WT1 TCR gene therapy for leukaemia: a phase I/II safety and toxicity study (WT1 TCR-001)

ISRCTN	ISRCTN11622375
DOI	https://doi.org/10.1186/ISRCTN11622375
EudraCT/CTIS number	2006-004950-25
Secondary identifying numbers	5099

Submission date: 31/03/2010
Registration date: 31/03/2010
Last edited: 21/04/2020

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-a-type-of-gene-therapy-for-acute-myeloid-leukaemia-and-chronic-myeloid-leukaemia

Contact information

Dr Emma Morris
Scientific

Royal Free Hospital
Pond Street
London
NW3 2QG
United Kingdom

Study information

Study design	Non-randomised interventional multicentre treatment
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	A phase I/II safety and toxicity study on the use of WT1 TCR gene therapy for adult patients with acute and chronic myeloid leukaemia
Study acronym	WT1 TCR-001
Study objectives	One of the main functions of the immune system is to protect the body from infection. It is now clear that the immune system also plays a role in preventing the development or controlling the growth of some cancers. The most important cells of the immune system for this particular task are a group of white blood cells called the T lymphocytes (T cells). It is known from bone marrow transplantation and T cell infusions that leukaemia can be controlled or cured by a strong T cell immune response. Despite this, many other patients develop leukaemia even with a normal immune system. This study wants to test a new way of strengthening the patient's own immune response to their leukaemia by increasing the number of patient T cells which can recognise and kill the leukaemia cells. The T cells have a receptor (the T cell receptor [TCR]), which enables them to recognise particular abnormalities on the surface of the target cells (virally infected cells or cancer/leukaemia cells). Each TCR recognises a particular fragment of a protein (peptide epitope). Normally, patients have a wide range of different T cells, which recognise many different epitopes on the surface of 'target cells'. It is possible that they have only a very few, or no T cells, which are able to recognise the abnormal leukaemia cells. The Wilms' tumour antigen 1 (WT1) is a protein, peptides of which are present at abnormally high levels on the surface of leukaemia cells. In the research laboratory we have identified T cells, which specifically kill leukaemia cells by recognising the WT1 on their cell surface. The TCR determines the specificity of the T cell. Not all patients have T cells with the WT1-specific TCR. We can generate T cells, which recognise WT1 (and can therefore kill leukaemia cells) by transferring the genes for the WT1-specific TCR into T cells, which normally recognise something else.
Ethics approval(s)	Gene Therapy Advisory Committee, 20/12/2007, ref: GTAC 128
Health condition(s) or problem(s) studied	Topic: National Cancer Research Network; Subtopic: Haematological Oncology; Disease: Leukaemia (chronic), Leukaemia (acute myeloid)
Intervention	Leucapheresis, After recruitment to the study, patients will undergo leucapheresis to harvest peripheral blood lymphocytes. The peripheral blood T-lymphocytes will be cultured for up to 9 days in vitro for transduction with replication defective retroviral vectors containing the WT1-specific TCR. Bulk transduced T-lymphocytes will be intravenously administered using escalating doses of = 2 x 10^7/kg and = 10^8/kg bulk TCR-td T cells (doses based on numbers of allogeneic T cells safely infused post Allo SCT and t). Follow Up Length: 12 month(s)
Intervention type	Genetic
Primary outcome measure	1. Transduction efficiency - at QP release of genetically modified (transduced) T cells 2. Toxicity and Side effects - every trial visit 3. Integration site analysis of transduced T cells - batched and to be performed at end of study
Secondary outcome measures	1. Persistence of TCR-Td T cells - blood sample taken at every trial visit after infusion of T cells (analysis to be performed in batches) 2. WT1-specific Immune Responses - blood sample taken at every trial visit after infusion of T cells (analysis to be performed in batches) 3. Disease responses - BM aspirate and trephine at +8 weeks; qPCR at 7 days, 28 days then monthly until 12 months post T cell infusion
Overall study start date	18/01/2010
Completion date	17/01/2012

