Safety, Efficacy and Cellular Metabolic Dynamics of CT1195E in Patients With Refractory / Progressive SSC

A Clinical Study Exploring the Safety, Efficacy and Cellular Metabolic Dynamics of CT1195E Car-t Cell Injection in Refractory / Progressive Systemic Sclerosis (SSC)

This study is a single arm, open label, exploratory dose escalation clinical study to evaluate the safety, efficacy, and cellular metabolic dynamics of ct1195e cells in patients with SSc.

The study was divided into dose escalation phase and dose expansion phase.

Inclusion Criteria:

• voluntarily sign the informed consent form (ICF): I fully understand and know this study and sign the informed consent form. I am willing to follow and be able to complete all research procedures;

• when signing ICF, the age is between 18 and 60 years old (including 18 and 60 years old), regardless of gender;

• no systemic active infection (such as infectious pneumonia and tuberculosis) within 2 weeks before screening;

• women with fertility (defined as all women who are physically able to conceive) must agree to use efficient contraceptive methods from at least 28 days before the start of gonorrhea to 1 year after ct1195e infusion, and it is absolutely prohibited to donate eggs within 1 year after receiving study treatment infusion during the study period. Men whose partners are fertile must agree to use effective barrier contraception from the beginning of gonorrhea to 1 year after ct1195e infusion, and should not donate semen or sperm during the entire study period;

• women with fertility must be tested negative for serum β human chorionic gonadotropin (β -hcg) at the time of screening and within 48 hours before gonorrhea treatment.

• meet the 2013 eular/acr classification criteria for systemic sclerosis, and meet the diffuse manifestations, and the disease duration is ≤ 7 years (the onset time of the disease duration is defined as the time of the initial diagnosis of SSC);

• complicated with interstitial pneumonia, that is, the interstitial changes of ground glass exudation suggested by chest HRCT;

• meet the following definitions of refractory or progressive disease:

  1. Definition of refractory: the conventional treatment for more than 6 months is still ineffective, or the disease relapses after remission. Definition of conventional treatment: use of glucocorticoids (more than 1 mg/kg/d) or cyclophosphamide, as well as one or more of the following immunomodulatory drugs: antimalarial drugs, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biological agents, including yamerol, rituximab, belizumab, etanercept, etc;

  2. According to the definition of progressiveness, 2 of the following three items can be met in the past 1 year (within the past 1 year):

     1. Aggravation of symptoms;
     2. FVC estimated value decreases by 5%, or DLCO estimated value decreases by 10%;
     3. Pulmonary imaging aggravated;

• important organ functions:

  1. Renal function: defined as creatinine clearance (Cockcroft Gault) ≥ 50 ml/min calculated without hydration assistance;
  2. Bone marrow function: defined as neutrophil (ANC) ≥ 1.0 × 109/l, hemoglobin (HB) ≥ 90 g/l. Blood transfusion and growth factors shall not be used to meet the above requirements within 7 days before the eligibility screening;
  3. Liver function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2 × upper limit of normal (ULN), total bilirubin ≤ 2 × upper limit of normal (ULN)
  4. Coagulation function: INR ≤ 1.5 × ULN, prothrombin time (PT) ≤ 1.5 × ULN;
  5. Cardiac function: good hemodynamic stability, left ventricular ejection fraction (LVEF) ≥ 40%.

Exclusion Criteria:

• FVC ≤ 30% predicted value or DLCO (corrected by hemoglobin) ≤ 30% predicted value;
• study participants with severe kidney disease or signs of renal crisis;
• there is active tuberculosis risk during screening: there are signs or symptoms of active tuberculosis judged by the investigator (such as fever, cough, night sweat and weight loss); Records of chest imaging (e.g., chest X-ray, chest CT scan) performed at screening or any time within 6 months before screening showed active tuberculosis.
• have previously received car-t cell or other gene modified T cell therapy, or have a history of major organ transplantation (such as heart, lung, kidney, liver) or hematopoietic stem cell / bone marrow transplantation;
• have used drugs targeting B cells (such as rituximab) within 3 months before screening;
• allergic or intolerant to Qinglin drugs and tocilizumab, or life-threatening allergic reaction, hypersensitivity reaction or intolerance to ct1195e preparation or its excipients (including dimethyl sulfoxide (DMSO), or previous history of other serious allergies such as allergic shock;
• prednisone (≥ 10 mg / day) (or equivalent drug) is used for hormones within 2 weeks before ct1195e infusion, and physiological replacement, local and inhalation hormones are allowed;
• received immunosuppressants affecting T cells (mycophenolate mofetil, methotrexate, cyclosporine, azathioprine, leflunomide, tacrolimus) within 2 weeks before infusion of ct1195e;
• received JAK inhibitors (tofacitinib, baricitinib tablets, lucotinib, etc.) within 2 weeks before ct1195e infusion;
• have been vaccinated with live attenuated vaccine, inactivated vaccine or RNA vaccine within 1 month before screening;
• suffering from malignant tumor within 2 years before signing ICF. Except for the following cases: non melanoma skin cancer after radical treatment, local prostate cancer, cervical carcinoma in situ confirmed by biopsy or squamous intraepithelial lesions detected by cervical smear, and breast carcinoma in situ that has been completely removed;
• major surgery has been performed within 4 weeks before signing the informed consent, or major surgery is planned to be required during the study, which the investigator believes will bring unacceptable risks to the study participants;
• HIV, syphilis infection, active hepatitis B virus infection (HBsAg positive and HBV-DNA above the detection limit), or active hepatitis C virus infection (HCV antibody and HCV-RNA positive) were present at the time of screening;
• those with CNS diseases before screening include but are not limited to: cerebrovascular accident, encephalitis, epilepsy, convulsion / convulsion, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, CNS vasculitis, cognitive dysfunction, cerebral organic syndrome or psychosis;
• have a history of any of the following cardiovascular diseases within 1 month before screening: Grade III or IV heart failure, myocardial infarction, unstable angina, uncontrolled or symptomatic atrial arrhythmia, any ventricular arrhythmia or other heart disease with significant clinical significance as defined by the New York Heart Association (NYHA);
• participate in other clinical studies within 3 months before screening or still within five half lives after the last medication.
• there is currently any uncontrollable active infection, including but not limited to active tuberculosis;
• if there is a history of suicidal thoughts or evidence within 6 months before signing the ICF, or any suicidal behavior within 12 months before signing the ICF, the investigator believes that there is a significant risk of suicide;
• pregnant or lactating women;
• the investigator judged that the study participants had poor compliance, were unable or unwilling to comply with the requirements of the study protocol, or were not suitable to participate in the clinical study for other reasons.