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

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.

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.

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.

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)