Clinical Trials Register

Summary
EudraCT Number:	2018-000515-24
Sponsor's Protocol Code Number:	RG_17-247
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:
Date on which this record was first entered in the EudraCT database:	2021-09-23
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-000515-24

A.3

Full title of the trial

An overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma

Uno studio globale su bambini e adulti con RabdoMioSarcoma frontline e recidivante

A.3.1

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

An overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma

Uno studio globale su bambini e adulti con RhabdoMyoSarcoma frontline e recidivante

A.3.2

Name or abbreviated title of the trial where available

FaR-RMS

A.4.1

Sponsor's protocol code number

RG_17-247

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	UNIVERSITY OF BIRMINGHAM
B.1.3.4	Country	United Kingdom
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	The University of Birmingham
B.5.2	Functional name of contact point	Louise Moeller
B.5.3	Address:
B.5.3.1	Street Address	University of Birmingham, Edgbaston
B.5.3.2	Town/ city	Birmingham
B.5.3.3	Post code	B15 2TT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01214142996
B.5.5	Fax number	01214142996
B.5.6	E-mail	farrms@trials.bham.ac.uk

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.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Ciclofosfamide
D.3.2	Product code	[Ciclofosfamide]
D.3.4	Pharmaceutical form	Powder for solution for injection/infusion
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	CICLOFOSFAMIDE
D.3.9.1	CAS number	50-18-0
D.3.9.2	Current sponsor code	ciclofosfamide
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	20
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Irinotecan
D.3.2	Product code	[Irinotecan]
D.3.4	Pharmaceutical form	Concentrate for solution for injection/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	IRINOTECAN CLORIDRATO TRIIDRATO
D.3.9.1	CAS number	97682-44-5
D.3.9.2	Current sponsor code	Irinotecan
D.3.10	Strength
D.3.10.1	Concentration unit	mg/l milligram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Vinorelbina
D.3.2	Product code	[Vinorelbina]
D.3.4	Pharmaceutical form	Concentrate for solution for injection/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	VINORELBINA
D.3.9.1	CAS number	71486-22-1
D.3.9.2	Current sponsor code	vinorelbina
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	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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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: 4
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Vinorelbina
D.3.2	Product code	[Vinorelbina]
D.3.4	Pharmaceutical form	Tablet
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	VINORELBINA
D.3.9.2	Current sponsor code	vinorelbina
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 30
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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: 5
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Ciclofosfamide
D.3.2	Product code	[Ciclofosfamide]
D.3.4	Pharmaceutical form	Powder for solution for injection/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	CICLOFOSFAMIDE
D.3.9.1	CAS number	50-18-8
D.3.9.2	Current sponsor code	ciclofosfamide
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	20
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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: 6
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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	ciclofosfamide
D.3.2	Product code	[ciclofosfamide]
D.3.4	Pharmaceutical form	Capsule, hard
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	CICLOFOSFAMIDE
D.3.9.1	CAS number	50-18-0
D.3.9.2	Current sponsor code	ciclofosfamide
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	50
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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: 7
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.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Temozolomide
D.3.2	Product code	[Temozolomide]
D.3.4	Pharmaceutical form	Capsule, hard
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	TEMOZOLOMIDE
D.3.9.1	CAS number	85622-93-1
D.3.9.2	Current sponsor code	temozolomide
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20 to 100
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Rhabdomyosarcoma

Rabdomiosarcoma

E.1.1.1

Medical condition in easily understood language

Rhabdomyosarcoma: cancer of soft tissue (such as muscle), connective tissue (such as tendon or cartilage), or bone

Rabdomiosarcoma: cancro dei tessuti molli (come i muscoli), del tessuto connettivo (come i tendini o la cartilagine) o le ossa

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

Determine recommended Phase II (RP2D) dose of new systemic therapy regimens. Compare systemic therapy regimes for patients with VHR disease to diagnosis (CT1A). Compare new systemic therapy regimens with standard chemotherapy for patients with HR disease at diagnosis (CT1B). Determining whether standard preoperative or post-operative radiotherapy is better for patients with resecatable disease (RT1A),Determining whether increased radiotherapy dose improves outcome in patients with higher local failure risk (RT1B/C),Determine whether radiotherapy treatment of all disease sites, compared to primary site radiotherapy treatment, improves outcome for patients with unfavorable metastatic disease (RT2). Determining whether adding an additional 12 cycles of vinorelbine and cyclophosphamide (VnC) to 12 standard cycles of maintenance chemotherapy (i.e. 24 cycles in total) improves outcome for patients with VHR disease at diagnosis (CT2A)

