Clinical trial NCT05798117: An Open-label, Study to Assess Safety, Efficacy and Cellular Kinetics of YTB323 in Severe, Refractory Systemic Lupus Erythematosus
Official title: An Open-label, Multi-center, Phase 1/2 Study to Assess Safety, Efficacy and Cellular Kinetics of YTB323 in Participants With Severe, Refractory Systemic Lupus Erythematosus
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Systemic Lupus Erythematosus
Lupus Nephritis
Keywords: CAR-T, YTB323, Lupus, SLE, LN, severe refractory SLE
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2023-04-04
Enrollment: 21
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: The study is intended to assess safety, efficacy and cellular kinetics of YTB323 treatment in participants with severe refractory systemic lupus erythematosus.


Eligibility 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:
* Renal
* At least moderate or severe peri/myocarditis
* At least moderate or severe pleuritis or other lung involvement
* Vasculitis
* Failure to respond 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. Patients who have had at least one severe infection that required prolonged hospitalization in the intensive care setting within 5 years prior to screening and/or at least one severe infection that required prolonged hospitalization within one year prior to screening.
* 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
* 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
* Any patients requiring medications prohibited by the protocol
* Any psychiatric condition or disability making compliance with treatment or informed consent impossible
* Prior treatment with anti-CD19 therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR-T cell therapy)
* History of bone marrow/hematopoietic stem cell or solid organ transplantation
* Female participants who are pregnant or breastfeeding, or intending to conceive during the course of the study
* 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 (or longer if required as per local regulations) 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
* 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, that in the opinion of the Investigator renders CD19 CAR-T cell therapy would be unlikely to benefit the patient
* B cell aplasia

Primary outcomes:
measure: Number of participants with AEs and SAEs
timeFrame: Day 1 to 2 years
Secondary outcomes:
measure: CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood (Maximum observed blood concentration Cmax)
timeFrame: Pre-dose, up to 2 years
measure: CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood (Area under plasma concentration -time AUC)
timeFrame: Pre-dose, up to 2 years
measure: CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood (Time to reach maximum concentration Tmax)
timeFrame: Pre-dose, up to 2 years
measure: CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood (Terminal elimination half-life T1/2)
timeFrame: Pre-dose, up to 2 years
measure: CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood (Last measurable concentration Clast)
timeFrame: Pre-dose, up to 2 years
measure: CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood (Time to reach last measurable concentration Tlast)
timeFrame: Pre-dose, up to 2 years
measure: Number of patients with anti-drug antibodies
timeFrame: Pre-dose, up to 2 years
measure: Level of T cell activation by YTB323
timeFrame: Pre-dose, up to 2 years
measure: Number of patients infused with planned target dose
timeFrame: Day 1
measure: Change from pre-dose up to 2 years in the Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score
timeFrame: Pre-dose, up to 2 years
measure: Change from pre-dose up to 2 years in Physician's global assessment (PGA)
timeFrame: Pre-dose, up to 2 years
measure: Change from pre-dose up to 2 years in Lupus Low Disease Activity State (LLDAS)
timeFrame: Pre-dose, up to 2 years
measure: Remission rate
timeFrame: Up to 2 years
measure: Change from pre-dose up to 2 years in Urinary protein creatinine ratio (UPCR)
timeFrame: Pre-dose, up to 2 years
measure: Incidence of Complete renal response (CRR)
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Division of Rheumatology Immunology
state: Alabama
city: Clayton
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Lille
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Pessac
country: France
facility: Novartis Investigative Site
city: Strasbourg Cedex
country: France
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Bern
country: Switzerland
facility: Novartis Investigative Site
city: Lausanne
country: Switzerland
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceutical
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: