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)

Phase 1

Conditions: Acute myeloid leukaemia and myelodysplastic syndromes in adults
MedDRA version: 20.0Level: PTClassification code 10000880Term: Acute myeloid leukaemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: PTClassification code 10028533Term: Myelodysplastic syndromeSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2014-003111-10-DE

Lead Sponsor: Cell Medica Ltd

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 40

Inclusion Criteria

Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the trial:
Diagnosis and main criteria for admission to screening phase of trial:
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

IWG response is defined as complete remission; partial remission; marrow complete remission; cytogenetic response; stable disease with haematological improvement.

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:
o Refractory anaemia with excess blasts (RAEB)
o 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 positive for WT1 over expression at 50 copies WT1 transcript per 104 ABL copies assessed via analysis of peripheral venous blood samples
4. Subjects with less than 30 per cent bone marrow blasts
5. Subjects with relapsed disease must have less than 5 per cent peripheral blasts
6. Subjects with stable disease must have less than 10 per cent peripheral blasts
7. Subjects with less than a doubling of bone marrow blast count between the start of hypomethylating agent therapy and the date of screening
8. 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.
9. Subjects with ECOG status 0, 1 or 2
10. Subjects who have at least one cytopenia (ANC < 1000/µL, platelet count < 75,000/µL, Hgb <11g/dL or RBC transfusion dependence)
11. Willing, able and available for collection of Peripheral Blood Mononuclear Cells (PBMC)/ T cells by leukapheresis
12. Subjects must understand and be able, willing and likely to fully comply with all trial procedures and restrictions
13. Written, signed and dated informed consent to participate in the study must be given by the subject or legally authorised representative in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6, and applicable regulations, before completing any trial-related procedures.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 10
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 30

Exclusion Criteria

Subjects presenting with any of the following criteria will not be included in the trial:

1. Subjects with CMML who have a white blood cell count > 13000 million / L
2. Subjects with peripheral blood total lymphocyte count < 500 million / L
3. Subjects with acute promyelocytic leukaemia (FAB M3 Classification)
4. Subjects who are a current candidate for allogeneic stem cell transplantation and have a suitable donor
5. Subjects requiring concurrent use of systemic steroids at time of leukapheresis or in a 14 day window around time of cell infusion
6. Subjects who have an immediate or anticipated need for induction chemotherapy, or are receiving agents that could confound the interpretation of trial results, in the opinion of the Investigator
7. Subjects with any active malignancy, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast
8. Subjects with uncontrolled intercurrent illness including, but not limited to, clinically significant ischaemic heart disease, cardiac arrhythmia, concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/ IV cardiac disease, uncontrolled hypertension (defined as systolic pressure =160 mmHg and/or diastolic pressure =110 mmHg) or clinically significant pulmonary disease
9. Subjects with active infection (bacterial, viral or fungal) which is clinically significant at the time of leukapheresis or cell infusion
10. Subjects with known history of Human Immunodeficiency Virus (HIV), Hepatitis C virus (HCV) or Hepatitis B virus (HBV) or who test positive for HTLV or Syphilis. Subjects who are positive for HIV, Hepatitis B or Hepatitis C must have a negative polymerase chain reaction (PCR) result prior to leukapheresis
11. Subjects with active auto-immune disease including, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Sjögren’s syndrome, sarcoidosis, vasculitis, polymyositis, psoriasis, relapsing polychondritis or glomerulonephritis)
12. Subjects with clinically significant non-haematologic toxicity after prior chemotherapy higher than grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) (v 4.0)
13. Subjects with clinically significant renal and liver parameters, defined as total bilirubin =1.5 mg/dL not related to haemolysis or Gilbert's disease; alanine transaminase (ALT)/aspartate transaminase (AST) =2.5 x upper limit of normal (ULN) and/or serum creatinine =2.0 mg/dL
14. Subjects who require haemodialysis or peritoneal dialysis
15. Subject of childbearing potential unable to take adequate contraceptive precautions, has a positive pregnancy test result at screening, is otherwise known to be pregnant or is currently breast-feeding
16. Male subjects unwilling or unable to use adequate contraceptive precautions (barrier method or abstinence) at screening and throughout the trial
17. Subjects who have undergone major surgery without full recovery within last 28 days prior to screening
18. Subjects with known hypersensitivity to fludarabine, methylprednisolone or IL-2
19. Subjects who have participated in any other interventional clinical trial or received treatment with any investigational agent, chemotherapy, or immunotherapy within 28 days prior to infusion. Growth factors and erythropoietin allowed before and during the trial as clinically indicated
20. Subjects who have received previous treatment with gene modified T cell therapy
21. Subjects