Phase I/II Evaluation of QEL-001, Autologous CAR T Regulatory Cells, for Safety in HLA-A2 Mismatch Liver Transplant Rejection Prevention

Trial ID: 2024-516193-30-01
Protocol: QEL-001-CLN-01
Sponsor: Quell Therapeutics Limited

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Diseases & Conditions

Liver transplant rejection

Objectives

The primary objective of this study is to evaluate the **safety** and tolerability of a single target dose of QEL-001, an autologous CAR T regulatory cell treatment, in the context of preventing liver transplant rejection. This is clinically relevant as it aims to address the challenge of immune-mediated rejection in patients who have received an HLA-A2 positive liver transplant, potentially improving transplant outcomes and patient survival.

Secondary objectives include:

Assessing the clinical activity of QEL-001 in Part 2 of the study, which is crucial for understanding the therapeutic efficacy of the treatment.
Evaluating safety-related events to ensure the treatment's risk profile is acceptable for clinical use.
Determining the absence or presence of exposure to replication-competent lentivirus (RCL), which is important for ensuring the genetic safety of the therapy.

Participants

The clinical trial involves a total of **18 participants** who are being evaluated for the **prevention of liver transplant rejection**. The study population includes both male and female subjects, aged between **18 to 75 years**. Participants are required to be in a stable health condition, specifically having been on stable maintenance of immunosuppression for at least 12 weeks prior to study entry. The selection criteria include individuals who have received a liver transplant 12 months to 5 years prior to study entry, with no episodes of rejection in the previous 12 months, except for early rejection within the first 3 months post-transplantation. Participants must have specific health parameters, such as an **alanine aminotransferase (ALT)** level of less than 60 U/L, and either alkaline phosphatase (ALP) less than 200 U/L or gamma-glutamyl transferase (GGT) less than 100 U/L. Additionally, an estimated glomerular filtration rate (eGFR) of at least 40 mL/min/1.73 m² is required. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must also have adequate bone marrow function and be capable of giving informed consent. The trial population was selected based on these criteria to ensure the safety and tolerability of a single target dose of QEL-001 are accurately assessed.

Plans and Procedures

The clinical trial is a **single-arm, open-label, multi-centre, phase I/II study** designed to evaluate the safety and clinical activity of QEL-001, an **autologous CAR T regulatory cell treatment** targeting HLA-A2, in patients who have received an HLA-A2 positive liver transplant. The primary objective is to assess the safety and tolerability of a single target dose of QEL-001. The trial is expected to run until July 31, 2039, with recruitment having commenced on January 31, 2023. Participants will be involved in the study for a duration that includes initial screening, treatment, and follow-up visits.

The trial involves a sequence of study visits beginning with an inclusion (screening) visit to determine eligibility based on criteria such as age, stable maintenance of immunosuppression, and liver function tests. Following the screening, eligible participants will receive the investigational product via **intravenous use**. Subsequent follow-up visits will monitor the incidence of dose-limiting toxicities and treatment-emergent adverse events, as well as the potential for successful withdrawal from immunosuppression. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes such as operational tolerance and incidence of infections.

Participants are expected to remain in the study for a period that allows for comprehensive evaluation of both primary and secondary endpoints, including the incidence of adverse events and the proportion of subjects achieving stable liver function tests post-immunosuppression withdrawal. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or failure to comply with study protocols. The trial is not categorized as low intervention, reflecting its phase I/II status and the investigational nature of the treatment.

Treatment

The clinical trial involves the administration of **QEL-001**, an experimental medication formulated as a **suspension for injection**. This investigational product consists of **autologous T regulatory cells expressing an HLA-A2-specific chimeric antigen receptor**. The cells are derived from non-mobilized mononuclear cells obtained from peripheral blood. The pharmaceutical form of QEL-001 is a suspension intended for **intravenous use**. The administration of QEL-001 is designed to be a single target dose, with the primary objective of evaluating its safety and tolerability in the study participants. The product is not a pediatric formulation and is not classified as an orphan drug.

In this study, QEL-001 is the sole investigational treatment, and no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is a single-arm, open-label, multi-centre, phase I/II study, specifically targeting HLA-A2/A28neg patients who have received an HLA-A2pos liver transplant. The study does not specify a maximum daily dose, total dose, or treatment period for QEL-001, as the focus is on a single administration to assess initial safety and clinical activity. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the incidence of protocol-defined Dose-Limiting Toxicities (DLTs) within 28 days post-infusion and the incidence and severity of Treatment Emergent Adverse Events (TEAEs), including serious adverse events (SAEs), evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Secondary endpoints focus on the proportion of subjects that can be successfully withdrawn from immunosuppression (IS), defined as the percentage of subjects who maintain stable Liver Function Tests (LFTs) and remain IS-free for specified durations, such as 2 months and 1 year following IS withdrawal. Additionally, the incidence and severity of infections from treatment to 1 year post full wean of all immune suppressive medication will be monitored.

