Summary
AID is a phase I multi-cohort study to assess the safety and tolerability of zamtocabtagene autoleucel (zamto-cel) in patients with refractory autoimmune diseases (SLE-Non renal, SLE-LN, SSc/dcSSc) after receiving standard therapy.
Detailed Description
This is a Phase 1, multicohort, dose-finding study evaluating autologous T cells engineered to target dual CD19 and CD20 antigens in subjects with refractory autoimmune diseases following standard therapy. The investigational product, Zamto-cel, is a chimeric antigen receptor T-cell (CAR-T) therapy genetically engineered to enable subjects' T cells to express CARs on their surfaces.
Eligible subjects will undergo leukapheresis for the collection of cells required for manufacturing. Prior to infusion of the fresh CAR-T product, subjects will receive a lymphodepleting regimen consisting of cyclophosphamide and fludarabine. The CAR-T cell infusion will be administered intravenously at a dose of 2.5 x 10\^6 or 1.0 x 10\^6 CAR+ cells/kg body weight, based on the dose level assigned to the cohort.
The study will initially enroll 3 subjects per cohort in a staggered manner to evaluate safety. Upon confirmation of safety, the study will proceed to cohort-specific recommended Phase 2 dose (RP2D) and dose expansion phases. Subjects will be monitored for up to 1 year to assess safety, preliminary efficacy, and health-related quality of life (HRQoL). Additional long-term follow-up will be conducted under a separate long-term follow-up protocol.
Eligibility Criteria
Age Range: 18 years to No maximum
General Key Inclusion/Exclusion Criteria Across All Cohorts
Inclusion Criteria:
•Confirmed diagnosis of autoimmune disease (SLE-Non-renal, SLE-LN, SSc/ dcSSc)
Exclusion Criteria:
* Prior gene therapy treatment
* Active malignancy within past 5 years
* Significant active fungal or bacterial infection
* History or presence of CNS lupus or other CNS disease
* eGFR \< 45 mL/min/1.73 m\^2
* Total bilirubin outside the normal range (unless congenital hyperbilirubinemia such as Gilbert syndrome has been confirmed).
Systemic Lupus Erythematosus-Non-renal Key Inclusion/Exclusion Criteria
Inclusion Criteria:
* Positive for at least 1 of the following autoantibodies at Screening: anti- double stranded DNA or anti-Smith
* Systemic Lupus Erythematosus Disease Activity Index-2000 score ≥ 8 AND at least 1 British Isles Lupus Assessment Group (BILAG)-2004 Class A (severe manifestation) organ scores
* Inadequate response to glucocorticoids and to at least 2 of the following treatments, used for at least 3 months each: cyclophosphamide, mycophenolic acid or its derivatives, belimumab, azathioprine, anifrolumab, methotrexate, rituximab, or obinutuzumab
Exclusion Criteria:
* Subjects with neuropsychiatric SLE.
* Drug-induced SLE.
Systemic Lupus Erythematosus - Lupus Nephritis Key Inclusion/Exclusion Criteria
Inclusion Criteria:
* Positive for at least 1 of the following autoantibodies at Screening: anti- double stranded DNA or anti-Smith
* Confirmed LN diagnosis by kidney biopsy during screening or within the previous 6 months, with severe active phase of the disease.
* Progressing despite maintenance on maximally tolerated doses of renin- angiotensin system (RAS) blocking agents, unless allergic to or intolerant of ACE inhibitors and ARBs
* Inadequate response to glucocorticoids and hydroxychloroquine and at least 1 of the following treatments, used for at least 3 months each: cyclophosphamide, mycophenolic acid derivatives, belimumab, azathioprine, methotrexate, rituximab, obinutuzumab, calcineurin inhibitor (cyclosporin, tacrolimus or voclosporin)
Exclusion Criteria:
•Evidence of Rapidly progressive glomerulonephritis (defined as a doubling of serum creatinine within 3 months prior to enrollment) or as determined by the study investigator.
Systemic Sclerosis/Diffuse Cutaneous Systemic Sclerosis Cohort Key Inclusion/ Exclusion Criteria
Inclusion Criteria:
* Active disease defined as:
* Modified Rodnan skin score (mRSS) ≥ 16 units, in the prior 6 months, with 1 or more of the following:
* Increase in mRSS by ≥ 3 units or 10%
* Involvement of 1 new body area with increase in mRSS by ≥ 2 units
* Involvement of 2 new body areas with increase by ≥ 1 mRSS unit OR
* Progressive interstitial lung disease (ILD) defined as:
\- Worsening of respiratory symptoms and an increased extent of fibrosis evaluated by high-resolution computed tomography
* Lack of response to standard therapy (e.g., failure of ≥ 2 immunosuppressive therapies)
Exclusion Criteria:
* "Active" gastric antral vascular ectasia, as evidenced by bleeding (ie, on esophagogastroduodenoscopy) in the past 6 months or as per Investigator's assessment.
* History of SSc renal crisis within 1 year prior to Screening; presence of kidney impairment due to conditions other than SSc