To Evaluate the Safety and Tolerability of Anti-Human CD70 T-Cell Injection in Subjects With Advanced/Metastatic Renal Cancer

A Phase I Clinical Study to Evaluate the Safety and Tolerability of Anti-Human CD70 T-Cell Injection in Subjects With Advanced/Metastatic Renal Cell Carcinoma

This is a single-arm, open-label, dose-escalating Phase 1 clinical study. It aims to evaluate the safety, tolerability and pharmacokinetic(PK) profiles of the investigational agent, and preliminarily assess its efficacy in subjects with advanced/metastatic renal cell carcinoma, and determine the recommended dose and infusion regimen for Phase 2 trials.

This study is a single-arm, open-label, dose-escalation Phase 1 clinical trial designed to evaluate the safety, tolerability, and pharmacokinetic (PK) profiles of the investigational agent. It also aims to preliminarily assess its efficacy in subjects with advanced/metastatic renal cell carcinoma (RCC) and to determine the appropriate clinical dose and administration regimen for Phase 2.

Subjects who sign the informed consent form (ICF) will undergo screening based on the inclusion/exclusion criteria. Eligible subjects will be sequentially enrolled into treatment cohorts receiving total doses of 2.0 × 10⁸ chimeric antigen receptor-positive (chimeric antigen receptor (CAR)+) T cells, 5.0 × 10⁸ CAR+ T cells, and 1.0 × 10⁹ CAR+ T cells, with each subject receiving a single infusion. The dose-escalation study utilizes a standard "3+3" design, in which 3-6 subjects per cohort will complete a single infusion.

For the first subject enrolled in the initial dose cohort, a safety assessment will be conducted 28 days after the single infusion. If no significant safety concerns are identified, subsequent subjects in the same cohort may receive the infusion, with a total of 3 subjects to be enrolled.

If no dose-limiting toxicity (DLT) occurs among the 3 subjects, the study may escalate to the next dose cohort. If 1 of the 3 subjects in a given cohort experiences a DLT, an additional 3 subjects must be enrolled in the same cohort (for a total of 6 subjects completing DLT evaluation in that cohort): (1) If no DLT occurs among the additional 3 subjects, dose escalation will continue. (2) If 1 of the additional 3 subjects experiences a DLT, dose escalation will stop, and this cohort will be defined as the maximum tolerated dose (MTD). (3) If more than 1 of the additional 3 subjects experiences a DLT, dose escalation will stop. On this basis, if 6 subjects had already been enrolled in the preceding dose cohort, the study will be terminated and that cohort will be defined as the MTD; if only 3 subjects were enrolled in the preceding dose cohort, an additional 3 subjects must be enrolled in that cohort for DLT evaluation.

When more than 1 of 3 subjects in a given cohort experience a DLT, dose escalation will stop. On this basis: (1) If 6 subjects had already been enrolled in the preceding dose cohort, the study will be terminated and that cohort will be defined as the MTD. (2) If only 3 subjects were enrolled in the preceding dose cohort, an additional 3 subjects must be enrolled in that cohort for DLT evaluation.

If the MTD is not reached at the highest pre-specified dose cohort, the investigators and the sponsor will jointly discuss and decide whether to add further dose cohorts, taking into account preclinical data, clinical safety and tolerability findings, and pharmacokinetic parameters.

During the study, the number of dose cohorts may be increased or decreased, or doses within cohorts may be adjusted, upon joint discussion among the investigators, the sponsor, and the relevant regulatory authorities, based on accumulating PK data and other relevant findings, to ultimately determine the recommended Phase 2 dose (RP2D).

For the selected RP2D cohort, additional subjects may be enrolled if necessary to further characterize the safety profile.

