αPD1-MSLN-CAR T Cells for the Treatment of MSLN-positive Advanced Solid Tumors

An Exploratory Study of MSLN-CAR T Cells Secreting PD-1 Nanobodies for the Treatment of MSLN-positive Advanced Solid Tumors

This is a single arm, open-label, dose escalation clinical study to evaluate the safety and tolerability of autologous mesothelin (MSLN)-targeted chimeric antigen receptor (MSLN-CAR) T cells secreting PD-1 nanobodies (αPD1-MSLN-CAR T cells) in patients with solid tumors.

Study Overview

• Status: Unknown
• Conditions: Non-small-cell Lung Cancer; Mesothelioma
• Intervention / Treatment: Biological: αPD1-MSLN-CAR T cells

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Lu Wen; Phone Number: 027-85872859; Email: wenlu2808@126.com
• Study Contact Backup: Name: Xiaoli Lu; Phone Number: 027-85872859; Email: 52548791@qq.com

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430000
      • Recruiting
      • Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology
      • Contact: Lu Wen; Phone Number: 027-85872589; Email: wenlu2808@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have a histological or cytological diagnosis of advanced solid tumors, such as non-small-cell lung cancer and mesothelioma；
• Patients must have failed established standard medical anti-cancer therapies；
• Greater than or equal to 18 years of age and less than or equal to 70 years of age on day of signing informed consent；
• Life expectancy >3 months；
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1；
• Subjects must meet blood coagulation parameters and have adequate venous peripheral access for apheresis. Patients must also have adequate mononuclear cells for CAR T cell manufacturing；
• Staining of MSLN must be greater than 50% of the cells in the tumor tissue and with apparent expression in the membrane. PD-L1 expression must be positive. Tissue obtained for the biopsy must be ≤1 year prior to enrollment for screening, not have been previously irradiated or exposed to chemotherapy. If unavailable, new tissue material from a recently obtained surgical or diagnostic biopsy is mandatory for this trial；

• Satisfactory organ and bone marrow function as defined by the following:

  1. Adequate bone marrow function in the opinion of the Investigator for lymphocyte-depleting chemotherapy: absolute neutrophil count must be greater than ≥ 1.5×109/L, lymphocyte count must be greater than ≥ 0.5×109/L, platelets must be greater than ≥ 90×109/L, hemoglobin must be greater than ≥ 90g/L without transfusion within 7 days or dependency on EPO;
  2. Total bilirubin must be less than or equal to two times (≤2.0x) the institutional normal upper limit; transaminases, serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST), must be less than or equal to 2.5 times (≤2.5x) the institutional normal upper limit (≤2.5x if there is hepatic metastasis);
  3. Creatinine must be less than or equal to one and one half times (≤ 1.5x) the institutional normal upper limit or eGFR ≥ 60ml/min/1.73m^2 [eGFR=186×（age）-0.203×SCr-1.154（mg/dl）,for female the eGFR shoud be timed by 0.742];
  4. International normalized ratio (INR) or the PT is not greater than one and one half times (≤ 1.5) the upper limit of normal;
  5. Lung function: ≤ CTCAE grade 1 dyspnea and SaO2≥ 91%
  6. Cardiac function: cardiac ejection fraction (LVEF) must be greater than fifty percent (≥50%) by echocardiogram or MUGA one month before enrollment.
• Subjects must have measureable disease as defined by RECIST 1.1 criteria;
• Subjects sufficiently understand the trial and willingly sign the informed consent;

• For concurrent medication:

  1. Systemic therapeutic corticosteroids must be stopped 72 hours before CAR-T infusion. However, patients using physiologic replacement doses of corticosteroids, or its equivalent, will be considered eligible;
  2. Immunosuppressive therapy must be stopped within four (4) weeks prior to enrollment;
• Male and Female subjects agree to use approved contraceptive methods (e.g. birth control pills, barrier device, intrauterine device, abstinence) during the study and for at least 12 months following the last dose of the study cell infusion and until no CAR-T cells can be detected after two consecutive PCR tests.

