A Clinical Study of CEA-targeted CAR-T in the Treatment of CEA-positive Advanced Malignant Solid Tumors

Colorectal Cancer Clinical Trial

Official title:

A Phase I Clinical Study of Anti-CEA CAR-T Therapy in the Treatment of CEA-positive Advanced Malignant Solid Tumors

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05396300
• Other study ID #: PBC039
• Status: Recruiting
• Phase: Phase 1
• Start date: May 25, 2022
• Est. completion date: May 15, 2025

Study information

• Verified date: April 2024
• Source: Zhejiang University
• Contact: Weijia Fang, M.D
• Phone: 13758211655
• Email: weijiafang[@]zju.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase I clinical study to evaluate the safety and tolerability of CAR-T in patients with CEA-positive advanced malignant solid tumors, and to obtain the maximum tolerated dose of CAR-T and phase II Recommended dose.

Description:

This is a single-center, double-arm, open-label study. The study plans to set up 2 groups,Intravenous infusion group have 3 dose groups, adopting a dose-escalating 3+3 design, and plan to recruit about 9-18 subjects with CEA-positive advanced malignant solid tumors.Intraperitoneal injection group have 4 dose groups, adopting a dose-escalating 3+3 design, and plan to recruit about 12-24 subjects with CEA-positive advanced malignant solid tumors.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: May 15, 2025
• Est. primary completion date: May 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age =18 years old, male or female;

2. Advanced, metastatic or recurrent malignant tumors diagnosed by histology or pathology, mainly colorectal cancer, esophageal cancer, gastric cancer, and pancreatic cancer;

3. After receiving at least second-line standard treatment and failing (disease progression or intolerance, such as surgery, chemotherapy, radiotherapy, etc.) or lack of effective treatment methods;

4. Immunohistochemical staining of tumor samples within 3 months confirmed that the tumor was CEA positive (clear membrane staining, positive rate = 10%); If over 3 months, the patient's serum CEA should exceed 10ug/L.

5. At least one assessable lesion according to RECIST 1.1 criteria;

6. ECOG score 0-2 points;

7. No serious mental disorder;

8. Unless otherwise specified, the function of the vital organs of the subject shall meet the following conditions:

1. Blood routine: white blood cells>2.0×109/L, neutrophils>0.8×109/L, lymphocytes cells>0.5×109/L, platelets>50×109/L, hemoglobin>90g/L;

2. Cardiac function: echocardiography showed cardiac ejection fraction =50%, and no obvious abnormality was found on electrocardiogram;

3. Renal function: serum creatinine=2.0×ULN;

4. Liver function: ALT and AST =3.0×ULN (for those with liver tumor infiltration, it can be relaxed to=5.0×ULN);

5. Total bilirubin=2.0×ULN;

6. Oxygen saturation > 92% in non-oxygen state.

9. Have apheresis or venous blood collection standards, and have no other contraindications for cell collection;

10. Subjects agree to use reliable and effective contraceptive methods for contraception within 1 year after signing the informed consent form to receiving CAR-T cell infusion (excluding rhythm contraception);

11. The patients themselves or their guardians agree to participate in this clinical trial and sign the ICF, indicating that they understand the purpose and procedures of this clinical trial and are willing to participate in the research.

Exclusion Criteria:

1. CNS metastases or meningeal metastases with clinical symptoms at the time of screening, or there is other evidence that the patient's central nervous system metastases or meningeal metastases have not been controlled, and are judged by the investigator to be unsuitable for inclusion;

2. Participated in other clinical studies within 1 month before screening;

3. vaccinated with live attenuated vaccine within 4 weeks before screening;

4. Received the following anti-tumor treatments before screening: Received chemotherapy, targeted therapy or other experimental drug treatments within 14 days or at least 5 half-lives (whichever is shorter);

5. Active infection or uncontrollable infection requiring systemic treatment;

6. Patients with intestinal obstruction, active gastrointestinal bleeding, or a history of gastrointestinal bleeding within 3 months;

7. Except for alopecia or peripheral neuropathy, the toxicity of previous anti-tumor therapy has not improved to the baseline level or = grade 1;

8. Suffering from any of the following heart diseases:

1. New York Heart Association (NYHA) stage III or IV congestive heart failure;

2. Myocardial infarction or coronary artery bypass grafting (CABG) within 6 months before enrollment;

3. Clinically significant ventricular arrhythmia, or history of syncope of unknown origin (caused by vasovagal except those caused by neurosis or dehydration);

