Clinical Trials Register

Summary
EudraCT Number:	2009-011613-24
Sponsor's Protocol Code Number:	HOVON102AML/SAKK30/09
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-07-03
Trial results	View 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

Netherlands - Competent Authority

A.2

EudraCT number

2009-011613-24

A.3

Full title of the trial

Randomized study with a run-in feasibility phase to assess the added value of Clofarabine in combination with standard remission-induction chemotherapy in patients aged 18-65 years with previously untreated acute myeloid leukemia (AML) or myelodysplasia (MDS) (RAEB with IPSS ≥ 1.5)

HOVON 102: Onderzoek naar de verdraagbaarheid en de werkzaamheid van Clofarabine, wanneer het wordt toegevoegd aan de standaard inductie chemotherapie bij patiënten, tussen 18 en 65 jaar, met onbehandelde acute myeloïde leukemie (AML) of myelodysplasie type refractaire anemie met toename blasten (RAEB)

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

HOVON 102 AML / SAKK 30/09

A.4.1

Sponsor's protocol code number

HOVON102AML/SAKK30/09

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	Dutch Cancer Society
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Genzyme
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	HOVON
B.5.2	Functional name of contact point	HOVON Data Center
B.5.3	Address:
B.5.3.1	Street Address	's Gravendijkwal 230
B.5.3.2	Town/ city	Rotterdam
B.5.3.3	Post code	3015 CE
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	310107041560n.a.
B.5.5	Fax number	310107041028n.a.
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	Yes
D.2.1.1.1	Trade name	Evoltra 1 mg/ml concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Genzyme Europe BV
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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/3/01/082 (ALL), EU/3/03/141 (AML)
D.3 Description of the IMP
D.3.1	Product name	Evoltra
D.3.4	Pharmaceutical form	Concentrate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLOFARABINE
D.3.9.1	CAS number	123318-82-1
D.3.9.2	Current sponsor code	Hovon 102
D.3.9.3	Other descriptive name	clolar
D.3.9.4	EV Substance Code	SUB21902
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	20
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

- a cytopathologically confirmed diagnosis of AML according WHO classification
(excluding acute promyelocytic leukaemia) or
- a diagnosis of refractory anemia with excess of blasts (RAEB) and IPSS score ≥1.5
or
- patients with therapy-related AML/RAEB or
- patients with biphenotypic leukemia (Appendices A1 and A2).

Acute myeloïde leukemie (AML) of myelodysplasie type
refractaire anemie met een toename van blasten (afgekort: RAEB).

E.1.1.1

Medical condition in easily understood language

Acute Myeloid Leukemia or refractory anemia with excess of blasts (RAEB)

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10054592
E.1.2	Term	Refractory anemia with an excess of blasts
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	18.1
E.1.2	Level	PT
E.1.2	Classification code	10038270
E.1.2	Term	Refractory anaemia with an excess of blasts
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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10066353
E.1.2	Term	Treatment related 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	18.1
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.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

For part A of the study:
¨ To determine the feasibility of Clofarabine when given at three possible dose levels together with standard induction cycles I and II in patients with AML/ RAEB with IPSS>=1.5 in a prospective comparison to standard induction cycles I and II without Clofarabine.
For part B of the study:
¨ To evaluate the effect of Clofarabine at the selected feasible dose level when combined with remission induction chemotherapy cycles I and II as regards clinical outcome (“event-free survival”) in comparison to remission induction cycles I and II with no addition of Clofarabine in a phase III study.

E.2.2

Secondary objectives of the trial

To investigate the clinical efficacy of Clofarabine when combined with remission induction I & II:
in Part A with regard to complete remission (CR) rate at different dose levels of Clofarabine.
In Part B with regard to the CR rate, disease free survival (DFS), risk of relapse and overall survival (OS) in all patients, in molecularly and cytogenetically distinguishable subsets with regard to the CR rate, DFS, risk of relapse and OS and the tolerance and toxicity
To investigate
- the effect of Clofarabine on peripheral CD34 cell numbers for autologous peripheral blood transplantation
- the prognostic value of molecular markers and gene expression profiles of the leukemia assessed at diagnosis
- the treatment effects according minimal residual disease measurements following therapy by standardized sampling of marrow/blood
- the outcome of allogeneic sibling or unrelated donor SCT and autologous SCT in cytogenetically and molecularly defined prognostic subgroups of patients

