Clinical Trials Register

Summary
EudraCT Number:	2009-014455-68
Sponsor's Protocol Code Number:	HOVON103AMLTosedostat
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2011-06-16
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

2009-014455-68

A.3

Full title of the trial

A randomized phase II multicenter study with a safety run-in to assess the tolerability and efficacy of the addition of oral tosedostat to standard induction therapy in AML and RAEB ≥ 66 years and very poor risk AML ≥ 18 years.

A study in the frame of the masterprotocol of parallel randomized phase II studies in elderly AML

A.3.1

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

Stuyd for the treatment of patients with leukemic cells (cancer) in their bone marrow

A.3.2

Name or abbreviated title of the trial where available

HOVON 103 AML Tosedostat

A.4.1

Sponsor's protocol code number

HOVON103AMLTosedostat

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	HOVON Foundation
B.1.3.4	Country	Netherlands
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	HOVON Foundation
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Chrma Therapeutics Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Erasmus MC
B.5.2	Functional name of contact point	HOVON Data Center
B.5.3	Address:
B.5.3.1	Street Address	P.O. Box 2040
B.5.3.2	Town/ city	Rotterdam
B.5.3.3	Post code	3000 CA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31(0)107041560
B.5.5	Fax number	+31(0)107041028
B.5.6	E-mail	hdc@erasmusmc.nl

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	Yes
D.2.5.1	Orphan drug designation number	EU/3/09/659
D.3 Description of the IMP
D.3.1	Product name	tosedostat
D.3.2	Product code	CHR-2797
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tosedostat
D.3.9.1	CAS number	238750-77-1
D.3.9.2	Current sponsor code	CHR-2798
D.3.9.3	Other descriptive name	BB-76163
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	120
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
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)	No
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

patients ≥ 66 years with:
o a diagnosis of AML and related precursor neoplasms according to WHO 2008 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease (e.g. MDS) and therapy-related AML, or
o acute leukemia's of ambiguous lineage according to WHO 2008 or
o a diagnosis of refractory anemia with excess of blasts (MDS) and IPSS-R > 4.5

E.1.1.1

Medical condition in easily understood language

Leukemis, cancer of the bone marrow

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10000886
E.1.2	Term	Acute myeloid leukemia
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10037803
E.1.2	Term	RAEB
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	PT
E.1.2	Classification code	10000880
E.1.2	Term	Acute myeloid leukaemia
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

For part A of the study (if applicable):
1. To assess the safety and tolerability of lenalidomide added to standard induction chemotherapy for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) and select the feasible dose level for part B
2. To assess in a randomized comparison the effect of lenalidomide on the CR rate.

For part B:
1. To assess the safety and tolerability of lenalidomide added to standard induction chemotherapy for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) as regards the selected dose level of lenalidomide
2. To assess in a randomized comparison the effect of lenalidomide on the CR rate.

E.2.2

Secondary objectives of the trial

For part B:
1. To determine the efficacy profile (event free survival and disease free survival and overall survival) associated with the two therapy regimens.
2. To measure MRD by immunophenotyping in relation to clinical response parameters.
3. To identify potential biomarkers predictive of response, event free survival and disease free survival by exploratory proteomic and genomic analysis (microarray, gene mutations)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patients eligible for standard chemotherapy.
• Patients 66 years and older
• Patients with:
o a diagnosis of AML and related precursor neoplasms according to WHO 2008 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease (e.g. MDS) and therapy-related AML, or
o acute leukemia's of ambiguous lineage according to WHO 2008
or
o a diagnosis of refractory anemia with excess of blasts (MDS)
and IPSS-R > 4.5
• Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:
o Serum creatinine ≤1.0 mg/dL (≤88.7 µmol/L); if serum creatinine >1.0 mg/dL (>88.7 µmol/L), then the estimated glomerular filtration rate (GFR) must be >60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where the Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine in mg/dL)-1.154 x (age in years)-0.203 x (0.742 if patient is female) x (1.212 if patient is black) NOTE: if serum creatinine is measured in µmol/L, recalculate it in mg/dL according to the equation: 1 mg/dL = 88.7 µmol/L and use the above mentioned formula.
o Serum bilirubin ≤ 2.5 x upper limit of normal (ULN)
o Aspartate transaminase (AST) ≤ 2.5 x ULN
o Alanine transaminase (ALT) ≤ 2.5 x ULN
o Alkaline phosphatase ≤ 2.5 x ULN
• WHO performance status 0, 1 or 2 (see Appendix F)
• Written informed consent.
• Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.

E.4

Principal exclusion criteria

• Acute promyelocytic leukemia
• Patients previously treated for AML (any antileukemic therapy including investigational agents), a short treatment period (< 2 weeks)

with Hydroxyurea is allowed
• Concurrent history of active malignancy in the two past years prior to diagnosis except for:
o Basal and squamous cell carcinoma of the skin o in situ carcinoma of the cervix
• Blast crisis of chronic myeloid leukemia
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etcetera)
• Cardiac dysfunction as defined by:
o Myocardial infarction within the last 6 months of study entry,
or
o Reduced left ventricular function with an ejection fraction <
50% ad measured by MUG scan or echocardiogram or o Unstable angina or
o New York Heart Association (NYHA) grade II or greater congestive heart failure (see Appendix I) or
o Unstable cardiac arrthythmias
• Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance
• Patients with any serious concomitant medical condition which could, in the opinion of the investigator, compromise participation in the study.
• Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.
• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

E.5 End points

E.5.1

Primary end point(s)

- Incidence of DLT (part A)
- The effect of lenalidomide on the CR rate (part B of study)

E.5.1.1

Timepoint(s) of evaluation of this end point

The final analysis of the primary endpoints will be done one year after last patient is registered in the tosedostat arm.

E.5.2

Secondary end point(s)

1. To determine the efficacy profile (event free survival (EFS) disease free survival (DFS) and overall survival (OS)) associated with the two therapy regimens.
2. To measure MRD by immunophenotyping in relation to clinical
response parameters.
3. To identify potential biomarkers predictive of response, EFS, DFS and OS by exploratory genomic analysis (microarray, gene mutations)

E.5.2.1

Timepoint(s) of evaluation of this end point

The final analysis of the secondary endpoints will be done one year after last patient is registered in the tosedostat arm.

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

Yes

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

addition of tosedostat

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

Netherlands

Norway

Switzerland

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

See protocol

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

230

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

F.3.3.1

Women of childbearing potential not using contraception