the investigator necessitate discontinuation of treatment and withdrawal from the study.

This study consists of three phases: screening, treatment (visit), and follow-up. All subjects must meet the inclusion and exclusion criteria. The screening period will not exceed 28 days. After passing the screening examination and evaluation, subjects will enter the treatment period. The treatment period consists of 21-day cycles, during which subjects must receive treatment and undergo regular visits as specified in the protocol.

Safety follow-up begins on day 30 (±7 days) from the start of the last study treatment, with participants required to undergo evaluation at the research center. Following the safety follow-up period, participants will enter a 2-year survival follow-up period, with follow-ups conducted at the end of every two treatment cycles. Follow-ups can be conducted via telephone or other effective methods, primarily collecting information on participant survival status and subsequent anti-tumor treatment. For participants without radiographic evidence of disease progression, imaging examinations will continue at the established efficacy assessment frequency until disease progression, death, loss to follow-up, withdrawal of informed consent, initiation of other anti-tumor treatments, or investigator termination of the study.

2.2 Study Endpoints

1. Primary endpoint: Objective response rate (ORR);
2. Secondary endpoints: Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), 12-month progression-free survival rate (PFS rate), 12-month overall survival rate (OS rate), 24-month overall survival rate (OS rate), safety, and health-related quality of life (HRQoL).

2.3 Study Location and Duration

This study is planned to be conducted at a single center from April 2026 to April 2030, with the Cancer Hospital of the Chinese Academy of Medical Sciences as the main center. It is expected to enroll 20-40 patients with advanced or metastatic clear cell renal cell carcinoma.

2.4 Study Drugs

1. Axitinib (Inritar)

   Dosage Form: Tablets

   Strength: 5mg/tablet

   Dosage: Oral

   The initial dose is 5mg twice daily, and the dose can be gradually adjusted according to patient tolerance.

2. Toripalimab Injection (Tuoyi)

   Dosage Form: Injection

   Strength: 80mg/2ml

   Dosage: Intravenous Infusion

   Administer intravenously every 3 weeks at a dose of 240mg, continuously until disease progression or adverse reactions occur.

3. Atorvastatin Calcium Tablets (Lipitor)

Dosage Form: Tablets

Strength: 10mg/tablet

Dosage: Oral

The initial dose is 10mg once daily, which can be gradually adjusted according to patient tolerance.

2.5 PTC Construction Procedure

This study used a patient-derived tumor cell cluster (PTC) model to assess drug sensitivity. The specific procedure included:

1. Collecting tumor tissue samples from patients with advanced renal cell carcinoma and culturing them in vitro in the laboratory.
2. Promoting the formation of tumor-like organoids by tumor cells under specific culture conditions, maintaining their biological characteristics in vitro.
3. Performing drug sensitivity testing to evaluate two drug combinations: targeted therapy combined with immunotherapy (axitinib + toripalimab) or targeted therapy combined with immunotherapy and atorvastatin calcium tablets (axitinib + toripalimab + atorvastatin).
4. Evaluating the inhibitory effect of different drug combinations on tumor cells in the PTC model by exposing them to different drug combinations, and deciding whether to provide combination therapy to patients based on the drug sensitivity results.

Inclusion Criteria:

1. Voluntarily agree to participate in the study and be willing and able to sign the informed consent form.

2. Histologically confirmed clear cell renal cell carcinoma.

3. Advanced renal cell carcinoma not suitable for curative surgery or radiotherapy, or metastatic renal cell carcinoma, AJCC stage IV.

4. No prior systemic therapy for renal cell carcinoma, except for prior adjuvant or neoadjuvant therapy for completely resectable renal cell carcinoma, provided that the therapy did not include agents targeting VEGF or VEGFR and recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy.

