Clinical Trials Register

Summary
EudraCT Number:	2014-000999-26
Sponsor's Protocol Code Number:	13-006
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-07-22
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

Spain - AEMPS

A.2

EudraCT number

2014-000999-26

A.3

Full title of the trial

An Open-Label, Single-Arm, Multicenter Pharmacokinetic Study of Intramuscular Erwinaze® (asparaginase Erwinia chrysanthemi)/Erwinase® (crisantaspase) Administered Following Hypersensitivity to E. coli Asparaginase in Young Adults with Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

Estudio farmacocinético multicéntrico, sin enmascaramiento y con un solo grupo de tratamiento, de Erwinaze® (asparaginasa de Erwinia chrysanthemi)/Erwinase® (crisantaspasa), administrados por vía intramuscular tras la aparición de hipersensibilidad a asparaginasa de E. coli en adultos jóvenes con leucemia linfoblástica aguda o linfoma linfoblástico

A.3.1

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

An open label, single arm, multicenter pharmacokinetic study designed to investigate the serum asparaginase activity associated with the administration of Erwinase dosed intramuscularly in young adult subjects diagnosed with Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL) with a documented hypersensitivity reaction to native E.coli Asparginase

Estudio farmacocinético multicéntrico, sin enmascaramiento y con un solo grupo de tratamiento diseñado para investigar la actividad de la asparaginasa sérica asociada a la administración de Erwinase por vía intramuscular en pacientes adultos jóvenes con diagnóstico de leucemia linfoblástica aguda (LLA) o linfoma linfoblástico (LL) que hayan presentado una reacción de hipersensibilidad documentada a la asparaginasa nativa de E. coli

A.4.1

Sponsor's protocol code number

13-006

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02150928

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	Jazz Pharmaceuticals, Inc.
B.1.3.4	Country	United States
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	Jazz Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Jazz Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Bengt Bergstrom
B.5.3	Address:
B.5.3.1	Street Address	3180 Porter Drive
B.5.3.2	Town/ city	Palo Alto
B.5.3.3	Post code	CA 94304
B.5.3.4	Country	United States
B.5.4	Telephone number	+3493547 5533
B.5.5	Fax number	+1650 4962871
B.5.6	E-mail	bengt.bergstrom@jazzpharma.com

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	Erwinase
D.2.1.1.2	Name of the Marketing Authorisation holder	EUSA Pharma SAS
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	Erwinase
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	crisantaspase
D.3.9.1	CAS number	1349719-22-7
D.3.9.3	Other descriptive name	CRISANTASPASE
D.3.9.4	EV Substance Code	SUB33789
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10000
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	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

1) Acute Lymphoblastic Leukemia
2) Lymphoblastic Lymphoma

1) Leucemia linfoblástica aguda (LLA)
2) Linfoma linfoblástico (LL)

E.1.1.1

Medical condition in easily understood language

1) Acute Lymphoblastic Leukemia (form of blood cancer characterised by excess of immature white blood cells), 2) Lymphoblastic Lymphoma (form of blood cancer, result of abnormal adaptive immune cells)

1) LLA (tipo de cáncer de la sangre caracterizado por un exceso de glóbulos blancos inmaduros), 2) LL (tipo de cáncer de la sangre, resultado de una adaptación anormal de las células inmunitarias)

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10000845
E.1.2	Term	Acute lymphoblastic leukemia
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	HLT
E.1.2	Classification code	10036544
E.1.2	Term	Precursor T-lymphoblastic lymphomas/leukaemias
E.1.2	System Organ Class	100000004851

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	HLT
E.1.2	Classification code	10036524
E.1.2	Term	Precursor B-lymphoblastic lymphomas
E.1.2	System Organ Class	100000004851

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the proportion of subjects with 2-day nadir serum asparaginase activity (NSAA) levels (48-hour levels taken after the 5th dose) that are ? 0.1 IU/mL in the first 2 consecutive weeks of Erwinase treatment

Determinar la proporción de sujetos con niveles mínimos de actividad de la asparaginasa sérica (NMAS) > 0,1 UI/ml a los 2 días (los niveles a las 48 horas se determinarán después de administrar la 5.ª dosis) durante las 2 primeras semanas consecutivas de tratamiento con Erwinase.

E.2.2

Secondary objectives of the trial

To determine the proportion of subjects with 3-day NSAA levels (72-hour levels taken after the 6th dose) that are ? 0.1 IU/mL in the first 2 consecutive weeks of Erwinase treatment.
? To describe the NSAA over time following repeated administration of Erwinase
? To evaluate the safety of Erwinase in young adult subjects as follows:
- To describe the incidence and severity of asparaginase-related toxicities
- To measure the presence of anti-Erwinase antibodies and neutralizing antibody responses

? Determinar la proporción de sujetos con NMAS a los 3 días > 0,1 UI/ml (los niveles a las 72 horas se determinarán después de administrar la 6.ª dosis) durante las 2 primeras semanas consecutivas de tratamiento con Erwinase.
? Describir el NMAS a lo largo del tiempo tras la administración repetida de Erwinase
? Evaluar la seguridad de Erwinase en los adultos jóvenes, de la siguiente forma:
- Describir la incidencia y la intensidad de las toxicidades relacionadas con la asparaginasa
- Determinar la presencia de anticuerpos anti-Erwinase y las respuestas a los anticuerpos neutralizantes

