A Study to Evaluate Safety and Efficacy of Armored CAR-T Cell Injection C-CAR031 in Advanced Hepatocellular Carcinoma

Inclusion Criteria:

• 1.Voluntary participation and able to sign the informed consent form

• 2. Aged 18 to 75 years at screening
• 3. Patients with histologically confirmed hepatocellular carcinoma (HCC) who meetthe following requirements: a. Barcelona Clinic Liver Cancer Stage B or C (BCLC B/C)b. Child-Pugh score ≤ 6 c. GPC3 is possibly expressed in tumor tissues
• 4. Patients with relapsed / progressive disease after at least one prior standardsystemic therapy for HCC, or ineligible to accept/unable to tolerate the systemictherapies. Standard systemic therapies may include targeted drugs (such asSorafenib, Lenvatinib, Donafenib, Apatinib), immune checkpoint inhibitors (such asAtezolizumab, Pembrolizumab, Camrelizumab, Sintilimab, Nivolumab, Toripalimab,Tislelizumab) or chemotherapeutic drugs (such as Oxaliplatin and 5-Fu). Subjects intheC-CAR031 plus Lenvatinib group must meet the following criteria: (1)have notreceived prior Lenvatinib therapy; (2) Progression or intolerance to one prior lineof systemic therapy containing both immune checkpoint inhibitors and VEGF/VEGFR-targeted agents. Subjects in the C-CAR031 combination with Regorafenib group mustmeet the following criteria: (1)have not received prior Regorafenib therapy; (2)Progression or intolerance to one prior line of systemic therapy containing bothimmune checkpoint inhibitors and VEGF/VEGFR- targeted agents. Subjects intheC-CAR031 plus Durvalumab group must meet the following criteria:(1) Progressionor intolerance to one prior line of systemic therapy containing both immunecheckpoint inhibitors and VEGF/VEGFR-targeted agents; (2) no prior immune-relatedtoxicity leading to permanent discontinuation of immunotherapy;(3) no history of ≥Grade 3 immune-related adverse events (irAEs), or any grade immune-relatedneurological/ocular AEs. (Note: Subjects with ≤ Grade 2 endocrine AEs may enroll ifasymptomatic on stable replacement therapy, excluding those: a. requiringnon-corticosteroid immunosuppressants, b. experiencing AE recurrence uponimmunotherapy rechallenge, c. or using corticosteroids at >10 mg/day prednisone orequivalent.) (4) All AEs associated with prior immunotherapy must have resolved orreturned to pre-treatment levels prior to screening; (5) Body weight more than 30kg.
• 5. At least one measurable target lesion (as per RECIST v1.1)
• 6. WHO/ECOG performance status (PS) score of 0 or 1 point
• 7. Expected survival ≥ 12 weeks
• 8. Left ventricular ejection fraction (LVEF) by echocardiography ≥ 45%
• 9. No active pulmonary infection; no known history of pneumonitis requiringsteroids; absence of acute onset or progressive pneumonitis at baseline.
• 10. Laboratory tests: a. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L b. Lymphocytecount ≥ 0.4 × 109/L c. Platelet count ≥ 60 × 109/L d. Hemoglobin ≥ 80 g/L e. Totalbilirubin (TBIL) ≤ 2 × upper limit of normal (ULN) f. AST and ALT ≤ 5 × ULN g. Serumcreatinine ≤ 1.5 × ULN h. Prothrombin time (PT): prolonged PT ≤ 4 s
• 11. Patients without history of HBV infection, or with HBV DNA < 2000 IU/mL (or 10000 copies/mL) at screening who agree to receive anti-virus therapies throughoutthe study according to the guidelines
• 12. Negative serum or urine pregnancy test results for females of child-bearing ageat screening; In addition, they should agree to take effective contraceptivemeasures throughout the study
• 13. Patients who agree to abstain from drinking throughout the study

Exclusion Criteria:

