Exploratory Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of UCLM802 (Anti-Mesothelin CAR-T) Cell Injection in Patients With Mesothelin-positive Advanced Malignant Solid Tumors

Zhejiang University1 site in 1 country87 target enrollmentApril 27, 2023

ConditionsMesothelin-positive Advanced Malignant Solid Tumors

Overview

Phase: Phase 1
Intervention: Not specified
Conditions: Mesothelin-positive Advanced Malignant Solid Tumors
Sponsor: Zhejiang University
Enrollment: 87
Locations: 1
Primary Endpoint: Adverse Events (AEs)
Status: Recruiting
Last Updated: 2 years ago

Overview Investigators Eligibility Criteria Outcomes Sites Similar Trials

Overview

Brief Summary

This is a single-arm, open-label, exploratory clinical study to evaluate the safety, tolerability and preliminary efficacy of UCLM802 (Anti-Mesothelin CAR-T) cell injection in patients with Mesothelin-positive advanced malignant solid tumors.

Detailed Description

This study comprises a dose-escalation component and a dose-expansion component. In dose escalation phase, this study will adopt accelerated titration and 3+3 design to reduce the number of subjects exposed to potentially ineffective doses who may not benefit from treatment. In dose expansion phase, there are three cohorts in dose-expansion component. Cohort 1: To explore the effects of different conditioning chemotherapy regimens on safety, tolerability and efficacy; Cohort 2: To explore the effects of different administration modes on safety, tolerability and efficacy; Cohort 3: To explore the effects of combination immune checkpoint inhibitors on safety, tolerability and efficacy. All eligible participants will receive a conditioning chemotherapy regimen of fludarabine and cyclophosphamide followed by UCLM802 cell injection.

Registry

clinicaltrials.gov

Start Date

April 27, 2023

End Date

July 2025

Last Updated

2 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

Zhejiang University

Responsible Party

Principal Investigator

Weijia Fang, MD

Professor of Medicine

Zhejiang University

Eligibility Criteria

Inclusion Criteria

•Subjects are≥18 years old (including cut-off value), gender is not limited.
•Solid tumors that histological diagnosis of malignancy refractor to, or relapsing after standard therapy, including but not limited to mesothelioma, pancreatic cancer, biliary tract cancer, lung cancer, ovarian cancer, gastric cancer, bowel cancer, thymic carcinoma, esophageal cancer, breast cancer, endometrial cancer. Subjects have failed with standard treatment or cannot tolerate treatment recommended by clinical treatment guidelines form relevant international and domestic authoritative organization (Chinese Anti-Cancer Association(CACA), Chinese Society of Clinical Oncology(CSCO), National Health Commission, etc.)
•At least one measurable lesion according to RECIST v1.
•Mesothelin should be positive confirmed by Immunohistochemistry/Immunocytochemistry (IHC/ICC) in tumor tissue samples.
•Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
•Life expectancy ≥ 3 months.
•Adequate function defined as:
•Hematological functions: Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L (Patients should not receive G-CSF support within 7 days before laboratory examination); Absolute Lymphocyte Count (ALC) ≥ 0.5 × 10\^9/L; Hemoglobin (HGB) ≥ 80 g/L (Patients should not be transfused red cells within 7 days before the laboratory examination); Platelet count (PLT) ≥ 75 × 10\^9/L (Patients should not receive transfusion support within 7 days before the laboratory examination).
•Hepatic functions: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × upper limit of normal (ULN); AST and ALT of patients with liver metastasis ≤ 5 × ULN; Total bilirubin (TBIL) ≤ 1.5 × ULN; TBIL of patients with liver metastasis must ≤ 3.0 × ULN; TBIL of patients with Gilbert's Syndrome ≤ 3.0 × ULN and Direct bilirubin (DBIL) ≤ 1.5 × ULN.
•Coagulation functions: International normalized ratio (INR) ≤ 1.5 × ULN; Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (Except for patients who are receiving therapeutic anticoagulants.).

Exclusion Criteria

•Patients have received systemic therapy with cytotoxic chemicals, monoclonal antibodies, or immunotherapy within 4 weeks or 5 half-lives (which is shorter) prior to signing informed consent; Patients have received systemic glucocorticoids (prednisone at a dose of ≥10 mg per day or equivalent) or other immune-suppressive therapy within 2 weeks prior to signing informed consent; Patients have received systemic antitumor therapy with a biologic agent or other approved targeted small-molecule inhibitor within 1 week or five half-lives (which is shorter) prior to signing informed consent; Patients have received Chinese herbal medicine or Chinese patent medicine with anti-tumor indication within 1 week prior to signing informed consent.
•Pregnant or lactating women.
•Patients with hepatitis B surface antigen (HBsAg) positive. Patients who is hepatitis B core antibody (HBcAb) positive and the quantification of HBV DNA in peripheral blood is higher than the lower limit of detection. Patients who is hepatitis C virus (HCV) antibody positive and quantification of HCV RNA in peripheral blood is higher than the lower limit of detection. Patients with human immunodeficiency virus (HIV) antibody positive, or syphilis antibody positive.
•The toxicities caused by the prior therapy (surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, etc.) have not recovered to grade 1 according to CTCAE, except for hair loss and peripheral sensory nerve disorders.
•Have received any allogeneic tissue/organ transplantation (including bone marrow transplantation, stem cell transplantation, liver transplantation, kidney transplantation), except for the transplantation that does not require immunosuppressive therapy (such as: corneal transplantation, hair transplantation.)
•Patients have received anti-mesothelin CAR-T cell therapy.
•Patients who have history of major surgery and unrecovered severe trauma within 4 weeks prior to signing informed consent; or plan to have major surgery within 12 weeks of cell therapy.
•Presence of known central nervous system metastases, but the following patients will be allowed: a) Asymptomatic brain metastases; b) Clinically stable (no radiographic progression within 4 weeks before apheresis and return of any neurologic symptoms to baseline), and with no need for corticosteroids or other treatment for brain metastases for ≥ 4 weeks.
•Patients with clinically significant systemic disease (such as: severe active infection or significant cardiac, pulmonary, hepatic, nervous system, or other organ dysfunction) that evaluated by the investigator would impair the patients' ability to tolerate the treatments used in this study or significantly increase the risk of complications.
•Uncontrolled severe active infection (sepsis, bacteremia, viremia, etc.);

Outcomes

Primary Outcomes

Adverse Events (AEs)

Time Frame: 2 years

Incidence and severity of adverse events.

Serious Adverse Events (SAEs)

Time Frame: 2 years

Incidence and severity of serious adverse events.

Identification of Maximum Tolerated Dose (MTD)

Time Frame: 4 weeks after the CAR-T cells infusion

Incidence and severity of dose-limiting toxicities (DLTs) following infusion of UCLM802 cell injection, at each dose level tested in dose escalation phase.

Adverse Events of Special Interest (AESI)

Time Frame: 2 years

Incidence and severity of adverse event of special interest.