Phase I/II study of QEL-001 in A2-mismatch liver transplant patients

Phase 1/2

Recruiting

Conditions: Prevention of liver transplant rejection

Registration Number: 2024-516193-30-01

Lead Sponsor: Quell Therapeutics Limited

Brief Summary: To evaluate the safety and tolerability of a single target dose of QEL-001

Detailed Description: This study is a multicenter, first-in-human, open-label, single-arm study of an autologous CAR T regulatory (CAR-Treg) in HLA-A2 mismatched liver transplant recipients. The aim is for the CAR-Tregs to be activated on recognition of HLA-A2 antigens present on the donated liver and subsequently induce and maintain immunological tolerance to the organ.

Recruitment & Eligibility

Status: Ongoing, recruiting

Sex: Not specified

Target Recruitment: 14

Inclusion Criteria

Subjects (regardless of gender) must be 18 to 75 years of age inclusive, at the time of signing the informed consent.

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

HLA A2/A28neg (including split antigens A68neg and A69neg) subjects 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 subjects and female subjects 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

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 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 subjects or QTc > 470 msec for female subjects or QTc > 480 msec in subjects with bundle branch block

Having any contraindications to receive rATG, EVR (notably subjects 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

Having received prior non-liver solid organ or hematopoietic stem cell transplant.

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 subject'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

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 subjects 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 subjects who are <2 years post-transplant: a) RETREAT score greater than or equal to 3. b. For subjects 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) subjects 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 subjects 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 subjects 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 subject is already under dual therapy TAC/EVR

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Incidence of protocol-defined Dose-Limiting Toxicities (DLTs) within 28 days post infusion		Incidence of protocol-defined Dose-Limiting Toxicities (DLTs) within 28 days post infusion
Incidence and severity of Treatment Emergent Adverse Events (TEAE) including serious adverse events (SAE) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0		Incidence and severity of Treatment Emergent Adverse Events (TEAE) including serious adverse events (SAE) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

Secondary Outcome Measures

Name	Time	Method
Proportion of subjects that can be successfully withdrawn from IS defined as the percentage of subjects who have stable Liver Function Tests (LFTs) and are IS free for 2 months following Immunosuppression withdrawal		Proportion of subjects that can be successfully withdrawn from IS defined as the percentage of subjects who have stable Liver Function Tests (LFTs) and are IS free for 2 months following Immunosuppression withdrawal
Proportion of subjects that can be successfully withdrawn from IS defined as the percentage of subjects who have stable LFTs and are IS free for 1 year following Immunosuppression withdrawal.		Proportion of subjects that can be successfully withdrawn from IS defined as the percentage of subjects who have stable LFTs and are IS free for 1 year following Immunosuppression withdrawal.
Incidence and severity of infections from treatment to 1 year post full wean of all immune suppressive medication		Incidence and severity of infections from treatment to 1 year post full wean of all immune suppressive medication
Proportion of subjects with detectable RCL assessed by polymerase chain reaction (PCR) to vesicular stomatitis virus G glycoprotein (VSV-G) protein [time frame: pre-treatment and Week 14, Week 26 and Week 54]		Proportion of subjects with detectable RCL assessed by polymerase chain reaction (PCR) to vesicular stomatitis virus G glycoprotein (VSV-G) protein [time frame: pre-treatment and Week 14, Week 26 and Week 54]
Proportion of subjects meeting criteria for operational tolerance defined as (1) successfully withdrawn from IS and remaining IS free for 1 year following Immunosuppression withdrawal; (2) having stable LFTs and (3) meeting histological criteria of operational tolerance		Proportion of subjects meeting criteria for operational tolerance defined as (1) successfully withdrawn from IS and remaining IS free for 1 year following Immunosuppression withdrawal; (2) having stable LFTs and (3) meeting histological criteria of operational tolerance
Incidence rate composite efficacy failure from treatment to 1 year following Immunosuppression withdrawal. Composite efficacy failure endpoint is defined as AR, biopsy proven acute rejection (BPAR), reintroduction of IS or graft loss		Incidence rate composite efficacy failure from treatment to 1 year following Immunosuppression withdrawal. Composite efficacy failure endpoint is defined as AR, biopsy proven acute rejection (BPAR), reintroduction of IS or graft loss

Trial Locations

Locations (7): Hospital Clinic De Barcelona
🇪🇸
Barcelona, Spain
Hospital Universitario Reina Sofia
🇪🇸
Cordoba, Spain
Hospital General Universitario Gregorio Maranon
🇪🇸
Madrid, Spain
Erasme Hospital
🇧🇪
Belgium
Cliniques Universitaires Saint-Luc
🇧🇪
Sint-Lambrechts-Woluwe, Belgium
Institut Jules Bordet
🇧🇪
Anderlecht, Belgium
UZ Leuven
🇧🇪
Leuven, Belgium
Hospital Clinic De Barcelona
🇪🇸Barcelona, Spain
Jordi Colmenero
Site contact
+34669392860
jcolme@clinic.cat