CDH17 CAR-T Therapy in Advanced Malignant Solid Tumors

Exploratory Study on the Safety and Preliminary Efficacy of UCLH80-1 Cells in Patients With CDH17-Positive Advanced Malignant Solid Tumors

The investigational product used in this study, UCLH801 cells, is a CAR-T cell therapy specifically targeting CDH17. The proposed indication includes CDH17-positive advanced solid tumors, such as but not limited to colorectal cancer, gastric cancer, pancreatic cancer, biliary tract tumors, neuroendocrine tumors, ovarian cancer, and lung cancer. The primary objective of this study is to evaluate the safety and tolerability of UCLH801 cells in patients with CDH17-positive advanced malignant solid tumors. The secondary objectives include assessing the preliminary efficacy of UCLH801 cells, their pharmacokinetics and pharmacodynamics in the body, and their immunogenicity.

This study aims to observe how the infusion of UCLH801 cells affects patients 's body, including any discomfort or changes in laboratory test results. Additionally, it will evaluate whether UCLH801 cells have any effect on tumor. Furthermore, the study will investigate how UCLH801 cells are metabolized; the mechanisms through which they exert their effects, and how to develops any immune response or rejection against UCLH801 cells.

The trial progresses through sequential Phase Ia (dose-finding) and Phase Ib (dose-expansion) stages. Phase Ia cessation triggers include either confirmation of Recommended Phase II Dose (RP2D) or investigator-verified favorable therapeutic index at any dose level. Post-Phase Ia completion, protocol amendment submission to the Institutional Review Board precedes Phase Ib initiation, featuring multi-cohort expansion (n=9-18/cohort) across specified malignancies: colorectal adenocarcinoma (CRC), gastric carcinoma (GC), high-grade serous ovarian carcinoma (HGSOC), breast cancer (BC), non-small cell lung cancer (NSCLC), SCLC, metastatic castration-resistant prostate cancer (mCRPC), clear cell renal cell carcinoma (ccRCC), and cervical squamous cell carcinoma (CSCC), etc.

This is a single-center, open-label, dose-escalation study consisting of two distinct treatment cohorts for patients with CDH17-positive advanced malignant solid tumors: Cohort 1 (CDH17 CART): A dose-escalating (3+3 design) study with 3 dose levels: 1.0×10^6, 3.0×10^6, and 6.0×10^6 CAR+ cells/kg. Cohort 2 (FAST LACO-Stim CDH17 CART): A dose-escalating (3+3 design) study with 2 dose levels: 3.0×10^4, and 1.0×10^5 CAR+ cells/kg. During dose escalation, the investigator may adjust the dose level as appropriate based on the accumulated human safety and tolerability, pharmacokinetic, and pharmacodynamic data.

The final sample size will depend on the occurrence of dose-limiting toxicities (DLTs), the number of dose escalation groups before observing DLTs, and the maximum tolerated dose (MTD). The observation period for dose-limiting toxicity (DLT) is set from the start of cell infusion to 4 weeks after the completion of cell infusion (D0 to D28).

Inclusion Criteria:

• Histopathologically confirmed malignant solid tumors, including but not limited to colorectal cancer, gastric cancer, pancreatic cancer, and biliary tract tumors.
• Patients must have failed standard treatments, be intolerant to standard treatments, or lack effective treatment options.
• At least one measurable lesion as defined by RECIST v1.1 criteria.
• Tumor tissue must be available either from prior tumor biopsy or by providing new tumor specimens.
• Tumor specimens must be confirmed as CDH17-positive by immunohistochemistry (IHC) or immunocytochemistry (ICC) staining.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Expected survival time ≥ 3 months.
• Appropriate organ function: hematological: Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; Absolute lymphocyte count (ALC) ≥ 0.5 × 10⁹/L. Hemoglobin (HGB) ≥ 80 g/L; Platelet count (PLT) ≥ 75 × 10⁹/L. Liver Function: aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3.0 × ULN (≤ 5.0 × ULN for patients with primary liver tumors or liver metastases); total bilirubin ≤ 1.5 × ULN (≤ 3.0 × ULN for patients with primary liver tumors or liver metastases; ≤ 3 × ULN for Gilbert's syndrome with direct bilirubin ≤ 1.5 × ULN). Coagulation: international normalized ratio (INR) ≤ 1.5 × ULN (unless on therapeutic anticoagulants); activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (unless on therapeutic anticoagulants). Renal Function: serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance rate ≥ 60 mL/min (based on Cockcroft-Gault formula). Cardiac Function: left ventricular ejection fraction (LVEF) ≥ 50% (confirmed by echocardiography). Pulmonary Function: resting oxygen saturation (SpO₂) > 92% without supplemental oxygen.
• Female participants of childbearing potential must have a negative pregnancy test.
• Female participants of childbearing potential or male participants with partners of childbearing potential must agree to use effective contraception during the study and for 1 year after the final cell infusion.
• Willingness to sign the informed consent form, demonstrating understanding of the study and agreement to comply with study procedures.

Exclusion Criteria:

• Women who are pregnant or breastfeeding.
• Positive hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb) with peripheral HBV DNA levels above the lower limit of detection.
• Positive hepatitis C virus (HCV) antibody with peripheral HCV RNA levels above the lower limit of detection.
• Positive HIV antibody.
• Positive syphilis-specific and non-specific antibody tests.
• Non-hematological toxicity from prior treatment (surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, etc.) has not resolved to ≤ CTCAE grade 1 (except for hair loss and peripheral sensory neuropathy).
• Prior allogeneic tissue or organ transplant (including bone marrow, stem cell, liver, kidney, etc.), except for transplants not requiring immunosuppression (e.g., corneal or hair transplantation).
• Patients who have previously received CDH17 CAR-T therapy, except those who received CAR-T infusion within this study.
• Underwent major surgery within 4 weeks prior to signing informed consent and has not fully recovered, or has a history of serious unresolved trauma.
• Known central nervous system (CNS) metastases (with exceptions for asymptomatic brain metastases or stable clinical symptoms).
• Severe active infections or pulmonary diseases requiring systemic corticosteroid treatment within 6 months prior to signing informed consent.
• Symptomatic congestive heart failure (NYHA class II-IV), severe aortic stenosis, or symptomatic mitral stenosis.
• ECG showing QTc > 450 ms or QTc > 480 ms with bundle branch block.
• Uncontrolled hypertension (SBP ≥ 160 mmHg and/or DBP ≥ 100 mmHg).
• Cerebrovascular accidents within 6 months prior to signing informed consent.
• Active, chronic, or recurrent severe autoimmune diseases requiring immunosuppressive treatment (with exceptions).
• Any form of primary or secondary immunodeficiency.
• Risk of organ perforation or bleeding as judged by the investigator.
• Severe systemic hypersensitivity reactions to study drugs/components. - Received live attenuated vaccines within 4 weeks prior to signing informed consent.
• Participated in another clinical study within 4 weeks prior to signing informed consent.
• History of another malignancy within the past 5 years, except for adequately treated non-melanoma skin cancer or in situ cancers.
• Diagnosed with neuropsychiatric disorders or any condition deemed by the investigator as unsuitable for participation.