Autologous Tregs for Aplastic Anaemia (TIARA)
Primary Purpose
Aplastic Anemia
Status
Recruiting
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
Expanded autologous T regulatory cells
Sponsored by
About this trial
This is an interventional treatment trial for Aplastic Anemia
Eligibility Criteria
Inclusion Criteria:
- Acquired idiopathic AA
- No evidence of constitutional/inherited AA based on clinical findings, absence of family history of AA, normal DEB test and normal Kings bone marrow failure gene panel
- Very severe, severe or non-severe AA
- Lack a matched sibling donor (MSD) or matched unrelated donor (MUD), or ineligible for MSD/MUD HSCT
- Transfusion dependent
- Failed or ineligible for a course of ATG and CSA
- Failed / intolerant or inappropriate to treat with Eltrombopag or fails to meet Blueteq approval for use of Eltrombopag using NHS England guidance
- AST < 3 x upper limit of normal (ULN), bilirubin < 1.5 x ULN (unless Gilbert's syndrome)
- eGFR >50mL/min
- Age ≥ 18 years, male or female
- Willing and able to provide written and informed consent
- If female of child-bearing potential, have a negative serum pregnancy test and agree to use adequate contraceptive methods if of reproductive age
- Diffusing capacity for carbon monoxide (DLCO) ≥ 45% predicted corrected for haemoglobin
- LVEF > 40%.
- Performance status ≤ 2
Exclusion Criteria:
- Constitutional AA
- Age < 18 years' old
- Have a MSD and are eligible for MSD HSCT
- Have a MUD and are eligible for MUD HSCT
- Hypocellular myelodysplastic syndrome (Hypo MDS) or AA/Hypo MDS overlap
- Uncontrolled ongoing infection
- Active malignancy
- Treatment of cancer in the last 5 years (except in situ carcinoma of the cervix or basal cell carcinoma)
- Unable to give informed consent
- Active or uncontrolled infection not responding to appropriate antibiotics and antifungal agents.
- Human immunodeficiency virus (HIV) sero-positivity, hepatitis B, hepatitis C or hepatitis E infection.
- Abnormal organ function: AST/ALT >3 x upper limit of normal (ULN), bilirubin >1.5 x ULN, eGFR ≤50mL/min
- Heart failure (= grade III New York Heart Association)
- Pregnant or lactating women
- Unable or unwilling to comply with the contraceptive requirements
Sites / Locations
- King's College HospitalRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Expanded autologous T regulatory cells
Arm Description
This is an open-label, non-randomised interventional trial.
Outcomes
Primary Outcome Measures
Expandability of functional T-regulatory cells from AA patients
This will be assessed through measuring the T regulatory cell count (1) during manufacturing production using a NC-200 cell counter and (2) through FACS analysis on peripheral blood research samples collected at the following 7 time points: pre-dose day 1, days 15, 29, 58 and at 6, 12 and 24 months
Assessment of safety and toxicity profile of the administrated autologous T-regulatory cells in AA patients
This will be assessed through physical examinations prior to each infusion and at every follow up visit. ECOG assessments prior to each infusions and at 6, 12 and 24 months. Bloods tests (FBC, Biochemistry, coagulation screen, d-dimer) prior to each infusion as well as 1 hour after infusion and 6 hours after the end of infusion). Bone marrow assessment prior to initial infusion and at 6, 12 and 24 months. AEs, SARs and SUSARs will be monitored from date of informed consent until 24 months. SAEs will be monitoring from date of informed consent until 30 days post final infusion. Adverse Events will be graded using CTCAE Version 5.0
Evaluation of safety and toxicity profile following 2 doses of autologous T-regulatory cells in AA patients
This will be assessed through physical examinations prior to each infusion and at every follow up visit. ECOG assessments prior to each infusions and at 6, 12 and 24 months. Bloods tests (FBC, Biochemistry, coagulation screen, d-dimer) prior to each infusion as well as 1 hour after infusion and 6 hours after the end of infusion). Bone marrow assessment prior to initial infusion and at 6, 12 and 24 months. AEs, SARs and SUSARs will be monitored from date of informed consent until 24 months. SAEs will be monitoring from date of informed consent until 30 days post final infusion. Adverse Events will be graded using CTCAE Version 5.0
Secondary Outcome Measures
Response rate and duration of haematological response
This will be assessed by examining serial full blood counts, transfusion requirements and IV antibiotic usage on days D1, D2 D8, D15, D22, D29 and at 6, 12 and 24 months
Overall survival
Survival status will be determined by the trial clinician at 6, 12 and 24 months
Number and severity of infections
The number and severity of infections during first 30 days prior to starting Tregs will be compared to monthly average during therapy with Tregs until 24 months. This will be assessed through clinical examination and results of infection screening tests as recorded on EPR (Electronic Patient Records). Severity infections will be classified using the NCI Common Terminology Criteria for Adverse Events (CTCAE) for recording AEs and grade.
