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A Phase I Clinical Study of Autologous T cells modified with chimeric antigen receptor targeting EpCAM ( EPCAM CAR-T) in Patients with malignant tumors of the digestive system (including advanced gastric cancer, colorectal cancer, liver cancer and pancreatic cancer) .
This is a phase I open-label, single and multiple infusion, dose escalation/cohort expansion study to evaluate the safety, cell pharmacokinetics, and preliminary efficacy of EPCAM CAR-T, infused intravenously in subjects who have been diagnosed with advanced malignant tumors of the digestive system (including advanced gastric cancer, colorectal cancer, liver cancer and pancreatic cancer) and refractory or intolerant to current standard systemic treatment.
Primary objectives:
•To evaluate the safety and tolerability of EPCAM CAR-T infused intravenously at escalating doses in patients with advanced malignant tumors of the digestive system.
Secondary objectives:
Exploratory purpose:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| EPCAM CAR-T | Experimental | The first stage: single dose escalation The classic "3+3" dose escalation test. The starting dose refers to the results of the previous test of subsequent subjects. In this study, 3 increasing dose levels were set up, with 3 to 6 cases per dose.
The second stage: combined radiofrequency/microwave ablation for the treatment of advanced digestive system malignant tumors with liver metastases |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| EPCAM CAR-T | Drug | Pretreatment with fludarabine and cyclophosphamide EpCAM CAR-T Cells infusion |
|
| Measure | Description | Time Frame |
|---|---|---|
| Dose limited toxicity （DLT） | Safety | 28 days |
| Maximum Tolerated Dose（MTD） | Tolerability evaluation | 28 days |
| Adverse Event(AE) | Incidence rate | 28 days |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Cells | Pharmacokinetics is the "Implantation endpoint" which is defined as the number of copies of the IMC001 DeoxyriboNucleic Acid（DNA）in peripheral blood detected at each visit after infusion until any two consecutive test results are negative or below the detection limit. Duration of IMC001 Cell persistence is the period from the day of infusion to the first negative test result or result lower than the detection limit |
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Inclusion Criteria:
Age between 18 and 70 years old (including boundary value), both male and female.
The first stage requires patients with malignant tumors of the digestive system (including advanced gastric cancer, advanced colorectal cancer, advanced pancreatic cancer, advanced liver cancer) who have failed previous standard treatments and have no other feasible effective treatment methods. The documents for the diagnosis of advanced digestive system malignancies include imaging reports (CT/MRI) or pathological examination results. The second stage requires patients with liver metastases of advanced digestive system malignancies (including gastric cancer liver metastasis, colorectal cancer liver metastasis, and pancreatic cancer liver metastasis) who have previously failed standard treatment and have no other feasible effective treatment methods. The investigator can judge it. Perform radiofrequency/microwave ablation therapy. Documents for diagnosing liver metastases from advanced digestive system malignancies include imaging reports (CT/MRI) or pathological examination results.
The subject's expected survival period is ≥12 weeks.
According to the RECIST V.1.1 standard, subjects participating in the first phase of dose escalation must have at least one target lesion that can be evaluated stably. Participants participating in the second phase of EpCAM CAR-T infusion therapy combined with local radiofrequency/microwave ablation therapy must have at least one non-target disease in the liver that is suitable for radiofrequency/microwave ablation therapy.
The histological staining of EpCAM in the biopsy tumor tissue sample is positive.
Subjects in the second stage require Child-Pugh classification of liver function as A or B (score ≤ 7 points).
ECOG stamina score 0～1.
The subject has sufficient organ and bone marrow function. Laboratory screening must meet the following standards (refer to NCI CTCAE 5.0). All laboratory test results should be within the following stable range and there is no continuous supportive treatment.
The left ventricular ejection fraction (LVEF)>45% in cardiac color Doppler ultrasound examination within one month.
Fertility status: female patients of childbearing age or male patients whose sexual partners are females of childbearing age are willing to take effective contraceptive measures from the signing of the informed consent form to 6 months after the last cell infusion (females of childbearing age include premenopausal women and premenopausal women). Women within 2 years after menopause).
The subject must sign and date a written informed consent form.
The subject must be willing and able to comply with the predetermined treatment plan, laboratory examination, follow-up and other research requirements.
Exclusion Criteria:
Subjects who meet any of the following conditions cannot be selected for this study;
Women during pregnancy and lactation.
Known history of human immunodeficiency virus (HIV) infection; acute or chronic active hepatitis B (HBsAg positive); acute or chronic active hepatitis C (HCV antibody positive). Syphilis antibody is positive; Epstein-Barr virus DNA quantitative> 500 copies; Cytomegalovirus (CMV) infection (IgM positive).
