Phase I/II Study of QEL-005 in Patients With Diffuse Cutaneous Systemic Sclerosis (dcSSc) and in Patients With Difficult to Treat Rheumatoid Arthritis (D2TRA).
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 16
- 试验地点
- 10
- 主要终点
- D2TRA & SSc: Incidence of Protocol-Defined Dose Limiting Toxicities (DLTs) to Assess Safety and Tolerability (Dose Escalation Phase Only)
研究概览
简要总结
This study is a Phase 1/2, open-label clinical trial to test an experimental treatment called QEL-005 in adults with two autoimmune conditions: diffuse cutaneous systemic sclerosis (dcSSc) and difficult-to-treat rheumatoid arthritis (D2TRA). The main goals are to find out whether QEL-005 is safe, how well people tolerate it, and whether it may help reduce disease activity or improve symptoms.
QEL-005 is made from a participant's own white blood cells (autologous cells). These cells are collected and then changed in a laboratory using genetic methods to create specialized immune cells called CAR-T regulatory cells that target a protein on B cells called CD19. These modified cells are then given back to the participant by intravenous (IV) infusion.
To take part, eligible participants will first have a procedure called leukapheresis, where some of their white blood cells are removed from the blood. The study team will use these cells to manufacture QEL005. After QEL005 is ready, participants will receive an IV infusion of their modified cells, stay in hospital overnight for monitoring, and will then be followed closely in the clinic.
Throughout the trial, participants will have regular safety checks, which may include blood tests, imaging scans, questionnaires about symptoms and daily functioning, and biopsies taken from involved tissues, to help understand how QEL005 is working in the body. Detailed follow up will be for 1 year after QEL-005 infusion, and there is long-term follow up for a total of 15 years, which is standard for cell therapies. The information from this Phase 1/2 study will help determine an appropriate dose and dosing schedule of QEL005 for future studies.
详细描述
This is a single-arm, open label, multicentre, Phase 1/2, first in human study of QEL005 in adult participants with diffuse cutaneous systemic sclerosis (dcSSc) or difficult to treat rheumatoid arthritis (D2TRA). QEL005 is an autologous chimeric antigen receptor regulatory T-cell (CAR-Treg) therapy directed against the CD19 marker found on B cells.
The primary objective of this study is to evaluate the safety and tolerability of single IV infusions of QEL005 across different dose levels in participants with dcSSc or D2TRA. Secondary and exploratory objectives include assessment of preliminary clinical efficacy (for example, changes in disease activity scores, skin involvement, or joint symptoms, as appropriate for each disease) and evaluation of biological activity (including effects on B cell populations, immune biomarkers, and other laboratory measures).
The study uses a dose escalation phase then a dose expansion phase. In the dose escalation phase, sequential cohorts of participants receive increasing doses of QEL005 under close safety monitoring. Safety assessments include recording of adverse events, vital signs and laboratory abnormalities.
QEL005 is manufactured from autologous leukapheresis material obtained at baseline. Participants undergo leukapheresis for collection of peripheral blood mononuclear cells, which are then genetically modified ex vivo to express a CD19directed CAR-T regulatory cell.
Over the course of the trial, participants will attend scheduled visits for clinical evaluations, laboratory tests, imaging studies, and patient reported outcome questionnaires, as well as tissue biopsies, to characterize the safety profile and to explore pharmacodynamic and immunologic effects of QEL005. There are detailed assessments over the first year following QEL-005 infusion, and then additional long-term follow up for 15 years, standard for cell therapy trials. Data from this Phase 1/2 trial will inform the recommended dose, regimen, and patient population for subsequent studies of QEL005 in autoimmune diseases.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must be at least 18 years of age at the time of signing the informed consent.
- •Up to date vaccination status and no planned vaccinations for post 3 months infusion
- •Adequate haematological, liver and renal function
- •Willing to undergo annual influenza vaccination
- •Willing to enter a 15-year follow-up
- •Eastern Cooperative Oncology Group (ECOG) performance status grade < 3
- •Able and willing to use a highly effective method of contraception
- •Stable dose of steroid prior to screening
- •Specific inclusion criteria for participants with difficult to treat rheumatoid Arthritis (D2TRA) only:
- •Diagnosis of Rheumatoid Arthritis (RA) per 2010 ACR-EULAR criteria
- •Diagnosis of D2TRA per 2021 EULAR criteria
- •Evidence of clinically active disease a defined by validated clinical or laboratory results consistent with standard definitions of active RA
- •Evidence of inflammation in target joints used for the DAS28 CRP assessment
- •Specific inclusion criteria for participants with diffuse cutaneous systemic sclerosis (dcSSc) only:
- •Diagnosis of dcSSc as per the 2013 ACR-EULAR criteria
- •Serologically positive for antinuclear antibodies
- •Failure to respond sufficiently to immunomodulatory disease modifying anti-rheumatic drugs (DMARDs).
