Safety and Immunogenicity of Recombinant WT1 Antigen-Specific Cancer Immunotherapeutic Combined With Infusion of Treg Depleted T Cells for Adult WT1 Acute Myeloid Leukemia

A Phase I/II Study to Assess the Safety and Immunogenicity of WT1-A10 + AS01B Antigen-Specific Cancer Immunotherapeutic (ASCI) Combined With Infusions of ex Vivo Regulatory T Cells Depleted T Lymphocytes in in Vivo Regulatory T Cells Depleted Patients as Post-consolidation Therapy for Adult Patients With WT1-positive Acute Myeloid Leukemia (AML) in CR1 (for High Risk Patients) or in CR2 or CR3 Who Are Not Eligible for Allogeneic Stem Cell Transplantation (SCT).

The purpose of this study is to evaluate the safety and the efficacy of combined treatment strategy of WT1ASCI, infusion of ex vivo regulatory T cells depleted T lymphocytes and in vivo regulatory T cells depletion as post-consolidation therapy in patients with WT1-positive Acute Myeloid Leukemia. The study will also evaluate the clinical activity and immune response of this approach in bad risk patients in CR1 and all patients in CR2 or CR3, non eligible for an allogeneic Hematopoietic Stem Cell Transplantation

High-risk and intermediate-high risk CR1 AML patients who are not eligible for allo-SCT after chemotherapy have an unfavorable prognosis, and there is currently no treatment able to improve their survival. New approaches to treat these patients are thus urgently needed. Active immunization against tumor antigens is certainly one of these approaches. The tumor antigen targeted in this study is WT1, which is overexpressed and acts as an oncogene in leukemia and several types of solid tumors. WT1-positive acute myeloid Leukemia patients in complete remission (CR) will first undergo two cytaphereses, one of which being frozen, after CD25+ T cell depletion, the second, being frozen unmanipulated as a Treg back-up. Next, patients will be treated for 5 weeks with oral cyclophosphamide according to the so-called "metronomic regimen" to achieve in vivo Treg depletion. Patients will thereafter receive WT1 ASCI combined with CD25+ T cell depleted lymphocytes. The total duration of the treatment period will last 48 months (4 years).

Inclusion Criteria:

1. The patient has cytologically proven AML, as defined by the WHO classification. The leukemia is a de novo or a secondary leukemia.

2. The patient is in complete morphologic remission Note: Cytogenetic CR (CRc) or molecular CR (CRm) is not required.

   • AML patients in first complete remission (CR1) who are not eligible for allo-HSCT following the institution's standard of care(except the favourable genetic group subset which is excluded from this study).
   • All AML patients in second or third complete morphological remission(CR2 or CR3) who are not eligible for allo-HSCT.

3. The patient received the following therapy according to the institution's standard of care:

   • For patients ≤ 60 years old, at least two cycles of intensive chemotherapy (induction and consolidation)
   • For patients > 60 years old, at least one induction chemotherapy. Any patients with severe co-morbidity for which consolidation is unacceptable, can receive only one induction therapy.

4. The patient's blasts cells show over-expression of WT1 transcripts, detected in peripheral blood by qRT-PCR at diagnosis or at first relapse.

5. Written informed consent has been obtained prior to the performance of any protocol-specific procedure.

6. The patient is ≥ 18 years of age at the time of signing of the ICF.

7. ECOG performance status of 0, 1, or 2 at the time of enrollment.

8. Adequate hepatic and renal function defined as:

   • Serum bilirubin < 1.5 times the Upper Limit of Normal (ULN).
   • Serum alanine aminotransferase ALAT < 2.5 times the ULN.
   • Calculated creatinine clearance > 40 mL/min.

9. If the patient is female, then she must be of non-childbearing potential, i.e., have a current tubal ligation, hysterectomy, ovariectomy or be post-menopausal, or if she is of childbearing potential, then she must practice adequate contraception for 30 days prior to treatment administration, have a negative pregnancy test, and continue such precautions for two months after completion of the treatment administration series.

10. Under the investigator criteria, the patient is able to comply with the protocol requirements during the duration of the study.

11. In the investigator's opinion and in compliance with the Institution hematology guidance, the patient should not be eligible for an approved standard of care such as induction with chemotherapy or allo-HSCT.

Exclusion Criteria:

1. The patient is in morphologic leukemia-free state or in morphologic complete remission but with incomplete blood count recovery as defined by IWG Response Criteria
2. The patient is in CR1 and is in the category of low-risk for relapse patients, i.e. belong to the favourable genetic group subset .
3. The patient was diagnosed with leukemic central nervous system (CNS) disease (E.g. before chemotherapy) or presents neurological symptoms at baseline suggestive of a CNS involvement.
4. The patient has received, is receiving (or is due to receive) allo-HSCT.
5. The patient has (or has had) concomitant malignancies, except effectively treated malignancy that is considered by the investigator highly likely to have been cured.
6. The patient is known to be human immunodeficiency virus (HIV)-positive.
7. The patient has symptomatic autoimmune disease such as, but not limited to, multiple sclerosis, lupus, rheumatoid arthritis and inflammatory bowel disease.
8. The patient has a history of allergic reactions likely to be exacerbated by any component of the study investigational product.
9. The patient has other concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk.
10. The patient has congestive heart failure, symptomatic coronary artery disease, or previous myocardial infarction.
11. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent, or to comply with the study procedures.
12. The patient has received any investigational or non-registered medicinal product other than the study medication within 30 days preceding the first dose of study medication, or plans to receive such a drug during the study period.
13. The patient requires concomitant treatment with systemic corticosteroids or any other immunosuppressive agents. The use of prednisone, or equivalent, < 0.5 mg/kg/day (absolute maximum 40 mg/day), inhaled corticosteroids or topical steroids is permitted.
14. The patient has an active infection and/or is receiving antibiotics. The patient has received i.v. administration of antibiotics within two weeks prior to first study treatment or oral antibiotics within one week prior to first study treatment.
15. For female patients: the patient is pregnant or lactating.