Exclusion Criteria:

• Prior therapy with targeted therapy or cell therapy against MSLN；
• Prior therapy with any gene therapy (including CAR-T cell therapy) or any T cell therapy home and abroad；
• Active bacteria, viral or fungal infection, and not contained after anti-infective therapy (positive results in the blood ≤72 hours before infusion);
• Patient is positive for Syphilis, Human Immunodeficiency Virus (HIV) , active Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA (qualitative) is detected);
• Patient has a medical condition such as autoimmune disease or organ transplantation that requires chronic systemic steroid therapy or requires any other form of immunosuppressive medication;
• History of severe cardiac or pulmonary disease, including hypertension that cannot be controlled by medication, and any of the conditions occurred within the past 6 months: congestive heart failure (New York Heart Association functional classification ≥3), cardiac angioplasty and stents, myocardial infarction, unstable angina, or other clinically significant heart disease；
• Detectable clinically relevant central nervous system (CNS) metastases and/or pathology such as epilepsy/seizure, brain Ischemia/ hemorrhage, dementia, cerebellar disease, or autoimmune disease affecting central nervous system；
• Patient has a history or current evidence of any condition such as neurotic, psychiatric, immune, metabolic and infectious disease, on any therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator；

• Patient has a known history of a hematologic malignancy, or of another malignant primary solid tumor concurrently, with the exception of :

  1. Patients with in situ cervical cancer or breast cancer with no evidence of disease for ≥ 3 years after curative treatments;
  2. Patients who underwent successful definitive resection of in situ cancer with no evidence of disease for ≥5 years;
• Has had chemotherapy, radioactive, small molecules, biological cancer therapy, immunotherapy or other investigational drugs within 4 weeks prior to the initiation of the study；
• Pregnant or breastfeeding women;
• Investigators think that patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study and cooperation with the requirements of the trial, uncontrolled medical, psychological, familial, sociological, or geographical conditions, or is not in the best interest of the patient to participate.

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: CAR T cells therapy; The safety and efficacy of αPD1-MSLN-CAR T cells will be assessed in a standard 3+3 dose escalation approach. Four doses of CAR T cells will be evaluated in this study: 1×10^5 CAR+ T cells/kg, 3×10^5 CAR+ T cells/kg, 1×10^6 CAR+ T cells/kg, and 3×10^6 CAR+ T cells/kg.

Biological: αPD1-MSLN-CAR T cells; Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of αPD1-MSLN-CAR T cells. During αPD1-MSLN-CAR T cells production, subjects will receive cyclophosphamide for the purpose of lymphocytes depletion，Cyclophosphamide 300 mg/m2/day IV infusion on days -5, -4 and -3. After lymphodepletion, subjects will receive one dose treatment with αPD1-MSLN-CAR T cells by intravenous (IV) injection. The initial dose of 1×10^5 CAR+ T cells/kg will be infused on day 0.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicity （DLT）	Safety	After 28 days of single infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD)	Tolerability	After 28 days of single infusion
Progression-free survival (PFS)	PFS of patients receiving αPD1-MSLN-CAR T cells	Month 12
Pharmacodynamics (PD)	PD of IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, IFN-γ, TNF-α and MCP1 will be analysed after CAR T cell infusion	Day 28
Objective response rate (ORR)	Clinical response will be assessed by RECIST 1.1.	Month 12
Overall survival (OS)	OS of patients receiving αPD1-MSLN-CAR T cells.	Month 12
Peak Plasma Concentration (Cmax)	Pharmacokinetics (PK	Month 12

Collaborators and Investigators

• Sponsor: Wuhan Union Hospital, China
• Collaborators: Shanghai Cell Therapy Group Co.,Ltd

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2020
• Primary Completion (Anticipated): June 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: July 21, 2020
• First Submitted That Met QC Criteria: July 27, 2020
• First Posted (Actual): July 28, 2020

Study Record Updates

• Last Update Posted (Actual): July 28, 2020
• Last Update Submitted That Met QC Criteria: July 27, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: MSLN-CAR T; PD-1 nanobodies
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Adenoma; Neoplasms, Mesothelial; Mesothelioma
• Other Study ID Numbers: BZDS1901

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