Clinical Trials Register

Summary
EudraCT Number:	2017-004814-24
Sponsor's Protocol Code Number:	17SARC04
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-01-15
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

France - ANSM

A.2

EudraCT number

2017-004814-24

A.3

Full title of the trial

Pharmacologic interaction between Ifosfamide and Aprepitant in treated patients with soft tissue sarcoma.

Interaction Pharmacologique entre Ifosfamide et APrépitant chez les patients traités pour un sarcome des tissus mous.

A.3.1

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

Pharmacologic interaction between Ifosfamide and Aprepitant in treated patients with soft tissue sarcoma.

Interaction Pharmacologique entre Ifosfamide et APrépitant chez les patients traités pour un sarcome des tissus mous.

A.3.2

Name or abbreviated title of the trial where available

IPIAP-STM Study

Etude IPIAP-STM

A.4.1

Sponsor's protocol code number

17SARC04

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	INSTITUT CLAUDIUS REGAUD
B.1.3.4	Country	France
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	INSTITUT CLAUDIUS REGAUD
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	INSTITUT UNIVERSITAIRE DU CANCER TOULOUSE - ONCOPOLE
B.5.2	Functional name of contact point	Coordinating Investigator
B.5.3	Address:
B.5.3.1	Street Address	IUCT-O - 1, avenue Irène Joliot-Curie
B.5.3.2	Town/ city	TOULOUSE Cedex 09
B.5.3.3	Post code	31059
B.5.3.4	Country	France
B.5.4	Telephone number	+33 531 15 51 51
B.5.5	Fax number	+33 531 15 58 96
B.5.6	E-mail	valentin.thibaud@iuct-oncopole.fr

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	IFOSFAMIDE EG
D.2.1.1.2	Name of the Marketing Authorisation holder	EG Labo
D.2.1.2	Country which granted the Marketing Authorisation	France
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	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	IFOSFAMIDE
D.3.9.1	CAS number	3778-73-2
D.3.9.4	EV Substance Code	SUB08125MIG
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	DOXORUBICINE (All generics can be used)
D.2.1.2	Country which granted the Marketing Authorisation	France
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	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	DOXORUBICIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB01827MIG
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: 3
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	EMEND
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Capsule
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	APREPITANT
D.3.9.3	Other descriptive name	APREPITANT
D.3.9.4	EV Substance Code	SUB20017
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

Soft tissue sarcoma (localized, local recidive or metastatic)

Sarcome des Tissus Mous (localisé, en récidive locale ou métastatique)

E.1.1.1

Medical condition in easily understood language

Soft tissue sarcoma (localized, local recidive or metastatic)

Sarcome des Tissus Mous (localisé, en récidive locale ou métastatique)

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10075333
E.1.2	Term	Soft tissue sarcoma
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

The main objective of this study is to show that in patients treated with the association doxorubicin and Ifosfamide for an STM, the plasma concentrations of 2d-Ifo are increased by the co-administration of Aprepitant.

L’objectif principal de cette étude est de montrer que chez les patients traités par l’association doxorubicine et ifosfamide pour un STM, les concentrations plasmatiques de 2d-Ifo sont augmentées par la co-administration d’aprépitant.

E.2.2

Secondary objectives of the trial

The secondary objectives are the following:
• Compare the frequency and intensity of adverse events (according to CTCAE v 4.03) occurring in patients exposed to Aprepitant to those occurring in unexposed patients
• Compare the plasma concentrations of ifosfamide and its serum metabolites (4OH-IFO, 2d-IFO, 3d-Ifo, CAA) of patients co-exposed to Aprepitant, to those of patients not exposed to this molecule
• Assess the impact of co-medications on the occurrence of adverse events
• Assess the impact of serum albumin on the occurrence of adverse events
• Assess the rate of objective responses (if applicable)
• Perform an analysis of population pharmacokinetics including all data (cycle 1 and Cycle 2) by evaluating the impact of the Covariate "co-administration Aprepitant ".

Les objectifs secondaires sont les suivants :
• Comparer la fréquence et l’intensité des événements indésirables (selon le CTCAE V4.03) survenant chez les patients exposés à l’aprépitant à ceux survenant chez les patients non exposés
• Comparer les concentrations plasmatiques de l’ifosfamide et de ses métabolites sériques (4OH-Ifo, 2d-Ifo, 3d-Ifo, CAA) des patients co-exposés à l’aprépitant, à ceux des patients non exposés à cette molécule
• Évaluer l’impact des co-médications sur la survenue d’effets indésirables
• Évaluer l’impact du taux d’albumine sérique sur la survenue d’effets indésirables
• Évaluer le taux de réponses objectives (si applicable)
• Réaliser une analyse de pharmacocinétique de population intégrant l’ensemble des données (cycle 1 et cycle 2) en évaluant l’impact de la covariable « co-administration aprépitant ».

