Human Chimeric Antigen Receptor Macrophages Targeting C-MET for C-MET-positive Advanced Stage of Pancreatic Cancer Patients: A Single-arm, Single-center, IIT Study
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Dose-Limiting Toxicity (DLT)
研究概览
简要总结
Chemotherapy is the first-line treatment for advanced-stage pancreatic cancer patients. However, drug resistance always occurs within 6 months. For these patients, no effective treatment is available. Chimeric antigen receptor macrophage targeting C-MET( CAR-M-C-MET) is a novel cellular therapy for these patients. In this clinical trial, advanced-stage pancreatic cancer patients when tumor progression after chemotherapy are enrolled to test the safety and anti-tumor efficacy of this novel cellular therapy.
详细描述
Chimeric antigen receptor macrophages (CAR-M) represent one of the most promising cellular immunotherapies for solid tumors. Patients with advanced-stage pancreatic cancer face an extremely dismal prognosis, particularly following the failure of chemotherapy. This trial investigates the role of CAR-M cellular therapy in advanced pancreatic cancer patients who have progressed after prior chemotherapy.
C-MET is a target highly expressed in the majority of pancreatic cancer tissues. In this study, a chimeric antigen receptor targeting c-MET is designed and cloned into an adenoviral vector. Peripheral blood mononuclear cells are collected from participants, and CD14-positive monocytes are isolated. These monocytes are then induced and expanded using Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), and subsequently transduced with the c-MET-specific CAR-adenoviral vector to generate CAR-M-c-MET. The final cell product is cryopreserved and later administered via intraperitoneal infusion. Each patient receives a single dose of cell infusion.
Following infusion, the safety, efficacy, and pharmacokinetics of CAR-M-c-MET therapy are comprehensively evaluated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able to understand and voluntarily sign a written informed consent form.
- •Willing and able to comply with the scheduled visit and treatment plan, laboratory tests, and other study requirements.
- •Aged ≥ 18 years and ≤ 75 years on the day of signing the informed consent form, male or female.
- •ECOG performance status of 0-
- •Histologically or cytologically confirmed locally unresectable or abdominopelvic metastatic pancreatic ductal adenocarcinoma.
- •Pancreatic cancer patients who have failed at least one prior line of therapy or are intolerant to such therapy.
- •Medium to high expression of C-MET in pancreatic cancer tissue (defined as ++ or higher, with positive cells > 25%).
- •At least one measurable lesion according to RECIST v1.1 criteria.
- •Expected survival ≥ 4 months.
- •Adequate organ function as defined by the following laboratory requirements:
- •Note: Subjects must not receive transfusions or growth factor support within 7 days prior to the first dose for hematology assessments.
- •Hematology:
- •Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L.
- •Platelet Count (PLT) ≥ 100 × 10⁹/L.
- •Hemoglobin (HGB) ≥ 90 g/L or ≥ 5.6 mmol/L.
- •Liver and Kidney Function:
- •Creatinine (Cr) ≤ 1.5 × ULN.
- •Albumin ≥ 30 g/L (Albumin infusion is not permitted within 14 days prior to the first dose).
- •Total Bilirubin (TBIL) ≤ 1.5 × ULN (For subjects with liver metastases, TBIL ≤ 3 × ULN).
- •Alanine Aminotransferase (ALT) ≤ 2.5 × ULN.
- •Aspartate Aminotransferase (AST): For subjects with liver metastases, ALT and AST ≤ 5 × ULN.
- •Urinalysis:
- •Urine protein ≤ 1+, without accompanying edema or serum albumin levels below the lower limit of normal (LLN).
- •Coagulation:
- •International Normalized Ratio (INR) and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN; unless the subject is receiving anticoagulant therapy, in which case PT or aPTT must be within the intended therapeutic range of the anticoagulant.
- •Prothrombin Time (PT) must be within the normal range.
- •Females of childbearing potential must have a negative serum pregnancy test result within 7 days prior to the first dose and must not be lactating.
排除标准
- •Received the following anti-tumor treatments prior to apheresis: Immunomodulatory therapy within 7 days; Cytotoxic therapy within 14 days; Investigational medication, targeted therapy, or anti-tumor traditional Chinese medicine within 28 days.
- •Previously received CAR-T cell therapy or other cell therapies targeting any antigen.
- •Liver metastases occupying more than 30% of the total liver volume.
