Clinical Trials Register

Summary
EudraCT Number:	2009-012437-30
Sponsor's Protocol Code Number:	BUS‐2009/01
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2010-04-16
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

Sweden - MPA

A.2

EudraCT number

2009-012437-30

A.3

Full title of the trial

Clofarabine based remission induction followed by haploidentical stem cell
transplantation in children with refractory hematological malignancies

A.4.1

Sponsor's protocol code number

BUS‐2009/01

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Skånes University Hospital
B.1.3.4	Country	Sweden
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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
D.2.1.1.2	Name of the Marketing Authorisation holder	Genzyme Europe BV
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Clofarabine
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	ETOPOSIDE PHOSPHATE
D.3.9.1	CAS number	117091642
D.3.9.2	Current sponsor code	Etoposid
D.3.9.3	Other descriptive name	Etopofos
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	100
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CYCLOPHOSPHAMIDE
D.3.9.1	CAS number	50180
D.3.9.2	Current sponsor code	Cyclophosphamide
D.3.9.3	Other descriptive name	Sendoxan
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	200 to 2000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MELPHALAN
D.3.9.1	CAS number	148-82-3
D.3.9.2	Current sponsor code	Melfalan
D.3.9.3	Other descriptive name	Alkeran
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	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	THIOTEPA
D.3.9.1	CAS number	52244
D.3.9.2	Current sponsor code	Tiotepa
D.3.9.3	Other descriptive name	Thiotepa
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	15
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MUROMONAB-CD3
D.3.9.1	CAS number	0
D.3.9.2	Current sponsor code	OKT3
D.3.9.3	Other descriptive name	Orthoclone
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.2	Current sponsor code	Rituximab
D.3.9.3	Other descriptive name	Mabthera
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	100 to 500
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MYCOPHENOLATE MOFETIL
D.3.9.1	CAS number	115007-34-6
D.3.9.2	Current sponsor code	MMF
D.3.9.3	Other descriptive name	Cellcept
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METHYLPREDNISOLONE HEMISUCCINATE
D.3.9.1	CAS number	2921575
D.3.9.2	Current sponsor code	Steroid
D.3.9.3	Other descriptive name	SoluMedrol
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	40 to 500
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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

Therapy resitant leukemia in children and young adults

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1.2 Primary Objectives
a) To improve event free survival for children with acute leukemia resistant to conventional therapy using “bridge to transplant” approach
b) To demonstrate graft versus leukemia effect in children with therapy resistant leukemia who underwent haploidentical stem cell transplantation with subsequent cell therapy (DLI)

E.2.2

Secondary objectives of the trial

1.3 Secondary Objectives
a) Evaluation of induction efficacy measured by response rate and the number of children proceeding to transplant
b) Tolerance, safety and quality of life
c) To evaluate hematological and immunological recovery

