Clinical Trials Register

Summary
EudraCT Number:	2018-004045-16
Sponsor's Protocol Code Number:	ET18-272
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-01-23
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

2018-004045-16

A.3

Full title of the trial

REGOSTA – A randomized, placebo-controlled, double-blinded, multicentre study evaluating the efficacy and safety of regorafenib as maintenance therapy after first-line treatment in patients with bone sarcomas

REGOSTA – Essai randomisé, contrôlé contre placebo, en double aveugle, multicentrique évaluant l’efficacité et la tolérance du regorafenib en maintenance après la première ligne de traitement chez des patients présentant des sarcomes osseux

A.3.1

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

Study evaluating the efficacy and safety of regorafenib as maintenance therapy after first-line treatment in patients with bone sarcomas

Essai évaluant l’efficacité et la tolérance du regorafenib en maintenance après la première ligne de traitement chez des patients présentant des sarcomes osseux

A.3.2

Name or abbreviated title of the trial where available

REGOSTA

A.4.1

Sponsor's protocol code number

ET18-272

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	Centre Léon Bérard
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	Bayer AG
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	Centre Léon Bérard
B.5.2	Functional name of contact point	DRCI
B.5.3	Address:
B.5.3.1	Street Address	28 rue Laennec
B.5.3.2	Town/ city	LYON Cedex 08
B.5.3.3	Post code	69378
B.5.3.4	Country	France
B.5.4	Telephone number	+33426 55 68 29
B.5.5	Fax number	+33478 78 27 15
B.5.6	E-mail	julien.gautier@lyon.unicancer.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	Stivarga
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Regorafenib
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with bone sarcomas other than Ewing sarcoma or chondrosarcoma or chordoma, who have no residual disease after neoadjuvant chemotherapy, surgery and/or adjuvant chemotherapy.

Patient présentant un sarcome osseux autre que sarcome d’Ewing ou chondrosarcome ou chordome, et ne présentant pas de maladie résiduelle après la chimiothérapie néoadjuvante, chirurgie et/ou chimiothérapie adjuvante.

E.1.1.1

Medical condition in easily understood language

Patients with bone sarcomas.

Patient présentant un sarcome .

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

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

The primary objective is to compare the antitumor efficacy of regorafenib versus placebo as maintenance treatment in patients with bone sarcomas.

Comparer l’efficacité anti-tumorale du regorafenib versus placebo en traitement de maintenance chez des patients présentant un sarcome osseux.

E.2.2

Secondary objectives of the trial

• The Time to Treatment Failure (TTF),
• The Overall Survival,
• The Quality of Life (EORTC QLQ-C30),
• The tolerance profile (NCI-CTC AE version 5),
• Compliance to study treatment

• Le temps à échec du traitement (TTF),
• Survie totale,
• Qualité de vie (questionnaire EORTC QLQ-C30),
• Profil de tolérance (NCI-CTC AE version 5),
• Compliance au traitement de l’étude.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

I1. Age ≥ 16 years at the day of consenting to the study;
I2. Patients must have histologically confirmed diagnosis of primary bone sarcoma of one of the following histotypes:
• Osteosarcomas (conventional-intramedullary/central high grade, small cell, telangiectatic or high-grade surface osteosarcomas);
• Bone sarcomas other than Ewing sarcoma, chondrosarcoma and chordoma.
I3. Availability of archival Formalin-Fixed Paraffin Embedded (FFPE) block.
I4. Prior treatment for localized or metastatic disease for bone sarcoma must have been completed. It should include:
• Neoadjuvant chemotherapy with documented assessment of histological response,
• Local procedure: Surgery (or radiotherapy if tumour is unresectable)
• Adjuvant chemotherapy (Nota Bene: patients with histotype different from osteosarcoma may not have received adjuvant treatment).
For OS, (excepted head and neck localisations), neoadjuvant and/or adjuvant chemotherapy should include methotrexate-based regimen for patients < 18 years old or anthracycline and cisplatin-based regimen for patients ≥ 18 years old.
For head and neck OS, neoadjuvant and adjuvant chemotherapy should include adriamycin, cisplatin or ifosfamide-based regimen.
For non-OS, neoadjuvant and/or adjuvant chemotherapy should include adriamycine and/or cisplatine-based regimen.
I5. Recovery to NCI-CTCAE v5 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure related toxicity (except alopecia, anaemia, and hypothyroidism);
I6. Interval between the last chemotherapy administration and the date of randomisation: at least 4 weeks but no longer than 2 months;
...See the protocol

I1. Age ≥ 16 ans le jour d’obtention du consentement éclairé du patient
I2. Patient ayant un diagnostic de sarcome osseux primaire histologiquement confirmé de type :
• Ostéosarcome conventionnel, ostéosarcome intramédullaire/central de haut grade, ostéosarcome télangiectasique, ostéoarcome à cellules rondes ou ostéosarcome de surface de haut grade ;
• Sarcome osseux autre que sarcome d’Ewing, chondrosarcome et chordome
I3. Disponibilité de tissu tumoral fixé au formol et inclus en paraffine
I4. Traitement antérieur du sarcome osseux terminé, en situation localisée ou métastatique incluant :
• Chimiothérapie néoadjuvante avec réponse histologique documentée,
• Procédure locale : Chirurgie (ou radiothérapie si tumeur non résécable),
• Chimiothérapie adjuvante (NB : les patients présentant un type histologique autre qu’un ostéosarcome peuvent ne pas avoir reçu de traitement adjuvant).
Pour les ostéosarcomes, à l’exception des ostéosarcomes de la tête et du cou, la chimiothérapie néoadjuvante et/ou adjuvante doit avoir comporté du méthotrexate pour les patients < 18 ans ou des anthracyclines et du cisplatine pour les patients ≥ 18 ans.
Pour les ostéosarcomes de la tête et du cou, la chimiothérapie néoadjuvante et/ou adjuvante doit avoir comporté de l’adrimaycine, du cisplatine ou de l’ifosfamide.
Pour les non-ostéosarcomes : la chimiothérapie néoadjuvante et/ou adjuvante doit avoir comporté de l’adriamycine et du cisplatine.
I5. Retour à un grade 0 ou 1 de la classification NCI-CTCAE v5 ou retour à l’état initial avant le dernier traitement ou la dernière procédure (à l’exception de l’alopécie, l’anémie et l’hypothyroïdie)
I6. Intervalle entre la dernière chimiothérapie et la date de randomisation : Au minimum 4 semaines, au maximum 2 mois
...Voir le protocole