- •History of other concurrent malignancies, except for the following: Completely resected or eradicated basal cell carcinoma and squamous cell carcinoma of the skin, cervical carcinoma in situ, minute/microscopic papillary thyroid carcinoma, minute/microscopic breast cancer, and other malignancies with an extremely low risk of recurrence or metastasis.
- •Patients with a history of autoimmune disease requiring immunosuppressive medication or hormone therapy (excluding physiological replacement doses).
- •History of severe Central Nervous System (CNS) disease, such as grand mal seizures, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, or psychosis.
- •Patients with a left ventricular ejection fraction (LVEF) < 50%, severe structural cardiac abnormalities, or arrhythmias requiring medical treatment.
- •Patients with a history of medical treatment for intestinal obstruction, or those with imaging findings during screening indicating intestinal obstruction requiring treatment.
- •Moderate to severe hepatic steatosis (fatty liver).
- •Patients with moderate to severe cirrhosis (Child-Pugh Class A or worse) and significant portal hypertension.
- •Patients with a history of gastrointestinal bleeding within the past 6 months requiring blood transfusion, emergency room observation, or hospitalization.
- •Patients with active peptic ulcers.
- •Patients with a history of severe intra-abdominal infection.
- •History of abdominal surgery within the past 3 months.
- •Any uncontrolled active infection.
- •Infectious diseases, including but not limited to: 1) Known Human Immunodeficiency Virus (HIV) infection or Acquired Immunodeficiency Syndrome (AIDS)-related illness; 2) Hepatitis B (HBsAg positive) or Hepatitis C (HCV RNA positive); 3) Active tuberculosis infection, or currently receiving anti-tuberculosis therapy, or having received anti-tuberculosis therapy within 1 year prior to the first dose of study drug; 4) Positive for Treponema pallidum antibody; 5) Other infectious diseases deemed unsuitable for participation in this study by the investigator.
- •Previous anti-tumor therapy-related Adverse Events (AEs) that have not resolved to Grade
- •Patients with deep vein thrombosis (DVT) or other conditions requiring anticoagulation therapy (e.g., heparin, warfarin).
- •Patients with a history of any arterial embolism.
- •Presence of other serious conditions prior to apheresis that could potentially limit the subject's participation in this trial, such as: Poorly controlled diabetes (glycated hemoglobin [HbA1c] > 8% despite treatment), inadequately controlled hypertension (blood pressure > 160 mmHg / 100 mmHg despite medication), myocardial infarction within the last 6 months, severe arrhythmia or unstable angina not well controlled by medication, pulmonary embolism, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), etc.
- •Pregnant or lactating women; women or men of childbearing potential planning pregnancy during the study period.
- •Substance abuse (medication or drugs), or clinical, psychological, or social factors that would impair informed consent or study conduct.
- •Patients with a history of severe allergies (e.g., allergies to three or more substances including food, drugs, etc.).
- •Presence of moderate or severe ascites.
- •Currently participating in another interventional clinical trial.
- •Any uncertainty that could affect patient safety or compliance.
- •Any other condition deemed by the investigator to make the subject unsuitable for enrollment.
研究组 & 干预措施
CAR-M-C-MET TREATMENT
CAR-M-C-MET INTRAPERITONEAL INFUSION FOR TREATMENT
干预措施: CAR-M-C-MET cell intraperitoneal infusion (Biological)
结局指标
主要结局
Dose-Limiting Toxicity (DLT)
时间窗: from the start point of cell infusion to 28 days after cell infusion for each patient
Any clinically significant Grade 3 or higher toxicity involving a major organ system, as defined by NCI CTCAE version 5, occurring within 28 days post-infusion and persisting for more than 72 hours; II. Any Grade 4 Cytokine Release Syndrome (CRS) occurring during the treatment period that does not resolve to Grade 2 or lower within 72 hours, or any death attributed to CRS; III. Any Grade 3 CRS occurring during the treatment period that does not resolve to Grade 2 or lower within 7 days; IV. Any Grade 3 or higher autoimmune toxicity occurring during the
Objective response rate（ORR）
时间窗: From date of signing the informed consent until the date of first documented progression from any cause, whichever came first, assessed up to 96 weeks
Stable disease (SD）+ Partial remission （PR）+Complete remission （CR） in accordance with RECIST v1.1 criteria
次要结局
- Progression free survial（PFS）(From date of signing the informed consent until the date of first documented progression or death from any cause, whichever came first, assessed up to 96 weeks)
- Pharmacokinetics of CAR-M(6 hours, 12 hours, 24 hours, 72 hours, 7 days, 14 days, 28 days, 60 days, 90 days, after cell infusion)