Clinical Trials Register

Summary
EudraCT Number:	2012-001494-91
Sponsor's Protocol Code Number:	CCRG12-001
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2012-08-01
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2012-001494-91

A.3

Full title of the trial

Wilms’ tumor (WT1) antigen-targeted dendritic cell vaccination to prevent relapse in adult patients with acute myeloid leukemia: a multicenter randomized phase II trial

Wilms’ tumor (WT1) antigengerichte dendritische celvaccinatie ter voorkoming van herval bij volwassen patiënten met acute myeloïde leukemie: een multicentrische, gerandomiseerde fase II studie

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Dendritic cell-based immunotherapy targeting the tumor protein WT1 to treat adult patients with acute myeloid leukemia

A.3.2

Name or abbreviated title of the trial where available

WIDEA

A.4.1

Sponsor's protocol code number

CCRG12-001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01686334

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Antwerp University Hospital
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Government - National Cancer Plan
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	Kom op tegen Kanker
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	Stichting tegen Kanker
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	Fonds Wetenschappelijk Onderzoek -TBM
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Antwerp University Hospital
B.5.2	Functional name of contact point	Barbara Stein
B.5.3	Address:
B.5.3.1	Street Address	Drie Eikenstraat 655
B.5.3.2	Town/ city	Edegem
B.5.3.3	Post code	B-2650
B.5.3.4	Country	Belgium
B.5.4	Telephone number	003238213122
B.5.5	Fax number	003238214456
B.5.6	E-mail	Barbara.Stein@uza.be

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Cryopreserved Wilms' tumor 1 (WT1) mRNA-electroporated dendritic cells
D.3.2	Product code	WT1 mRNA-EP DC
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intradermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Wilms' tumor 1 (WT1) mRNA-electroporated dendritic cell vaccine
D.3.9.2	Current sponsor code	WT1 mRNA-EP DC
D.3.9.3	Other descriptive name	cell suspension containing dendritic cells
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	8.10e6 to 10.10e6
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Adult patients with acute myeloid leukemia in complete remission

E.1.1.1

Medical condition in easily understood language

Adult patients with acute myeloid leukemia in complete remission

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10046859
E.1.2	Term	Vaccination
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10024329
E.1.2	Term	Leukemia
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this trial is to determine the clinical efficacy of WT1 mRNA-electroporated DC vaccination as a post-remission strategy to prevent relapse and prolong overall survival in adult AML patients.

E.2.2

Secondary objectives of the trial

The secondary objectives of this trial are (i) to assess relapse rate at two years and relapse-free survival to evaluate clinical response, (ii) to monitor molecular and immunological responses and (iii) to evaluate patient-reported outcomes.
For the molecular response, the efficacy of the DC vaccine strategy will be determined to control or eradicate minimal residual disease (MRD) in AML. Monitoring of MRD will be performed by sequential measurement of WT1 transcript levels in peripheral blood.
For the immunological response, different immunoassays will be used to investigate if the WT1 mRNA-electroporated DC vaccines are immunogenic and capable of inducing anti-leukemic immune responses in vivo.
To evaluate patient-reported outcomes, changes in general and disease-specific quality of life will be determined using EQ-5D-5L and QLQ-C30 questionnaires at regular time-points.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Diagnosis of acute myeloid leukemia (AML) according to the 2008 criteria of the World Health Organization (WHO).

o all French-American-British (FAB) subtypes, except:
- M3 (acute promyelocytic leukemia)

o all cases of de novo AML or secondary AML with ≥ 20 % blasts in peripheral blood and/or bone marrow, except:
- AML secondary to myeloproliferative neoplasms (MPN)
- AML secondary to exposure of leukemogenic agents (t-AML), unless treated with CPX-351 chemotherapy or hypomethylating agents combined with venetoclax .

• Completion of one of the following treatment options:

I) Intensive chemotherapy:
(1) at least one cycle of induction chemotherapy and one cycle of consolidation chemotherapy (low-dose cytarabine as consolidation therapy is allowed) OR
(2) one to two cycles of CPX-351 induction treatment and up to two cycles of CPX-351 consolidation treatment OR
II) Low-intensity chemotherapy:
(3) at least two cycles to maximum six cycles of hypomethylating agents (HMA) whether or not combined with venetoclax (VEN) (hereafter referred as HMA+/- VEN) OR
(4) at least two cycles to maximum six cycles of low-dose cytarabine (LDAC) combined with venetoclax (hereafter referred as LDAC+VEN);

resulting in:

o morphological complete remission (CR), i.e. bone marrow blast count <5% with neutrophil count >1000 cells/µL and platelet count >100,000 cells/µL.
OR
o morphological complete remission with incomplete blood recovery (CRi), i.e. bone marrow blast count <5% with neutrophil count <1000 cells/µL or platelet count <100,000 cells/µL.
For the purpose of this study protocol, platelet count must be >50,000 cells/µL.

