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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
Sponsor:
Collaborators:
University College, London
Cell Therapy Catapult
Information provided by (Responsible Party):
Cell Medica Ltd

Brief Summary:

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

Detailed Description:

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)
Primary Purpose: Treatment
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


Arm Intervention/treatment
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



Primary Outcome Measures :
  1. Safety following gene-modified WT1 TCR T cell therapy as measured by suspected unexpected serious adverse reactions (SUSARS) [ Time Frame: 12 Months ]
  2. Proportion of subjects achieving one or more IWG response criteria following gene-modified WT1 TCR T cell therapy [ Time Frame: 12 Months ]

Secondary Outcome Measures :
  1. Safety and tolerability of gene-modified WT1 TCR therapy as measured by clinical laboratory parameters and adverse events [ Time Frame: 12 Months ]
  2. 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.


  3. Technical feasibility of gene-modified WT1 TCR therapy in subjects with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukaemia (AML). [ Time Frame: 12 Months ]
  4. 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.

  5. 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.

  6. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion criteria:

  • The trial will recruit subjects with MDS or AML who have received hypomethylating agent therapy (at least 6 cycles of azacitidine or 4 cycles of decitabine), and are EITHER:
  • Relapsed, defined as failing to maintain an initial IWG response

OR

• Stable, defined as failing to achieve an IWG response

Subjects who have received hypomethylating agent therapy as part of a combination regimen may be eligible after discussion with the Sponsor.

  1. Subjects aged 18 years or older who have a diagnosis of, EITHER:

    • MDS with an IPSS of intermediate -2, or high and one of the following FAB types:

      • Refractory anaemia with excess blasts (RAEB)
      • Chronic myelomonocytic leukaemia (CMML) with at least 10% bone marrow blasts (WHO CMML II) OR
    • AML (diagnosed according to WHO classification 2008 revision)
  2. Subjects with documented HLA-A*0201 positive serotype
  3. Subjects with less than 30 per cent bone marrow blasts
  4. Subjects with relapsed disease must have less than 5 per cent peripheral blasts
  5. Subjects with stable disease must have less than 10 per cent peripheral blasts
  6. Subjects with less than a doubling of bone marrow blast count between the start of hypomethylating agent therapy and the date of screening
  7. Subjects to complete screen 1 visit within a minimum of 28 days and maximum of 90 days since completion of azacitidine or decitabine therapy. Subjects who have exceeded the 90 day window may be eligible after discussion with the Sponsor.
  8. Subjects with ECOG status 0, 1 or 2
  9. Subjects who have at least one cytopenia (ANC <1000/μL, platelet count <75,000/μL, Hgb <11g/dL or RBC transfusion dependence)

Key Exclusion criteria:

improvement or molecular response following azacitidine treatment

  • CMML patients who have a white blood cell count > 13 x 109/L
  • Acute promyelocytic leukaemia (FAB M3 Classification)
  • Uncontrolled intercurrent illness
  • Active malignancy, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast
  • Known history of Human Immunodeficiency Virus (HIV), Hepatitis C virus (HCV) or Hepatitis B virus (HBV) or positive for Human T-Lymphocyte Virus (HTLV) or Syphilis. • Active auto-immune disease
  • Clinically significant non-hematologic toxicity after prior therapy chemotherapy higher than grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) (v 4.0)
  • Subjects who require haemodialysis or peritoneal dialysis
  • Pregnant and lactating women
  • Subjects unwilling or unable to use adequate contraceptive precautions at screening and throughout the trial
  • Subjects who have undergone major surgery without full recovery within last 28 days prior to screening
  • Subjects with known hypersensitivity to cyclophosphamide, fludarabine, methylprednisolone or IL-2 (Interleukin-2)

Information from the National Library of Medicine

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


Contacts
Contact: Sarah El Farhi +44 (0) 2075544054 sarah.elfarhi@cellmedica.com

Locations
Belgium
AZ St Jan Brugge-Oostende AV Recruiting
Brugge, Belgium, B-8000
Contact: Dominik Selleslag, MD       Dominik.Selleslag@azsintjan.be   
Principal Investigator: Dominik Selleslag, MD         
UZ Leuven Recruiting
Leuven, Belgium, B - 3000
Contact: Johan Maertens, MD         
Principal Investigator: Johan Maertens, MD         
Germany
Uniklinikum Dresden Recruiting
Dresden, Germany, 01307
Contact: Uwe Dr Platzbecker       uwe-platzbecker@uniklinikum-dresden.de   
Principal Investigator: Uwe Platzbecker         
United Kingdom
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       e.payne@ucl.ac.uk   
Principal Investigator: Beth Payne, MD         
Sponsors and Collaborators
Cell Medica Ltd
University College, London
Cell Therapy Catapult
Investigators
Principal Investigator: Emma Morris, MD University College London Hospitals

Responsible Party: Cell Medica Ltd
ClinicalTrials.gov Identifier: NCT02550535     History of Changes
Other Study ID Numbers: D-00272-CT2014002
First Posted: September 15, 2015    Key Record Dates
Last Update Posted: April 20, 2018
Last Verified: April 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cell Medica Ltd:
Gene Therapy
WT1 TCR
Gene modified T cels

Additional relevant MeSH terms:
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions