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

• ClinicalTrials.gov Identifier: NCT04489862
• Recruitment Status: Unknown
• First Posted: July 28, 2020
• Last Update Posted: July 28, 2020
• Sponsor: Wuhan Union Hospital, China
• Collaborator: Shanghai Cell Therapy Group Co.,Ltd
• Information provided by (Responsible Party): Xiaorong Dong, Wuhan Union Hospital, China

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Non-small-cell Lung Cancer; Mesothelioma	Biological: αPD1-MSLN-CAR T cells	Early Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Exploratory Study of MSLN-CAR T Cells Secreting PD-1 Nanobodies for the Treatment of MSLN-positive Advanced Solid Tumors
• Actual Study Start Date: May 13, 2020
• Estimated Primary Completion Date: June 2022
• Estimated Study Completion Date: December 2022

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Dose-limiting toxicity （DLT） [ Time Frame: After 28 days of single infusion ]
   Safety

Secondary Outcome Measures :

1. Maximum tolerated dose (MTD) [ Time Frame: After 28 days of single infusion ]
   Tolerability
2. Objective response rate (ORR) [ Time Frame: Month 12 ]
   Clinical response will be assessed by RECIST 1.1.
3. Progression-free survival (PFS) [ Time Frame: Month 12 ]
   PFS of patients receiving αPD1-MSLN-CAR T cells
4. Overall survival (OS) [ Time Frame: Month 12 ]
   OS of patients receiving αPD1-MSLN-CAR T cells.
5. Peak Plasma Concentration (Cmax) [ Time Frame: Month 12 ]
   Pharmacokinetics (PK
6. Pharmacodynamics (PD) [ Time Frame: Day 28 ]
   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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Lu Wen; 027-85872859; wenlu2808@126.com

Contact: Xiaoli Lu; 027-85872859; 52548791@qq.com

Locations

China, Hubei

Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology; Recruiting

Wuhan, Hubei, China, 430000

Contact: Lu Wen 027-85872589 wenlu2808@126.com

Sponsors and Collaborators

Wuhan Union Hospital, China

Shanghai Cell Therapy Group Co.,Ltd

Investigators

• Principal Investigator: Xiaorong Dong; Wuhan Union Hospital, China

More Information

• Responsible Party: Xiaorong Dong, Director, Wuhan Union Hospital, China
• ClinicalTrials.gov Identifier: NCT04489862
• Other Study ID Numbers: BZDS1901
• First Posted: July 28, 2020
• Last Update Posted: July 28, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Xiaorong Dong, Wuhan Union Hospital, China:

MSLN-CAR T; PD-1 nanobodies

Additional relevant MeSH terms:

Mesothelioma; Neoplasms; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Mesothelial