Relmacabtagene Autoleucel for the Treatment of Systemic Sclerosis

Official title

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

Overview

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.

Interventions

• Biological Relma-cel
  All participants will receive Relma-cel once at different dose levels: 25×10\^6 CAR+ T cells、50×10\^6 CAR+ T cells、75×10\^6 CAR+ T cells

Primary outcome measures

• DLT rate [Time frame: 28 days]
• Occurrence of AEs and SAEs [Time frame: 3 months]

Secondary outcome measures (12)

• Relma-cel cell numbers and transgene copy numbers and duration in blood [Time frame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration]
• the changes of CD19+ cells and other B cell subsets [Time frame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration]
• the change from baseline in Composite Response Index in Systemic Sclerosis (CRISS) [Time frame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration]
• the change from baseline in Sclerodema Clinical Trial Consortium-Damage Index (SCTC-DI) [Time frame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration]
• the change from baseline in modified Rodnan Skin Score (mRSS) [Time frame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration]
• the change from baseline in pulmonary function (forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO)) [Time frame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration]
• the change from baseline in cardiac function (left ventricular ejection fraction, LVEF) [Time frame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration]
• the change from baseline in high resolution computed tomography (HRCT) [Time frame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration]
• the change from baseline in disease activity score -28 (DAS-28) if any joint involvement [Time frame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration]
• the change from baseline in the levels of inflammation biomarkers including C-reactive protein (CRP), erythropoietin sedimentation rate (ESR) and ferritin [Time frame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration]
• systemic sclerosis specific antibodies, e.g., anti-scl-70 antibodies, anti-RNA polymerase III antibodies, anti-centrosome antibodies, antinuclear antibody (ANA) [Time frame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration]
• the change from baseline in skin biopsy pathology, e.g., the number of lymphocytes, the thickness of epiderm [Time frame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration]

Eligibility criteria

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:

• 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;
• progressive: having below manifestations within 6 months

• mRSS increases by >= 3
• 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:

• Renal function: CrCl ≥50 ml/min (Cockcroft/Gault equation)
• 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.
• 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)
• Coagulation: INR ≤ 1.5 x ULN, PT ≤1.5 x ULN
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Renji Hospital, Shanghai Jiaotong University School of Medicine — Shanghai

Identifiers

NCT: NCT06414135 · JWCAR029029

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