Clonal evolution to MDS/AML post treatment with Tregs
This will be assessed through (a) BM morphology (b) SNP-A karyotyping and (c) mutational profile, using Kings myeloid gene panel that includes 44 myeloid specific genes, at baseline (screening), 6, 12 and 24 months
Full Information
NCT ID
NCT05386264
First Posted
February 18, 2022
Last Updated
October 4, 2023
Sponsor
King's College Hospital NHS Trust
1. Study Identification
Unique Protocol Identification Number
NCT05386264
Brief Title
Autologous Tregs for Aplastic Anaemia
Acronym
TIARA
Official Title
Production of Expanded Autologous Regulatory T Cells to Treat Patients With Refractory Aplastic Anaemia in a Phase I Dose Finding Study
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 14, 2022 (Actual)
Primary Completion Date
September 30, 2024 (Anticipated)
Study Completion Date
April 30, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
King's College Hospital NHS Trust
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This Phase I study will determine the safety and optimal dose of expanded autologous Tregs to treat patients with Aplastic Anaemia (AA) (who have failed, or are considered ineligible for IST (immunosuppressive therapy) / other treatments) using expanded autologous T regulatory cells (Tregs) from AA patients at King's College Hospital, that have been prepared at the licensed Good Manufacturing Practices (GMP) production facility at Guy's Hospital, London
Detailed Description
The clinical trial will examine the safety of giving AA patients who have failed other treatment(s), their own ('autologous') expanded Tregs - a form of 'cellular therapy - to treat the AA. The investigators will study the changes in the immune system and determine if healthy bone marrow stem cells recover, thereby improving the blood counts after giving Tregs to patients. Expanded autologous Tregs are currently being looked at to treat other autoimmune disorders such as type I diabetes mellitus, multiple sclerosis, Crohn's disease and systemic lupus erythematosus. Results so far indicate that they are safe to give and do improve these diseases, but significantly this will be the first trial in AA.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aplastic Anemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
Open-label dose finding phase 1
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Expanded autologous T regulatory cells
Arm Type
Experimental
Arm Description
This is an open-label, non-randomised interventional trial.
Intervention Type
Other
Intervention Name(s)
Expanded autologous T regulatory cells
Intervention Description
A 3+3 dose escalation design with expanded T regulatory cells administered on Day 1 and Day 15
Primary Outcome Measure Information:
Title
Expandability of functional T-regulatory cells from AA patients
Description
This will be assessed through measuring the T regulatory cell count (1) during manufacturing production using a NC-200 cell counter and (2) through FACS analysis on peripheral blood research samples collected at the following 7 time points: pre-dose day 1, days 15, 29, 58 and at 6, 12 and 24 months
Time Frame
Manufacturing to 24 months post final infusion
Title
Assessment of safety and toxicity profile of the administrated autologous T-regulatory cells in AA patients
Description
This will be assessed through physical examinations prior to each infusion and at every follow up visit. ECOG assessments prior to each infusions and at 6, 12 and 24 months. Bloods tests (FBC, Biochemistry, coagulation screen, d-dimer) prior to each infusion as well as 1 hour after infusion and 6 hours after the end of infusion). Bone marrow assessment prior to initial infusion and at 6, 12 and 24 months. AEs, SARs and SUSARs will be monitored from date of informed consent until 24 months. SAEs will be monitoring from date of informed consent until 30 days post final infusion. Adverse Events will be graded using CTCAE Version 5.0
Time Frame
Baseline to 24 months post final infusion
Title
Evaluation of safety and toxicity profile following 2 doses of autologous T-regulatory cells in AA patients
Description
