US Zamto-cel Autoimmune Diseases

Miltenyi Biotec

Status and phase: Not yet enrolling; Phase 1

Conditions: Diffuse Cutaneous Systemic Sclerosis; Lupus Nephritis; Systemic Sclerosis (SSc); Systemic Lupus Erythematosus

Treatments: Drug: Cyclophosphamide; Biological: zamtocabtagene autoleucel; Drug: Fludarabine

Study type: Interventional

Funder types: Industry

Identifiers

NCT06708845

M-2024-423

Details and patient eligibility

About

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.

Full 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.

Enrollment: 48 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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48 participants in 2 patient groups

Dose Level 1

Experimental group

Treatment:

Drug: Fludarabine

Biological: zamtocabtagene autoleucel

Drug: Cyclophosphamide

Dose Level 2

Experimental group

Treatment:

Drug: Fludarabine

Biological: zamtocabtagene autoleucel

Drug: Cyclophosphamide