• Adult (≥ 18 years) at very high risk of relapse according to:
o Age ≥ 60 years, and/or
o Adverse biological features (e.g. adverse cytogenetics, adverse morphological features, adverse molecular features, hyperleukocytosis (> 100000 cells/µL)), and
o Ineligible for or unwilling to receive hematopoietic stem cell transplantation.

• WHO performance status: grade 0, 1 or 2 at the time of enrollment.
For definition of performance status, see: http://www.ecog.org/general/perf_stat.html

• Absence of any psychological, familial, sociological, geographical or physical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before study entry.

E.4

Principal exclusion criteria

• Participation in any other interventional clinical trial during the study period.

• History or concomitant presence of any other malignancy, except for:

o non-melanoma skin cancer
o carcinoma in situ of the cervix
o any other effectively treated malignancy that has been in remission for >5 years or that is highly likely to be cured at the time of enrollment.

• Concomitant presence of any immunosuppressive disease (e.g. HIV) or any active autoimmune condition, except for vitiligo.

• Concomitant use of systemic corticosteroids in immunosuppressive doses (>1 mg/kg/day of prednisone, or equivalent dose for other corticosteroid preparations) or any other immunosuppressive agent. A minimum of 4 weeks must have elapsed between the last dose of immunosuppressive therapy and the first vaccination. Topical corticosteroids are permitted, except if applied at the sites of DC injection.

• pregnancy or breast-feeding

E.5 End points

E.5.1

Primary end point(s)

Primary end point: overall surival
Clinical response analysis will be performed on all efficacy-evaluable patients according to the ‘Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia’.

E.5.1.1

Timepoint(s) of evaluation of this end point

Analysis will be performed after inclusion of 130 efficacy-evaluable patients. Study-related follow up of the included patients is intended to be 5 years after the first vaccination. An interim analysis will be performed (i) after inclusion of 49 patients in each group in the study or (ii) after observation of 62 events (total for both groups) or (iii) when 40 patients in each group have at least finished 2 year follow-up or died.

E.5.2

Secondary end point(s)

Secondary end point 1 and 2:
Clinical response analysis will be performed on all efficacy-evaluable patients according to the ‘Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia’. Secondary endpoins that will be analyzed are relapse-free survival and relapse rate at two years.

Secondary end point 3:
Both for the control group and the intervention group, tumor marker levels will be monitored in peripheral blood. This will be done by measuring WT1 mRNA levels using specific primers and quantitative real-time RT-PCR. Molecular response is defined as the normalization of WT1 transcript levels in peripheral blood below background.

Secondary end point 4:
Both for the control group and the intervention group, activation of the immune system will be monitored. Peripheral blood samples will be examined by using flow cytometry for functional WT1-specific T cell responses (e.g. WT1-reactive IFN-γ+ T cells), WT1-specific CD8+ T cells (by tetramer analysis in HLA-A*0201+ patients) and changes in lymphocyte subset distribution and activation state.

Secondary end point 5:
Patient-reported outcomes: To evaluate changes in general and disease-specific quality of life using EQ-5D-5L and QLQ-C30 questionnaires at regular time points.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary end point 1 and 2:
see time point primary endpoint

Secondary end point 3:
Monitoring will be done biweekly during the first 4 vaccines, then bimonthly at the time of the booster vaccines (for the control group at similar time points, although no vaccination is given).

Secondary end point 4:
Peripheral blood samples will be gathered in the intervention group before the first vaccination (pre-vaccination) and at the time of the fourth vaccination (post-vaccination); and at comparable timepoints in the non-vaccinated control group.

Secondary end point 5: quality of life questionnaires at regular time points.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Control group: no IMP treatment

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last visit of last subject

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

130

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Normal treatment and follow-up

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Belgian Hematology Society
G.4.3.4	Network Country	Belgium

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-10-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-30

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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