A Phase I/II Study of Gene-modified WT1 TCR Therapy in MDS & AML Patients
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|ClinicalTrials.gov Identifier: NCT02550535|
Recruitment Status : Recruiting
First Posted : September 15, 2015
Last Update Posted : April 20, 2018
This is a Phase I/II trial to determine safety, clinical efficacy and feasibility of a gene-modified WT1 TCR therapy in patients with myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML).
Patient's white blood cells (T cells) will be modified by transferring a gene which enables them to make a new T cell receptor (TCR) that can recognize fragments of a protein called WT1 (Wilms' tumour 1) which is present at abnormally high levels on the surface of myelodysplastic and leukaemic cells.
In this trial, approximately 25 participants with an Human Leukocyte Antigen A2 (HLA-A*0201) tissue type who have failed to achieve or maintain an IWG defined response following hypomethylating agent therapy will be recruited.
|Condition or disease||Intervention/treatment||Phase|
|Myelodysplastic Syndromes (MDS) Acute Myeloid Leukaemia (AML)||Genetic: Gene-modified WT1 TCR-transduced T cells intravenous infusion||Phase 1 Phase 2|
This is a Phase I/II trial to determine safety, clinical efficacy and feasibility of a gene-modified WT1 TCR therapy. Following provision of informed consent, each subject will undergo screening assessments, including HLA-A*0201 screening (if not already documented) and a bone marrow aspirate/biopsy (BMA) to determine subject eligibility for the trial.
Subjects will undergo leukapheresis within 14 days of screening.
Once successful manufacture of the WT1 TCR-transduced T cells has been confirmed by the Sponsor, each subject will be administered a lymphodepletive conditioning regimen for five days consisting of fludarabine x 5 days 30mg/m2 intravenous (i.v.) and methylprednisolone x 1 day 500 mg i.v. Upon completion of the conditioning regimen, subjects will receive an infusion of WT1 TCR-transduced T cells of ≤2 x 107/kg, followed by daily IL-2 subcutaneous injections (1 x 106 units/m2 subcutaneous (s.c.) od) for 5 days.
If an IWG response has not been reported (one or more criteria met) at 3 months post-infusion then, if agreed by both the Investigator and Sponsor, the subject will be offered to have a repeat infusion of WT1 TCR-transduced T cells.
Following infusion, subjects will enter an intensive period of out-patient follow-up to observe them for any acute complications and toxicities. Subjects will then be followed monthly in the clinic for the first 6 months for routine safety and clinical evaluations, including disease response evaluations. All subjects will be followed-up for a minimum of 12 months.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||25 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Single Arm Phase I/II Study of the Safety and Efficacy of Gene-modified WT1 TCR Therapy in Patients With Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukaemia (AML) Who Have Failed to Achieve or Maintain an IWG Defined Response Following Hypomethylating Agent Therapy.|
|Study Start Date :||September 2015|
|Estimated Primary Completion Date :||July 2019|
|Estimated Study Completion Date :||July 2019|
Experimental: Gene-modified WT1 TCR-transduced T cells
A single dose of bulk WT1 TCR-transduced T cells (≤ 2 x 107/kg) will be intravenously (i.v.) administered following protocol-specified lymphodepletive conditioning regimen. Additionally, daily IL-2 subcutaneous injections (1x106 units/m2 subcutaneously (s.c.)) will be administered for 5 days concomitantly to each subject, following infusion of the ATIMP.
Genetic: Gene-modified WT1 TCR-transduced T cells intravenous infusion
- Safety following gene-modified WT1 TCR T cell therapy as measured by suspected unexpected serious adverse reactions (SUSARS) [ Time Frame: 12 Months ]
- Proportion of subjects achieving one or more IWG response criteria following gene-modified WT1 TCR T cell therapy [ Time Frame: 12 Months ]
- Safety and tolerability of gene-modified WT1 TCR therapy as measured by clinical laboratory parameters and adverse events [ Time Frame: 12 Months ]
- Efficacy of WT1 TCR therapy as measured by haematological improvement, overall remission rate, marrow remission, cytogenetic response, molecular response, stable disease, AML transformation, progression free, event free and overall survival [ Time Frame: 12 Months ]
Haematologic Response (peripheral blood): Haematological response will be assessed by haematology results and capturing data on number of RBC/platelet transfusions given to the subject.
Marrow Response: Bone marrow aspirate and/or biopsy morphology results will be recorded and assessed for marrow response in combination with peripheral blood response Cytogenetic response: cytogenetic evaluations will be performed on bone marrow aspirates/biopsies obtained during the trial.
Molecular response: molecular profile evaluations will be performed on bone marrow aspirates/biopsies obtained during the trial.
Disease response: Investigator will determine response (CR, PR, stable disease (SD), PD/TF) to administration of WT1 transduced T cells based on bone marrow blast count and peripheral blood assessments.
Subject disease events, progression and survival will be reviewed, assessed and recorded by the Investigator.
- Technical feasibility of gene-modified WT1 TCR therapy in subjects with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukaemia (AML). [ Time Frame: 12 Months ]
- Persistence of WT1 TCR-transduced T cells [ Time Frame: 12 Months ]Persistence of infused WT1 TCR-transduced T cells by Vβ2.1 and tetramer staining and PCR for Vβ2.1 and TCR-vector fragments.
- Functionality and phenotype of WT1 TCR-transduced T cells [ Time Frame: 12 Months ]Function will be evaluated by measuring antigen-specific intracellular cytokine production in response to target cells that express HLA-A*201 alleles as well as WT1. Surface differentiation and memory phenotype will be determined using multi-parameter flow cytometry.
- WT1 Transcript analysis in AML/MDS cells [ Time Frame: 12 Months ]WT1 overexpression will be used as a measure of disease monitoring on peripheral blood and BMA samples. RT-qPCR will be used to detect WT1 transcripts.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02550535
|Contact: Sarah El Farhi||+44 (0) firstname.lastname@example.org|
|AZ St Jan Brugge-Oostende AV||Recruiting|
|Brugge, Belgium, B-8000|
|Contact: Dominik Selleslag, MD Dominik.Selleslag@azsintjan.be|
|Principal Investigator: Dominik Selleslag, MD|
|Leuven, Belgium, B - 3000|
|Contact: Johan Maertens, MD|
|Principal Investigator: Johan Maertens, MD|
|Dresden, Germany, 01307|
|Contact: Uwe Dr Platzbecker email@example.com|
|Principal Investigator: Uwe Platzbecker|
|University Hospitals Bristol NHS Foundation Trust||Recruiting|
|Bristol, United Kingdom, BS2 8ED|
|Contact: Rachel Protheroe, MD Rachel.Protheroe@UHBristol.nhs.uk|
|Principal Investigator: Rachel Protheroe, MD|
|The Leeds Teaching Hospitals NHS Trust||Recruiting|
|Leeds, United Kingdom, LS2 9LN|
|Contact: Richard Kelly, MD +44 (0) 113 2068139|
|Principal Investigator: Richard Kelly, MD|
|University College London Hospitals NHS Trust||Recruiting|
|London, United Kingdom, NW1 2PG|
|Contact: Beth Payne, MD firstname.lastname@example.org|
|Principal Investigator: Beth Payne, MD|
|Principal Investigator:||Emma Morris, MD||University College London Hospitals|