This will be assessed through physical examinations prior to each infusion and at every follow up visit. ECOG assessments prior to each infusions and at 6, 12 and 24 months. Bloods tests (FBC, Biochemistry, coagulation screen, d-dimer) prior to each infusion as well as 1 hour after infusion and 6 hours after the end of infusion). Bone marrow assessment prior to initial infusion and at 6, 12 and 24 months. AEs, SARs and SUSARs will be monitored from date of informed consent until 24 months. SAEs will be monitoring from date of informed consent until 30 days post final infusion. Adverse Events will be graded using CTCAE Version 5.0
Time Frame
Baseline to 24 months post final infusion
Secondary Outcome Measure Information:
Title
Response rate and duration of haematological response
Description
This will be assessed by examining serial full blood counts, transfusion requirements and IV antibiotic usage on days D1, D2 D8, D15, D22, D29 and at 6, 12 and 24 months
Time Frame
Baseline to 24 months post final infusion
Title
Overall survival
Description
Survival status will be determined by the trial clinician at 6, 12 and 24 months
Time Frame
6 months to 24 months post final infusion
Title
Number and severity of infections
Description
The number and severity of infections during first 30 days prior to starting Tregs will be compared to monthly average during therapy with Tregs until 24 months. This will be assessed through clinical examination and results of infection screening tests as recorded on EPR (Electronic Patient Records). Severity infections will be classified using the NCI Common Terminology Criteria for Adverse Events (CTCAE) for recording AEs and grade.
Time Frame
Baseline to 24 months post final infusion
Title
Clonal evolution to MDS/AML post treatment with Tregs
Description
This will be assessed through (a) BM morphology (b) SNP-A karyotyping and (c) mutational profile, using Kings myeloid gene panel that includes 44 myeloid specific genes, at baseline (screening), 6, 12 and 24 months
Time Frame
Baseline to 24 months post final infusion
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Acquired idiopathic AA
No evidence of constitutional/inherited AA based on clinical findings, absence of family history of AA, normal DEB test and normal Kings bone marrow failure gene panel
Very severe, severe or non-severe AA
Lack a matched sibling donor (MSD) or matched unrelated donor (MUD), or ineligible for MSD/MUD HSCT
Transfusion dependent
Failed or ineligible for a course of ATG and CSA
Failed / intolerant or inappropriate to treat with Eltrombopag or fails to meet Blueteq approval for use of Eltrombopag using NHS England guidance
AST < 3 x upper limit of normal (ULN), bilirubin < 1.5 x ULN (unless Gilbert's syndrome)
eGFR >50mL/min
Age ≥ 18 years, male or female
Willing and able to provide written and informed consent
If female of child-bearing potential, have a negative serum pregnancy test and agree to use adequate contraceptive methods if of reproductive age
Diffusing capacity for carbon monoxide (DLCO) ≥ 45% predicted corrected for haemoglobin
LVEF > 40%.
Performance status ≤ 2
Exclusion Criteria:
Constitutional AA
Age < 18 years' old
Have a MSD and are eligible for MSD HSCT
Have a MUD and are eligible for MUD HSCT
Hypocellular myelodysplastic syndrome (Hypo MDS) or AA/Hypo MDS overlap
Uncontrolled ongoing infection
Active malignancy
Treatment of cancer in the last 5 years (except in situ carcinoma of the cervix or basal cell carcinoma)
Unable to give informed consent
Active or uncontrolled infection not responding to appropriate antibiotics and antifungal agents.
Human immunodeficiency virus (HIV) sero-positivity, hepatitis B, hepatitis C or hepatitis E infection.
Abnormal organ function: AST/ALT >3 x upper limit of normal (ULN), bilirubin >1.5 x ULN, eGFR ≤50mL/min
Heart failure (= grade III New York Heart Association)
Pregnant or lactating women
Unable or unwilling to comply with the contraceptive requirements
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jen Lewis
Phone
07890254538
Email
jen.lewis@kcl.ac.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ghulam Mufti
Organizational Affiliation
King's College London
Official's Role
Study Director
Facility Information:
Facility Name
King's College Hospital
City
London
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shreyans Gandhi
Email
shreyans.gandhi@nhs.net
First Name & Middle Initial & Last Name & Degree
Maclaine Hipolito
Email
mhipolito@nhs.net
First Name & Middle Initial & Last Name & Degree
Shreyans Gandhi
12. IPD Sharing Statement
Learn more about this trial
Autologous Tregs for Aplastic Anaemia
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