A Clinical Study to Evaluate B4T2-001 CAR T Cells in the Treatment of Advanced Solid Tumors

This is a first in human (FIH), open-label, dose escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of B4T2-001 Autologous CAR T cells 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).

This is an open-label dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of B4T2-001 Autologous CAR T cells in subjects with BT-001 expressing advanced solid tumors. Patients who meet the eligibility criteria will receive B4T2-001 CAR T infusion after lymphodepletion. The lymphodepleting chemotherapy is administered on days -5, -4, and -3 before CAR T infusion using cyclophosphamide 300mg/m2 once daily and fludarabine 30mg/m2 once daily for 3 consecutive days. Doses may be adjusted for renal and/or hepatic insufficiency, or other comorbidities. The study is designed to include the following sequential steps: patient screening, pre-treatment, treatment and follow up for up to 2 years.

Eligibility Criteria:
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. Histologically or cytologically confirmed locally advanced or metastatic BT-001 positive malignant solid tumors (including but not limited to gastric or gastroesophageal junction adenocarcinoma, pancreatic cancer, non-small cell lung cancer and breast cancer), who have failed standard treatment, or for whom standard treatment is not available or applicable at this stage;
6. Having measurable or evaluable lesions according to RECIST 1.1 or the latest version;
7. Having sufficient bone marrow, liver and kidney functions (based on the normal value of the clinical trial site):

   * Absolute neutrophil count (ANC) ≥ 1.5×109/L, platelets ≥ 75×109/L;
   * Total serum bilirubin ≤ 1.5×upper limit of normal (ULN);
   * Without liver metastases, alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) ≤ 2.5×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.
8. Adequate oxygen saturation (≥ 95%) can be maintained without oxygen inhalation;
9. Male or female patients of childbearing potential must 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;
   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;
   4. Immunomodulatory therapy within 7 days;
   5. Radiotherapy within 14 days;
   6. Traditional Chinese medicine with anti-tumor indications within 14 days;
   7. Investigational agents or treatment within 28 days.
2. Previously treated with CAR-T/TCR-T cells therapy against any target or other cell therapies or therapeutic tumor vaccine;
3. Previously treated with any BT-001-targeted therapy;
4. Brain metastases with central nervous system symptoms;
5. Pregnant (positive pregnancy test prior to dosing) or breast-feeding women;
6. Allergic reaction to any drug and related excipients specified in protocol, e.g., lymphodepletion regimen (cyclophosphamide and fludarabine) and pre-infusion medication (acetaminophen and diphenhydramine), human serum albumin, tocilizumab, Erbitux/cetuximab, dimethyl sulfoxide (DMSO), and dextran 40;
7. Patients with active hepatitis B (hepatitis B surface antigen (HBsAg) is positive and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) \> 500IU/ml or lower limit of the research center \[Only when the detection limit of the research center is higher than 500IU/ml\]), or active hepatitis C (patients with positive HCV antibody but HCV-RNA \< lower limit of detection at the site are allowed), but patients receiving prophylactic antiviral therapy other than interferon are allowed;
8. 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;
9. Patients with autoimmune diseases;
10. Patients with active infection requiring intravenous anti-infective therapy based on the investigator's judgment;
11. Patients who underwent major surgeries within 2 weeks prior to apheresis and not fully recovered;
12. The toxicity of previous anti-cancer therapy 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);
13. Patients with severe complications such as active gastrointestinal bleeding, intestinal obstruction, intestinal paralysis, interstitial pneumonia, pulmonary fibrosis, renal failure, and uncontrolled diabetes;
14. 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;
15. 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);
16. Patients with the third space effusion that cannot be controlled clinically are not suitable for inclusion in the group according to the judgment of the investigator;
17. Patients with a history of uncontrollable mental illness;
18. Patients with gastric cancer have gastric perforation, pyloric obstruction, or complete biliary obstruction;
19. Patients with pancreatic cancer who have tumor causing biliary obstruction;
20. Any condition in which the investigator considers that the subject is not suitable to participate in the study.