Clinical trial NCT06414135: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Systemic Sclerosis
Keywords: CAR-T cell therapy
systemic sclerosis
B cell depletion
Lead sponsor: RenJi Hospital
Sponsor class: OTHER
Collaborators: name: Shanghai Ming Ju Biotechnology Co., Ltd.
First posted: 2024-05-16
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


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:

  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

Primary outcomes:
measure: DLT rate
timeFrame: 28 days
measure: Occurrence of AEs and SAEs
timeFrame: 3 months
Secondary outcomes:
measure: Relma-cel cell numbers and transgene copy numbers and duration in blood
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
measure: the changes of CD19+ cells and other B cell subsets
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
measure: the change from baseline in Composite Response Index in Systemic Sclerosis (CRISS)
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
measure: the change from baseline in Sclerodema Clinical Trial Consortium-Damage Index (SCTC-DI)
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
measure: the change from baseline in modified Rodnan Skin Score (mRSS)
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
measure: the change from baseline in pulmonary function (forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO))
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
measure: the change from baseline in cardiac function (left ventricular ejection fraction, LVEF)
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
measure: the change from baseline in high resolution computed tomography (HRCT)
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
measure: the change from baseline in disease activity score -28 (DAS-28) if any joint involvement
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
measure: the change from baseline in the levels of inflammation biomarkers including C-reactive protein (CRP), erythropoietin sedimentation rate (ESR) and ferritin
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
measure: systemic sclerosis specific antibodies, e.g., anti-scl-70 antibodies, anti-RNA polymerase III antibodies, anti-centrosome antibodies, antinuclear antibody (ANA)
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
measure: the change from baseline in skin biopsy pathology, e.g., the number of lymphocytes, the thickness of epiderm
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
measure: the change from baseline in nailfold capillaroscopy examination, e.g., the capillary density, the diameter of capillaries
timeFrame: 12 months
measure: the change from baseline in skin stiffness (measuring the thickness of epiderm and dermis) by skin ultrasound
timeFrame: 12 months
measure: the change from baseline in health assessment questionnaire -damage index (HAQ-DI)
timeFrame: 12 months
measure: the change from baseline in IgG, IgM, IgE, IgA
timeFrame: baseline prior to Relma-cel administration, then through study completion, an average of 2 years after Relma-cel administration
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Renji Hospital, Shanghai Jiaotong University School of Medicine
Study officials:
affiliation: RenJi Hospital
name: Liangjing Lu
role: STUDY_CHAIR
References: