B4T2-001 CAR-T（自体 CAR-T 细胞）治疗晚期实体瘤：I 期临床试验

Inclusion Criteria:

1. The subjects have been fully informed of the possible risks and benefits of participating in this study and have voluntarily signed the informed consent form (ICF).
2. Age: 18-70 years (including 18 and 70 years).
3. ECOG 0-1.
4. With an expected survival of more than 3 months.
5. Patients with histologically or cytologically confirmed locally advanced or metastatic "BT-001 positive" solid tumors. IHC should be within 6 months of apheresis, but maybe extended.
6. Preference for patients who have failed first- or second-line therapy.
7. Having measurable lesions according to RECIST 1.1 (or the latest version).
8. Maximum tumor size less than 4 cm according to RECIST 1.1 (or the latest version).
9. Having sufficient bone marrow, liver, kidney, and lung functions (based on the normal value of the clinical trial sites).

   * ANC and PLT ≥ LLN.
   * Without liver metastases, ALT, AST, or ALP ≤ 2.5×upper limit of normal (ULN); with liver metastases, ALT, AST, or ALP ≤ 5×ULN.
   * Serum creatinine (ScR) ≤ 1.5×ULN, or creatinine clearance \> 50 mL/min (calculated according to Cockcroft Gault formula).
   * International normalized ratio (INR) ≤ 1.5×ULN, APTT ≤ 1.5×ULN.
   * Adequate oxygen saturation (≥ 95%) can be maintained without oxygen inhalation.
10. Male or female patients of childbearing potential agree to use effective methods of contraception (such as double-barrier contraceptive methods, condoms, oral or injectable contraceptives, and intrauterine devices) during the study period and within 1 year after infusion.

Exclusion Criteria:

1. Patients who have received the following anti-tumor treatments prior to apheresis:

   1. Cytotoxic therapy within 14 days or 28 days (for chemotherapy with high lymphocytic toxicity such as bendamustine, cyclophosphamide, ifosfamide, fludarabine, cladribine, etc.).
   2. Small molecule targeted therapy within 14 days or at least 5 half-lives, whichever is longer.
   3. Therapy with monoclonal antibody within 21 days including cetuximab.
   4. Therapy with immune checkpoint inhibitors and/or Avastin within 30 days of apheresis.
   5. Immunomodulatory therapy within 14 days.
   6. Radiotherapy within 14 days of apheresis.
   7. Traditional Chinese medicine with anti-tumor indications within 14 days of apheresis.
   8. Investigational agents or treatment within 28 days of apheresis.
   9. Previously treated with CAR-T/TCR-T cells and/or vaccine within 28 days of apheresis.
2. Previously treated with any BT-001-targeted therapy.
3. Brain metastases with central nervous system symptoms.
4. Pregnant (positive pregnancy test prior to dosing) or breast-feeding.
5. Allergic or suspected allergic reaction to any drug and related excipients specified in protocol, e.g., camelid antibody, pre-infusion medication (acetaminophen and diphenhydramine), serum albumin, tocilizumab (or biosimilars of tocilizumab that have been approved for CRS indication), Erbitux/ cetuximab, dimethyl sulfoxide (DMSO), and dextran 40.
6. Patients with positive hepatitis B surface antigen (HBsAg) or hepatitis B virus (HBV) deoxyribonucleic acid (DNA) \> 100IU/mL or lower limit of the research center \[Only when the detection limit of the research center is higher than 100IU/mL\]), or patients with positive HCV antibody.
7. Patients with a history of immunodeficiency, including those who are HIV-positive, or patients with other acquired or congenital immune deficiency, or a history of organ transplantation.
8. Patients with concomitant or previous history of interstitial lung disease or interstitial pneumonia; presence of multiple metastatic lesions in the lungs or a single metastatic lesion ≥ 3 cm in length; patients with inflammation in the lungs or have received extensive radiotherapy.
9. Patients with uncontrolled active infection based on the investigator's judgment.
10. Patients who underwent major surgery within 2 weeks prior to apheresis and not fully recovered.
11. The toxicity of previous anti-cancer therapy, including immunotherapy has not returned to less than or equal to Grade 1 as specified in CTCAE v5.0 or the latest version (except for hair loss, Grade 2 peripheral neuropathy, and stable hypothyroidism treated with hormone replacement therapy).
12. Patients with a history of acute myocardial infarction, unstable angina pectoris, stroke, or transient ischemic attack within 6 months prior to the enrollment, or with NYHA Class 2 or higher congestive heart failure.
13. Patients with chronic diseases requiring treatment with systemic corticosteroids or other immunosuppressants, received systemic corticosteroids (≥ 70 mg prednisone or equivalent dose of other corticosteroids) or other immunosuppressants within 7 days before apheresis, except for the following cases: local, ocular, intra-articular, intranasal, and inhaled glucocorticoid treatment; short term use of glucocorticoids for preventive treatment (such as prevention of contrast medium allergy).
14. Patients with autoimmune diseases.
15. Patients with Crohn's Disease.
16. Patients with a history of uncontrollable mental illness.
17. Any condition in which the investigator considers that the subject is not suitable to participate in the study.

主要终点：Safety and tolerability of B4T2-001 CAR-T will be assessed by the incidence of serious adverse events (SAEs), incidence and severity of adverse events (AEs). · Multiple infusions of B4T2-001 CAR-T. · 2 years after B4T2-001 CAR-T；To determine the MTD and RP2D of B4T2-001 CAR-T · The MTD will be determined based on the occurrence of the DLTs according to dose escalation design. RP2D will be defined based on MTD, safety, PK, and preliminary efficacy data. · 2 years after B4T2-001 CAR-T
次要终点：PK parameters: maximum concentration (Cmax)；PK parameters: time of peak concentration (Tmax)；PK parameters: the last measurable time point (Tlast)；PK parameters: area under the curve (AUCs)；Overall response rate (ORR) after administration；Duration of Response (DOR) after administration；Progress Free Survival (PFS) after administration；Overall Survival (OS) after administration

• B4T2-001 CAR T · EXPERIMENTAL · Single Arm and Open Label study consisting of dose escalation study design followed by dose expansion phase at determined MTD.

This is an open-label, dose escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of autologous B4T2-001 CAR-T in subjects with advanced solid tumors including but not limited to advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, advanced pancreatic cancer, advanced non-small cell lung cancer (NSCLC), colorectal cancers (CRC) and metastatic breast cancer that tests positive for BT-001 target antigen according to Immunohistochemistry (IHC). The trial builds off first-in-human results from pilot study per clinicaltrials.gov ID: NCT05621486 to administer multiple infusions of B4T2-001 CAR-T without the need to give preparative chemotherapy (lymphodepletion).