An Open-label, Study to Assess Safety, Efficacy and Cellular Kinetics of YTB323 in Severe, Refractory Autoimmune Disorders
Study Details
Study Description
Brief Summary
The study is intended to assess safety, efficacy and cellular kinetics of YTB323 treatment in participants with severe refractory systemic lupus erythematosus.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: YTB323 Single infusion of YTB323 |
Drug: YTB323
Single infusion of YTB323
|
Outcome Measures
Primary Outcome Measures
- Number of participants with AEs and SAEs [Day 1 to 2 years]
Long term safety follow up
Secondary Outcome Measures
- CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood [Pre-dose, up to 2 years]
Blood samples will be collected to assess cellular kinetics.
- Number of patients with anti-drug antibodies [Pre-dose, up to 2 years]
Blood samples will be collected to measure anti-drug antibodies against YTB323.
- Level of T cell activation by YTB323 [Pre-dose, up to 2 years]
Blood samples will be collected to measure the level of T cell activation by YTB323.
- Number of patients infused with planned target dose [Day 1]
Feasibility of the manufacturing process in autoimmune disorders.
- Change from pre-dose up to 2 years in the Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score [Pre-dose, up to 2 years]
SLEDAI-2K scores are between 0 and 105, a higher score represents a higher disease activity.
- Change from pre-dose up to 2 years in British Isles Lupus Activity Group (BILAG) score [Pre-dose, up to 2 years]
BILAG consists of 97 items that covers 9 organ domains. The range is from a to E, A is very active disease and E no disease.
- Change from pre-dose up to 2 years in Physician's global assessment (PGA) [Pre-dose, up to 2 years]
The Physician's Global assessment is a visual analog scale from 0 to 3, 0 represents no activity and 3 represents severe disease activity.
- Change from pre-dose up to 2 years in Lupus Low Disease Activity State (LLDAS) [Pre-dose, up to 2 years]
LLDAS is a composite measure based on: SLEDAI-2K ≤ 4, with no activity in major organ system (renal, central nervous system, cardiopulmonary, vasculitis, and fever) and no hemolytic anemia or gastrointestinal activity, current, no new lupus disease activity compared with the previous assessment, prednisone (or its equivalent) dose ≤ 7.5 mg/day, PGA (scale 0-3) ≤ 1, well tolerated standard maintenance doses of immunosuppressive lupus therapy.
- Remission rate [Up to 2 years]
Remission as specified by Definitions Of Remission In Systemic Lupus Erythematosus (DORIS) criteria: Clinical SLEDAI=0, PGA<0.5 (0-3) irrespective of serology. The patient may be on antimalarials, low-dose glucocorticoids (prednisolone ≤5 mg/day), and/or stable immunosuppressive therapy including biologics.
- Change from pre-dose up to 2 years in Systemic Lupus Erythematosus Responder Index -4 (SRI-4) [Pre-dose, up to 2 years]
SRI-4 response is defined as a greater than or equal to 4-point decrease in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and no new British Isles Lupus Assessment Group (BILAG) 2004 A score, no greater than 2 new BILAG B domain scores compared with baseline, and a less than 0.3-point worsening from baseline in Physician Global Assessment (PGA) (scale 0 to 3).
- Change from pre-dose up to 2 years in British Isles Lupus Assessment Group based Composite Lupus Assessment (BICLA) [Pre-dose, up to 2 years]
BICLA is a composite assessment based on BILAG, SLEDAI-2K PGA and use of restricted or rescue medications, other than defined in the protocol.
- Incidence of Major Clinical Response (MCR) [After 6 months and 12 months]
Number of participants who achieved MCR.
- Change from pre-dose up to 2 years in Urinary protein creatinine ratio (UPCR) [Pre-dose, up to 2 years]
Change in the value of UPCR.
- Incidence of Complete renal response (CRR) [Up to 2 years]
Number of participants who achieved CRR.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Signed informed consent
-
Adequate renal, hepatic, cardiac, hematological and pulmonary function
-
Men and women with SLE, aged ≥18 years and ≤65 years at screening, fulfilling the 2019 European League Against Rheumatism EULAR/ACR classification criteria for SLE.
-
Patient must be positive for at least one of the following autoantibodies at screening: antinuclear antibodies (ANA) at a titer of ≥1:80, or anti dsDNA (above the ULN); or anti-Sm (above the ULN)
-
Active (severe) disease as defined by SLEDAI-2K ≥ 8 (not including the SLEDAI-2K domains of lupus headache, cerebrovascular accident, organic brain syndrome*) and at least one of the following significant SLE related organ involvements:
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Renal
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Peri/myocarditis
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Pleuritis or other lung involvement
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Other types of serositis such as peritoneal
-
Vasculitis
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Failure to respond (i.e. having high disease activity as defined in criterion above despite the following therapy) to two or more standard immunosuppressive therapies (including one of mycophenolate or cyclophosphamide), unless contraindicated or having experienced documented adverse events or intolerance related to such immunosuppressive drugs not allowing their further use, in combination with glucocorticoids and failure to respond to at least one biological agent (unless contraindicated, the patient deemed ineligible by the Investigator or not available in a country).
Exclusion Criteria:
-
Clinically significant active, opportunistic, chronic or recurrent infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, such as COVID-19 etc.) one month prior to or during screening
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Uncontrolled diabetes mellitus, lung diseases or any other illness that are not related to SLE that in the opinion of the Investigator would jeopardize the ability of the patient to tolerate lymphodepletion and CD19 CAR-T cell therapy
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Prior history of malignancy except for localized basal cell or squamous skin cancer. Other malignancies for which the patient is judged to be cured by local surgical therapy, such as head and neck cancer, or stage I breast cancer will be considered on an individual basis
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Any patients requiring medications prohibited by the protocol
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Any psychiatric condition or disability making compliance with treatment or informed consent impossible
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Prior treatment with anti-CD19 therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR-T cell therapy)
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History of bone marrow/hematopoietic stem cell or solid organ transplantation
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Female participants who are pregnant or breastfeeding, or intending to conceive during the course of the study
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Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using a highly effective method of contraception starting from the time of enrollment to at least 12 months after the YTB323 infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests
-
Sexually active males unwilling to use a condom during intercourse from the time enrollment for at least 12 months after the YTB323 infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests
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Any acute, severe lupus related flare during screening that needs immediate treatment and/or makes the immunosuppressive washout impossible; thus, makes the patient ineligible for CD19 CAR-T therapy as judged by the Investigator, such as acute central nervous system (CNS) lupus (e.g. psychosis, epilepsy) or catastrophic antiphospholipid syndrome
-
Significant, likely irreversible organ damage related to SLE, e.g. end stage renal disease, where, in the opinion of the Investigator CD19 CAR-T cell therapy would be unlikely to benefit the patient
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Novartis Investigative Site | Barcelona | Catalunya | Spain | 08035 |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceutical
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CYTB323G12101
- 2022-001796-14