US Zamto-cel Autoimmune Diseases

Official title

A Phase I Multicohort Trial of Zamtocabtagene Autoleucel (Zamto-Cel) in Subjects With Severe Refractory Autoimmune Diseases

Overview

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.

Interventions

• Biological zamtocabtagene autoleucel
  chimeric antigen receptor T-cell (CAR-T) therapy
• Drug Cyclophosphamide
  Lymphodepleting chemotherapy
• Drug Fludarabine
  Lymphodepleting chemotherapy

Primary outcome measures

• The incidence and severity of adverse events (AEs), adverse events of special interest (AESIs), and serious adverse events (SAEs) [Time frame: From enrollment through study completion 12 months post zamto-cel infusion]
• The proportion of subjects with dose-limiting toxicities (DLTs) up to Day 28 and determination of recommended Phase 2 dose (RP2D) [Time frame: From enrollment through Day 28 post zamto-cel infusion]

Secondary outcome measures (4)

• The incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) [Time frame: From enrollment through study completion 12 months post zamto-cel infusion]
• Clinical response at Week 4, 12, 24, and 52 evaluated by defined disease-specific activity measures in SLE-Non renal, SLE-LN, and SSc/dcSSc [Time frame: From enrollment through study completion 12 months post zamto-cel infusion]
• The duration of remission or low disease activity status in respective diseases under the study [Time frame: From enrollment through study completion 12 months post zamto-cel infusion]
• Persistence, maximal drug concentration (Cmax), time to reach Cmax, area under the concentration curve, and phenotype of zamto-cel [Time frame: From enrollment through study completion 12 months post zamto-cel infusion]

Eligibility 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

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

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Froedtert Hospital and the Medical College of Wisconsin — Milwaukee

Identifiers

NCT: NCT06708845 · M-2024-423

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