• 1. History of severe allergic or hypersensitivity to DMSO. Subjects with knownallergies to the active components of Lenvatinib, Regorafenib, or Durvalumab will beexcluded from respective combination treatment groups.
• 2. History of liver transplantation
• 3. History of prior cell therapy
• 4. Tumor volume > 50% of the liver.
• 5. portal stem vein tumor thrombus
• 6. Moderate to severe ascites.
• 7. Metastases to bones or central nervous system (CNS), or involved CNSdiseasesincluding hepatic encephalopathy, epilepsy, cerebrovascular accidents, etc.
• 8. Receipt of radiotherapy within 6 weeks prior to apheresis
• 9. Receipt of Local therapy (such as surgery, ablation, and intervention) within 4weeks prior to apheresis or presence of unhealed wounds before apheresis
• 10. Receipt of systemic treatment and failure to meet the minimum requirements forwash-out periods before apheresis: a. Immune checkpointinhibitors: 2 weeks; b. Smallmolecule target therapy: < 7 days; c. Systemic anti-tumor therapies usingexperimental anticancer drugs or other Chinese herbal medicines and Chinese patentmedicines with unclear mechanisms: 2 weeks; d. Steroids (except inhaled steroids) orother immunomodulators (including interleukins, interferons, and thymosins) ofsystemic therapeutic dose: 2 weeks; e. Any unresolved toxicity ≥ NCI CTCAE Grade 2from prior anticancer therapy, except alopecia, vitiligo, and laboratoryabnormalities explicitly permitted by the inclusion criteria.
• 11. Other history of primary cancers, excluding:a. Nonmelanoma skin cancer cured byresection (such as basal cell carcinoma) b. Cured carcinoma in situ (such ascervical cancer, bladder cancer, and breast cancer)
• 12. Active hepatitis C virus infection (HCV RNA positive)
• 13. Syphilis infection
• 14. History of active/immunodeficient diseases (including but not limited to HIV,systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis,myasthenia gravis, Graves' disease, and hypophysitis; excluding: vitiligo oralopecia, hypothyroidism in patients with stable medical conditions after hormonereplacement therapy, any chronic skin conditions that need no systemic treatment,and other diseases judged by the investigator to be of no clinical significance)
• 15. Persistent and active infections (excluding prophylactic anti-infectives)
• 16. Uncontrolled hypertension, diabetes, arrhythmia, and symptomatic congestiveheart failure
• 17. Dementia or mental state changes supported by obvious clinical evidence
• 18. Cardiac insufficiency: class III or IV, according to the New York HeartAssociation (NYHA) functional classifications
• 19. Unstable heart or lung diseases
• 20. Obvious bleeding risks or tendencies
• 21. Females who are pregnant or breastfeeding or expect to be pregnant orbreastfeeding during the study
• 22. Other diseases that may add further risks to the subject or interfere with thestudy results as judged by the investigators
• 23. For combination with Lenvatinib, Regorafenib or Durvalumab, the following willbe excluded: a. History of renal disease or nephrotic syndrome; b. Refractory nauseaand vomiting, chronic gastrointestinal disease, inability to swallow formulation, orprevious intestinal resection that precludes adequate absorption, distribution,metabolism, or excretion of Lenvatinib or Regorafenib; c. History of ≥ Grade 3bleeding disorder, vasculitis, or significant gastrointestinal bleeding episodeswithin 28 days prior to screening; d. History of arterial thromboembolic events (ATEs), including myocardial infarction, cerebrovascular accident, or transientischemic attack within 6 months prior to screening; e. Serious or non-healing wound,active gastrointestinal ulcer, or bone fracture within 28 days prior to screening;f. Use of full-dose anticoagulants or thrombolytics for non-prophylactic purposeswithin 10 days prior to screening; g. History of deep vein thrombosis, pulmonaryembolism, or any other clinically significant thromboembolism within 3 months priorto screening; h. Presence of symptomatic or uncontrolled hypertension.
• 24. Uncontrolled intermittent severe chronic gastrointestinal disorders associatedwith diarrhea (excluded from the durvalumab treatment group).