Clinical Trials Register

Summary
EudraCT Number:	2015-000087-34
Sponsor's Protocol Code Number:	XM22-08
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-05-04
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

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2015-000087-34

A.3

Full title of the trial

An Open-Label, Randomized, Active-Controlled, Multicenter Study to Evaluate the Efficacy, Pharmacokinetics, Pharmacodynamics, Safety, Tolerability, and Immunogenicity of Lipegfilgrastim 100 μg/kg Body Weight in Comparison to Filgrastim 5 μg/kg Body Weight in Pediatric Patients Diagnosed with Ewing Family of Tumors or Rhabdomyosarcoma Receiving Chemotherapy

Otvorené, randomizované, aktívne kontrolované, multicentrické klinické skúšanie na vyhodnotenie účinnosti, farmakokinetiky, farmakodynamiky, bezpečnosti, znášanlivosti a imunogenicity 100 μg lipegfilgrastimu /kg telesnej hmotnosti v porovnaní s 5 μg filgrastimu /kg telesnej hmotnosti u pediatrických pacientov s Ewingovým sarkómom alebo rabdomyosarkómom, ktorí podstupujú chemoterapiu.

A.3.1

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

Clinical trial comparing Lipegfilgrastim to Filgrastim in Pediatric Patients Diagnosed with Ewing Family of Tumors or Rhabdomyosarcoma Receiving Chemotherapy.

A.4.1

Sponsor's protocol code number

XM22-08

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/116/2014

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Merckle GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Merckle GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merckle GmbH
B.5.2	Functional name of contact point	Dr. med. Andreas Lammerich
B.5.3	Address:
B.5.3.1	Street Address	Graf Arco-Strasse 3
B.5.3.2	Town/ city	Ulm
B.5.3.3	Post code	89079
B.5.3.4	Country	Germany
B.5.4	Telephone number	497314023891
B.5.5	Fax number	497314027656
B.5.6	E-mail	andreas.lammerich@ratiopharm.de

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	LONQUEX
D.2.1.1.2	Name of the Marketing Authorisation holder	Sicor Biotech UAB
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Lipegfilgrastim
D.3.2	Product code	XM22
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lipefilgrastim
D.3.9.1	CAS number	1117844-87-7
D.3.9.2	Current sponsor code	XM22
D.3.9.3	Other descriptive name	glyco-PEGylated r-metHuG-CSF
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	10
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)	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	Yes
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Neupogen 30 MU (0.3 mg/ml) solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V.
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Neupogen
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FILGRASTIM
D.3.9.1	CAS number	121181-53-1
D.3.9.4	EV Substance Code	SUB07627MIG
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	0.3
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)	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	Yes
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

Neutropenia in pediatric patients diagnosed with Ewing family of Tumors or rhabdomyosarcoma receiving chemotherapy

E.1.1.1

Medical condition in easily understood language

treatment of chemotherapy induced neutropenia (white blood cell decrease)

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10029354
E.1.2	Term	Neutropenia
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10016288
E.1.2	Term	Febrile neutropenia
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to assess the efficacy of a single subcutaneous (sc) dose of 100 μg/kg body weight (BW) of lipegfilgrastim per cycle compared to daily 5 μg/kg BW of filgrastim doses in children receiving CTX

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are to assess pharmacodynamics, pharmacokinetics, safety, tolerability, and immunogenicity of a single sc dose of 100 μg/kg BW of lipegfilgrastim per cycle compared to daily doses of 5 μg/kg BW of filgrastim.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

a. Male or female children and adolescents aged 2 to <18 years at screening.
b. Written informed consent provided by parent(s)/legal representative(s) of the pediatric patient and patient’s assent if appropriate, before screening procedures are initiated.
c. Able to understand and/or follow study instructions alone or with parental assistance.
d. Diagnosed with the Ewing family of tumors, or rhabdomyosarcoma.
e. Scheduled to receive 1 of the following CTX regimens (inpatient or outpatient):
For the Ewing Family of Tumors:
- Vincristine/Ifosfamide/Doxorubicin/Etoposide (VIDE); with concomitant sodium 2-mercaptoethane sulfonate (MESNA) according to local standards.
- Vincristine/Doxorubicin/Cyclophosphamide alternating with Ifosfamide/Etoposide (VDC/IE); with concomitant MESNA treatment according to local standards.
For Rhabdomyosarcoma:
- Vincristine/Actinomycin/Cyclophosphamide (VAC); with concomitant MESNA treatment according to local standards.
- VDC/IE; with concomitant MESNA treatment according to local standards.
- Ifosfamide, Vincristine, and Actinomycin D (IVA); with concomitant MESNA treatment according to local standards.
f. Minimum BW 12.5 kg.
g. Life expectancy of at least 3 months with appropriate therapy.
h. White blood cell (WBC) count >2.5 × 10^9/L, absolute neutrophil count (ANC) ≥1.5 × 10^9/L, and platelet count ≥100 × 10^9/L (at screening and prior to CTX).
i. For patients aged ≥12 years, Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
j. Fertile patients (male or female) must use highly reliable contraceptive measures for the entire duration of the study.
k. Female patients who have attained menarche must have a negative urine pregnancy test at the screening visit.

