Clinical trial NCT06333483: A Study of CD19 Targeted CAR T Cell Therapy in Patients With Severe, Refractory Systemic Lupus Erythematosus (SLE)
Official title: A Single-Arm, Open-Label, Phase I Study to Determine the Safety, Tolerability and Preliminary Efficacy of Obecabtagene Autoleucel in Patients With Severe, Refractory Systemic Lupus Erythematosus
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Systemic Lupus Erythematosus
Keywords: AUTO1
Obecabtagene autoleucel (obe-cel)
CD19-positive chimeric antigen receptor T cell
CAR-T
Lead sponsor: Autolus Limited
Sponsor class: INDUSTRY
First posted: 2024-03-27
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a Phase I study of obecabtagene autoleucel (obe-cel), autologous T cells engineered with a chimeric antigen receptor (CAR) targeting CD19, to establish the tolerability, safety, preliminary efficacy, and pharmacokinetics of obe-cel in patients with severe, refractory SLE.

Detailed description: This is a single-arm, open-label Phase I Study to determine the safety, tolerability, and preliminary efficacy of obe-cel in patients with severe, refractory SLE. A maximum of n=12 patients will be treated in a maximum of 3 dose levels.

By using the Bayesian Optimal Interval (BOIN) design for overdose control, the Sponsor will review the Safety Review Committee (SRC) and Independent Data Monitoring Committee (IDMC) recommendation and determine if a dose level is suitable for a subsequent study.

Eligibility criteria: Inclusion Criteria:

-Key Inclusion Criteria-

* Women or men ≥ 18 years
* Diagnosis of SLE fulfilling the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) Classification Criteria for Systemic Lupus Erythematosus
* Positive for at least one of the following autoantibodies: antinuclear antibodies (ANA) at a titer of ≥ 1:80, or anti-dsDNA (≥ 30 IU/mL) or anti-Smith (\> upper limit of normal \[ULN\]), anti-histone or anti-chromatin (\> ULN)
* Severe, refractory SLE

Exclusion Criteria:

-Key Exclusion Criteria-

* Medications

  * Within 2 months of leukapheresis: use of anti-CD20 therapy
  * Prior treatment with anti-CD19 therapy (including bispecifics), adoptive T cell therapy or any prior gene therapy product (e.g., CAR T cell therapy)
  * Immunization with a live or attenuated vaccine within 2 months of leukapheresis
* SLE and Autoimmunity:

  * Recurrent neuropsychiatric lupus or active, severe or unstable neuropsychiatric lupus within 2 years from screening
  * Diagnosis of drug-induced SLE rather than idiopathic SLE
  * Any acute, severe lupus-related flare during screening that needs immediate treatment and/or makes the immunosuppressive washout impossible; thus, making the patient ineligible for CD19 CAR T therapy as judged by the Investigator or Sponsor
  * 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 unlikely to benefit the patient
  * Diagnosis of another non-SLE autoimmune disease (e.g., dermatomyositis, polymyositis, scleroderma, rheumatoid arthritis) or overlap syndrome
* Medical History:

  * History or presence of: (Within 3 months before screening visit)

    * Clinically relevant central nervous system (CNS) pathology such as epilepsy, paresis, aphasia, or stroke
    * Evidence of deep venous thrombosis or pulmonary embolism
  * History or presence of severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or psychosis
  * Clinically significant, uncontrolled heart disease not due to SLE (New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled cardiac arrhythmia, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless the patient has a pacemaker) or a recent (within 12 months of screening) cardiac event
  * Active or uncontrolled fungal, bacterial, viral (including COVID-19), or other infection requiring systemic antimicrobials for management
  * Active or latent hepatitis B or active hepatitis C
  * Human immunodeficiency virus, human T-cell leukemia virus (HTLV)-1, HTLV-2 or syphilis positive test at screening
  * History of malignant neoplasms unless disease free for at least 24 months (basal cell or squamous cell carcinoma in situ, or in situ breast cancer on hormonal therapy allowed)
  * History of heart, lung, kidney, liver transplant or hematopoietic stem cell transplant
  * Pregnancy or lactating
* Laboratory and Organ Function:

  * Left ventricular ejection fraction \< 45% (or \< institutes lower limit of normal) confirmed by ECHO
  * Oxygen saturation (SpO2) \< 90% in the absence of oxygen support
  * B cell aplasia

Primary outcomes:
measure: Dose limiting toxicities
timeFrame: Up to 28 days from obe-cel infusion
measure: Adverse events
timeFrame: Up to Month 12
Secondary outcomes:
measure: Remission rate according to Definition of Remission in SLE (DORIS)
timeFrame: Up to Month 12
measure: Response over time according to Definition of Remission in SLE (DORIS)
timeFrame: Up to Month 12
measure: Time to response according to Definition of Remission in SLE (DORIS)
timeFrame: Up to Month 12
measure: Change over time in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)
timeFrame: Up to Month 12
measure: Change over time in Physician's global assessment (PGA)
timeFrame: Up to Month 12
measure: Pharmacokinetics (maximum serum concentration [Cmax]): Detection of CAR-T cells by polymerase chain reaction (PCR) in peripheral blood
timeFrame: Pre-infusion at Day -6, and at 9 timepoints post infusion between Days 1 and 28, followed by Month 2, Month 3 then 3 monthly to Month 12 and finally 6 monthly through study completion, up to a total of 3 years
measure: Pharmacokinetics (time to reaching maximum serum concentration [Tmax]): Detection of CAR-T cells by polymerase chain reaction (PCR) in peripheral blood
timeFrame: Pre-infusion at Day -6, and at 9 timepoints post infusion between Days 1 and 28, followed by Month 2, Month 3 then 3 monthly to Month 12 and finally 6 monthly through study completion, up to a total of 3 years
measure: Pharmacokinetics (area under the curve [AUC]): Detection of CAR-T cells by polymerase chain reaction (PCR) in peripheral blood
timeFrame: Pre-infusion at Day -6, and at 9 timepoints post infusion between Days 1 and 28, followed by Month 2, Month 3 then 3 monthly to Month 12 and finally 6 monthly through study completion, up to a total of 3 years
measure: Pharmacokinetics (last observed quantifiable concentration [Clast]): Detection of CAR-T cells by polymerase chain reaction (PCR) in peripheral blood
timeFrame: Pre-infusion at Day -6, and at 9 timepoints post infusion between Days 1 and 28, followed by Month 2, Month 3 then 3 monthly to Month 12 and finally 6 monthly through study completion, up to a total of 3 years
measure: Pharmacokinetics (time to reach last observed quantifiable concentration [Tlast]): Detection of CAR-T cells by polymerase chain reaction (PCR) in peripheral blood
timeFrame: Pre-infusion at Day -6, and at 9 timepoints post infusion between Days 1 and 28, followed by Month 2, Month 3 then 3 monthly to Month 12 and finally 6 monthly through study completion, up to a total of 3 years
measure: Pharmacodynamics: B cell aplasia
timeFrame: Screening, pre-infusion Day -6, Day 1, Day 3, Day 28, Month 2, Month 3, Month 4, Month 6, Month 9, Month 12 then 6 monthly through study completion, up to a total of 3 years
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Hospital Universitari Vall Hebrón
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary, Manchester University NHS Foundation Trust,
Study officials:
References: