Anti-mesothelin CAR-T Cells With Advanced Refractory Solid Tumors (Amaretto)

An Open, Single-center, Exploratory Clinical Trial to Evaluate the Safety and Efficacy of mRNA CAR-mesothelin T Cells in Patients With Advanced Refractory Solid Tumors

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.

Study Overview

• Status: Recruiting
• Conditions: Refractory Malignant Solid Neoplasm
• Intervention / Treatment: Biological: anti-MESO CAR T cells

Detailed 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.

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jun Zhang, MD, PhD; Phone Number: 0086-13818332497; Email: junzhang10977@sjtu.edu.cn
• Study Contact Backup: Name: Yan Shi, MD, PhD; Phone Number: 0086-13810561979; Email: sy_rjh@aliyun.com

Study Locations

• China
  • Shanghai, China, 200025
    • Recruiting
    • Department of Oncology, Ruijin Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: anti-MESO CAR-T cells; The subjects in this arm will receive Cyclophosphamide 300mg/m2/d and Fludarabine 30mg/m2/d from day-4 to day-2. Subjects will be treated with six administrations of anti-MESO CAR-T cells three times weekly (Monday-Wednesday-Friday) for two weeks. In the first week, total 1×109 or 3×109 will be infused, the second week is to plan three times consecutive infusions of 1x109 or 3×109 anti-MESO CAR-T cells each time. Subjects will be enrolled serially. For subject safety, the preceding subject must have completed therapy and be 28 days from their last infusion before the next subject can be treated. Interventions: Drug: anti-MESO CAR-T cells; Drug: Fludarabine; Drug: Cyclophosphamide

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TEAEs	Incidence of Treatment Emergent Adverse Event	4 weeks after the last infusion
TRAEs	Incidence of Treatment Related Adverse Events	4 weeks after the last infusion
SIAEs and SAEs	Incidence of AEs of Special Interest and Serious Adverse Events	4 weeks after the last infusion
DLTs	Incidence of dose-limiting toxicities	4 weeks after the last infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
ORR by IR	Objective response rate based on investigator's evaluation	12 weeks after the last infusion
ORR by IRC	ORR based on independent review committee evaluation	12 weeks after the last infusion
DCR by IR	Disease control rate based on the investigator's evaluation	12 weeks after the last infusion
DCR by IRC	DCR based on IRC evaluation	12 weeks after the last infusion
DOR by IR	Duration of Remission based on the investigator's evaluation	12 weeks after the last infusion
TTR by IR	Time to remission based on the investigator's evaluation	12 weeks after the last infusion
PFS by IR	Progression-free survival (PFS) based on the investigator's evaluation	24 weeks after the last infusion
PFS by IRC	PFS based on IRC evaluation	24 weeks after the last infusion
OS	Overall survival	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.	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	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	4 weeks after the last infusion
HACA	Positive rate of Human Anti-CAR Antibodies after CAR T cell infusion	4 weeks after the last infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Ruijin Hospital
• Collaborators: UTC Therapeutics Inc.
• Investigators: Principal Investigator: Jun Zhang, MD, PhD, Ruijin Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2021
• Primary Completion (Anticipated): January 9, 2022
• Study Completion (Anticipated): July 9, 2022

Study Registration Dates

• First Submitted: July 7, 2021
• First Submitted That Met QC Criteria: July 26, 2021
• First Posted (Actual): July 29, 2021

Study Record Updates

• Last Update Posted (Actual): September 17, 2021
• Last Update Submitted That Met QC Criteria: September 16, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Phase I clinical trial; Mesothelin; Refractory Solid Tumors; Chimeric Antigen Receptor T-Cell
• Other Study ID Numbers: Amaretto

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No