CD40 Ligand Expressing MSLN-CAR T Cell Therapy in MSLN Positive Advanced/Metastatic Solid Tumors
Study Details
Study Description
Brief Summary
In preclinical study, investigators have demonstrated that the newly developed CD40 ligand expressing MSLN-CAR T cells possess more powerful antitumor activity than previously reported CAR-MSLN T cells in animal models. In this clinical trial, at least 9 eligible patients in dose escalation period will be enrolled to receive 3 doses of CD40 ligand expressing MSLN-CAR cell therapy according to the "3+3" principle. In dose expansion period, additional 10 to 21 patients will be enrolled to receive CD40 ligand expressing MSLN-CAR T cell therapy at dose of RP2D.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
In this study, investigators have developed a novel CAR T cell system targeting both mesothelin (MSLN) antigen-expressing cells and CD40 ligand-expressing cells, termed as CD40 ligand expressing MSLN-CAR T. Preclinical study demonstrated that the CD40 ligand expressing MSLN-CAR T cells possess more powerful antitumor activity than previously reported CAR-MSLN T cells in animal models. In this clinical trial, at least 9 eligible patients in dose escalation period will be enrolled to receive 3 doses of CD40 ligand expressing MSLN-CAR T cell therapy (1×106 cells/kg, 3×106 cells/kg, 6×10^6 cells/kg) according to the "3+3" principle, in order to evaluate the safety, feasibility and preliminary antitumor activity of CD40 ligand expressing MSLN-CAR T cells. In dose expansion period, additional 10 to 21 patients will be enrolled to receive CD40 ligand expressing MSLN-CAR T cell therapy at dose of recommended phase 2 dose (RP2D), which is determined by data from dose escalation period, including dose limiting toxicities, maximum tolerated dose, pharmacokinetics/pharmacodynamics, efficacy and other parameters, in order to further assess the safety and efficacy profiles of CD40 ligand expressing MSLN-CAR T cell therapy.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: CD40 ligand expressing MSLN-CAR T cells Enrolled participants will be given a preconditioning regimen consisted of albumin-bound paclitaxel and cyclophosphamide before the infusion of CD40 ligand expressing MSLN-CAR T cells. |
Biological: CD40 ligand expressing MSLN-CAR T cells
Dose escalation: dose1 (1×10^6 cells/kg) ,dose 2 (3×10^6 cells/kg) ,dose 3 (6×10^6 cells/kg. Dose expansion: RP2D
Drug: Albumin-bound paclitaxel
Administered intravenously at dose of 100-200mg/m2 on day -5
Drug: Cyclophosphamide
Administered intravenously at dose of 15-30mg/kg on day -3 and day -2
|
Outcome Measures
Primary Outcome Measures
- Incidence of treatment related adverse events [Up to 12 months since the initiation of CD40 ligand expressing MSLN-CAR T cell therapy]
Treatment related adverse events are defined as any medical events since the initiation of CAR-MSLN T cell therapy. CRS or CRES will be graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria, and the others will be graded by CTCAE V5.0
- Incidence of dose limiting toxicities (DLTs) [Up to 28 days since the initiation of CD40 ligand expressing MSLN-CAR T cell therapy]
Dose limiting toxicities are defined as CD40 ligand expressing MSLN-CAR T cell related adverse events within the first 28 days that meet the following criteria: grade 3 or higher CRS or CRES, and any other grade 4 adverse events.
- Determine the maximum tolerated dose (MTD) [Up to 28 days since the initiation of CD40 ligand expressing MSLN-CAR T cell therapy]
Maximum tolerated dose is determined as the highest dose that is less than or equal to 2 DLT among 6 subjects.
Secondary Outcome Measures
- Number and copy number of CD40 ligand expressing MSLN-CAR T cells [Up to 3 years]
Number and copy number of CD40 ligand expressing MSLN-CAR T cells are evaluated by number in peripheral blood and tumor tissue.
- Objective response rate (ORR) [Up to 3 years]
Objective response rate includes complete response and partial response defined by investigators according to RECIST 1.1or iRECIST criteria.
- Progression Free Survival (PFS) [Up to 3 years]
Progression Free Survival is defined as the time from the initiation of CD40 ligand expressing MSLN-CAR T cell therapy to documented disease progression or death.
- Time to response (TTR) [Up to 3 years]
TTR is defined as the time from the initiation of CD40 ligand expressing MSLN-CAR T cell therapy to first assessed CR or PR by investigators according to RECIST 1.1or iRECIST criteria.
- Duration of response (DOR) [Up to 3 years]
Duration of response is defined as the time from objective response until documented tumor progression among responders.
- Overall Survival (OS) [Up to 3 years]
Overall Survival is defined as the time from the initiation of CD40 ligand expressing MSLN-CAR T cell therapy to documented disease progression or death.
Eligibility Criteria
Criteria
Inclusion Criteria:
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- Age from 18 to 75 years with estimated life expectancy >3 months.
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- Histopathological confirmed advanced or metastatic solid tumors failed to at least first-line treatment or initially diagnosed advanced/metastatic solid tumors that have no NCCN guideline recommended standard first-line therapy. Mesothelin antigen expression percentage ≥ 10%.
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- Have at least one measurable target lesion.
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- Fresh solid tumor samples or formalin-fixed paraffin embedded tumor archival samples within 6 months are necessary; Fresh tumor samples are preferred. Subjects are willing to accept tumor rebiopsy in the process of this study.
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- Previous treatment must be completed for more than 4 weeks prior to the enrollment of this study, and subjects have recovered to <= grade 1 toxicity.
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- Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 2 at the time of enrollment.
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- Have adequate organ function, which should be confirmed within 2 weeks prior to the first dose of study drugs.
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- Previous treatment with anti-PD-1/PD-L1 antibodies are allowed.
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- Ability to understand and sign a written informed consent document.
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- Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, and up to 90 days after the last dose of the drug.
Exclusion Criteria:
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- Active, known or suspected autoimmune diseases.
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- Known brain metastases or active central nervous system (CNS). Subjects with CNS metastases who were treated with radiotherapy for at least 3 months prior to enrollment, have no central nervous symptoms and are off corticosteroids, are eligible for enrollment, but require a brain MRI screening.
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- Subjects are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
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- History of severe hypersensitive reactions to other monoclonal antibodies.
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- History of allergy or intolerance to study drug components.
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- Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
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- History or concurrent condition of interstitial lung disease of any grade or severely impaired pulmonary function.
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- Uncontrolled intercurrent illness, including ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric illness/social situations and any other illness that would limit compliance with study requirements and jeopardize the safety of the patient.
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- History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
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- Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy test performed within 7 days before the enrollment, and a negative result must be documented.
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- Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
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- Vaccination within 30 days of study enrollment.
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- Active bleeding or known hemorrhagic tendency.
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- Subjects with unhealed surgical wounds for more than 30 days.
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- Being participating any other trials or withdraw within 4 weeks.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Kaichao Feng | Beijing | Beijing | China | 100853 |
Sponsors and Collaborators
- Chinese PLA General Hospital
- UTC Therapeutics Inc.
Investigators
- Study Director: Yangbin Zhao, PhD, UTC Therapeutics Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CHN-PLAGH-BT-077