Determinare dose raccomandata di fase II (RP2D) di nuovi regimi di terapia sistemica.Confrontare regimi terapia sistemica per pazienti con malattia VHR alla diagnosi (CT1A).Confrontare nuovi regimi terapia sistemica con chemioterapia standard per pazienti con malattia HR alla diagnosi (CT1B).Determinare se radioterapia preoperatoria o post-operatoria standard è migliore per pazienti con malattia resecabile (RT1A),Determinare se aumento dose radioterapia migliora risultato nei pazienti con rischio di fallimento locale più elevato (RT1B / C),Determinare se trattamento radioterapico di tutti i siti malattia, rispetto a trattamento radioterapico del sito primario, migliora l'esito per pazienti con malattia metastatica sfavorevole (RT2).Determinare se l'aggiunta di ulteriori 12 cicli di vinorelbina e ciclofosfamide (VnC) a 12 cicli standard di chemioterapia di mantenimento (cioè 24 cicli in totale) migliora l'esito per i pazienti con malattia VHR alla diagnosi (CT2A)

E.2.2

Secondary objectives of the trial

The secondary objectives for this trial are:

•To validate whether the use of fusion status (PAX3/PAX7-FOXO1) in place of histopathological diagnosis improves risk stratification
•To determine whether assessment of fusion status is necessary in tumours classified as Embryonal Rhabdomyosarcoma by histopathology
•To determine whether immunohistochemistry assessment for protein expression driven by the fusion protein is an accurate surrogate for fusion status
•To determine whether FDG PET- CT response assessment following induction chemotherapy is a prognostic biomarker for local failure and/ or survival.

Gli obiettivi secondari di questa sperimentazione sono:

• Verificare se l'uso dello stato di fusione (PAX3 / PAX7-FOXO1) al posto della diagnosi istopatologica migliora la stratificazione del rischio
• Verificare se la valutazione dello stato di fusione è necessaria nei tumori classificati come rabdomiosarcoma embrionale dall'istopatologia
• Determinare se la valutazione immunoistochimica per l'espressione proteica guidata dalla proteina di fusione è un accurato surrogato dello stato di fusione
• Determinare se la valutazione della risposta PET-CT FDG dopo la chemioterapia di induzione sia un biomarcatore prognostico di fallimento locale e / o sopravvivenza.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Fase 1b Inclusione specifica
• Malattia VHR
• Età> 12 mesi e = 25 anni
• Funzionalità epatica adeguata: ALT o AST <2,5 X ULN per età
• Funzionalità renale adeguata: clearance della creatinina stimata o misurata = 60 ml / min / 1,73 m2
• Conta assoluta dei neutrofili = 1,0 x 10 ^ 9 / L
• Piastrine = 80 x 10 ^ 9 / L

Inclusione specifica CT1a
• Malattia VHR
• Età = 6 mesi
• Disponibile per la randomizzazione = 60 giorni dopo biopsia / chirurgia diagnostica
• Accorciamento frazionale = 28%
• Conta assoluta dei neutrofili = 1,0 x 10 ^ 9 / L (tranne nei pazienti con malattia del midollo osseo documentata)
• Piastrine = 80 x 109 / L (tranne nei pazienti con malattia del midollo osseo documentata)

Inclusione specifica CT1b
• malattia HR
• Età = 6 mesi
• Disponibile per la randomizzazione = 60 giorni dopo biopsia / chirurgia diagnostica
• Conta assoluta dei neutrofili = 1,0 x 10 ^ 9 / L
• Piastrine = 80 x 10 ^ 9 / L

