The goal of this clinical trial is to study the safety, efficacy, and pharmacokinetics of mRNA-engineered anti-Mesothelin (MESO) Chimeric Antigen Receptor T-Cell (CAR-T cells) therapy in patients with mesothelin expression-positive, advanced solid tumors that have failed at least first-line or second-line therapy.
This phase I study is being conducted to establish safety, pharmacokinetics, and preliminary efficacy of intravenous (IV) mRNA electroporated fully-humanized anti-MESO re-directed autologous T cell administration in patients with chemotherapy-refractory metastatic solid tumors. The study will adopt the "3+3" dose escalation design exploring two doses of 1×109 and 3×109. The administration is planned to infuse 3 times a week for 2 consecutive weeks. • The subjects will receive a total dose of 1x109 RNA transduced anti-MESO CAR-T cells in the first week, following lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days by intravenous infusion. If there is no obvious dose-limiting toxicity (DLT) after the first week of infusion, three times consecutive infusions of 1x109 anti-MESO CAR-T cells each time is planned in the second week. Each subject needs to be observed for at least 2 weeks (14 days) after completing the last infusion. Lymphodepleting chemotherapy will not be repeated prior to additional infusions of anti-MESO CAR-T cells.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Autologous genetically modified anti-MESO CAR T cells
Department of Oncology, Ruijin Hospital
Shanghai, China
RECRUITINGTEAEs
Incidence of Treatment Emergent Adverse Event
Time frame: 4 weeks after the last infusion
TRAEs
Incidence of Treatment Related Adverse Events
Time frame: 4 weeks after the last infusion
SIAEs and SAEs
Incidence of AEs of Special Interest and Serious Adverse Events
Time frame: 4 weeks after the last infusion
DLTs
Incidence of dose-limiting toxicities
Time frame: 4 weeks after the last infusion
TEAEs,TRAEs, SIAEs and SAEs
Incidence of Treatment Emergent Adverse Event, Treatment Related adverse events, AEs of special interest and serious adverse events
Time frame: 12 weeks after the last infusion
ORR by IR
Objective response rate based on investigator's evaluation
Time frame: 12 weeks after the last infusion
ORR by IRC
ORR based on independent review committee evaluation
Time frame: 12 weeks after the last infusion
DCR by IR
Disease control rate based on the investigator's evaluation
Time frame: 12 weeks after the last infusion
DCR by IRC
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DCR based on IRC evaluation
Time frame: 12 weeks after the last infusion
DOR by IR
Duration of Remission based on the investigator's evaluation
Time frame: 12 weeks after the last infusion
TTR by IR
Time to remission based on the investigator's evaluation
Time frame: 12 weeks after the last infusion
PFS by IR
Progression-free survival (PFS) based on the investigator's evaluation
Time frame: 24 weeks after the last infusion
PFS by IRC
PFS based on IRC evaluation
Time frame: 24 weeks after the last infusion
OS
Overall survival
Time frame: 52 weeks after the last infusion
QOL
According to the EUROPEAN Organization for Research and Treatment of Cancer, Eortc, Quality of Life QuestionNare-Core 3, QOQ-C30), ERTC QLQ-C30, evaluated subject's quality of life.
Time frame: 12 weeks after the last infusion
Cmax
the highest concentration (Cmax) of anti-human MESO T cells in the peripheral blood after CAR T cell infusion
Time frame: 4 weeks after the last infusion
AUC
the area under the curve of 28 days of anti-human MESO T cells in the peripheral blood after CAR T cell infusion
Time frame: 4 weeks after the last infusion
HACA
Positive rate of Human Anti-CAR Antibodies after CAR T cell infusion
Time frame: 4 weeks after the last infusion