E.4

Principal exclusion criteria

E1. Prior treatment with any VEGFR inhibitor (thus, any prior exposure to sunitinib, sorafenib, pazopanib, bevacizumab, or other VEGFR inhibitor);
E2. All soft tissue sarcomas (including but not limited to soft tissue osteosarcoma and Ewing soft tissue sarcoma), and Ewing sarcoma, chondrosarcoma and chordoma;
E3. Prior history of other malignancies other than study disease (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) within 3 years prior to randomization;
E4. Cardiovascular dysfunction:
• Left ventricular ejection fraction (LVEF) < 50%,
• Congestive heart failure ≥ New York Heart Association (NYHA) class 2,
• Myocardial infarction < 6 months prior to first study drug administration,
• Cardiac arrhythmias requiring therapy (beta blockers or digoxin are permitted),
• Unstable (angina symptoms at rest) or new-onset angina within the last 3 months prior to first study drug administration;
E5. Uncontrolled hypertension (systolic blood pressure > 150mmHg or diastolic pressure > 90 mmHg despite optimal treatment);
E6. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the last 6 months before the first study drug administration;
...See the protocol

E1. Traitement antérieur avec un inhibiteur du VEGFR (sunitinib, sorafenib, pazopanib, bevacizumab ou tout autre inhibiteur du VEGFR)
E2. Tout sarcome des tissus mous (incluant mais non limités aux ostéosarcomes des tissus mous et Ewing des tissus mous), sarcome d’Ewing, chondrosarcome et chordome
E3. Antécédents de tumeurs malignes autres que celle de l’étude (à l’exception des carcinomes basocellulaires ou épidermoïdes ou carcinome in situ du col utérin) durant les 3 ans précédant la randomisation
E4. Trouble cardiovasculaire :
• Fraction d’éjection ventriculaire gauche (FEVG) < 50%
• Insuffisance cardiaque ≥ classe 2 de la classification “New York Heart Association (NYHA)”
• Infarctus du myocarde < 6 mois précédant la première administration du traitement
• Arythmie cardiaque nécessitant un traitement (les bêtabloquants ou la digoxine sont autorisés)
• Angor instable (symptomatique au repos) ou angor nouvellement diagnostiqué dans les 3 mois précédant l’administration du traitement
E5. Hypertension non contrôlée (PAS > 150mmHg ou PAD > 90 mmHg malgré un traitement optimal)
E6. Evénements thromboemboliques ou artériels tels que AVC (incluant les AVC ischémiques transitoires), thrombose veineuse profonde ou embolie pulmonaire durant les 6 derniers mois précédant la première administration du traitement à l’étude ;
...Voir le protocole

E.5 End points

E.5.1

Primary end point(s)

the Relapse-Free Survival (RFS).

la survie sans rechute (RFS).

E.5.1.1

Timepoint(s) of evaluation of this end point

assessment according to the RECISTv1.1.

évaluation selon les RECIST v1.1.

E.5.2

Secondary end point(s)

• the Time to Treatment Failure (TTF),
• the Overall Survival,
• the Quality of Life (EORTC QLQ-C30),
• the tolerance profile (NCI-CTC AE version 5).

• Le temps à échec du traitement (TTF),
• Survie totale (OS),
• Qualité de vie (questionnaire EORTC QLQ-C30),
• Profil de tolérance (NCI-CTC AE version 5),

E.5.2.1

Timepoint(s) of evaluation of this end point

• Throughout the study
• Each tumor assessment

• Tout au long de l'étude
• Evaluation de chaque tumeur

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

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

LVLS

dernière visite 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 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

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

168

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)

Patients will receive regorafenib or its matching placebo as maintenance therapy for a maximum of 12 months, or until disease recurrence, unacceptable toxicity or willingness to stop, whichever occurs first.
After the completion of the maintenance therapy, all the patients will be followed until disease recurrence or end of the study. If recurrence occurs before the study termination, patients will then be followed up for the subsequent antineoplastic treatments...

Les patients recevront un traitement de maintenance par regorafenib ou placebo pendant au maximum 12 mois ou jusqu’à récidive, toxicité inacceptable ou retrait de l’étude, selon le premier événement survenu.
A l’issue du traitement de maintenance, tous les patients entreront dans une période de surveillance jusqu’à la rechute ou la fin de l’étude. Si la rechute intervient avant la fin de l’étude, les patients seront alors suivis pour les traitements néoplasiques ultérieurs...

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Groupe Sarcome Français (GSF)
G.4.3.4	Network Country	France

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-03-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-26

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

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