- •Skin involvement with a total modified Rodnan Skin Score of at least 15
- •Evidence of lung fibrosis based on imaging or pulmonary function testing
- •Evidence of active disease based on a validated SSc activity assessment
排除标准
- •Presence of a significant medical condition(s), or clinically significant laboratory abnormality
- •History or concern of autoimmune diseases other than those under study
- •Active infection, or recurrent chronic infection requiring intervention
- •Immunodeficiency or receiving immunoglobulin replacement therapy
- •Past or current infection with hepatitis B or C, tuberculosis, syphilis, or HIV
- •Clinically significant cardiac dysfunction or severe pulmonary impairment
- •Use of investigational agents within a pre-defined period prior to study screening
- •Received a previous cell therapy
- •Received certain B cell related experimental therapies in a clinical trial with the past year
- •Any solid organ, bone marrow or stem cell transplant
- •History of malignancy in the past 5 years
- •Receiving prohibited medication that cannot be stopped at screening
研究组 & 干预措施
Dose Escalation
Dose escalation will involve 3 distinct dose level ranges. Each dose level will enrol at least 3 participants
干预措施: QEL-005 (Drug)
Dose Expansion
The dose selected for dose expansion will be based on safety and any relevant additional data emerging from the Dose Escalation phase
干预措施: QEL-005 (Drug)
结局指标
主要结局
D2TRA & SSc: Incidence of Protocol-Defined Dose Limiting Toxicities (DLTs) to Assess Safety and Tolerability (Dose Escalation Phase Only)
时间窗: up to 28 days post-infusion
Assessment of safety and tolerability of QEL-005 during the Dose Escalation Phase, as measured by the incidence of protocol-defined dose limiting toxicities (DLTs).
D2TRA & SSc: Incidence and grade of treatment-emergent adverse events (TEAEs), adverse events (AEs) and adverse events of special interest (AESIs)
时间窗: From time of signing the informed consent form (ICF) through to week 52
Assessment of safety and tolerability of D2TRA \& SSc through the collection and evaluation of the incidence and severity grades of all TEAEs, AEs, and AESIs using the Common Terminology Criteria for Adverse Events (CTCAE)
D2TRA & SSc: Incidence of clinically significant abnormalities in safety laboratory parameters, electrocardiogram (ECG) findings, and vital signs
时间窗: Up to week 52
Evaluation of safety through the assessment of clinically significant abnormalities in safety laboratory parameters, ECG findings, and vital signs.
次要结局
- D2TRA: Change from baseline in American College of Rheumatology (ACR) response criteria(Week 4,8,12,24,38 and 52)
- D2TRA: Change from baseline in a disease activity score-28 C-reactive protein (DAS28-CRP)(Week 4,8,12,38 and 52)
- D2TRA: Change from baseline in Health Assessment Questionnaire Disability Index(Week 4,8,12,24,38 and 52)
- D2TRA: Change from baseline in Ultrasound Outcome Measure in Rheumatology (OMERACT) score(Week 12 and 52)
- D2TRA: Clinical response status(Week 12 and 52)
- D2TRA & SSc: Use of additional background disease modifying therapy(Week 12 and 52)
- D2TRA: Cumulative steroid exposure(Baseline to week 12 and baseline to week 52)
- D2TRA: Ability to reduce glucocorticoid dose(Up to week 52)
- D2TRA & SSc: Change from baseline in autoantibodies(Baseline to week 52)
- D2TRA & SSc: Presence of replication competent viral vector(Week 52)
- SSc: Change From Baseline in a Modified Rodnan Skin Score (mRSS)(Week 12,24,38 and 52)
- SSc: Change from baseline in Digital ulcers(Week 12, 24, 38 and 52)
- SSc: Change From Baseline in a Standardised Lung Function Assessment Score(Week 12, 24, 38 and 52)
- SSc: Change From Baseline in a Standardised High Resolution Computed Tomography (HRCT) Based Pulmonary Fibrosis Assessment Score(Week 24 and 52)
- SSc: Change From Baseline in a Standardised Positron Emission Tomography (PET) Based Pulmonary Fibrosis Assessment Score(Week 24 and 52)
- SSc: Change from baseline in Health Assessment Questionnaire Disability Index(Week 12, 24, 38 and 52)
- SSc: Change From Baseline in the EUropean Scleroderma Trials And Research group (EUSTAR) Activity Index(Week 12, 24, 38 and 52)
- SSc: Change From Baseline in the Sclerderma Clinical Trial Consortium (SCTC) Disease Damage Index(Week 12, 24, 38 and 52)
- Change from Baseline in the European Alliance of Associations for Rheumatology Systemic Sclerosis Impact of Disease (EULAR ScleroID)(Week 12, 24, 38 and 52)