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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Quell Therapeutics Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Immune system processes [G12]

Trial duration

2 Oct 2023 → ongoing

Decision date (initial)

2024-09-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Quell Therapeutics Limited

External identifiers

EU CT number

2024-516193-30-01

EudraCT number

2021-001379-18

ClinicalTrials.gov

NCT05234190

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Efficacy, Safety, Therapy, Pharmacokinetic

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

Secondary objectives 3

1. To assess the clinical activity of QEL-001 (Part 2 only)
2. To assess safety-related events
3. To determine absence or presence of exposure to replication-competent lentivirus (RCL)

Conditions and MedDRA coding

Prevention of liver transplant rejection

Regulatory references

Scientific advice from competent authorities

Federal Agency For Medicines And Health Products, Medicines And Healthcare Products Regulatory Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Participants (regardless of gender) must be 18 to 75 years of age inclusive, at the time of signing the informed consent.
2. HLA A2/A28neg (including split antigens A68neg and A69neg) participants who have received an A2pos liver transplant.
3. 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.
4. Having alanine aminotransferase (ALT) <60 U/L and either alkaline phosphatase (ALP) <200 U/L or gamma-glutamyl transferase (GGT) <100 U/L
5. Having eGFR ≥ 40 mL/min/1.73 m2 using the MDRD formula
6. 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
7. Having an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
8. 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
9. 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
10. 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
11. Being on stable maintenance of immunosuppression for at least 12 weeks prior to study entry

Exclusion criteria 26

1. 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.
2. Having received prior non-liver solid organ or hematopoietic stem cell transplant.
3. Have had any major surgical intervention in the last 3 months prior to study entry (such as open surgeries requiring general anaesthetic)
4. History of autoimmune disease requiring systemic immunosuppression, systemic disease modifying agents or biologics within the last 24 months prior to study entry
5. History of autoimmune hepatitis, primary sclerosing cholangitis or primary biliary cholangitis
6. 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
7. 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
8. 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
9. Having urine protein to creatinine ratio > 25mg/mmol or > 50mg/mmol if the participant is already under dual therapy TAC/EVR
10. Having triglycerides ≥ 3.95 mmol/L (350 mg/dL) despite appropriate therapy
11. Having cholesterol ≥ 7.8 mmol/L (301.5 mg/dL) despite appropriate therapy
12. Having QTc > 450 msec for male participants or QTc > 470 msec for female participants or QTc > 480 msec in participants with bundle branch block
13. 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
14. Receiving any other concurrent investigational agents within 3 months prior study entry
15. Having an active infection as defined in the study protocol
16. Having previous history of human immunodeficiency virus (HIV)
17. 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
18. Recent history of reactivation of Cytomegalovirus (CMV) defined as positive DNA test within 6 months prior entry to the study
19. Females who are pregnant (i.e., positive blood or urine β human Chorionic Gonadotropin (β- hCG) test) or lactating
20. 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
21. Have known or suspected hypersensitivity or allergy to DMSO present in QEL-001 as excipients
22. Having a non-adequate bilateral venous access for leukapheresis, or not willing to undergo a central venous catheter insertion
23. Having contraindications to undergo a leukapheresis
24. 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
25. Having history of liver cirrhosis or advanced fibrosis post-transplantation
26. Receiving prohibited medications that cannot be stopped at study entry

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Incidence of protocol-defined Dose-Limiting Toxicities (DLTs) within 28 days post infusion
2. 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 endpoints 6

1. 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
2. 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.
3. Incidence and severity of infections from treatment to 1 year post full wean of all immune suppressive medication
4. 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]
5. 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
6. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Quell Therapeutics Limited

Sponsor organisation

Quell Therapeutics Limited

Address

3rd Floor, Translation And Innovation Hub, 84 Wood Lane Translation And Innovation Hub 84 Wood Lane

City

London

Postcode

W12 0BZ

Country

United Kingdom

Scientific contact point

Organisation

Quell Therapeutics Limited

Contact name

Head of Regulatory Affairs

Public contact point

Organisation

Quell Therapeutics Limited

Contact name

Head of Regulatory Affairs

Third parties 3

Locations

2 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 37 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications