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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT04981691
Other study ID # Amaretto
Secondary ID
Status Recruiting
Phase Phase 1
First received
Last updated
Start date October 1, 2021
Est. completion date July 9, 2022

Study information

Verified date September 2021
Source Ruijin Hospital
Contact Jun Zhang, MD, PhD
Phone 0086-13818332497
Email junzhang10977@sjtu.edu.cn
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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.


Description:

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.


Recruitment information / eligibility

Status Recruiting
Enrollment 12
Est. completion date July 9, 2022
Est. primary completion date January 9, 2022
Accepts healthy volunteers No
Gender All
Age group 18 Years to 80 Years
Eligibility Inclusion Criteria: 1. Ability to understand and the willingness to provide written informed consent. 2. Advanced pancreatic cancer, ovarian cancer, malignant mesothelioma, gastric cancer, bowel cancer, etc., diagnosed by histopathological or cytological examination, but not limited to subjects with various advanced solid tumors. 3. IHC test showed Mesothelin positive expression at least 1+ in tumor tissue 4. Age no less than 18 years. 5. Life expectancy greater than 3 months. 6. According to the RECIST (Response Evaluation Criteria in Solid Tumors) standard, there must be measurable lesions. 7. Evidence of metastatic disease and failure of at least 1 prior chemotherapy for metastatic disease. During the last treatment or after the treatment, the disease progressed and was confirmed (the investigator judged according to the RECIST 1.1 standard). 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 during the screening period and before apheresis. 9. Adequate liver/bone marrow function. 10. Female subjects must meet the following conditions: infertility or fertility and use high-efficiency contraceptive measures. 11. Male subjects agree to use approved contraceptive methods (e.g. birth control pills, barrier device, intrauterine device, abstinence) during the study and for 3 months following the last dose of the study cell infusion. Moreover, all men are absolutely prohibited from donating sperm within 1 year after receiving the last study treatment infusion. Exclusion Criteria: 1. Participated in any other trial in which receipt of an investigational study drug occurred within 28 days prior to entry into the study. 2. Received any anticancer medication in the 2 weeks prior to receiving their first dose of study treatment, including but not limited to surgery, systemic chemotherapy, radiotherapy, intervention, etc. 3. Uncontrolled thyroid dysfunction (serum thyroid hormone determination TT4, TT3, FT3, FT4, and serum thyroid-stimulating hormone TSH) are not suitable for enrolling in the study; 4. Pregnant or breastfeeding female, or not willing to take contraception measures during the study. 5. Any uncontrollable active infection, including but not limited to active tuberculosis; HBV infection (including HBsAg positive, or HBcAb positive and HBV DNA positive); HIV, syphilis, hepatitis C positive or suffering from other fatal viruses, Bacterial disease 6. Administrated with steroids (5 mg/day or more dexamethasone, or equivalent hormone drugs) within the past two weeks; 7. Other uncontrolled diseases may cause abnormal death of the patient; 8. Active autoimmune disease (including but not limited to: systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, etc.) requiring immunosuppressive therapy within the past 4 weeks. 9. Previously allergic to immunotherapy, tocilizumab, cyclophosphamide, fludarabine, and other related drugs, previous history of severe allergies, to research product excipients (such as human serum albumin, DMSO, and dextran 40 ); people who have a history of penicillin allergy and have a positive skin test at the time of screening. 10. Congestive heart failure, uncontrolled cardiac arrhythmia, etc. 11. Uncontrollable massive ascites, that cannot be drained by standard methods; 12. Intestinal obstruction or CT suggesting omental cake-like peritoneal metastasis, or repeated uncontrollable incomplete intestinal obstruction. 13. Have received any genetic engineering modified T cell therapy (including CAR T, TCR T cell). 14. Uncontrolled brain metastasis or mental illness. 15. Suffered from other uncured malignant tumors within the past 3 years or at the same time. 16. The blood oxygen saturation =95% at the time of screening and before apheresis. 17. Can't be followed up or obey protocol. 18. The investigator believes that it is not appropriate to participate in the trial.

Study Design


Related Conditions & MeSH terms

  • Refractory Malignant Solid Neoplasm

Intervention

Biological:
anti-MESO CAR T cells
Autologous genetically modified anti-MESO CAR T cells

Locations

Country Name City State
China Department of Oncology, Ruijin Hospital Shanghai

Sponsors (2)

Lead Sponsor Collaborator
Ruijin Hospital UTC Therapeutics Inc.

Country where clinical trial is conducted

China, 

Outcome

Type Measure Description Time frame Safety issue
Other mesothelin expression and efficacy Immunohistochemical method to detect the expression of mesothelin, CT or magnetic resonance image(MRI) evaluation efficacy, statistical method (SPSS 24.0) to assess the correlation between mesothelin expression level and efficacy 12 weeks after the last infusion
Primary TEAEs Incidence of Treatment Emergent Adverse Event 4 weeks after the last infusion
Primary TRAEs Incidence of Treatment Related Adverse Events 4 weeks after the last infusion
Primary SIAEs and SAEs Incidence of AEs of Special Interest and Serious Adverse Events 4 weeks after the last infusion
Primary DLTs Incidence of dose-limiting toxicities 4 weeks after the last infusion
Secondary TEAEs,TRAEs, SIAEs and SAEs Incidence of Treatment Emergent Adverse Event, Treatment Related adverse events, AEs of special interest and serious adverse events 12 weeks after the last infusion
Secondary ORR by IR Objective response rate based on investigator's evaluation 12 weeks after the last infusion
Secondary ORR by IRC ORR based on independent review committee evaluation 12 weeks after the last infusion
Secondary DCR by IR Disease control rate based on the investigator's evaluation 12 weeks after the last infusion
Secondary DCR by IRC DCR based on IRC evaluation 12 weeks after the last infusion
Secondary DOR by IR Duration of Remission based on the investigator's evaluation 12 weeks after the last infusion
Secondary TTR by IR Time to remission based on the investigator's evaluation 12 weeks after the last infusion
Secondary PFS by IR Progression-free survival (PFS) based on the investigator's evaluation 24 weeks after the last infusion
Secondary PFS by IRC PFS based on IRC evaluation 24 weeks after the last infusion
Secondary OS Overall survival 52 weeks after the last infusion
Secondary 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. 12 weeks after the last infusion
Secondary Cmax the highest concentration (Cmax) of anti-human MESO T cells in the peripheral blood after CAR T cell infusion 4 weeks after the last infusion
Secondary AUC the area under the curve of 28 days of anti-human MESO T cells in the peripheral blood after CAR T cell infusion 4 weeks after the last infusion
Secondary HACA Positive rate of Human Anti-CAR Antibodies after CAR T cell infusion 4 weeks after the last infusion
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