E.4

Principal exclusion criteria

a. Previous exposure to filgrastim, pegfilgrastim, lenograstim or other granulocyte colony stimulating factors (G-CSFs) / granulocyte macrophage colony-stimulating factors (GM-CSFs) in clinical development within 6 weeks prior to the first lipegfilgrastim/filgrastim administration in this study.
b. Known hypersensitivity to filgrastim, pegfilgrastim, lenograstim, any other G-CSF in clinical development or any LONQUEX (lipegfilgrastim) excipients.
c. History of congenital neutropenia or cyclic neutropenia.
d. Patients with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation, as determined by medical history, physical examinations, electrocardiogram (ECG), laboratory tests, or imaging.
e. Pregnancy or breast feeding (if a patient becomes pregnant during the study she will be withdrawn from the study).
f. Prior bone marrow or stem cell transplant, or prior radiation to ≥25% of bone marrow (eg, whole pelvic radiation) for any reason, or any therapeutic radiation within the 3 weeks prior to the first dose of study drug (lipegfilgrastim/filgrastim).
g. Major surgery or serious infection within 3weeks before first administration of study drug (lipegfilgrastim/filgrastim), serious trauma or compound medical procedure within the 4 weeks prior to the first study drug dose.
h. Treatment with lithium at screening or planned during the study.
i. Participation in a clinical study within 30 days before randomization.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the duration of severe neutropenia (DSN) in cycle 1, defined as the number of days with severe neutropenia in cycle 1 (from start of CTX until day 15). Severe neutropenia is defined as grade 4 neutropenia, with ANC <0.5 × 10^9/L.

E.5.1.1

Timepoint(s) of evaluation of this end point

Samples for ANC assessments in cycles 1 to 4 will be obtained on day 1 prior to study drug administration, on days 2, 4, 5, 6, 7, 8, 9, 10, 12, and 15 and at EOS/(or ET) visit.

E.5.2

Secondary end point(s)

Secondary Efficacy Variables and Endpoints:
The secondary efficacy endpoints for this study are as follows:
- Incidence of severe neutropenia (ANC <0.5 × 10^9/L) in each cycle (1-4).
- Incidence of very severe neutropenia (ANC <0.1 × 10^9/L) in each cycle (1-4).
- Incidence of febrile neutropenia (FN) (defined as body temperature >38.3°C or 2 consecutive readings higher than 37.8°C measured at axilla or external ear for 2 hours and ANC <0.5 × 10^9/L or expected to fall below 0.5 × 10^9/L) per cycle and across all cycles.
- DSN in cycles 2-4 per cycle.
- Duration of very severe neutropenia in cycles 1-4 per cycle.
Efficacy evaluations will be performed on blood samples taken for the pharmacodynamic assessments in combination with temperature measurements.

Secondary Pharmacodynamic Variables and Endpoints:
- Area under the curve of ANC (AUCANC) until day 15 in cycle 1.
- ANC nadir, ie, the lowest ANC value recorded, per cycle.
- Time to ANC nadir per cycle, defined as the time from start of CTX until occurrence of the ANC nadir in the cycle.
- Time to ANC nadir per cycle, defined as the time from first study drug administration in a cycle until occurrence of the ANC nadir in the cycle.
- Time to ANC recovery (ANC >1.0 × 10^9/L and ANC >2.0 × 10^9/L) from first day of CTX.
- Time to ANC recovery (ANC >1.0 × 10^9/L and ANC >2.0 × 10^9/L) from nadir per cycle.

E.5.2.1

Timepoint(s) of evaluation of this end point

Samples for PD assessments (ANC) in cycles 1 to 4 will be obtained on day 1 prior to study drug administration, on days 2, 4, 5, 6, 7, 8, 9, 10, 12, and 15 and at EOS/(or ET) visit.

Continous tempareture measurements during the days 1-21 of each cycle.

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

Yes

E.6.7

Pharmacodynamic

Yes

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

Yes

E.6.13.1

Other scope of the trial description

tolerability, immunogenicity

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

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

Bulgaria

Czech Republic

Germany

Hungary

Lithuania

Poland

Romania

Russian Federation

Slovakia

Spain

Ukraine

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

LVLS

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

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

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

None

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

2015-06-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-06-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-04-18

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