A study to assess the safety and immunogenicity of an anti leukemia Antigen-Specific Cancer Immunotherapeutic (ASCI) combined with infusions of T lymphocytes in in vivo regulatory T cells depleted patients as post-consolidation therapy for adult patients with WT1-positive Acute Myeloid Leukemia (AML).

• Register: EUCTR
• Last refreshed on: 7 October 2014
• Main ID: EUCTR2011-004144-22-BE
• Date of registration: 27/09/2011
• Prospective Registration: Yes
• Primary sponsor: Institut Jules Bordet - Université Libre de Bruxelles
• Public title: A study to assess the safety and immunogenicity of an anti leukemia Antigen-Specific Cancer Immunotherapeutic (ASCI) combined with infusions of T lymphocytes in in vivo regulatory T cells depleted patients as post-consolidation therapy for adult patients with WT1-positive Acute Myeloid Leukemia (AML).
• Scientific title: 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)
• Date of first enrolment: 12/01/2012
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-004144-22
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no

Countries of recruitment

Belgium

Contacts

• Name: Philippe Lewalle
• Affiliation: Institut Jules Bordet

• Name: Philippe Lewalle
• Affiliation: Institut Jules Bordet

Key inclusion & exclusion criteria

Inclusion criteria:
The following criteria are to be checked at the time of study entry. Patients may only be included in the study if all of the following criteria are met:
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 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.
3. The patient is in complete morphologic remission, as detailed in Appendix G
a)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 as defined in Table 1 below which is excluded from this study.
According to the EBMT treatment consensus: favourable risk group AML patients should not be transplanted upfront, whilst high and intermediate-II risk group patients should be transplanted as first treatment option (The EBMT handbook 5th edition, 2008). The benefit of transplant for the intermediate group-I is still an open question and a center decision.
b)All AML patients in second or third complete morphological remission (CR2 or CR3) according to response criteria who are not eligible for allo-SCT.
4. The patient's blasts cells show over-expression of WT1 transcripts, detected in peripheral blood by qRT-PCR at diagnosis or in first relapse.
Note: WT1 expression analysis will be done using peripheral blood obtained before chemotherapy.
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 enrolment.
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, 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.


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 7
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 13

Exclusion criteria:
The following criteria should be checked at the time of study entry. If any are met, then the patient must not be included in the study:
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 (Appendix G)
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 (as described in table 1).
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) allogeneic HSCT.
5. The patient has 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 positive.
7. The patient has 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 trial 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 immunosuppressive agents. The use of inhaled corticosteroids or topical steroids is permitted.
14. The patient has an active infection and/or is receiving antibiotics. Enrolment will be allowed 48h00 after the end of the treatment.
15. For female patients: the patient is pregnant or lactating.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

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)

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: WT1-A10 + AS01B
Product Code: WT1-A10 + AS01B
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: WT1-A10
Other descriptive name: WT1-A10
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: - first patient : December 2011
- interim analysis : November 2012
- last patient : November 2013.
- last patient follow-up : November 2015

Main Objective: Co-primary Objectives :
To evaluate the safety of combined treatment strategy of WT1-A10 + AS01B, infusions of ex vivo regulatory T cells depleted T lymphocytes and in vivo regulatory T cells depletion as post-consolidation therapy.
To evaluate the safety of Treg depletion (including auto-immunity).

Primary end point(s): The two co-primary endpoints of this study are:
•Occurrence of severe toxicities during the study treatment phase related or possibly related to ASCI, to Treg depletion or to the combination of both and defined as:
-An ASCI-related or possibly ASCI-related Grade 4 toxicity (exception: ASCI-related or possibly ASCI related Grade 4 fatigue including lethargy, asthenia and malaise must have a duration of at least 48 hours to be taken into account).
-An ASCI-related toxicity or possibly ASCI-related Grade 3 toxicity lasting for at least 48 hours, (exceptions: myalgia, arthralgia, headache and fever, regardless of duration).
-An allergic reaction/hypersensitivity Grade 2 toxicity (i.e. rash, flushing, urticaria and dyspnea). Drug fever will not be part of this definition.
-An ASCI-related or possibly ASCI-related decrease in renal function, with a calculated creatinine clearance < 40 ml/min.
-An ASCI-related or possibly ASCI-related Grade 2 cardiac ischemia/infarction (i.e. asymptomatic and testing suggesting ischemia; stable angina).
-A Treg depletion-related or possibly related Grade 2 toxicity. (i.e. potential immune-related diseases (pIMDs))

Secondary Objective: To evaluate the immune (humoral and cellular) response induced by WT1-A10 + AS01B in AML patients, in vivo depleted in Tregs by metronomic doses of cyclophosphamide, administered concomitantly with Tregs-depleted T cells add-back.
To evaluate the clinical activity of this approach in bad risk patients in CR1 and all patients in CR2 or CR3, non eligible for an allo-HSCT

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: - first patient : December 2011
- interim analysis : November 2012
- last patient : November 2013.
- last patient follow-up : November 2015

Secondary end point(s): • Immunogenicity endpoints:
-The anti-WT1 humoral response.
-The anti-WT1 cellular (T-cell) response.
-Blood Treg level during and after completion of the study compared to Treg at pre-treatment.

Immunogenicity of the WT1-A10 + AS01B ASCI will be described at different time points.
• Safety endpoints:
-Occurrence of adverse events and serious adverse events during the study treatment period and ending 30 days after the last study treatment administration, including abnormal hematological and biochemical parameters.
-Occurrence of serious adverse events related to study treatment during the whole study duration.
• Clinical activity endpoints:
-Time to study treatment failure; defined as withdrawal from investigational product because of disease progression or death. Persistence of Complete Response (CR), or stabilisation of minor recurring disease status (MRDS).
-Progression-free survival, calculated as the time from first treatment to either the first progression of the disease or the date of death, whichever occurs first.
-Induction of molecular CR (CRm) (for patients with patients with molecular abnormality detected before starting ASCI treatment). (CRm is defined in Appendix G).
Induction of cytogenetic CR (CRc) (for patients with aberrant cytogenetics detected before starting ASCI treatment).
WT1 mRNA transcripts levels in peripheral blood samples.
Induction of molecular CR (CRm) (for patients with patients with molecular abnormality detected before starting ASCI treatment).
Induction of cytogenetic CR (CRc) (for patients with aberrant cytogenetics detected before starting ASCI treatment).
WT1 mRNA transcripts levels in peripheral blood samples.

Secondary ID(s)

BORLEUWT01

Source(s) of Monetary Support

Fonds National de la Recherche Scientifique (FNRS)