CIB In Vivo CAR-T Lentiviral Injection in Patients With Advanced Malignant Tumors

A Phase 1, Open-Label, Single-Arm, Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of CIB In Vivo CAR-T Lentiviral Injection in Patients With Advanced Malignant Tumors

This is an open-label, single-arm, phase 1 dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of CIB in vivo CAR-T lentiviral injection in patients with advanced malignant tumors.

The study will enroll patients with histologically or cytologically confirmed advanced solid tumors that have progressed on or are intolerant to standard therapies. A "3+3" dose-escalation design will be used, with planned dose levels including 1×10⁵ TU/kg, 3×10⁵ TU/kg, 1×10⁶ TU/kg, 3×10⁶ TU/kg, 1×10⁷ TU/kg, and 3×10⁷ TU/kg. The primary objective is to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) based on dose-limiting toxicities (DLTs) observed within 28 days after administration. Secondary objectives include evaluating adverse events, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and pharmacokinetic parameters of the study drug.

This is a single-center, open-label, phase 1 dose-escalation study. Eligible patients will receive CIB in vivo CAR-T lentiviral injection at escalating dose levels. Safety assessments include adverse events, laboratory tests, vital signs, and physical examinations. Efficacy assessments include tumor response evaluation according to RECIST v1.1. Pharmacokinetic and immunogenicity assessments will also be performed.

Inclusion Criteria:

1. Age ≥ 18 years and ≤ 75 years.

2. At least one measurable target lesion according to RECIST version 1.1 at screening.

3. Histologically or cytologically confirmed advanced or metastatic malignant tumor, with positive target expression confirmed by validated assay methods.

4. Patients who have failed prior standard systemic therapy (including but not limited to VEGF-targeted tyrosine kinase inhibitors and/or immune checkpoint inhibitors), or are intolerant to standard therapy.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Expected survival time ≥ 3 months as assessed by the investigator.

7. Adequate organ function at baseline (no growth factor support or transfusion within 14 days prior to screening):

   a. Bone marrow function: i. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; ii. Hemoglobin (Hb) ≥ 90 g/L; iii. Platelet count (PLT) ≥ 75 × 10⁹/L. b. Liver function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN); if liver metastases are present, ALT and AST ≤ 5 × ULN; total bilirubin (TBIL) ≤ 1.5 × ULN.

   c. Renal function: Serum creatinine ≤ ULN or creatinine clearance rate ≥ 80 mL/min.

8. For female patients of childbearing potential, serum β-HCG test result must be negative within 7 days prior to enrollment.

9. Patients must agree to use effective contraception from the signing of the informed consent form (ICF) until at least 90 days after the end of the study.

10. Voluntarily sign the informed consent form (ICF) and be able to understand and comply with the requirements of the study protocol.

Exclusion Criteria:

1. Asymptomatic untreated brain metastases; symptomatic central nervous system (CNS) metastases or carcinomatous meningitis; or other evidence of uncontrolled CNS/meningeal metastases that are considered unsuitable for enrollment by the investigator.

2. Presence of clinically significant cardiovascular, pulmonary, neurological, or systemic disease at baseline that may increase study participation risk or interfere with safety assessments.

3. Presence of severe chronic or active infection at baseline, including:

   1. Active hepatitis B (HBsAg positive with HBV DNA > ULN);
   2. Active hepatitis C (anti-HCV positive with detectable HCV RNA);
   3. Known history of or positive test for human immunodeficiency virus (HIV);
   4. Systemic anti-infective therapy required within 4 weeks prior to first administration, including hospitalization for infectious complications, bacteremia, severe pneumonia, or active tuberculosis.

4. History of active autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, vasculitis) or receipt of long-term systemic corticosteroids (prednisone > 10 mg/day or equivalent) or other immunosuppressive agents within 4 weeks prior to first administration.

5. Prior allogeneic tissue or solid organ transplantation.

6. Evidence of severe immunodeficiency, such as primary immunodeficiency (e.g., severe combined immunodeficiency, SCID) or concurrent opportunistic infections.

7. Prior gene therapy using lentiviral or retroviral vectors.

8. Prior treatment with drugs targeting the same antigen.

9. Requiring therapeutic anticoagulation that cannot be discontinued prior to administration.

10. History of severe cardiovascular disease, including:

    1. NYHA class ≥ II congestive heart failure;
    2. Left ventricular ejection fraction (LVEF) < 50%;
    3. Corrected QT interval (QTcF) > 470 ms or long QT syndrome;
    4. Acute coronary syndrome, aortic dissection, severe arrhythmia, stroke, or other grade ≥ 3 cardiovascular events within 6 months prior to first administration;
    5. Uncontrolled hypertension.

11. Prior anti-tumor therapy within 4 weeks or 5 half-lives (whichever is longer) prior to first administration, including chemotherapy, radiotherapy, biotherapy, endocrine therapy, immunotherapy; prior oral small-molecule targeted therapy within 2 weeks or 5 half-lives (whichever is longer); prior palliative radiotherapy within 14 days; prior participation in other anti-tumor clinical trials within 4 weeks; prior use of any anti-tumor traditional Chinese medicine within 2 weeks.

12. Pregnant or breastfeeding women, or women of childbearing potential who refuse to use effective contraception during the study period.

13. Any other disease or laboratory abnormality that, in the investigator's opinion, makes the patient unsuitable for participation in this study.