Clinical Study of CEA Targeting Chimeric Antigen Receptor T Lymphocytes（CAR-T） for CEA Positive Advanced Malignant Solid Tumors

Chimeric Antigen Receptor T Lymphocytes (CAR-T) Targeting CEA in the Treatment of CEA Positive Clinical Study of Advanced Malignant Solid Tumors

This study is a open-label, dose-escalating + dose-expansion clinical study, aiming to evaluate the safety and efficacy of CEA-targeted CART cell preparations, and to reliminarily observe the study drug in CEA-positive advanced malignant tumors. The pharmacokinetic characteristics of CART cell preparations for the treatment of patients with CEA-positive advanced malignancies were obtained and the recommended dose and infusion schedule.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Gastric Cancer; Lung Cancer; Rectal Cancer; Cholangiocarcinoma; Colon Cancer; Pancreas Cancer; Esophagus Cancer
• Intervention / Treatment: Biological: CEA-targeted CAR-T cells; Biological: CEA-targeted CAR-T cells

Detailed Description

According to the infusion ways, it is divided into two subgroups: intravenous infusion and intraperitoneal injection. Each subgroup includes a dose exploration stage and a dose expansion stage. 3 patients were explored, starting from the low-dose group, and in the dose expansion phase, the safety and efficacy were further verified according to the safe recommended dose obtained in the dose exploration phase.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: lili Sheng, M.D; Phone Number: 13605535185; Email: shenglili@yjsyy.com

Study Locations

• China
  • Anhui
    • Wuhu, Anhui, China
      • Recruiting
      • The First Affiliated Hospital of Wannan Medical College
      • Contact: lili Sheng, MD; Phone Number: 13605535185; Email: shenglili@yjsyy.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 failure (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%); , the positive rate ≥ 10%), the serum CEA of the patient is required to exceed 10ug/L.
5. At least one assessable lesion according to RECIST 1.1 criteria,For extranodal lesions, the length and diameter should be ≥10mm. For nodular lesions, the short diameter of the lymph node should be ≥15mm;
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>3.0×10^9/L,neutrophils>0.8×10^9/L, lymphocytes cells>0.5×10^9/L,platelets>75×10^9/L, hemoglobin>80g/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 patients with liver tumor infiltration, it can be relaxed to ≤5.0×ULN);
   5. Total bilirubin≤3.0×ULN;
   6. Oxygen saturation ≥95% 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. Those who have central nervous system metastasis or meningeal metastasis at the time of screening 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. There is a large amount of uncontrolled fluid accumulation in the serous cavity;
8. Except for alopecia or peripheral neuropathy, the toxicity of previous anti-tumor therapy has not improved to the baseline level or ≤ grade 1;

9. 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 a history of unexplained syncope (except those caused by vasovagal or dehydration);
   4. History of severe non-ischemic cardiomyopathy;
10. Patients with active autoimmune disease, or other patients requiring long-term immunosuppressive therapy;
11. 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;
12. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer test 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;
13. Women who are pregnant or breastfeeding;
14. Other investigators deem it unsuitable to participate in the research.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous of CEA-targeted CAR-T; Infusion of CEA-targeted CAR-T cells by dose of 3-10x10^6 cells/kg	Biological: CEA-targeted CAR-T cells; Administration method: intravenous infusion Subjects will receive conditioning therapy by ludarabine and Cyclophosphamide before cell infusion.; Biological: CEA-targeted CAR-T cells; Administration method: intraperitoneal injection Subjects will receive conditioning therapy by Fludarabine and Cyclophosphamide before cell infusion.
Experimental: intraperitoneal injection of CEA-targeted CAR-T; Infusion of CEA-targeted CAR-T cells by dose of 1-10x10^6 cells/kg	Biological: CEA-targeted CAR-T cells; Administration method: intravenous infusion Subjects will receive conditioning therapy by ludarabine and Cyclophosphamide before cell infusion.; Biological: CEA-targeted CAR-T cells; Administration method: intraperitoneal injection Subjects will receive conditioning therapy by Fludarabine and Cyclophosphamide before cell infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Obtained the recommended dose and infusion regimen of CAR-T cells for the treatment of patients with CEA-positive advanced malignancies[Safety and Tolerability]	Dose-limiting toxicity after CEA CAR-T cell infusion	28 days
Incidence of Treatment-associated Adverse Events [Safety and Tolerability]	The incidence of adverse events after CEA CAR-T cell infusion was assessed by the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0)	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUCS of CEA CAR-T cells [Cell dynamics]	AUCS is defined as the area under the curve in 90 days	3 months
CMAX of CEA CAR-T cells [Cell dynamics]	CMAX is defined as the highest concentration of CEA CAR-T cells expanded in peripheral blood	3 months
TMAX of CEA CAR-T cells[Cell dynamics]	TMAX is defined as the time to reach the highest concentration	3 months
Pharmacodynamics of CEA CAR-T cells[Cell dynamics]	The content of CEA in peripheral blood was detected by ELISA at the visit points specified in the research protocol	3 months
Assessing disease control rates of CAR-T cell preparations in CEA-positive advanced malignancies[Effectiveness]	Disease control rate: The proportion of subjects who achieved CR, PR, SD after CAR-T infusion accounted for all treated subjects (Assessed based on RECIST criteria),the minimum value is 0%,maximum value is 100%, and higher scores mean a better outcome.	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	2 years
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(Assessed based on RECIST criteria)	2 years
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 (Assessed by investigators based on IRECIST criteria)	2 years
Objective response rate (ORR) of CEA CAR-T treatment in patients with CEA-positive advanced malignancies[Effectiveness]	Objective response rate includes#The proportion of subjects who achieved CR, PR after CAR-T infusion accounted for all treated subjects (Assessed based on RECIST criteria) the minimum value is 0%,maximum value is 100%, and higher scores mean a better outcome.	2 years

Collaborators and Investigators

• Sponsor: Chongqing Precision Biotech Co., Ltd
• Collaborators: First Affiliated Hospital of Wannan Medical College
• Investigators: Principal Investigator: lili Sheng, M.D, The First Affiliated Hospital of Wannan Medical College

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2023
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: November 6, 2023
• First Submitted That Met QC Criteria: November 6, 2023
• First Posted (Estimated): November 10, 2023

Study Record Updates

• Last Update Posted (Estimated): November 13, 2023
• Last Update Submitted That Met QC Criteria: November 9, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: CAR-T; CEA; CEA-positive advanced/metastatic solid tumors
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Esophageal Diseases; Pancreatic Diseases; Pancreatic Neoplasms; Cholangiocarcinoma; Esophageal Neoplasms
• Other Study ID Numbers: PBC055

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No