Clinical Trials Register

Summary
EudraCT Number:	2012-001106-26
Sponsor's Protocol Code Number:	EC11-444-OSTEOSARC
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2012-04-17
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

Spain - AEMPS

A.2

EudraCT number

2012-001106-26

A.3

Full title of the trial

PHASE II MULTICENTRIC AND PROSPECTIVE TRIAL WITH GEMCITABINE AND RAPAMYCIN IN SECOND LINE OF METASTATIC OSTEOSARCOMA

ENSAYO FASE II MULTICENTRICO Y PROSPECTIVO CON GEMCITABINA Y RAPAMICINA EN SEGUNDA LÍNEA DE OSTEOSARCOMA METASTÁSICO

A.3.1

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

TRIAL PHASE II MULTICENTER FOR CANCER PATIENTS DIAGNOSED WITH OSTEOSARCOMA WITH METASTASIS WHO HAVE ALREADY BEEN TREATED PREVIOUSLY

ESTUDIO FASE II MULTICENTRICO PARA PACIENTES DIAGNOSTICADOS DE CANCER TIPO OSTEOSARCOMA CON METASTASIS QUE YA HAN SIDO TRATADOS PREVIAMENTE

A.3.2

Name or abbreviated title of the trial where available

OSTEOSARCOMA METASTASICO PREVIOUSLY TREATED

OSTEOSARCOMA METASTASICO TRATADOS PREVIAMENTE

A.4.1

Sponsor's protocol code number

EC11-444-OSTEOSARC

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	JAVIER MARTÍN BROTO
B.1.3.4	Country	Spain
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	Dirección General de Farmacia y Productos Sanitarios del Ministerio de Sanidad, Política Social e Igualdad
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sofpromed
B.5.2	Functional name of contact point	Patricio Ledesma
B.5.3	Address:
B.5.3.1	Street Address	Rambla dels Ducs, 13-1
B.5.3.2	Town/ city	Palma de Mallorca
B.5.3.3	Post code	07003
B.5.3.4	Country	Spain
B.5.4	Telephone number	34648414261
B.5.5	Fax number	34971570222
B.5.6	E-mail	ensayos@sofpromed.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	GEMCITABINE
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratorio STADA, S.L.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Concentrate and solvent for solution for infusion
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	GEMCITABINE HYDROCHLORIDE
D.3.9.1	CAS number	122111-03-9
D.3.9.4	EV Substance Code	SUB02324MIG
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	200
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.IMP: 2
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	RAPAMUNE
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER LTD.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Oral solution
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	SIROLIMUS
D.3.9.1	CAS number	53123-88-9
D.3.9.4	EV Substance Code	SUB10537MIG
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.3.11 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 diagnosed with metastatic osteosarcoma cancer types that have been treated with chemotherapy and have active disease that permits to receive this treatment combination.

Pacientes diagnosticados de osteosarcoma metastásico que han sido tratados con quimioterapia y tienen enfermedad que permite recibir esta combinación de tratamiento.

E.1.1.1

Medical condition in easily understood language

Patients with metastatic osteosarcoma cancer that have been treated with standard chemotherapy and have active disease requiring treatment.

Pacientes diagnosticados de cáncer tipo osteosarcoma metastásico que han sido tratados y tienen enfermedad activa, necesitando recibir tratamiento para su enfermedad.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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

Analyze progression free survival (PFS), measured as SLP index at 4 months, in patients with metastatic osteosarcoma who have previously received the more active drugs in this disease (methotrexate, cisplatin, adriamycin and ifosfamide) and are in metastatic progression or cannot be operated.

Analizar la supervivencia libre de progresión (SLP), medida como tasa de SLP a los 4 meses, en pacientes con osteosarcoma metastático que han recibido previamente los fármacos más activos en esta enfermedad (metotrexate, cisplatino, adriamicina e ifosfamida) y están en progresión metastática o inoperable.

E.2.2

Secondary objectives of the trial

Analyze the response rate (RECIST) of the study treatment (gemcitabine-rapamycin combination).
Analyze the toxicity of the combination.
Analyze the correlation with predictive biomarkers.
Analyze the impact of the combination in overall survival.

Analizar la tasa de respuesta (RECIST) del tratamiento del estudio (combinación gemcitabina-rapamicina).
Analizar la toxicidad de la combinación.
Analizar la correlación con biomarcadores predictivos.
Analizar el impacto de la combinación en la supervivencia global.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient must willingly sign the informed consent before any trial tests that may not be part of the usual patient care, knowing the patient that he/she can leave the trial when desired, without this affecting the future attention.
2. Age equal or superior to 16 years.
3. Histological diagnosis of high-grade osteosarcoma, metastatic or not operable in progression.
4. Previous treatment with drugs used in first line: Methotrexate, adriamycin, platin. It is not required having received ifosfamide for inclusion. They may have received mifamurtide in first line. Might have received bifosfonates though they will have to be interrupted 1 month before inclusion.
5. Measurable disease, according to RECIST criteria.
6. Functional state 0-2 (ECOG).
7. Baseline medullary function (hemoglobin > 10 g/dL, leukocytes ? 3.000/mm3, RAN? 1,5 x 109 /l, granulocytes ? 1.500/mm3, platelets ? 100.000/mm3). Acceptable patients with alteration of transaminases ? 2.5 times normal limits, bilirubin total ? LSN, CPK? 2.5 times normal limits, alkalyne phosphatase ? 2.5 times more the normal limits or creatinine levels ? 1,6 mg/dL.
8. Patients in fertile age (both male and female) must use an effective contraceptive method before study entry and during the study. Furthermore, women must keep contraceptive measures until 3 months after finishing treatment while men must keep these measures up to 5 months after treatment. Pregnancy must be ruled out by urine test (negative pregnancy test) for inclusion in trial.
9. Normal cardiac functionality, considering the normal ranges of the institution.

