Autologous T regulatory cells expressing an HLA-A2-specific chimeric antigen receptor for Liver transplant rejection

Inclusion criteria

• {"criterion_text":"-Participants (regardless of gender) must be 18 to 75 years of age inclusive, at the time of signing the informed consent.\n-HLA A2/A28neg (including split antigens A68neg and A69neg) participants who have received an A2pos liver transplant.\n-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.\n-Having alanine aminotransferase (ALT) <60 U/L and either alkaline phosphatase (ALP) <200 U/L or gamma-glutamyl transferase (GGT) <100 U/L\n-Having eGFR ≥ 40 mL/min/1.73 m2 using the MDRD formula\n-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\n-Having an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1\n-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\n-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\n-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\n-Being on stable maintenance of immunosuppression for at least 12 weeks prior to study entry"}

Exclusion criteria

• {"criterion_text":"-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.\n-Having received prior non-liver solid organ or hematopoietic stem cell transplant.\n-Have had any major surgical intervention in the last 3 months prior to study entry (such as open surgeries requiring general anaesthetic)\n-History of autoimmune disease requiring systemic immunosuppression, systemic disease modifying agents or biologics within the last 24 months prior to study entry\n-History of autoimmune hepatitis, primary sclerosing cholangitis or primary biliary cholangitis\n-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\n-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\n-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\n-Having urine protein to creatinine ratio > 25mg/mmol or > 50mg/mmol if the participant is already under dual therapy TAC/EVR\n-Having triglycerides ≥ 3.95 mmol/L (350 mg/dL) despite appropriate therapy\n-Having cholesterol ≥ 7.8 mmol/L (301.5 mg/dL) despite appropriate therapy\n-Having QTc > 450 msec for male participants or QTc > 470 msec for female participants or QTc > 480 msec in participants with bundle branch block\n-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\n-Receiving any other concurrent investigational agents within 3 months prior study entry\n-Having an active infection as defined in the study protocol\n-Having previous history of human immunodeficiency virus (HIV)\n-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\n-Recent history of reactivation of Cytomegalovirus (CMV) defined as positive DNA test within 6 months prior entry to the study\n-Females who are pregnant (i.e., positive blood or urine β human Chorionic Gonadotropin (β- hCG) test) or lactating\n-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\n-Have known or suspected hypersensitivity or allergy to DMSO present in QEL-001 as excipients\n-Having a non-adequate bilateral venous access for leukapheresis, or not willing to undergo a central venous catheter insertion\n-Having contraindications to undergo a leukapheresis\n-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\n-Having history of liver cirrhosis or advanced fibrosis post-transplantation\n-Receiving prohibited medications that cannot be stopped at study entry"}

Primary endpoints

• {"endpoint_text":"-Incidence of protocol-defined Dose-Limiting Toxicities (DLTs) within 28 days post infusion","definition_or_measurement_approach":"Incidence measured as occurrence of protocol-defined DLTs within 28 days after infusion (protocol-defined criteria for DLTs)."}
• {"endpoint_text":"-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","definition_or_measurement_approach":"TEAEs and SAEs graded and reported according to CTCAE v5.0; incidence and severity summarised per CTCAE definitions."}

Secondary endpoints

• {"endpoint_text":"-Proportion of participants 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","definition_or_measurement_approach":"Proportion defined as percentage meeting criteria: stable LFTs and IS-free for 2 months after immunosuppression withdrawal."}
• {"endpoint_text":"-Proportion of participants 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.","definition_or_measurement_approach":"Proportion defined as percentage meeting criteria: stable LFTs and IS-free for 1 year after immunosuppression withdrawal."}
• {"endpoint_text":"-Incidence and severity of infections from treatment to 1 year post full wean of all immune suppressive medication","definition_or_measurement_approach":"Incidence and severity of infections recorded from treatment until 1 year after full wean of immunosuppressive medication."}
• {"endpoint_text":"-Proportion of participants 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]","definition_or_measurement_approach":"RCL detection by PCR to VSV-G at pre-treatment and at Weeks 14, 26 and 54; proportion with detectable RCL reported."}
• {"endpoint_text":"-Proportion of participants 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","definition_or_measurement_approach":"Composite proportion meeting all three criteria: IS withdrawal and 1-year IS-free, stable LFTs, and histological criteria of operational tolerance."}
• {"endpoint_text":"-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","definition_or_measurement_approach":"Incidence rate of composite efficacy failure (AR, BPAR, reintroduction of IS, or graft loss) from treatment until 1 year after immunosuppression withdrawal."}

Methods

• GP letters (documents: K1_Recruitment arrangements_GP letter_EN/FR/NL) — channel: primary care physicians to inform and refer eligible transplant patients; country-specific copies available for Belgium and Spain.
• Site-based factsheets and patient factsheets (documents: K1_Recruitment arrangements_Factsheet_EN/FR/NL/ES; K2_Recruitment material_Quell science and study FACTSHEET) — channel: site recruitment materials for potential participants, targeted at liver transplant patients.
• Website screenshots and online materials (documents: K2_Recruitment material_Website Screenshots; K2_Recruitment material_Quell Txs Website Screenshots) — channel: digital recruitment via sponsor/study website targeting patients and caregivers.
• Animation/transcript educational materials (documents: K2_Recruitment material_Animation transcripts_EN/FR/NL/ES) — channel: digital multimedia to inform potential participants and the public about the science and study.

Belgium

Earliest CTIS Part Ii Submission Date

30-08-2024

Latest Decision Or Authorization Date

09-03-2026

Processing Time Days

556

Number Of Sites

4

Number Of Participants

5

Spain

Earliest CTIS Part Ii Submission Date

30-08-2024

Latest Decision Or Authorization Date

11-03-2026

Processing Time Days

558

Number Of Sites

3

Number Of Participants

9

Primary sponsor

Full Name

Quell Therapeutics Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

United Kingdom

Third parties

• {"country":"United Kingdom","full_name":"Precision For Medicine (UK) Limited","duties_or_roles":"sponsorDuties codes: [1,11,12,5,8,9]","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"King's College Hospital NHS Foundation Trust","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United Kingdom","full_name":"Vivos Technology Limited","duties_or_roles":"sponsorDuties codes: [6,7]","organisation_type":"Non-Pharmaceutical company"}