An Open-label, Study to Assess Safety, Efficacy and Cellular Kinetics of YTB323 in Severe, Refractory Systemic Lupus Erythematosus

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

The study is intended to assess safety, efficacy and cellular kinetics of YTB323 treatment in participants with severe refractory systemic lupus erythematosus.

Study Overview

• Status: Recruiting
• Conditions: Systemic Lupus Erythematosus; Lupus Nephritis
• Intervention / Treatment: Drug: YTB323

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals; Phone Number: +41613241111

Study Locations

• Australia
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Recruiting
      • Novartis Investigative Site
• France
  • Lille, France, 59037
    • Recruiting
    • Novartis Investigative Site
  • Paris 13, France, 75651
    • Recruiting
    • Novartis Investigative Site
  • Pessac Cedex, France, 33604
    • Recruiting
    • Novartis Investigative Site
  • Strasbourg, France, 97091
    • Recruiting
    • Novartis Investigative Site
• Germany
  • Freiburg, Germany, 79106
    • Recruiting
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Recruiting
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28009
    • Recruiting
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Recruiting
      • Novartis Investigative Site
• Switzerland
  • Bern, Switzerland, 3010
    • Recruiting
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: YTB323; Single infusion of YTB323	Drug: YTB323; Single infusion of YTB323

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with AEs and SAEs	Long term safety follow up	Day 1 to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with anti-drug antibodies	Blood samples will be collected to measure anti-drug antibodies against YTB323.	Pre-dose, up to 2 years
Level of T cell activation by YTB323	Blood samples will be collected to measure the level of T cell activation by YTB323.	Pre-dose, up to 2 years
Number of patients infused with planned target dose	Feasibility of the manufacturing process in autoimmune disorders.	Day 1
Change from pre-dose up to 2 years in the Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score	SLEDAI-2K scores are between 0 and 105, a higher score represents a higher disease activity.	Pre-dose, up to 2 years
Change from pre-dose up to 2 years in Physician's global assessment (PGA)	The Physician's Global assessment is a visual analog scale from 0 to 3, 0 represents no activity and 3 represents severe disease activity.	Pre-dose, up to 2 years
Change from pre-dose up to 2 years in Lupus Low Disease Activity State (LLDAS)	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.	Pre-dose, up to 2 years
Remission rate	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.	Up to 2 years
Change from pre-dose up to 2 years in Urinary protein creatinine ratio (UPCR)	Change in the value of UPCR.	Pre-dose, up to 2 years
Incidence of Complete renal response (CRR)	Number of participants who achieved CRR.	Up to 2 years
CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood (Maximum observed blood concentration Cmax)	Blood samples will be collected to assess cellular kinetics.	Pre-dose, up to 2 years
CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood (Area under plasma concentration -time AUC)	Blood samples will be collected to assess cellular kinetics.	Pre-dose, up to 2 years
CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood (Time to reach maximum concentration Tmax)	Blood samples will be collected to assess cellular kinetics.	Pre-dose, up to 2 years
CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood (Terminal elimination half-life T1/2)	Blood samples will be collected to assess cellular kinetics.	Pre-dose, up to 2 years
CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood (Last measurable concentration Clast)	Blood samples will be collected to assess cellular kinetics.	Pre-dose, up to 2 years
CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood (Time to reach last measurable concentration Tlast)	Blood samples will be collected to assess cellular kinetics.	Pre-dose, up to 2 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceutical

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2023
• Primary Completion (Estimated): October 9, 2026
• Study Completion (Estimated): October 9, 2026

Study Registration Dates

• First Submitted: February 27, 2023
• First Submitted That Met QC Criteria: March 22, 2023
• First Posted (Actual): April 4, 2023

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: CAR-T, YTB323, Lupus, SLE, LN, severe refractory SLE
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Connective Tissue Diseases; Glomerulonephritis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Lupus Erythematosus, Systemic; Nephritis; Lupus Nephritis
• Other Study ID Numbers: CYTB323G12101; 2022-001796-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No