Severe infections that are active or poorly clinically controlled.
At present, there is a heart disease requiring treatment or a poorly controlled hypertension (defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure >90 mmHg after treatment with standardized antihypertensive drugs).
The presence of any of the following cardiac clinical symptoms or diseases:
Abnormal blood coagulation function (INR>1.5×ULN), bleeding tendency or receiving thrombolysis or conventional anticoagulation therapy (such as warfarin or heparin), patients need long-term antiplatelet therapy (aspirin, dose> 300mg/day; Clopidogrel, dose>75mg/day).
Subjects who need to use corticosteroids or other immunosuppressive drugs for systemic therapy during the treatment period.
Before treatment, blood oxygen saturation ≤95% (referring to pulse oxygen detection).
Have received systemic steroids equivalent to >15 mg/day of prednisone within 2 weeks before apheresis, except for inhaled steroids.
Before the pretreatment of chemotherapy for removing lymphocytes, the subject developed a new arrhythmia, including but not limited to arrhythmia that cannot be controlled with drugs, hypotension that requires vasopressor, bacteria, fungi, or intravenous antibiotics that require intravenous antibiotics. Viral infection. Subjects who use test antibiotics to prevent infection are up to the investigator to determine whether participants can continue to participate in the test.
Known past or current hepatic encephalopathy requiring treatment; patients with current or history of central nervous system disease, such as epileptic seizures, cerebral ischemia/hemorrhage, dementia, cerebellar disease or any associated central nervous system involvement Autoimmune disease; central nervous system metastasis or meningeal metastasis with clinical symptoms, or other evidence that the patient's central nervous system metastasis or meningeal metastasis has not been controlled, and the investigator judged that it is not suitable for inclusion in the group.
The results of the imaging examination of the subjects in the second stage: the liver is replaced by tumors ≥50%, or the main portal vein tumor thrombus, or the tumor thrombus invades the mesenteric vein/inferior vena cava; or there are central or extensive non-metastatic lesions .
Patients who have had other malignant tumors before or at the same time, with the following exceptions:
Have received other CAR-T treatments and TCR-T treatments in the past.
Received anti-PD-1/PD-L1 monoclonal antibody treatment within 4 weeks before apheresis.
Subjects who have received other gene therapy in the past.
Subjects with severe mental disorders.
Participated in other clinical studies in the past month.
The researcher assesses that the subject is unable or unwilling to comply with the requirements of the research protocol.
The subject withdrew from the study due to various reasons and could not participate in the study again.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Bowen Peng | Contact | +86 18870300543 | bowen.peng@immunofoco.com | |
| Saixue Zhang | Contact | +86 19857143032/8657187237646 |
| Name | Affiliation | Role |
|---|---|---|
| Weijia Fang | First Affiliated Hospital of Zhejiang University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Renji Hospital, School of Medicine, Shanghai Jiao Tong University | Recruiting | Shanghai | Shanghai Municipality | China |
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single dose escalation The classic "3+3" dose escalation test. The starting dose refers to the results of the previous test of subsequent subjects. In this study, 3 increasing dose levels were set up, with 3 to 6 cases per dose.
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| 52 weeks |
| Treatment Emergent Adverse Events(TEAE) | Incidence rate | Through study completion, an average of 3 years |
| Antitumor efficacy-objective response rate (ORR) | The period from the first evaluation of CR or PR to the first evaluation of PD or death of any cause. The period from the first evaluation of CR or PR to the first evaluation of PD or death of any cause. | Through study completion, an average of 3 years |
| Antitumor efficacy-Progression-free survival (PFS) | The period from the day when the subject receives the first study treatment to the first recorded tumor progression(whether treated or not) or death of any cause, which occurs first | Through study completion, an average of 3 years |
| Antitumor efficacy-Duration of response (DOR) | The period from the first evaluation of CR or PR to the first evaluation of PD or death of any cause. | Through study completion, an average of 3 years |
| Antitumor efficacy-Overall survival (OS) | The period from the first study treatment to any cause of death | Through study completion, an average of 3 years |
| Antitumor efficacy-Disease control rate (DCR) | The number of cases in which response (PR + CR) and stable disease (SD) are achieved from the start of cell infusion/the total number of evaluable cases (%). | Through study completion, an average of 3 years |
| Number of circulating tumor cells (CTC) in peripheral blood | The number of CTC before and after treatment was evaluated | Through study completion, an average of 3 years |
| First affiliated hospital, School of Medicine, Zhejiang University | Recruiting | Hangzhou | China |
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