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

A study that aimed to assess the safety and anti-tumor activity of CCAR031 injection in unresectable HCC patients.

This study plans to enroll 8-44 patients to assess the safety of C-CAR031. Subjects who meet the eligibility criteria will either receive a single dose of C-CAR031 injection, and will be followed up post-treatment for safety monitoring，or further explore the treatment modality of combination with Lenvatinib or PD-1(L1) monoclonal antibody at explored safe and effective dose level(s) of C-CAR031 monotherapy in specific eligible advanced HCC patients to provide data support for the phase II study of CAR-T combination therapy. The follow-up period will be 12 months.

Eligibility Criteria:
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 meet the 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 standard systemic therapy for HCC, or ineligible to accept/unable to tolerate the systemic therapies. Standard systemic therapies may include targeted drugs (such as Sorafenib, Lenvatinib, Donafenib, Apatinib), immune checkpoint inhibitors (such as Atezolizumab, Pembrolizumab, Camrelizumab, Sintilimab, Nivolumab, Toripalimab, Tislelizumab) or chemotherapeutic drugs (such as Oxaliplatin and 5-Fu). Subjects in the C-CAR031 plus Lenvatinib group must meet the following criteria: (1) have not received prior Lenvatinib therapy; (2) Progression or intolerance to prior systemic therapy with first-line PD-1 (L1) monoclonal antibody, or contraindication to 1st line PD-1(L1) monoclonal antibody-based systemic therapy. Subjects in the C-CAR031 combination with PD-1 (L1) monoclonal antibody group must meet the following requirements: (1) have not received PD-1 (L1) monoclonal antibody therapy before; (2) Progression or intolerance to prior systemic therapy with first-line hepatocellular carcinoma targeted drugs (Sorafenib, Lenvatinib, Donafenib), or contraindications to first-line hepatocellular carcinoma targeted drugs (Sorafenib, Lenvatinib, Donafenib).
* 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 infection in the lungs
* 10. Laboratory tests: a. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L b. Lymphocyte count ≥ 0.4 × 109/L c. Platelet count ≥ 60 × 109/L d. Hemoglobin ≥ 80 g/L e. Total bilirubin (TBIL) ≤ 2 × upper limit of normal (ULN) f. AST and ALT ≤ 5 × ULN g. Serum creatinine ≤ 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 throughout the study according to the guidelines
* 12. Negative serum or urine pregnancy test results for females of child-bearing age at screening; In addition, they should agree to take effective contraceptive measures throughout the study
* 13. Patients who agree to abstain from drinking throughout the study

Exclusion Criteria:

* 1. History of severe allergies or allergic to the excipient DMSO of the cell product
* 2. History of liver transplantation
* 3. History of prior cell therapy
* 4. Tumor volume \> 70% of the liver
* 5. portal stem vein tumor thrombus
* 7. Metastases to bones or central nervous system (CNS), or involved CNS diseasesincluding 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 4 weeks prior to apheresis or presence of unhealed wounds before apheresis
* 10. Receipt of systemic treatment and failure to meet the minimum requirements for wash-out periods before apheresis: a. Immune checkpoint inhibitors: 6 weeks. b. Systemic anti-tumor therapies using experimental anticancer drugs or other Chinese herbal medicines and Chinese patent medicines with unclear mechanisms: 2 weeks c. Steroids (except inhaled steroids) or other immunomodulators (including interleukins, interferons, and thymosins) of systemic therapeutic dose: 2 weeks
* 11. Other history of primary cancers, excluding:a. Nonmelanoma skin cancer cured by resection (such as basal cell carcinoma) b. Cured carcinoma in situ (such as cervical 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 or alopecia, hypothyroidism in patients with stable medical conditions after hormone replacement 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 congestive heart failure
* 17. Dementia or mental state changes supported by obvious clinical evidence
* 18. Cardiac insufficiency: class III or IV, according to the New York Heart Association (NYHA) functional classifications
* 19. Unstable heart or lung diseases
* 20. Obvious bleeding risks or tendencies
* 21. Moderate or severe ascites
* 22. Females who are pregnant or breastfeeding or expect to be pregnant or breastfeeding during the study
* 23. Other diseases that may add further risks to the subject or interfere with the study results as judged by the investigators