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Have a diagnosis of ALL or LBL
2. Be 18 to <40 years of age at the time of enrollment
3. Have a documented ? Grade 2 clinical hypersensitivity reaction to native E. coli asparaginase (e.g., Elspar or Kidrolase) or pegaspargase (Oncaspar)
4. Have the following asparaginase doses remaining in their treatment plan:
- At least two (2) consecutive weeks of native E. coli asparaginase treatment OR
- At least one (1) dose of pegaspargase (Oncaspar)
5. Have a direct bilirubin ? Grade 2 (<3.0 mg/dL [52 ?mol/L])
6. Have amylase and lipase within normal limits (per institutional standards)
7. Have a serum asparaginase activity below the detectable limit during screening prior to the first dose of study drug (Erwinase)
8. Consent to use a medically acceptable method of contraception throughout the entire study period and for 4 weeks after the study is completed. Medically acceptable methods of contraception that may be used by the subject and/or the partner include abstinence, birth control pills or patches, diaphragm and spermicide, condom and vaginal spermicide, surgical sterilization, postmenopausal, vasectomy (>6 months prior to baseline), and progestin implant or injection.
9. Have signed informed consent

1. Haber recibido el diagnóstico de LLA o LL
2. Edad entre 18 y < 40 años en el momento de la inclusión en el estudio
3. Haber presentado una reacción de hipersensibilidad clínicamente documentada > grado 2 a la asparaginasa de E. coli nativa (por ejemplo, Elspar o Kidrolase) o a la pegaspargasa (Oncaspar)
4.Tener las siguientes administraciones de asparaginasa pendientes en su plan de tratamiento:
- Dos (2) semanas consecutiva, como mínimo, de tratamiento con asparaginasa nativa de E. coli, O BIEN
- Una (1) administración, como mínimo, de pegaspargasa (Oncaspar)
5. Presentar un valor de bilirrubina directa ? grado 2 (< 3,0 mg/dl [52 ?mol/l])
6. Presentar unos valores de amilasa y lipasa dentro de los límites de normalidad (de acuerdo con los valores de referencia del centro)
7. Presentar una actividad de la asparaginasa sérica por debajo de los límites detectables durante la selección previa a la primera administración del fármaco del estudio (Erwinase)
8. Estar de acuerdo en utilizar un método anticonceptivo médicamente aceptable durante todo el período del estudio, así como durante las 4 semanas posteriores a la finalización del mismo. Los métodos anticonceptivos médicamente aceptables que el sujeto o su pareja pueden emplear son: abstinencia completa, anticonceptivos orales o en parches, diafragma junto con espermicidas, preservativo junto con espermicidas vaginales, esterilización quirúrgica, posmenopausia, vasectomía (practicada con más de 6 meses de anterioridad respecto al inicio del estudio) y los implantes o inyecciones de progesterona.
9. Haber firmado el documento de consentimiento informado

E.4

Principal exclusion criteria

1. Prior history of ?Grade 3 pancreatitis
2. Prior history of a major thrombotic event as assessed by the investigator, or any subject with a history of asparaginase-associated serious hemorrhagic or thrombotic event requiring prolonged anticoagulation therapy with agents such as heparin
3. Prior treatment with Erwinase
4. Pregnant or lactating female subjects or female subjects of childbearing potential not willing to use an adequate method of birth control (listed above) for the duration of the study
5. Subjects with a history of human immunodeficiency virus (HIV) or hepatitis.
6. Any other condition that would cause a risk (in the investigator?s judgment) to subjects if they participate in the trial

1. Antecedentes de pancreatitis ? grado 3
2. Antecedentes de episodios tromboembólicos importantes (según la evaluación del investigador) o de cualquier episodio hemorrágico o tromboembólico grave asociado a la asparaginasa que haya requerido anticoagulación prolongada con fármacos como la heparina
3. Tratamiento previo con Erwinase
4. Mujeres embarazadas o en período de lactancia, así como las mujeres en edad fértil que no deseen utilizar un método anticonceptivo adecuado (de los anteriormente mencionados) durante la totalidad del estudio
5. Sujetos con antecedentes de infección por el virus de la inmunodeficiencia humana (VIH) o de hepatitis.
6. Cualquier otra patología que pudiese suponer un riesgo (a criterio del investigador) para los sujetos en caso de participar en el ensayo

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is the proportion of subjects with 2-day NSAA levels (measured 48 hours after the 5th dose) that are ? 0.1 IU/mL in the first 2 consecutive weeks of Erwinase treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

at 48 hours after the 5th dose

a las 48 horas después de administrar la 5.ª dosis

E.5.2

Secondary end point(s)

- Proportion of subjects with 3-day NSAA levels (72 hour levels taken after the 6th dose) that are ? 0.1 IU/mL in the first 2 consecutive weeks of Erwinase treatment
- NSAA levels over time following repeated administration of Erwinase

- Determinar la proporción de sujetos con NMAS a los 3 días > 0,1 UI/ml (los niveles a las 72 horas se determinarán después de administrar la 6.ª dosis) durante las 2 primeras semanas consecutivas de tratamiento con Erwinase.
- Describir el NMAS a lo largo del tiempo tras la administración repetida de Erwinase

E.5.2.1

Timepoint(s) of evaluation of this end point

at 72 hours taken after the 6th dose

a las 72 horas después de administrar la 6.ª dosis

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

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

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

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

Poland

Spain

United States

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

Última visita del último paciente

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:

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

ninguno

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

2014-09-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-09-05

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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