A Phase I/II Study of Gene-modified WT1 TCR Therapy in MDS & AML Patients

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Primary Purpose

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Autologous WT1 TCR transduced T cells

About this trial

This is an interventional treatment trial for Myelodysplastic Syndromes (MDS) focused on measuring Gene Therapy, WT1 TCR, Gene modified T cels

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

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)
Subjects with documented HLA-A*0201 positive serotype
Subjects with less than 30 per cent bone marrow blasts
Subjects with relapsed disease must have less than 5 per cent peripheral blasts
Subjects with stable disease must have less than 10 per cent peripheral blasts
Subjects with less than a doubling of bone marrow blast count between the start of hypomethylating agent therapy and the date of screening
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.
Subjects with ECOG status 0, 1 or 2
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)

Sites / Locations

AZ St Jan Brugge-Oostende AV
UZ Leuven
Uniklinikum Dresden
University Hospitals Bristol NHS Foundation Trust
The Leeds Teaching Hospitals NHS Trust
University College London Hospitals NHS Trust

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Gene-modified WT1 TCR-transduced T cells

Arm Description

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.

Outcomes

Primary Outcome Measures

Safety following gene-modified WT1 TCR T cell therapy as measured by suspected unexpected serious adverse reactions (SUSARS)

Proportion of subjects achieving one or more IWG response criteria following gene-modified WT1 TCR T cell therapy

Secondary Outcome Measures

Safety and tolerability of gene-modified WT1 TCR therapy as measured by clinical laboratory parameters and adverse events

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

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).

Persistence of WT1 TCR-transduced T cells

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

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

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.

Full Information

NCT ID

NCT02550535

First Posted

April 28, 2015

Last Updated

October 1, 2018

Sponsor

Cell Medica Ltd

Collaborators

University College, London, Cell Therapy Catapult

1. Study Identification

Unique Protocol Identification Number

NCT02550535

Brief Title

A Phase I/II Study of Gene-modified WT1 TCR Therapy in MDS & AML Patients

Official Title

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 Response Following Hypomethylating Agent Therapy

Study Type

Interventional

2. Study Status

Record Verification Date

October 2018

Overall Recruitment Status

Completed

Study Start Date

September 2015 (undefined)

Primary Completion Date

May 2018 (Actual)

Study Completion Date

May 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Cell Medica Ltd

Collaborators

University College, London, Cell Therapy Catapult

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 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myelodysplastic Syndromes (MDS), Acute Myeloid Leukaemia (AML)

Keywords

Gene Therapy, WT1 TCR, Gene modified T cels

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

3 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Gene-modified WT1 TCR-transduced T cells

Arm Type

Experimental

Arm Description

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.

Intervention Type

Genetic

Intervention Name(s)

Autologous WT1 TCR transduced T cells

Intervention Description

Gene therapy: Autologous WT1 TCR transduced T cells administered by intravenous infusion

Primary Outcome Measure Information:

Title

Safety following gene-modified WT1 TCR T cell therapy as measured by suspected unexpected serious adverse reactions (SUSARS)

Time Frame

12 Months

Title

Proportion of subjects achieving one or more IWG response criteria following gene-modified WT1 TCR T cell therapy

Time Frame

12 Months

Secondary Outcome Measure Information:

Title

Safety and tolerability of gene-modified WT1 TCR therapy as measured by clinical laboratory parameters and adverse events

Time Frame

12 Months

Title

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

Description

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.

Time Frame

12 Months

Title

Technical feasibility of gene-modified WT1 TCR therapy in subjects with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukaemia (AML).

Time Frame

12 Months

Title

Persistence of WT1 TCR-transduced T cells

Description

Persistence of infused WT1 TCR-transduced T cells by Vβ2.1 and tetramer staining and PCR for Vβ2.1 and TCR-vector fragments.

Time Frame

12 Months

Title

Functionality and phenotype of WT1 TCR-transduced T cells

Description

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.

Time Frame

12 Months

Title

WT1 Transcript analysis in AML/MDS cells

Description

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.

Time Frame

12 Months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

No

Eligibility 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. 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) Subjects with documented HLA-A*0201 positive serotype Subjects with less than 30 per cent bone marrow blasts Subjects with relapsed disease must have less than 5 per cent peripheral blasts Subjects with stable disease must have less than 10 per cent peripheral blasts Subjects with less than a doubling of bone marrow blast count between the start of hypomethylating agent therapy and the date of screening 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. Subjects with ECOG status 0, 1 or 2 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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Emma Morris, MD

Organizational Affiliation

University College London Hospitals

Official's Role

Principal Investigator

Facility Information:

Facility Name

AZ St Jan Brugge-Oostende AV

City

Brugge

ZIP/Postal Code

B-8000

Country

Belgium

Facility Name

UZ Leuven

City

Leuven

ZIP/Postal Code

B - 3000

Country

Belgium

Facility Name

Uniklinikum Dresden

City

Dresden

ZIP/Postal Code

01307

Country

Germany

Facility Name

University Hospitals Bristol NHS Foundation Trust

City

Bristol

ZIP/Postal Code

BS2 8ED

Country

United Kingdom

Facility Name

The Leeds Teaching Hospitals NHS Trust

City

Leeds

ZIP/Postal Code

LS2 9LN

Country

United Kingdom

Facility Name

University College London Hospitals NHS Trust

City

London

ZIP/Postal Code

NW1 2PG

Country

United Kingdom

Myelodysplastic Syndromes (MDS), Acute Myeloid Leukaemia (AML)

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial