- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05812326
PD-1 Knockout Anti-MUC1 CAR-T Cells in the Treatment of Advanced Breast Cancer
Exploratory Clinical Study of PD-1 Knockout Targeting MUC1 CAR-T Cells (AJMUC1) in the Treatment of MUC1-positive Advanced Breast Cancer
Study Overview
Status
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Guangdong
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Guangzhou, Guangdong, China, 510120
- Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Patient age: 18-70 years (including the boundary value);
- Pathologically diagnosed with recurrent/metastatic breast cancer (except for intracranial metastasis), who have received at least one standard treatment regimen in the past, the disease is in a stable or progressive state, and refuses to undergo subsequent chemotherapy;
- Abnormal glycosylated MUC1 expression confirmed by immunohistochemistry in tumor tissue or puncture tissue within 12 months;
- Expected survival period ≥ 4 months;
- ECOG score≤2 points;
- The subjects voluntarily joined the study, signed the informed consent form, had good compliance, and cooperated with the follow-up;
- Able to cooperate with tumor puncture;
- At least one measurable lesion that meets the RECIST v1.1 criteria;
- Female patients of childbearing age must not be breastfeeding, and serum or urine HCG test is negative within 72 hours before study enrollment. All subjects must use medically approved contraception during the study period and within 3 months after the end of the study. measures (eg, IUDs, birth control pills) for contraception;
- Organ function and bone marrow reserve are in good condition and the following requirements must be met: (1) The absolute value of neutrophils is ≥1.5×109/L; (2) Platelet count ≥75×109/L; (3) Hemoglobin ≥9g/dl; (4) Bilirubin value < 1.5 times the upper limit of normal (except for obstruction of the bile duct caused by tumor compression); (5) Creatinine value < 1.5 times the upper limit of normal or creatinine clearance rate ≥ 60ml/min; (6) ALT or AST < 2.5 times the upper limit of normal (with liver involvement < 5 times the upper limit of normal); (7) Stable coagulation function: INR≤1.5, PTT<1.2 times the upper limit of normal (except for tumor-related anticoagulation therapy).
Exclusion Criteria:
- Have used immunosuppressive drugs or hormones within 1 week prior to enrollment;
- Patients with moderate or more moderate pleural and ascites who need catheter drainage to relieve symptoms;
- Human immunodeficiency virus (HIV) positive;
- Active hepatitis B or C infection;
- Pregnant or lactating women;
- Past or concurrent history of other malignant tumors. Excluded: Patients with basal or squamous cell carcinoma of the skin and carcinoma in situ of the cervix who have been cured at any time prior to the study;
- Those with central transfer;
- Serious, uncontrollable concomitant diseases that may affect protocol compliance or interfere with the interpretation of results, or have any serious medical conditions that may affect the subject's safety (such as uncontrollable heart disease, high blood pressure, active or uncontrollable disease) infection, etc.);
- Active autoimmune diseases (including but not limited to, systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, etc.);
- Those with a history of organ transplantation;
- Subjects whose last medication was less than 2 weeks before enrollment, or subjects who participated in other relevant clinical studies at the same time;
- Those who have received gene therapy in the past;
- Vaccination with live vaccine within 4 weeks prior to study;
- History of myocardial infarction and severe arrhythmia within half a year; uncontrolled hypertension, coronary heart disease, stroke, liver cirrhosis, nephritis and other serious complications;
- Those who have a history of psychotropic substance abuse and cannot quit or who have a history of mental disorders;
- Hypersensitivity constitution, allergic to human serum albumin;
- Hemorrhagic and thrombotic tendency: patients with clinically significant bleeding symptoms or clear bleeding tendency within 3 months before the study, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, abnormal coagulation function (PT>16s, APTT>43s) , TT>21s, FIB<2g/L), hereditary or acquired bleeding and thrombosis tendency to (such as hemophilia, coagulation disorder, thrombocytopenia, hypersplenism, etc.), are receiving thrombolytic or anticoagulation therapy, arterial/venous thrombotic events occurred within the previous 6 months, such as cerebrovascular disease (including cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism;
- Other severe, acute, or chronic medical or psychiatric conditions that may increase the risks associated with participation in the study or may interfere with the interpretation of the study results, in the opinion of the investigator.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Sequential Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment with AJMUC1--PD-1 knockout CAR-T cells
Advanced breast cancer patients with positive MUC1 expression are the indications of this clinical study. Current conventional treatments are ineffective for these patients or there is no effective treatment plan available for them. No control group is established and a single arm design is used. This clinical study is the first application of AJMUC1 in the clinical treatment of MUC1-positive advanced breast cancer patients. The main purpose is to assess the safety and feasibility of the product in clinical use. Therefore, according to the principle of "3+3" dose escalation design, this study explored the maximum tolerated dose of AJMUC1 for the treatment of MUC1-positive advanced breast cancer. At the same time, the efficacy of AJMUC1 in the treatment of MUC1-positive advanced breast cancer will be observed and factors that could affect the safety and efficacy of the therapy will be exploringly evaluated. |
AJMUC1 is a genetically modified T cell therapeutic product targeting the aberrantly glycosylated MUC1 protein.
CAR targeting MUC1 is introduced into autologous T cells by lentiviral vector, so that T cells expressing the receptor can recognize and kill MUC1 positive tumor cells.
Preclinical studies have shown that binding of scFv targeting MUC1 to the MUC1 epitope on the surface of the target cell can induce the costimulatory CD28 and CD3ζ costimulatory domains to activate downstream signaling pathways and promote T cell activation and expansion.
Activated CAR-T cells secrete a series of inflammatory cytokines and chemokines, leading to apoptosis and necrosis of target tumor cells.
Following introduction of a CAR structure, the PD-1 gene of CAR-T cells is knocked out using CRISPR/Cas9, so that the CAR-T cell does not express PD-1, resulting in improved tumor killing efficiency of AJMUC due to the release of inhibition in the signaling pathway PD-1/PD-L1 in the tumor microenvironment.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Number of participants with adverse events and dose limiting toxicities as assessed by CTCAE v5.0
Time Frame: 3 years
|
3 years
|
Incidence of treatment-emergent adverse events [safety and tolerability] of dose of PD-1 Knockout CAR-T cells will be assessed using CTCAE v5.0
Time Frame: 3 years
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3 years
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Monitoring the numbers of circulating AJMUC1 after infusion will be evaluated.
Time Frame: up to 3 years
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up to 3 years
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Response rate will be assessed according to the revised RECIST guideline iRECIST
Time Frame: 3 years
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3 years
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Overall Survival - OS (Measure the time from enrollment to death)
Time Frame: 3 years
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3 years
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Progression free survival - PFS (Time from enrollment to date of first documented progression or date of death)
Time Frame: 3 years
|
3 years
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Median CAR-T cell persistence--Will be measured by quantitative RT-PCR
Time Frame: 3 years
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3 years
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To evaluate serum cytokine changes after AJMUC1 treatment of aberrantly glycosylated MUC1 expression in advanced breast cancer
Time Frame: 3 years
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The serum cytokine included IL-1β, IL-2R, IL-6, IL-8, TNF and IL-10
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3 years
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Erwei Song, MD, PhD, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2019-KY-001-003
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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