Inclusion Criteria:

1. Age 18 to 70 years (inclusive), regardless of gender;

2. Life expectancy of more than 12 weeks;

3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 1;

4. Subjects with advanced/metastatic renal cell carcinoma (RCC):

   1. Histologically confirmed clear cell renal cell carcinoma (ccRCC), with an International Metastatic RCC Database Consortium (IMDC) risk stratification of intermediate or high risk as evaluated by the investigator;
   2. Has at least one measurable lesion according to RECIST 1.1;
   3. Tumor tissue samples must test positive for CD70 expression via immunohistochemistry (IHC);
   4. Must have received at least one prior line of systemic therapy (must include at least: (1) immuno-oncology (IO) combination therapy: concomitant targeting of PD-1 and CTLA-4, or (2) an immune checkpoint inhibitor (PD-1/PD-L1 inhibitor) combined with a VEGF/VEGFR-targeted agent);

5. Venous access required for apheresis can be established; hemoglobin ≥ 90 g/L, absolute neutrophil count (ANC) ≥ 1.5×10^9/L, and platelet count ≥ 100× 10^9/L, and the leukepheresis can be carried according to the judgement of investigators;

6. Hepatic, renal, cardiac, and pulmonary functions must meet the following criteria:

   1. Creatinine clearance (CrCl) ≥ 50 mL/min (calculated by the Cockcroft-Gault formula);
   2. Left ventricular ejection fraction (LVEF) > 50%;
   3. Baseline peripheral oxygen saturation > 95%;
   4. Total bilirubin ≤2 × upper limit of normal (ULN);
   5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN;

7. Voluntary participation in the clinical study: Must understand and be informed about this study, voluntarily sign the Informed Consent Form (ICF), and be willing to complete all study procedures.

Exclusion Criteria:

1. Prior treatment with anti-CD70 targeted therapies;
2. Brain metastasis from renal cell carcinoma;
3. Concomitant with other uncontrolled malignancies, except for adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, localized prostate cancer after radical surgery, ductal carcinoma in situ after radical surgery, or thyroid cancer after radical surgery;
4. Any uncontrolled active infection, including but not limited to active tuberculosis; presence or suspicion of an uncontrolled infection, or an infection requiring systemic intravenous therapy within 14 days prior to enrollment (including fungal, bacterial, viral, or other infections);
5. Subjects who are hepatitis B surface antigen (HBsAg) positive or hepatitis B core antibody (HBcAb) positive, with peripheral blood HBV DNA titers above the lower limit of detection (LLOD) of the study site; those who are hepatitis C virus (HCV) antibody positive with peripheral blood HCV RNA positive; those who are human immunodeficiency virus (HIV) antibody positive; or those who test positive for syphilis;
6. Any unstable systemic disease, including but not limited to: unstable angina, cerebrovascular accident or transient ischemic attack within 6 months prior to screening, myocardial infarction within 6 months prior to screening, congestive heart failure (New York Heart Association [NYHA] classification ≥ III ), poorly controlled diabetes mellitus (glycated hemoglobin HbA1c > 8% at screening), poorly controlled severe arrhythmia, and hepatic, renal, or metabolic diseases by medication;
7. Pregnant or lactating woman, and female subject who plans to have a pregnancy within 1 year after cell transfusion, or male subject whose partner plans to have a pregnancy within 1 year after cell transfusion (except for subjects of childbearing potential who are willing to use highly effective and reliable methods of contraception uninterruptedly for 1 year after the study treatment);
8. Prior treatment with CAR-T therapy or other genetically modified cell therapies prior to screening;
9. History of implantation of a cardiac pacemaker or deep brain stimulator;
10. Vaccination with live attenuated vaccines within 4 weeks prior to leukapheresis;
11. History of autoimmune diseases (such as Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus) within the past 2 years that resulted in end-organ damage, or required systemic immunosuppressive therapy or other systemic disease-controlling medications;
12. History of central nervous system (CNS) diseases, such as seizures, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, or psychiatric disorders; or known active CNS involvement or history thereof;
13. Subjects who are receiving systemic steroid therapy prior to screening, and who are judged by the investigator to require long-term use of systemic steroids during the study treatment period (excluding inhaled or topical steroids);
14. Presence of medical conditions that interfere with the ability to sign the written Informed Consent Form (ICF) or comply with study procedures; or those who are unwilling or unable to comply with study requirements;
15. History of severe immediate hypersensitivity reactions to any of the medications to be used in this study;
16. Any other conditions that, in the opinion of the investigator, make the subject unsuitable for participation in this study.