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

3.1 Inclusion Criteria
I. Target population
1. Refractory acute lymphoblastic leukemia
a. Chemoresistant isolated or combined bone marrow relapse
• Relapse after during/after conventional treatment
• Relapse >6 months after allogeneic stem cell transplantation
b. Primary induction failure
c. Isolated extramedullary relapse after previous HSCT (>6
months)
2. Refractory acute myeloblastic leukemia including sAML
a. Chemoresistant relapse
• Relapse after during/after conventional treatment
• Relapse >6 months after allogeneic stem cell
transplantation[1]
b. Primary induction failure
II. Inclusion criteria to start induction treatment with multidrug regimen
1. Age > 1 and ≤21 years
2. Patients with previous HCST ≥ 6 m[1]
3. Provide signed written informed consent patients’, and patients’
parents/guardians
a. Older children should be capable of understanding the
investigational nature, potential risks and benefits of the study,
and able to provide valid informed consent as well.
4. Cardiac output SF ≥25%
5. Have adequate renal and hepatic functions as indicated by the
following laboratory values:
• Calculated creatinine clearance ≥90 ml/min/1.73 m2 as
calculated by the Schwartz formula for estimated glomerular
filtration rate (GFR) where GFR (ml/min/1.73 m2) = k*Height
(cm)/serum creatinine (mg/dl). k is a proportionality constant
which varies with age and is a function of urinary creatinine
excretion per unit of body size; 0.45 up to 12 months of age;
0.55 children and adolescent girls; and 0.70 adolescent boys.
• Serum bilirubin ≤1.5 × upper limit of normal (ULN)
• Aspartate transaminase (AST)/alanine transaminase (ALT) ≤2.5 × ULN
• Alkaline phosphatase ≤ 2.5 × ULN
6. Performance score of ≥70% (Lansky or Karnofsky)
7. A suitable haploidentical family member available for stem cell
donation, > 18 years of age, fulfilling institutional criteria for blood
and marrow donation.
8. Male and female patients must use an effective contraceptive
method during the study and for a minimum of 6 months after study
treatment.
III. Inclusion criteria to proceed to transplant after induction
1. Cardiac output SF ≥25%
2. Have adequate renal and hepatic functions as indicated by the
following laboratory values:
• Calculated creatinine clearance ≥90 ml/min/1.73 m2 as
calculated by the Schwartz formula for estimated glomerular
filtration rate (GFR) where GFR (ml/min/1.73 m2) = k*Height
(cm)/serum creatinine (mg/dl).
k is a proportionality constant which varies with age and is a
function of urinary creatinine excretion per unit of body size;
0.45 up to 12 months of age; 0.55 children and adolescent girls;
and 0.70 adolescent boys.
• Serum bilirubin ≤1.5 × upper limit of normal (ULN)
• Aspartate transaminase (AST)/alanine transaminase (ALT)
≤2.5 × ULN
• Alkaline phosphatase ≤ 2.5 × ULN
3. Performance score of ≥70% (Lansky or Karnofsky)
4. A suitable haploidentical family member available for stem cell
donation, > 18 years of age, fulfilling institutional criteria for blood
and marrow donation.
5. Capable of understanding the investigational nature, potential risks
and benefits of the study, and able to provide valid informed consent.
6. Female patients of childbearing potential must have a negative serum
pregnancy test within 2 weeks prior to enrolment.
7. 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

3.2 Exclusion Criteria
1. Current concomitant chemotherapy, radiation therapy, or
immunotherapy other than as specified in the protocol.
2. Use of investigational agents within 30 days or any anticancer
therapy within 2 weeks before study entry with the exception of
hydroxyurea.
The patient must have recovered from all acute toxicities from any
previous therapy.
3. Have any other severe concurrent disease, or have a history of
serious organ dysfunction or disease involving the heart, kidney,
liver, or other organ system that may place the patient at undue risk
to undergo treatment.
4. Patients with a systemic fungal, bacterial, viral, or other infection
not controlled (defined as exhibiting ongoing signs/symptoms
related to the infection and without improvement, despite
appropriate antibiotics or other treatment).
5. Pregnant or lactating patients.
6. Any significant concurrent malignant disease, illness, or psychiatric
disorder that would compromise patient safety or compliance,
interfere with consent, study participation, follow up, or
interpretation of study results.

E.5 End points

E.5.1

Primary end point(s)

1) The number of patients "bridged to transplant" with CLoEC induction
2) Overall survival day +100 and day +365 after stem cell transplantation
3) Event free survival day +100 and +365 after stem cell transplantation
4) Disease free survival day +100 and day +365 after stem cell transplantation
5) Incidence of garft versus host disease.
6) Immunological recovery

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

E.8.1.1

Randomised

E.8.1.2

Open

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

Information not present in EudraCT

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

2 years after stem cell transplantation of the last 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

Yes

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)

Yes

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.2

Adults (18-64 years)

Yes

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

F.3.3.2

Women of child-bearing potential using contraception

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

Routin follow up twice a year at the Department of Pediatric Oncology or in case of patiebts >18 years at the Department of Hematology and/or Late Effects Department.

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

2010-06-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-11-19

P. End of Trial
P.	End of Trial Status	Ongoing

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