4. History of severe non-ischemic cardiomyopathy;

9. Patients with active autoimmune disease, or other patients requiring long-term immunosuppressive therapy;

10. Suffering from other uncured malignant tumors in the past 3 years or at the same time, except cervical carcinoma in situ and basal cell carcinoma of the skin;

11. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer is greater than the normal range; hepatitis C virus (HCV) antibody positive and peripheral blood hepatitis C Virus (HCV) RNA test is greater than the normal range; human immunodeficiency virus (HIV) antibody positive; syphilis test positive;

12. Women who are pregnant or breastfeeding;

13. Other investigators deem it unsuitable to participate in the study.

Related Conditions & MeSH terms

• Colorectal Cancer
• Esophageal Cancer
• Metastatic Tumor
• Neoplasm Metastasis
• Pancreatic Cancer
• Recurrence
• Recurrent Cancer
• Stomach Cancer
• Stomach Neoplasms

Intervention

Biological:
• CEA CAR-T cells
Administration method: intravenous infusion or intraperitoneal injection; Subjects will be treated with Fludarabine and Cyclophosphamide before cell infusion.

Locations

Country	Name	City	State
China	First affiliated hospital, Zhejiang University	Hangzhou	Zhejiang

Sponsors (2)

Lead Sponsor	Collaborator
Weijia Fang, MD	Chongqing Precision Biotech Co., Ltd

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Objective response rate (ORR) of CEA- CAR-T treatment in patients with CEA-positive advanced malignancies[Effectiveness]	Objective response rate includes:CR?PR	1 years
Other	Duration of Response (DOR) of CEA- CAR-T treatment in patients with CEA-positive advanced malignancies[Effectiveness]	DOR will be assessed from the first assessment of CR/PR/SD to the first assessment of recurrence or progression of the disease or death from any cause	1 years
Other	Progress-free survival(PFS) of CEA- CAR-T treatment in patients with CEA-positive advanced malignancies[Effectiveness]	PFS will be assessed from the first CEA-CAR-T cell infusion to death from any cause or the first assessment of progression.	1 years
Other	Overall survival(OS)of CEA- CAR-T treatment in patients with CEA-positive advanced malignancies[Effectiveness]	OS will be assessed from the first CEA-CAR-T cell infusion to death from any cause	1 years
Other	Proportion of tumor cells in tumor tissue of CEA- CAR-T treatment in patients with CEA-positive advanced malignancies	The rate of tumor cell in tumor tissue will be measured by biopsy and immunohistochemistry	1 years
Other	CEA expression level of CEA- CAR-T treatment in patients with CEA-positive advanced malignancies	The CEA expression in tumor tissue will be measured by biopsy and immunohistochemistry	1 years
Other	Changes in the number of tumor-infiltrating immune cells of CEA- CAR-T treatment in patients with CEA-positive	the number of tumor-infiltrating immune cells will be measured by biopsy and immunohistochemistry	1 years
Primary	Incidence of Adverse events after CEA-CAR-T cells infusion [Safety and Tolerability]	Therapy-related adverse events were recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0)	28 days
Primary	Obtain the maximum tolerated dose of CEA-CAR-T cells[Safety and Tolerability]	Dose-limiting toxicity after cell infusion	28 days
Secondary	Disease control rate of CAR-T cell preparations in CEA-positive advanced malignancies [Effectiveness]	Disease control rate: including CR, PR and SD	3 months
Secondary	Changes in serum tumor markers of CAR-T cell preparations in CEA-positive advanced malignancies [Effectiveness]	Changes in serum tumor markers:CEA? CA199? CA125	3 months
Secondary	AUCS of CEA-CAR-T cells [Cell dynamics]	AUCS is defined as the area under the curve in 28 days and 90 days	1 years
Secondary	CMAX of CEA-CAR-T cells [Cell dynamics]	CMAX is defined as the highest concentration of CEA-CAR-T cells expanded in peripheral blood	1 years
Secondary	TMAX of CEA-CAR-T cells[Cell dynamics]	TMAX is defined as the time to reach the highest concentration	1 years
Secondary	Pharmacodynamics of CEA-CAR-T cells[Cell dynamics]	The content of free CEA in peripheral blood at each time point measured by Chemiluminescence immunoassay	1 years