Autoimmune Rheumatologic Disease, Diffuse Cutaneous Systemic Sclerosis, Rheumatoid Arthritis (RA), Systemic Sclerosis (SSc)
Conditions
Keywords
Regulatory T cells, Autologous, Genetically modified cells, Treg, Chimeric antigen receptor (CAR)
Brief summary
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.
Detailed description
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.
Interventions
DRUGQEL-005
QEL-005 is an autologous cell therapy that is composed of engineered regulatory T cells transduced with a lentiviral vector containing a CAR directed against the B cell marker CD19. Treatment will be given via an IV infusion.
Sponsors
Quell Therapeutics Limited
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study consists of two parts: (1) a dose escalation phase that includes three sequential cohorts receiving increasing dose levels, and (2) a dose expansion phase in which a selected dose level will be further evaluated.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| D2TRA & SSc: Incidence of Protocol-Defined Dose Limiting Toxicities (DLTs) to Assess Safety and Tolerability (Dose Escalation Phase Only) | 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) | 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 | Up to week 52 | Evaluation of safety through the assessment of clinically significant abnormalities in safety laboratory parameters, ECG findings, and vital signs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| D2TRA: Clinical response status | Week 12 and 52 | Proportion of participants achieving predefined levels of disease activity improvements and functional improvements |
| D2TRA & SSc: Use of additional background disease modifying therapy | Week 12 and 52 | Need for escalation of background disease modifying therapy above permitted baseline medication |
| D2TRA: Cumulative steroid exposure | Baseline to week 12 and baseline to week 52 | Total systemic steroid dose received over specified intervals |
| D2TRA: Ability to reduce glucocorticoid dose | Up to week 52 | Proportion of participants able to reduce systemic glucocorticoid use below a predefined daily threshold |
| D2TRA & SSc: Change from baseline in autoantibodies | Baseline to week 52 | Evaluation of change in blood levels of disease related autoantibodies |
| D2TRA & SSc: Presence of replication competent viral vector | Week 52 | Assessment of detectable replication competent viral vector in blood |
| SSc: Change From Baseline in a Modified Rodnan Skin Score (mRSS) | Week 12,24,38 and 52 | Assessment of absolute values and change from baseline in a validated, standardised skin involvement assessment score evaluating the extent and severity of cutaneous involvement in systemic sclerosis. |
| SSc: Change from baseline in Digital ulcers | Week 12, 24, 38 and 52 | Number of digital ulcers |
| D2TRA: Change from baseline in a disease activity score-28 C-reactive protein (DAS28-CRP) | Week 4,8,12,38 and 52 | Assessment of absolute values and change from baseline using a validated composite clinical disease activity score that incorporates clinician-reported joint assessments, patient-reported disease activity, and laboratory or physiological indicators of inflammation |
| SSc: Change From Baseline in a Standardised High Resolution Computed Tomography (HRCT) Based Pulmonary Fibrosis Assessment Score | Week 24 and 52 | Assessment of absolute values and change from baseline in a validated, standardised HRCT based scoring system of interstitial lung disease, quantifying the extent and severity of pulmonary fibrosis. |
| SSc: Change From Baseline in a Standardised Positron Emission Tomography (PET) Based Pulmonary Fibrosis Assessment Score | Week 24 and 52 | Assessment of absolute values and change from baseline in a validated, standardised PET based assessment of fibroblast activation and fibrosis activity in predefined lung regions. |
| SSc: Change from baseline in Health Assessment Questionnaire Disability Index | Week 12, 24, 38 and 52 | Assessment of absolute values and change from baseline in a standardised patient reported quality of life questionnaire evaluating overall disease impact |
| SSc: Change From Baseline in the EUropean Scleroderma Trials And Research group (EUSTAR) Activity Index | Week 12, 24, 38 and 52 | Assessment of absolute values and change from baseline in a validated composite clinical disease activity assessment score used to evaluate systemic sclerosis disease activity. |
| SSc: Change From Baseline in the Sclerderma Clinical Trial Consortium (SCTC) Disease Damage Index | Week 12, 24, 38 and 52 | Assessment of absolute values and change from baseline in a validated disease damage assessment score used to evaluate longer-term organ involvement. |
| Change from Baseline in the European Alliance of Associations for Rheumatology Systemic Sclerosis Impact of Disease (EULAR ScleroID) | Week 12, 24, 38 and 52 | Assessment of absolute values and change from baseline in a validated patient-reported outcome questionnaire designed to measure the overall impact of systemic sclerosis on patients' daily function and quality of life. |
| D2TRA: Change from baseline in American College of Rheumatology (ACR) response criteria | Week 4,8,12,24,38 and 52 | Assessment of absolute values and change from baseline using a validated functional assessment tool that incorporates patient-reported measures of physical function and clinician-reported evaluations of disease activity, joint involvement, and pain |
| SSc: Change From Baseline in a Standardised Lung Function Assessment Score | Week 12, 24, 38 and 52 | Assessment of absolute values and change from baseline using a validated, standardized lung function assessment score that evaluates pulmonary functional capacity |
| D2TRA: Change from baseline in Health Assessment Questionnaire Disability Index | Week 4,8,12,24,38 and 52 | Assessment of absolute values and change from baseline in a standardised patient reported quality of life questionnaire evaluating overall disease impact |
| D2TRA: Change from baseline in Ultrasound Outcome Measure in Rheumatology (OMERACT) score | Week 12 and 52 | Changes in standardised imaging score assessing synovitis and synovial vascularity in predefined joint. |
Countries
Germany, Spain, United Kingdom
Contacts
CONTACTQuell Therapeutics Clinical Trials
Outcome results
None listed