5. At least one measurable lesion according to RECIST version 1.1.

6. Karnofsky Performance Status score ≥70.

7. Estimated life expectancy of more than 3 months.

8. Aged 18 to 75 years.

9. Adequate major organ function and hematologic function, including:

   • Absolute neutrophil count ≥1500 cells/μL without granulocyte colony-stimulating factor support within 2 weeks before Cycle 1 Day 1.
   • Platelet count ≥80 × 10^9/L.
   • White blood cell count ≥2500/μL and ≤15000/μL without G-CSF support.
   • Lymphocyte count ≥500/μL.
   • Hemoglobin ≥9.0 g/dL, without erythropoietin dependence and without packed red blood cell transfusion within the previous 2 weeks.
   • ALT, AST, and alkaline phosphatase ≤3 × upper limit of normal; ≤5 × upper limit of normal is allowed for liver metastases. For participants with bone metastases, alkaline phosphatase ≤5 × upper limit of normal is allowed.
   • Total bilirubin ≤1.5 × upper limit of normal. Participants with known Gilbert syndrome may be enrolled if total bilirubin is ≤3 × upper limit of normal.
   • Serum albumin ≥2.8 g/dL.
   • Serum creatinine ≤2.0 × upper limit of normal or calculated creatinine clearance ≥30 mL/min.
   • Urine protein-to-creatinine ratio ≤1 mg/mg, equivalent to ≤113.2 mg/mmol.

10. Female participants who are not postmenopausal or surgically sterile must agree to use two adequate contraceptive methods, including at least one method with an annual failure rate of less than 1%.

11. Sexually active participants of reproductive potential and their partners must agree to use medically accepted contraceptive methods during the study and for 5 months after the last dose for female participants and 7 months after the last dose for male participants.

12. Female participants of childbearing potential must not be pregnant at screen

Exclusion Criteria:

1. Prior systemic therapy for renal cell carcinoma, unless the investigator can provide evidence that the participant was assigned to a placebo group.
2. Known central nervous system metastases.
3. Active malignancy within the past 24 months, except for renal cell carcinoma, definitively treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix or bladder. Participants with a history of localized low-risk prostate cancer may be eligible if they received curative treatment and have had no prostate-specific antigen recurrence within the past 5 years.
4. Radiotherapy within 21 days before initiation of study treatment, except palliative radiotherapy for bone lesions completed at least 2 weeks before study treatment.
5. Participation in another clinical study or receipt of an investigational drug within 4 weeks before initiation of study treatment.
6. Receipt of a live vaccine within 30 days before planned initiation of study treatment.
7. Proteinuria >1+ on urine dipstick. Participants with urine protein ≥1 g/24 hours on 24-hour urine collection are not eligible.
8. Fasting total cholesterol >300 mg/dL, equivalent to 7.75 mmol/L, and/or fasting triglycerides >2.5 × upper limit of normal.
9. Uncontrolled diabetes mellitus, defined as fasting blood glucose >1.5 × upper limit of normal. Participants may be enrolled after glucose-lowering treatment if adequately controlled.
10. Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued bisphosphonate or denosumab therapy.
11. QTc interval >480 ms.
12. Inadequate recovery from toxicity or complications caused by major surgery before treatment initiation.
13. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that may affect absorption of study drugs.
14. Clinically significant hematuria, hematemesis, or hemoptysis of more than 0.5 teaspoon, approximately 2.5 mL, of red blood within 12 weeks before the first dose, or any other significant bleeding history.
15. Significant cardiovascular impairment within 12 months before the first dose, including New York Heart Association class II or higher congestive heart failure, unstable angina, myocardial infarction, cerebrovascular accident, or hemodynamically unstable arrhythmia. Participants with left ventricular ejection fraction below the institutional lower limit of normal are also excluded.
16. Active infection requiring systemic treatment.
17. Positive human immunodeficiency virus test.
18. Active hepatitis B or hepatitis C infection.
19. Known history or evidence of interstitial lung disease.
20. History of non-infectious pneumonitis requiring steroids or current pneumonitis.
21. Diagnosis of immunodeficiency or receipt of chronic systemic steroid therapy or other immunosuppressive therapy within 7 days before the first dose. Physiologic corticosteroid doses up to prednisone 10 mg/day or equivalent are permitted.
22. Active autoimmune disease requiring systemic treatment within the past 2 years, except psoriasis. Replacement therapy, such as thyroxine, insulin, or physiologic corticosteroid replacement therapy, is not considered systemic treatment.
23. Breastfeeding or pregnancy at screening or baseline.
24. Female participants of childbearing potential who do not agree to use highly effective contraception during the study and for 120 days after study termination.
25. Male participants who have not undergone successful vasectomy and do not agree to use condoms with spermicide from the first dose until 120 days after the last dose, unless abstinent.
26. Known intolerance to any study drug or any excipient.
27. Prior allogeneic tissue or solid organ transplantation.
28. Participants requiring analgesics must be on a stable analgesic regimen at study entry.
29. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage once monthly or more frequently.
30. Uncontrolled hypertension, defined as persistent systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg.
31. Inability to swallow tablets or capsules.