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 18; UK Sample Size: 18
Total final enrolment	7
Key inclusion criteria	General inclusion criteria: All patients will undergo detailed laboratory based assessment prior to the procedure: 1. Aged greater than or equal to 18 years and less than or equal to 75 years 2. Life expectancy greater than 1626 weeks (46 months) 3. World Health Organisation (WHO) performance status of 0 - 2 4. HLA A0201 positive 5. Completed previous course of chemotherapy greater than or equal to 4 weeks prior to commencing the initial phase of the trial (leucapheresis for collection of patient peripheral blood mononuclear cells [PBMC]) 7. Peripheral blood total lymphocyte count greater than 0.5 x 10^9/L 8. Informed consent in writing and ability to co-operate with treatment and follow up 9. Willing, able and available for collection of PBMC/T-cells by leucapheresis 10. Hepatitis B and C, HTLV-1, human immunodeficiency virus (HIV) negative 11. Free from serious concurrent illness 12. Female patients of child-bearing age must have a negative pregnancy test and agree to use reliable contraceptive methods for the duration of the therapy and for 6 months afterwards 13. Male patients must agree to use appropriate medically approved contraception during the trial and for six months afterwards 14. Haematological and Biochemical Indices: 14.1. Haemoglobin (Hb) = 7.0 g/dl; neutrophils = 0.2 x 10^9/L; total lymphocytes >0.5 x 10^9/L; platelets (Plts) = 40 x 10^9/L 14.2. Serum bilirubin, Alanine amino-transferase (ALT) and/or aspartate amino-transferase (AST) less than 3 x upper normal limit 14.3. Calculated creatinine clearance = 30 ml/min (uncorrected value) or isotope clearance measurement = 30 ml/min Disease-specific inclusion criteria: AML or CML proven by morphology, histology, immunophenotyping and cytogenetics (where available): 1. Acute myeloid leukaemia (AML): Patients not eligible for BMT procedure with: 1.1. AML in 2nd CR or greater 1.2. Good and Standard Risk AML in 1st CR or PR in patients greater than 60 years; and 1.3. Poor Risk* AML in 1st CR CR/PR or later (slow remitters and/or adverse cytogenetics) 1.4. AML at 1st relapse post BMT in CR or PR after re-induction and consolidation. [NB, *risk category as defined by MRC criteria: Good Risk: t(15;17), t(8;21), inv 16; Poor Risk: -5; -7; del (5q); abn (3q) or complex (=/>4 abn)]. 2. Chronic myeloid leukaemia (CML): 2.1. Patients in chronic phase resistant to Glivec/Imatinib and 2nd generation tyrosine kinase inhibitors (e.g., Dasatinib), AND NOT eligible for allogeneic BMT 2.2. Patients in chronic phase resistant to Glivec/Imatinib and with an identified mutation known to be resistant to 2nd generation tyrosine kinase inhibitors, AND NOT eligible for allogeneic BMT 2.3. Patients = 50 years (and ineligible for myeloablative allo-BMT), with a suboptimal response to Glivec/Imatinib and an identified mutation known to be resistant to 2nd generation tyrosine kinase inhibitors. These patients are at high risk of disease progression. Patients in this group would stop Glivec/Imatinib prior to leucapheresis and receiving TCR-transduced T cells. They will have monthly quantitative RT-PCR for Bcr-Abl and restart Glivec/Imatinib in the event of a log increase in transcript numbers. 2.4. Patients in chronic phase, resistant to Glive/Imatininb and NOT eligible for allo BMT without access to 2nd generation tyrosine kinase inhibitors may be considered after discussion with the Chief Investigator and Sponsor Resistance to Glivec is defined as (European Leukemianet Criteria, 2006): No Haematological Response (HR) at 3 months Incomplete HR or No Cytogenetic Response (CgR) at 6 months Less than partial CgR (Ph+ >35%) at 12 months Less than complete CgR at 18 months Loss of HR or CgR Development of highly resistant mutations Suboptimal response to Glivec is defined as (European Leukemianet Criteria, 2006): Less than complete Haematological response at 3 months Less than partial CgR (Ph+ >35%) at 6 months Less than complete CgR at 12 months Less than major MoR at 18 months Loss of major MoR Development of a mutation
Key exclusion criteria	1. Aged less than 18 years or greater than 75 years 2. Patients should not receive concurrent systemic corticosteroids whilst on the study 3. Major thoracic and/or abdominal surgery in the preceding three to four weeks from which the patient has not yet recovered 4. Patients who are high medical risks because of non-malignant systemic disease, as well as those with active uncontrolled infection 5. Patients with any other condition, which in the Investigator's opinion would not make the patient a good candidate for the clinical trial 6. Patients known to be serologically positive for Hepatitis B, C, HTLV-1 or HIV 7. Concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/IV cardiac disease 8. Positive pregnancy test or reluctance to use contraception 9. Pregnant and lactating women are excluded 10. History of severe allergy
Date of first enrolment	18/01/2010
Date of final enrolment	17/01/2012

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

Royal Free Hospital

London
NW3 2QG
United Kingdom

Sponsor information

University College London (UCL) (UK)
University/education

Gower Street
London
WC1E 6BT
England
United Kingdom

Website	http://www.ucl.ac.uk/
"ROR"	https://ror.org/02jx3x895

Funders

Funder type

Government

Department of Health (UK) (ref: 66807)

No information available

Leukaemia Research Fund (UK) (ref: 08001)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results			21/04/2020	No	No

Editorial Notes

21/04/2020: The following changes were made to the trial record:
1. Added clinicaltrialsregister.eu link to basic results (scientific).
2. The total final enrollment was added.
18/12/2017: No publications found in PubMed, verifying study status with principal investigator.