Inclusione di radioterapia
• Ingresso nello studio FaR-RMS (alla diagnosi o prima della randomizzazione in radioterapia)
• VHR, HR e SR malattia
• = 2 anni di età
• Ricevere un trattamento di induzione in prima linea come parte dello studio FaR-RMS o con un regime chemioterapico basato su IVA / IVADo. Si noti che saranno eleggibili i pazienti per i quali ifosfamide è stata sostituita con ciclofosfamide
• Test di gravidanza negativo documentato per pazienti di sesso femminile in età fertile
• Inclusione specifica RT1a e RT1b
• Tumore primario ritenuto resecabile (resezione R0 / R1 prevista fattibile) dopo 3 cicli di chemioterapia di induzione (6 cicli per malattia metastatica)
• Radioterapia adiuvante richiesta in aggiunta alla resezione chirurgica (decisione locale).
• Disponibile per la randomizzazione dopo il ciclo 3 e prima dell'inizio del ciclo 6 della chemioterapia di induzione per malattia localizzata, o dopo il ciclo 6 e prima dell'inizio del ciclo 9 per la malattia metastatica

Inclusione specifica RT1b e RT1c
• Rischio di recidiva locale più elevato (HLFR) basato sulla presenza di uno dei seguenti criteri:
• Sito sfavorevole
• Età = 18 anni

Inclusione specifica RT1c
• Radioterapia primaria indicata (decisione locale)
• Disponibile per la randomizzazione dopo il ciclo 3 e prima dell'inizio del ciclo 6 della chemioterapia di induzione per la malattia localizzata, o dopo il ciclo 6 e prima dell'inizio del ciclo 9 per la malattia metastatica

Inclusione specifica RT2
• Disponibile per la randomizzazione dopo il ciclo 6 e prima dell'inizio del ciclo 9 della chemioterapia di induzione.
• Malattia metastatica sfavorevole, definita come punteggio prognostico di Oberlin modificato 2-4

Inclusione specifica per la manutenzione
• Ha ricevuto chemioterapia di induzione in prima linea come parte dello studio FaR-RMS o con una chemioterapia basata su IVA / IVADo
• regime
• Saranno idonei i pazienti per i quali ifosfamide è stata sostituita con ciclofosfamide
• Nessuna evidenza di progressione della malattia
• Assenza di neuropatia da vincristina grave, ovvero che richiede l'interruzione del trattamento con vincristina)

Inclusione specifica CT2a
• Malattia VHR
• Completati 11 cicli di trattamento di mantenimento VnC (regimi orali o IV)

Inclusione specifica CT2b
• malattia HR
• Completati 5 cicli di trattamento di mantenimento VnC

Recidiva Inclusione specifica CT3
• Accesso allo studio FaR-RMS (alla diagnosi o in qualsiasi momento successivo, inclusa la ricaduta)
• Età = 6 mesi
• Prima o successiva ricaduta di RMS
• Nessuna chemioterapia citotossica o altro medicinale sperimentale (IMP) nelle due settimane precedenti
• Test di gravidanza negativo documentato per pazienti di sesso femminile in età fertile

Criteri di inclusione per l'ingresso nello studio
1. Diagnosi istologicamente confermata di RMS (eccetto RMS pleomorfo)
2. Consenso informato scritto del paziente e / o del genitore / tutore legale
Criteri di inclusione per tutte le randomizzazioni e registrazioni:
• Il paziente accetta di utilizzare la contraccezione durante la terapia e per 12 mesi dopo l'ultimo trattamento (femmine) o 6 mesi
dopo l'ultimo trattamento (maschi), dove il paziente è sessualmente attivo
• Consenso informato scritto del paziente e / o del genitore / tutore legale
• Paziente idoneo dal punto di vista medico a ricevere cure
Inclusione specifica della chemioterapia di prima linea:
• Ingresso nello studio FaR-RMS al momento della diagnosi
• Nessun trattamento precedente per RMS diverso dalla chirurgia
• Test di gravidanza negativo documentato per pazienti di sesso femminile in età fertile
• Funzionalità epatica adeguata: bilirubina totale = 1,5 volte il limite superiore della norma (ULN) per l'età, a meno che il paziente non sia noto per avere la sindrome di Gilbert
...continua...