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

¨ Age 18-65 years, inclusive
¨ Subjects with
- a cytopathologically confirmed diagnosis of AML according WHO classification (excluding acute promyelocytic leukaemia) or
- a diagnosis of refractory anemia with excess of blasts (RAEB) and IPSS score ≥1.5 or
- patients with therapy-related AML/RAEB or
- patients with biphenotypic leukemia (Appendices A1 and A2).
¨ Adequate renal and hepatic function tests as indicated by the following laboratory values:
- Serum creatinine ≤1.0 mg/dl (≤ 88.7 micromol/L); if serum creatinine >1.0 mg/dl (>88.7 micromol/L), then the 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 micromol/L, recalculate it in mg/dl according to the equation: 1 mg/dl = 88.7 micromol/L) and used above mentioned formula.
- Serum bilirubin ≤1.5 × upper limit of normal (ULN)
- Aspartate transaminase (AST)/alanine transaminase (ALT) ≤2.5 × ULN
- Alkaline phosphatase ≤ 2.5 × ULN
¨ WHO performance status 0, 1 or 2 (see Appendix I)
¨ Written informed consent

E.4

Principal exclusion criteria

¨ Acute promyelocytic leukaemia
¨ Previous treatment for AML or RAEB, except hydroxyurea
¨ Concurrent history active malignancy in two past years prior to diagnosis except for:
- basal and squamous cell carcinoma of the skin
- in situ carcinoma of the cervix
¨ Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etcetera),
¨ Cardiac dysfunction as defined by:
- Myocardial infarction within the last 6 months of study entry, or
- Reduced left ventricular function with an ejection fraction < 50% as measured by MUGA
scan or echocardiogram (another method for measuring cardiac function is acceptable), or
- Unstable angina, or
- Unstable cardiac arrhythmias
¨ Pregnant or lactating females
¨ Unwilling or not capable to use effective means of birth control

E.5 End points

E.5.1

Primary end point(s)

Part A of study:
Occurrence of DLT and duration of myelosuppression of the combination of Clofarabine at three selected dose levels.

DLT is defined as
¨ Death
¨ Any non hematological toxicity CTCAE grade ≥ 4,
occurring within 30 days after start of cycles I or II and before the start of the next cycle or a new treatment respectively.

The duration of myelosuppression is defined as the median time to recovery of ANC > 0.5x109/L.

DLT and myelosuppression will be used in the decision process for dose escalation, dose reduction and/or dose dose selection (see 17.1).

Part B of study:
Event-free survival (EFS) (i.e., time from registration to induction failure, death or relapse whichever occurs first).

E.5.1.1

Timepoint(s) of evaluation of this end point

Three interim analyses are planned, primarily to guard against unfavourable results in the induction treatment arm with Clofarabine. Results of the interim analyses will be presented confidentially only to the DSMB. The main endpoint for the interim analyses is the overall failure rate on induction treatment. A patient counts as a failure in induction therapy if one of the following conditions apply:
- the patient does not complete cycle II
- the patient does not achieve CR on induction
- the patient dies due to side effects of cycle I or II.

E.5.2

Secondary end point(s)

- Response and especially CR (including CRi) to chemotherapy cycles I and II
- Overall survival (OS) measured from the time of registration
- Disease-free interval (duration of the first CR) measured from the time of achievement of CR to day of relapse or death from any cause (whichever occurs first).
- Occurence of toxicities and treatment related mortality (according to Appendix H)
- Time to hematopoietic recovery (ANC 0.5 and 1.0x109/L; platelets 50 and 100x109/L) after each treatment cycle.
- Number of platelet transfusions and last day of platelet transfusion after each cycle.

E.5.2.1

Timepoint(s) of evaluation of this end point

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

Yes

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)

Yes

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 clofarabine

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

Estonia

Norway

Spain

Switzerland

E.8.7

Trial has a data monitoring committee

Yes

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

At 7 months after registration and randomization of the finally enrolled patient

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)

Yes

F.1.2.1

Number of subjects for this age range:

890

F.1.3

Elderly (>=65 years)

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2009-07-03.

Yes

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

414

F.4.2

For a multinational trial

F.4.2.1

In the EEA

727

F.4.2.2

In the whole clinical trial

920

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)

see protocol

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2009-09-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-01-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-09-28

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