1. El paciente debe firmar voluntariamente el consentimiento informado antes de la realización de cualquier prueba del ensayo que no forme parte de la atención habitual de los pacientes, con el conocimiento por parte del paciente que puede abandonar el ensayo en el momento que quiera, sin que se vea perjudicado en ningún momento su atención posterior.
2. Edad igual o superior a 16 años.
3. Diagnóstico histológico de osteosarcoma de alto grado, metastático o no operable en progresión.
4. Tratamiento previo con las drogas usadas en primera línea: Metotrexate, Adriamicina, Platino. No es imperativo que hayan recibido ifosfamida previamente para su inclusión. Pueden haber recibido Mifamurtida en primera línea. Pueden haber recibido bifosfonatos aunque deberá estar suspendidos al menos 1 mes antes de la inclusión.
5. Enfermedad medible, de acuerdo con los criterios RECIST.
6. Estado funcional 0-2 (ECOG).
7. Función medular basal (hemoglobina > 10 g/dL, leucocitos ? 3.000/mm3, RAN? 1,5 x 109 /l, granulocitos ? 1.500/mm3, plaquetas ? 100.000/mm3). Son aceptables pacientes con alteración de las transaminasas ? 2,5 veces los límites normales, bilirrubina total ? LSN, CPK? 2.5 veces los límites normales, Fosfatasa alcalina ? 2,5 veces más los límites normales o cifras de creatinina ? 1,6 mg/dL.
8. Los pacientes en edad fértil (tanto los varones como las mujeres) deben usar un método eficaz anticonceptivo antes de la entrada en el estudio y durante la realización del estudio. Además, las mujeres deben mantener las medidas anticonceptivas hasta 3 meses después de finalizar el tratamiento mientras que los varones deben prolongar estas medidas hasta 5 meses después del tratamiento. Debe descartarse embarazo mediante prueba de orina (test de embarazo negativo) para la inclusión en el estudio.
9. Funcionalidad cardiaca (FEVI) normal, considerando los rangos normales de la institución.

E.4

Principal exclusion criteria

1. Patients having been irradiated in the target lesions.
2. Functional state > 2 (ECOG).
3. Bilirubin levels superior to normal level. Creatinine superior to 1.6 mg/dL.
4. History of other tumor disease except basal-cell carcinoma or carcinoma in situ of cervix adequately treated.
5. Serious cardiovascular diseases (Dyspnea >= 2 NYHA).
6. Systemic pathologies limiting survival to less than 2 years, limiting the availability of the patient, or that may interfere significantly with the treatment toxicity.
7. Infectious diseases: bacterial, viral or mycotic not controlled.
8. Pregnant patients or nurturing.
9. Psychological, familiar, sociological or geographical situations not allowing the fulfilment of the protocol or informed consent.
10. Patients currenly included in another clinical trial or receiving any agent under investigation.
11. Patients having participated in a clinical trial and/or having received an agent in investigation in the 30 days previous to inclusion.

1. Pacientes que hayan sido irradiados en las lesiones diana.
2. Estado funcional > 2 (ECOG).
3. Cifras de bilirrubina superior al nivel normal. Creatinina superior a 1,6 mg/dL.
4. Antecedentes de otra enfermedad neoplasia con excepción de basalioma o carcinoma in situ de cérvix adecuadamente tratados.
5. Enfermedades cardiovasculares graves (Disnea >= 2 NYHA p.ej.).
6. Patologías sistémicas de base que limiten la supervivencia a menos de 2 años, que limiten la disponibilidad del paciente, o que puedan, a juicio clínico, interferir de forma significativa con la toxicidad del tratamiento.
7. Enfermedades infecciosas bacterianas, víricas o micóticas no controladas.
8. Pacientes embarazadas o lactantes.
9. Situaciones psicológicas, familiares, sociológicas o geográficas que no permitan el cumplimiento del protocolo o del consentimiento informado.
10. Pacientes que estén actualmente en otro ensayo clínico o recibiendo cualquier agente en investigación.
11. Pacientes que hayan participado en un ensayo clínico y/o hayan recibido un agente en investigación en los 30 días anteriores a la inclusión.

E.5 End points

E.5.1

Primary end point(s)

Analyze progression-free survival (PFS), measured as SLP index at 4 months, in patients with metastatic osteosarcoma who have previously received the more active drugs in this disease (methotrexate, cisplatin, adriamycin and ifosfamide) and are in metastatic progression or cannot be operated.

E.5.1.1

Timepoint(s) of evaluation of this end point

4 months

4 meses

E.5.2

Secondary end point(s)

1. Analyze the response rate (RECIST) of the study treatment (gemcitabine-rapamycin combination).
2. Analyze the toxicity of the combination.
3. Analyze the correlation with predictive biomarkers.
4. Analyze the impact of the combination in the overall survival.

1. Analizar la tasa de respuesta (RECIST) del tratamiento del estudio (combinación gemcitabina-rapamicina).
2. Analizar la toxicidad de la combinación.
3. Analizar la correlación con biomarcadores predictivos.
4. Analizar el impacto de la combinación en la supervivencia global.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Continuously
2. Continuously
3. At the end of trial
4. Year 3

1. Contínuamente
2. Contínuamente
3. Al final del ensayo
4. Año 3

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)

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)

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

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

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

The end of the trial will take place in the date of the last visit of the last patient included in the study.

El final del ensayo tendrá lugar en la fecha de la última visita del último sujeto reclutado en el estudio.

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

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)

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)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

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)

It is not different from expected normal treatment of the condition.

No es diferente al tratamiento normal esperado.

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

2012-07-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-06-06

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

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