Pancreatic Cancer, Pancreatic Cancer Non-resectable, Pancreatic Cancer Stage IV, Pancreatic Carcinoma
Conditions
Keywords
Pancreatic Cancer, claudin 18.2, Pancreatic Carcinoma, CAR-T, Mesothelin
Brief summary
Autologous T-cells engineered to express CARs targeting Mesothelin and Claudin18.2, for Unresectable locally advanced or metastatic pancreatic adenocarcinoma (Pancreatic Ductal Adenocarcinoma, PDAC), administered as two separate sequential infusions following lymphodepleting chemotherapy
Detailed description
Pancreatic cancer is one of the most lethal malignancies, with a poor prognosis in advanced stages. Mesothelin (MSLN) and Claudin 18.2 (CLDN18.2) are tumor-associated antigens overexpressed in pancreatic adenocarcinoma cells. Both are promising immunotherapy targets, as they are prevalent in pancreatic tumors while largely restricted in normal tissues. CAR-T cell therapies directed at these antigens have shown early evidence of safety and anti-tumor activity. For example, mesothelin-specific CAR T cells have achieved stable disease and metabolic tumor regression in initial trials without dose-limiting toxicity. Similarly, CLDN18.2-specific CAR-T cells yielded objective remissions (including complete remission) in refractory pancreatic cancer, albeit with some gastric mucosal toxicity due to low-level target expression in normal stomach. Targeting two antigens may improve tumor control by addressing antigen heterogeneity and reducing immune escape. This trial evaluates a dual-target CAR-T strategy, in which two separate CAR-T products (one for mesothelin, one for claudin18.2) are given sequentially.
Interventions
BIOLOGICALMesothelin and Claudin 18.2 CAR-T cells
The intervention in this clinical trial involves a novel approach using Mesothelin and Claudin 18.2 Chimeric Antigen Receptor T (CAR T) cells combined with chemotherapy. The goal is to assess safety and efficacy in patients with specific hematologic malignancies. Treatment Regimen: Fludarabine Phosphate (Days -4 to -2): IV administration of fludarabine phosphate over 30 minutes on days -4 to -2. It's part of the preparatory regimen to enhance the body's response to CAR T-cell therapy. Cyclophosphamide (Day -2): IV cyclophosphamide over 60 minutes on day -2. Mesothelin and Claudin 18.2 Chimeric Antigen Receptor T Cells (Day 0): IV administration of investigational therapy, Mesothelin and Claudin 18.2 CAR T cells, over 10-20 minutes on day 0. Additional Doses: Eligible patients responding well to the initial Mesothelin and Claudin 18.2 CAR-T cell infusion without unacceptable side effects and sufficient CAR-T cell availability may receive 2 or 3 additional doses.
Sponsors
Essen Biotech
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-label clinical trials are a category of clinical research where the masking is minimal or nonexistent. In such trials, both the participants and the researchers are fully aware of the treatment assignments, which means participants know the treatment they are receiving, and researchers are aware of each participant's treatment group.
Intervention model description
This is a Phase 1/2, first-in-human, open-label, non-randomized trial of sequential dual-target CAR-T cell therapy in subjects with advanced pancreatic cancer
Eligibility
Sex/Gender
ALL
Age
21 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Expected survival time ≥3 months; * Histologically or cytologically confirmed pancreatic adenocarcinoma that is advanced (unresectable or metastatic). Patients should have received, or be intolerant of, standard first-line therapy (e.g., gemcitabine/nab-paclitaxel, FOLFIRINOX) for advanced disease. A short course of current first-line therapy is allowed for the purpose of bridging to manufacturing, but evidence of disease progression on or after at least one line is required prior to infusion (for the dose-expansion phase, patients must have progressed on ≥1 prior systemic regimen). * ECOG Performance Status: 0 or 1 (fully active or restricted in strenuous activity but ambulatory). * Liver and kidney function, cardiopulmonary function meet the following requirements: * Creatinine ≤1.5×ULN; (2) Electrocardiogram showed no clinically significant abnormal bands; * Blood oxygen saturation \>91% in non-oxygen state; * Total bilirubin ≤2×ULN; ALT and AST≤2.5 x ULN; ALT and AST abnormalities due to disease, such as liver infiltration or bile duct obstruction, were determined to be less than 5×ULN. If Gilbert syndrome is diagnosed, the total bilirubin index can be relaxed to ≤3.0×ULN and the direct bilirubin ≤1.5×ULN. * No serious mental disorders; * Can understand this test and has signed the informed consent.
Exclusion criteria
* Hepatitis B surface antigen (HBsAg) positive; Hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer detection is not within the normal reference value range; Hepatitis C virus (HCV) Antibody positive and peripheral blood hepatitis C virus (HCV) RNA positive; Human immunodeficiency virus (HIV) Antibody positive; Syphilis positive; * Serious heart disease, including but not limited to unstable angina, myocardial infarction or bypass or stent surgery (within 6 months prior to screening), congestive heart failure (NYHA classification ≥III), and severe arrhythmia; * Systemic diseases that are deemed unstable by researchers: including but not limited to severe liver, kidney, or metabolic diseases that require drug treatment; * Active or uncontrollable infections (except mild genitourinary and upper respiratory tract infections) that require systemic treatment within 7 days prior to administration; * Pregnant or lactating women, and female subjects who plan pregnancy within 2 years after cell transfusion or male subjects whose partners plan pregnancy within 2 years after cell transfusion; * Patients who received CAR-T therapy or other gene-modified cell therapy before screening; * Participated in other clinical studies 1 month before screening; * Evidence of central nervous system invasion during subject screening; * Mental patients with depression or suicidal thoughts; * Situations considered unsuitable for inclusion by other researchers.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of dose-limiting toxicities (DLTs) following chemotherapy preparative regimen and infusion of CD19/BCMA chimeric antigen receptor (CAR) T cells | 28 days | Will be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at three dose levels until the maximum tolerated dose (MTD) is determined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of successful manufacture and expansion of the Mesothelin and Claudin 18.2 chimeric antigen receptor (CAR) T cells | 60 days | satisfy the targeted dose level and meet the required release specifications outlined in the Certificate of Analysis (COA) |
Countries
China
Contacts
Primary ContactRhoda M Smith, Phd
Outcome results
None listed