a clinical study to evaluate b4t2-001 car t cells in the treatment of advanced solid tumors

Conditions: Advanced Solid Tumor

Summary: 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.