CD40 Ligand Expressing MSLN-CAR T Cell Therapy in MSLN Positive Advanced/Metastatic Solid Tumors

Study Overview
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Brief Summary
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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 MSLN-CAR T cells in animal models. In this clinical trial, at least 12 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 18 patients will be enrolled to receive CD40 ligand expressing MSLN-CAR T cell therapy at dose of RP2D.

Detailed Description
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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 MSLN-CAR T cells in animal models. In this clinical trial, at least 12 eligible patients in dose escalation period will be enrolled to receive 3 doses of CD40 ligand expressing MSLN-CAR T cell therapy (1×10^6 cells/kg, 3×10^6 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 18 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.

Official Title
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Phase I/II Study of CD40 Ligand Expressing MSLN-CAR T Cell Treatment in MSLN Positive Advanced/Metastatic Solid Tumors

Conditions
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Advanced or Metastatic Solid Tumors

Intervention / Treatment
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* Biological: CD40 ligand expressing MSLN-CAR T cells
* Drug: Albumin-bound paclitaxel
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Age from 18 to 75 years with estimated life expectancy >3 months. 2. 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%. 3. Have at least one measurable target lesion. 4. 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. 5. 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. 6. Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 2 at the time of enrollment. 7. Have adequate organ function, which should be confirmed within 2 weeks prior to the first dose of study drugs. 8. Previous treatment with anti-PD-1/PD-L1 antibodies are allowed. 9. Ability to understand and sign a written informed consent document. 10. 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: 1. Active, known or suspected autoimmune diseases. 2. 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. 3. Subjects are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment. 4. History of severe hypersensitive reactions to other monoclonal antibodies. 5. History of allergy or intolerance to study drug components. 6. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results. 7. History or concurrent condition of interstitial lung disease of any grade or severely impaired pulmonary function. 8. 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. 9. History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS). 10. 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. 11. 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)]. 12. Vaccination within 30 days of study enrollment. 13. Active bleeding or known hemorrhagic tendency. 14. Subjects with unhealed surgical wounds for more than 30 days. 15. Being participating any other trials or withdraw within 4 weeks.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CD40 ligand expressing MSLN-CAR T cells<br>Enrolled participants will be given a preconditioning regimen before the infusion of CD40 ligand expressing MSLN-CAR T cells. Patients enrolled in dose 1 will be assigned to cohort 1 and cohort 2 respectively. Three patients in cohort 1 will be given albumin-bound paclitaxel plus cyclophosphamide as conditioning treatment. Another three patients will be enrolled into cohort 2 to receive albumin-bound paclitaxel plus cyclophosphamide and fludarabine. The final preconditioning regimen in the following dose levels will be determined by investigators according to the results from cohort 1 and 2, including controllable safety, CAR T cell expansion levels and superior persistence in PB. | Biological: CD40 ligand expressing MSLN-CAR T cells<br>* 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<br>Drug: Albumin-bound paclitaxel<br>* Administered intravenously at dose of 100-200mg/m2 on day -5<br>Drug: Cyclophosphamide<br>* Administered intravenously at dose of 15-30mg/kg on day -3 and day -2<br>Drug: Fludarabine<br>* Administered intravenously at dose of 30mg/m2 on day -3 and day -2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment related adverse events | 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 | Up to 12 months since the initiation of CD40 ligand expressing MSLN-CAR T cell therapy | 
| Incidence of dose limiting toxicities (DLTs) | 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. | Up to 28 days since the initiation of CD40 ligand expressing MSLN-CAR T cell therapy | 
| Determine the maximum tolerated dose (MTD) | Maximum tolerated dose is determined as the highest dose that is less than or equal to 2 DLT among 6 subjects. | Up to 28 days since the initiation of CD40 ligand expressing MSLN-CAR T cell therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and copy number of CD40 ligand expressing MSLN-CAR T cells | Number and copy number of CD40 ligand expressing MSLN-CAR T cells are evaluated by number in peripheral blood and tumor tissue. | Up to 3 years | 
| Objective response rate (ORR) | Objective response rate includes complete response and partial response defined by investigators according to RECIST 1.1or iRECIST criteria. | Up to 3 years | 
| Progression Free Survival (PFS) | 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. | Up to 3 years | 
| Time to response (TTR) | 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. | Up to 3 years | 
| Duration of response (DOR) | Duration of response is defined as the time from objective response until documented tumor progression among responders. | Up to 3 years | 
| Overall Survival (OS) | 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. | Up to 3 years |