Further secondary endpoints include the proportion of subjects with detectable replication-competent lentivirus (RCL) assessed by polymerase chain reaction (PCR) to vesicular stomatitis virus G glycoprotein (VSV-G) protein at pre-treatment and at Weeks 14, 26, and 54. The trial will also evaluate the proportion of subjects meeting criteria for operational tolerance, defined as successful IS withdrawal, stable LFTs, and meeting histological criteria of operational tolerance. The incidence rate of composite efficacy failure, defined as acute rejection (AR), biopsy-proven acute rejection (BPAR), reintroduction of IS, or graft loss, will be assessed from treatment to 1 year following IS withdrawal.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participants (regardless of gender) must be 18 to 75 years of age inclusive, at the time of signing the informed consent.
HLA A2/A28neg (including split antigens A68neg and A69neg) participants who have received an A2pos liver transplant.
Having received a liver transplant 12 months to 5 years prior to study entry with: a. No episodes of rejection in the previous 12 months (except early rejection taking place in the first 3 months post-transplantation. b. No previous episodes of rejection requiring lymphodepleting antibody therapy.
Having alanine aminotransferase (ALT) <60 U/L and either alkaline phosphatase (ALP) <200 U/L or gamma-glutamyl transferase (GGT) <100 U/L
Having eGFR ≥ 40 mL/min/1.73 m2 using the MDRD formula
Having an adequate bone marrow (BM) function without requiring ongoing blood product(s) or granulocyte colony-stimulating factor (GCSF) and meeting the following criteria: a. Absolute neutrophil count ≥ 1.0 x 10e9/L b. Absolute lymphocyte count ≥ 0.3 x 10e9/L c. Leucocyte count ≥ 2.0 x 10e9/ L d. Haemoglobin ≥ 80 g/L e. Platelet greater or equal to 100 x 10e9/L
Having an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Able and willing to use a highly effective method of contraception (male participants and female participants with reproductive potential) from informed consent through and for at least 12 months
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) at Screening, prior to conditioning with rATG and prior/post QEL-001 infusion
Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
Being on stable maintenance of immunosuppression for at least 12 weeks prior to study entry

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Exclusion Criteria

Having any medical condition that, in the opinion of the principal investigator (PI), would interfere with safe completion of the trial including: a. Severe cardiac disease, severe respiratory disease with O2 blood saturation <92%. b. Any other major organ dysfunction.
Having received prior non-liver solid organ or hematopoietic stem cell transplant.
Have had any major surgical intervention in the last 3 months prior to study entry (such as open surgeries requiring general anaesthetic)
History of autoimmune disease requiring systemic immunosuppression, systemic disease modifying agents or biologics within the last 24 months prior to study entry
History of autoimmune hepatitis, primary sclerosing cholangitis or primary biliary cholangitis
Having any evidence of recurrent hepatocellular carcinoma (HCC) following clinical assessment; for participants with liver explant histology showing a RETREAT score greater than 0 the clinical assessment should include a thoraco-abdominal radiological scan (CT or MRI according to local clinical practice) performed within 1 month prior to enrolment
History of HCC with high risk of recurrence defined as: a. For participants who are <2 years post-transplant: a) RETREAT score greater than or equal to 3. b. For participants who are 2-5 years post-transplant: a) RETREAT score greater than or equal to 4. c. Additional explant-based exclusion criteria: i) presence of diffuse HCC in explant; ii) presence of extrahepatic extension or macrovascular invasion; iii) diagnostics of cholangiocarcinoma; iv) pariticipants who have undergone a downstaging procedure pretransplantation
Having active primary or recurrent malignant disease or have been in remission from clinically significant malignancy for less than 5 years. a. Except participants that have had a cervical carcinoma in situ that has been resected with no evidence of recurrence or metastatic disease for at least 3 years may participate in the study. b. Except participants that have had basal cell or squamous epithelial skin cancers that have been completely resected with no evidence of recurrence for at least 3 years may participate in the study
Having urine protein to creatinine ratio > 25mg/mmol or > 50mg/mmol if the participant is already under dual therapy TAC/EVR
Having triglycerides ≥ 3.95 mmol/L (350 mg/dL) despite appropriate therapy
Having cholesterol ≥ 7.8 mmol/L (301.5 mg/dL) despite appropriate therapy
Having QTc > 450 msec for male participants or QTc > 470 msec for female participants or QTc > 480 msec in participants with bundle branch block
Having any contraindications to receive rATG, EVR (notably participants with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption), TAC or rituximab
Receiving any other concurrent investigational agents within 3 months prior study entry
Having an active infection as defined in the study protocol
Having previous history of human immunodeficiency virus (HIV)
Evidence of active or latent tuberculosis (TB). After anti-TB treatment, patients with history of active or latent TB may become eligible according to national guidelines
Recent history of reactivation of Cytomegalovirus (CMV) defined as positive DNA test within 6 months prior entry to the study
Females who are pregnant (i.e., positive blood or urine β human Chorionic Gonadotropin (β- hCG) test) or lactating
Do not have: a. up-to-date vaccination status as per local immunization schedules/national guidelines (e.g., influenza and pneumococcal vaccination for >65 years old). b. any required vaccination (if required) at least 2 weeks prior to study entry, in accordance with national guidelines
Have known or suspected hypersensitivity or allergy to DMSO present in QEL-001 as excipients
Having a non-adequate bilateral venous access for leukapheresis, or not willing to undergo a central venous catheter insertion
Having contraindications to undergo a leukapheresis
Have any significant medical or social condition that, in the Investigator's opinion, may interfere with the participant's optimal participation or compliance with the study procedure
Having history of liver cirrhosis or advanced fibrosis post-transplantation
Receiving prohibited medications that cannot be stopped at study entry