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age > 18 years.
2. Anatomopathologic diagnosis of soft tissue sarcoma (localized, local recidive or metastatic).
3. Patient receiving doxorubicin and ifosfamide chemotherapy (treatment decided during Multidisciplinary consultation meetings) (neoadjuvant, adjuvant or palliative treatment).
4. Screening laboratory values must meet the following criteria:
a) Hemoglobin > 9.0 g/dL, Neutrophils > 1500/mm3, Platelets > 100000/mm3
b) Creatinine clearance (MDRD formula) > 60ml/min.
c) AST/ALT < 2.5 x ULN (5 x ULN in patients with hepatic metastasis).
5. Evaluable disease (measurable per RECIST or not), if applicable.
6. Patient must provide written informed consent prior to any study specific procedures.
7. Patient affiliated to a Social Health Insurance in France.

1. Age ≥ 18 ans
2. Diagnostic anatomopathologique de Sarcome des Tissus Mous (localisé, en récidive locale ou métastatique)
3. Patient devant recevoir une chimiothérapie par doxorubicine et ifosfamide proposée en RCP (traitement néo-adjuvant, adjuvant ou palliatif)
4. Fonctions d’organe adéquates définies comme suivant :
a) Hémoglobine > 9g/dl, Polynucléaires neutrophiles >1500/mm3, Plaquettes >100000/mm3
b) Clairance de la créatinine (formule MDRD) > 60ml/min
c) ASAT et ALAT < 2,5N (5N en cas de métastases hépatiques)
5. Maladie évaluable (mesurable selon RECIST ou non), si applicable
6. Signature du consentement éclairé par le patient avant l’inclusion dans l’étude et avant toute procédure spécifique pour l’étude
7. Patient affilié à un régime de Sécurité Sociale en France

E.4

Principal exclusion criteria

1. Previous treatment with Ifosfamide.
2. Patient who has already started doxorubicin and ifosfamide treatment.
3. Any medical condition that can increase the patient's risk
a. Active infection
b. Active hepatitis or cirrhosis
c. Recipients of organ transplants or immunocompromised patients, including Human Immunodeficiency Virus (HIV) infection
4. Pregnant or breastfeeding women
5. Any psychological, familial, geographical or sociological condition which does not allow to respect the medical follow-up and/or compliance to study procedure
6. Patient protected by law

1. Traitement antérieur par ifosfamide
2. Patient ayant déjà débuté son traitement par ifosfamide et doxorubicine
3. Toute affection médicale pouvant augmenter le risque pour le patient
a) Infection active
b) Hépatite active ou cirrhose
c) Patient porteur d’une greffe d’organe ou immunodéprimé, y compris infection par le virus du VIH
4. Patiente enceinte ou allaitante
5. Toute condition psychologique, familiale, géographique ou sociologique ne permettant pas de respecter le suivi médical et/ou les procédures prévues dans le protocole de l'étude
6. Patient protégé par la loi

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the evolution of 2d-Ifo plasma concentrations between the 1st cycle (without co-exposure to the Aprepitant) and the 2nd cycle (with co-exposure to the Aprepitant).

Le critère de jugement principal est l’évolution des concentrations plasmatiques de 2d-Ifo entre le 1er cycle (sans co-exposition à l’aprépitant) et le 2nd cycle (avec co-exposition à l’aprépitant).

E.5.1.1

Timepoint(s) of evaluation of this end point

Cycle 2 Day 3

Cycle 2 Jour 3

E.5.2

Secondary end point(s)

The secondary endpoints are:
- Toxicity is assessed according to the NCI-CTC version 4.03
- The evolution of plasma concentrations of ifosfamide and its serum metabolites (4OH-IFO, 2d-IFO, 3d-Ifo, CAA) between the first and second cycles.
- In case of an evaluable disease, the rate of objective responses will be determined according to the criteria RECIST v 1.1 (if applicable). An objective response is defined by a complete or partial response.

- La toxicité est évaluée selon l’échelle NCI-CTC version 4.03 (Annexe 2)
- L’évolution des concentrations plasmatiques de l’ifosfamide et de ses métabolites sériques (4OH-Ifo, 2d-Ifo, 3d-Ifo, CAA) entre le premier et le deuxième cycle.
- En cas de maladie évaluable, le taux de réponses objectives sera défini selon les critères RECIST v1.1 (si applicable). Une réponse objective est définie par une réponse complète ou partielle.

E.5.2.1

Timepoint(s) of evaluation of this end point

Cycle 3 Day 1

Cycle 3 Jour 1

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

E.6.4

Safety

Yes

E.6.5

Efficacy

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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.8.3

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

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

Dernière visite de suivi du dernier patient inclus.

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.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

2018-02-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-19

P. End of Trial
P.	End of Trial Status	Completed

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