Additional identifiers
EudraCT number
2006-004950-25
ClinicalTrials.gov number
Protocol/serial number
5099
Study information
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
Acronym
WT1 TCR-001
Study hypothesis
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
Gene Therapy Advisory Committee, 20/12/2007, ref: GTAC 128
Study design
Non-randomised interventional multicentre treatment
Primary study design
Interventional
Secondary study design
Non randomised study
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
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
Phase
Drug names
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 trial start date
18/01/2010
Overall trial end date
17/01/2012
Reason abandoned (if study stopped)
Eligibility
Participant 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 A*0201 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
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 18; UK Sample Size: 18
Participant 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
Recruitment start date
18/01/2010
Recruitment end date
17/01/2012
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Royal Free Hospital
London
NW3 2QG
United Kingdom
Sponsor information
Organisation
University College London (UCL) (UK)
Sponsor details
Gower Street
London
WC1E 6BT
United Kingdom
Sponsor type
University/education
Website
Funders
Funder type
Government
Funder name
Department of Health (UK) (ref: 66807)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Leukaemia Research Fund (UK) (ref: 08001)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list