Relmacabtagene Autoleucel for the Treatment of Systemic Sclerosis

A Dose Ranging Study to Evaluate the Safety, Tolerance, Pharmacokinetics and Pharmacodynamics of Relmacabtagene Autoleucel (Relma-cel) in Patients With Refractory/Progressive Systemic Sclerosis

Relma-cel is a product containing CD19-CAR-transduced T cells. The purpose of this study is to evaluate the safety of Relma-cel at different dose levels in patients with early diffuse systemic sclerosis. Efficacy will be explored too. If enrolled, participants will undergo leukapheresis, lymphodepleting chemotherapy and administration of Relma-cel.

Inclusion Criteria:

• voluntary to sign the ICF

• aged between 18-65 years old (inclusive)

• diagnosed with diffuse systemic sclerosis according to 2013 ACR Systemic Sclerosis Classification Criterion

• meet the definitions of refractory/progressive as below:

  1. refractory: non-respondent to or disease recurrence after remission with conventional therapies. Conventional therapies are defined as treated for more than 6 months with low dose steroids (≤ 15 mg prednisone equivalent), cyclophosphamide, antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporin or biologics such as rituximab, belimumab, telitacicept, tocilizumab;

  2. progressive: having below manifestations within 6 months

     1. mRSS increases by >= 3
     2. FVC decreases by > 10% or FVC decreases by > 5% and DLCO decreases by > 15%

• without systemic active infections within 2 weeks of leukapheresis, e.g., infectious pneumonia, tuberculosis

• available vascular access for leukapheresis

• major organ functions:

  1. Renal function: CrCl ≥50 ml/min (Cockcroft/Gault equation)
  2. Bone marrow function: ANC ≥ 1000/uL, absolute lymphocyte count ≥100/uL, Hb ≥90 g/L, Platelet count ≥75 x 10^9/L. Blood transfusion and infusion of growth factors within 7 days of eligibility assessment are not allowed.
  3. Liver function: ALT ≤ 3 x ULN, AST ≤ 3 x ULN, total bilirubin ≤ 2 x ULN (in case of Gilbert syndrome, total bilirubin ≤ 3 x ULN)
  4. Coagulation: INR ≤ 1.5 x ULN, PT ≤1.5 x ULN
  5. Cardiac function: LVEF ≥ 55%

• negative result of serum β-hCG measurement for women of childbearing potential at screening and within 48 hours of the first dose of lymphodepletion

• Female subjects with childbearing potential or male subjects with partners of childbearing potential should adopt medically effective contraception or abstinence from enrollment to 2 years after the end of the study; female subjects with childbearing potential should have a negative serum hCG test within 7 days of enrollment and not in lactation

Exclusion Criteria:

• NYHA class IV
• FVC predicted < 45% or DLCO predicted < 40%
• abnormalities on HRCT not attributable to systemic sclerosis
• history of autologous stem cell transplantation
• with manifestations of renal crisis
• with other autoimmune comorbidities that need systemic treatment
• with a history of severe drug allergy
• with congenital immunoglobulin deficiency
• with malignant tumors, except for nonmelanoma skin cancer, in situ cervical cancer, bladder cancer, breast cancer which has been disease free for more than 2 years
• with psychiatric diseases or severe cognition dysfunctions
• within 5 half-life cycles of the last administration of an investigational product
• pregnant, lactation or plan to be pregnant within one year
• a history of CAR-T therapy or other gene-modified T cell targeted therapies
• other conditions that are not suitable for enrollment of the study in the judgement of the investigator
• the use of any live vaccines against infections within one month of the screening
• with any manifestations of active tuberculosis at screening