A Study to Observe and Evaluate the Safety and Efficacy of c610 Injection for Treatment of Advanced Solid Tumor Patients

A Clinical Study on the Observation and Evaluation on the Safety and Efficacy of c610 Injection in the Treatment of Patients With Advanced Solid Tumors

This is an open-labeled, single-arm, multiple-dose escalation and single-dose expansion clinical study of cell therapy to observe and evaluate the safety and efficacy of c610 injection in the treatment of patients with advanced solid tumors.

Primary Objection:

1. The mainly purpose of dose-escalation stage is to observe and evaluate the safety and tolerability of c610 injection in patients with advanced solid tumor, including the dose-limited toxicity(DLT) and the maximum tolerated dose (MTD).
2. The mainly purpose of dose-expansion stage is to evaluate the safety and efficacy of c610 injection in the treatment of patients with advanced solid tumors.
3. To evaluate the objective remission rate (ORR) and disease control rate (DCR) of 3 months according by the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)

Secondary Objection:

1. To observe the pharmacokinetic (PK) characteristics of c610 injection in patients with advanced solid tumors and its retention in peripheral blood;
2. To evaluate the progression free survival (PFS), overall objective response rate (ORR), duration of response (DOR), and overall survival (OS) according by the Response Evaluation Criteria In Solid Tumors (RECIST 1.1);
3. To observe the change in cytokines release before and after c610 injection treatment;
4. To observe the variation of tumor biomarker before and after c610 injection treatment (e.g. prostate cancer serum PSA).

Exploratory objection:

To investigate the potential biological indicators of blood and tumor specimen, including ctDNA (circulating tumor DNA) sequencing, immune repertoire sequencing (tumor tissue is prior for single-cell sequencing), ADA and RCL detection.

Inclusion Criteria:

1. Age ≥18 and ≤80 years old, gender is not limited;
2. Life expectancy>3 months;
3. The Eastern Oncology Consortium (ECOG) performance status from 0 to 1;
4. Subjects with malignant solid tumors confirmed by pathological diagnosis（who have failed in previous treatment(s), or disease progression after systematic treatment, unable to tolerate during treatment, or who are currently in appropriate to receive standard treatment），including cervical cancer, head and neck tumor, liver cancer, urinary system tumor (renal cancer, urothelial cancer, prostate cancer), etc.
5. The percentage of PD-1 positive T lymphocytes in total T lymphocytes is more than 10%, and subjects should voluntarily receive peripheral blood mononuclear cell (PBMCs) apheresis collection.
6. At least one or more measurable lesions (CT slice thickness ≤ 5 mm, maximal diameter ≥ 10 mm, and lymph node with malignant metastasis minimal diameter of ≥15 mm) according by RECIST 1.1.

No serious hematological, hepatic, and renal function abnormalities, adequate function defined as :

1. Blood system (no blood transfusion or hematopoietic stimulating factor treatment within 14 days): Neutrophil count (ANC) ≥1.5×109/L, Platelet (PLT) ≥75×109/L, Hemoglobin (Hb) ≥80g/L, Lymphocyte count (LYM) ≥ 60%×lower limit of normal value;

2. Hepatic function: Total bilirubin (TBIL) ≤1.5×ULN, Alanine aminotransferase (ALT) ≤2.5×ULN,Aspartate aminotransferase (AST) ≤5×ULN of patients with liver metastasis, Creatinine≤1.5×ULN or creatinine clearance (eGFR) ≥60 mL/min (Cockcroft and Gault formula);

3. Blood coagulation function: Activated partial thrombin time (APTT) ≤1.5×ULN, International normalized ratio (INR) ≤1.5×ULN;

   8. Eligible subjects (male or female) must comply with effective contraception methods (hormonal or barrier method or abstinence, etc.) during the trial period at least 90 days after c610 injection; Female subjects of childbearing potential (definition refers to appendix) must undergo a pregnancy test (blood or urine) and the results must be negative within 7 days prior to first use of c610 injection.

   9. Subjects must be able to understand the protocol and be willing to enroll the study, sign the informed consent, and be able to comply with the study and follow-up procedures.

Exclusion Criteria:

1. Subjects with symptomatic and/or untreated brain metastases (of any size and number); However, patients may be eligible if they received documented treatment, and the intracranial lesion(s) remain stable for at least 2 months before starting screening;

2. Subjects suffered from other malignant tumors within two years prior screen or concurrent malignancy, except for basal cell skin cancer that has been cured, and in situ malignancies of cervical carcinoma or lung cancer;

3. Subjects received treatment with tislelizumab (excluding other PD-1 monoclonal antibodies) or any PD-L1 monoclonal antibody within the first 12 weeks of screening;

4. Subjects received systemic chemotherapy, radiotherapy, immunotherapy and targeted therapy within 2 weeks before screening; However, the restriction for Nitroso urea or Mitomycin C are within 6 weeks before screening;

5. Subjects received chronic systemic sex hormone treatment for any reason within 12 weeks before screening; However, the use of low-dose glucocorticoid replacement therapy due to adrenal cortex dysfunction is exempted.

6. Subjects received granulocyte Colony-stimulating factor (G-CSF) and Granulocyte-macrophage colony-stimulating factor (GM-CSF) for leukocytosis within 12 weeks before screening;

7. Any active autoimmune disease or autoimmune disease in history, which is included but not limited to: autoimmune hepatitis, interstitial pneumonia, enteritis, vasculitis, nephritis; and asthma requiring medical intervention by bronchiectasis, etc., except for vitiligo, psoriasis and alopecia without systemic treatment, well controlled type I diabetes, hypothyroidism with normal thyroid function after replacement therapy;

8. Recipients of any organ transplant, including allogeneic stem cell transplants, with exception of transplants requiring no immunosuppression (e.g, corneal transplants, hair transplants);

9. Subjects with any forms of primary immunodeficiency. e.g., SCID (severe combined immunodeficiency disease) and AIDS (acquired immunodeficiency syndrome).

10. Presence of major acute or chronic infections, including:

    1. Viral hepatitis, including hepatitis B (HBsAg positive and/or hepatitis B DNA copy number higher than the lower detection threshold of the research center)
    2. Hepatitis C, etc.; HIV antibody test positive; Patients with positive Treponema pallidum antibodies;
    3. Active bacterial or fungal infections that require systemic treatment;
    4. Active tuberculosis infection with clinical symptoms, physical examination or imaging, and laboratory findings;

11. Acute exacerbation of chronic obstructive pulmonary disease or other respiratory diseases;

12. Cardiovascular/Cerebrovascular disease with clinical significance, such as cerebrovascular accident/stroke (<6 months before enrollment), myocardial infarction (<6 months before enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Class II) or severe arrhythmia;

13. Clinically uncontrollable serious cavity effusion which is judged by researchers as unsuitable for inclusion;

14. Subjects received any genetically modified cell therapy in the past;

15. Subjects need anticoagulant treatment (Warfarin or heparin);

16. Subjects need long-term antiplatelet therapy (including but not limited to: aspirin> 300mg/d or clopidogrel >75mg/d, etc.);

17. Pregnant or lactating women;

18. Subjects with no/limited capacity for civil conduction, or mental disorders/ poor compliance;

19. Alcoholic or drug abuse;

20. Subjects or its families are incapable to understand the content and objectives of this clinical study;

21. Patients with other serious or uncontrolled systemic diseases, or other conditions deemed unsuitable for participation in this clinical trial as judged by the investigator.