E.4

Principal exclusion criteria

Phase 1b specific exclusion
• Weight <10kg
• Active > grade 2 diarrhoea
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter-current illness or active infection
• Pre-existing medical condition precluding treatment
• Known hypersensitivity to any of the treatments or excipients
• Second malignancy
• Pregnant or breastfeeding women
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)

CT1a and CT1b specific exclusion
• Active > grade 2 diarrhoea
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter-current illness or active infection
• Pre-existing medical condition precluding treatment
• Known hypersensitivity to any of the treatments or excipients
• Second malignancy
• Pregnant or breastfeeding women
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)

Radiotherapy specific exclusion
• Prior allo- or autologous Stem Cell Transplant
• Second malignancy
• Pregnant or breastfeeding women
• Receiving radiotherapy as brachytherapy

CT2a and CT2b specific Exclusion
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter current illness or active infection
• Second malignancy
• Pregnant or breastfeeding women
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)

CT3 specific exclusion
• Active > grade 2 diarrhoea
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter-current illness or active infection
• Pre-existing medical condition precluding treatment
• Known hypersensitivity to any of the treatments or excipients
• Second malignancy
• Pregnant or breastfeeding women

Esclusione specifica della fase 1b
• Peso <10 kg
• Diarrea attiva> grado 2
• Precedente trapianto allo o autologo di cellule staminali
• Malattia intercorrente incontrollata o infezione attiva
• Condizione medica preesistente che preclude il trattamento
• Nota ipersensibilità a uno qualsiasi dei trattamenti o eccipienti
• Seconda neoplasia
• Donne incinte o che allattano
• Ostruzione del deflusso urinario che non può essere risolta prima di iniziare il trattamento
• Infiammazione attiva della vescica urinaria (cistite)

Esclusione specifica CT1a e CT1b
• Diarrea attiva> grado 2
• Precedente trapianto allo o autologo di cellule staminali
• Malattia intercorrente incontrollata o infezione attiva
• Condizione medica preesistente che preclude il trattamento
• Nota ipersensibilità a uno qualsiasi dei trattamenti o eccipienti
• Seconda neoplasia
• Donne incinte o che allattano
• Ostruzione del deflusso urinario che non può essere risolta prima di iniziare il trattamento
• Infiammazione attiva della vescica urinaria (cistite)

Esclusione specifica della radioterapia
• Precedente trapianto allo o autologo di cellule staminali
• Seconda neoplasia
• Donne incinte o che allattano
• Ricevere radioterapia come brachiterapia

Esclusione specifica CT2a e CT2b
• Precedente trapianto allo o autologo di cellule staminali
• Malattia intercorrente incontrollata o infezione attiva
• Seconda neoplasia
• Donne incinte o che allattano
• Ostruzione del deflusso urinario che non può essere risolta prima di iniziare il trattamento
• Infiammazione attiva della vescica urinaria (cistite)

Esclusione specifica CT3
• Diarrea attiva> grado 2
• Precedente trapianto allo o autologo di cellule staminali
• Malattia intercorrente incontrollata o infezione attiva
• Condizione medica preesistente che preclude il trattamento
• Nota ipersensibilità a uno qualsiasi dei trattamenti o eccipienti
• Seconda neoplasia
• Donne incinte o che allattano

E.5 End points

E.5.1

Primary end point(s)

The primary outcome measures for this study are as follows:

Recommended Phase 2 Dose (RP2D) - Phase 1b
Event Free Survival for randomisations CT1a, CT1b, CT2, RT2 and CT3.
Local failure free survival for randomisations RT1a, RT1b and RT1c

Le misure di esito primarie per questo studio sono le seguenti:

Dose di Fase 2 Raccomandata (RP2D) - Fase 1b
Sopravvivenza libera da eventi per le randomizzazioni CT1a, CT1b, CT2, RT2 e CT3.
Sopravvivenza libera da errori locali per randomizzazioni RT1a, RT1b e RT1c

E.5.1.1

Timepoint(s) of evaluation of this end point

Event-free survival (EFS) time is defined as the time from the each relevant randomisation to first failure event.
Failure events are:
• Relapse or progression of existing disease, or occurrence of disease at new sites,
• Death from any cause without disease progression,
• Second malignant neoplasm

Local failure free survival (LFFS) time is defined as time from randomisation to first local failure event. A local failure event is relapse or progression of tumour at the primary site at any time even if there has been a prior concurrent local, regional or distant failure.

Il tempo di sopravvivenza libera da eventi (EFS) è definito come il tempo che intercorre tra ciascuna randomizzazione rilevante e il primo evento di fallimento
Gli eventi di errore sono:
• Ricaduta o progressione di una malattia esistente o insorgenza di malattia in nuovi siti,
• Morte per qualsiasi causa senza progressione della malattia,
• Seconda neoplasia maligna

Il tempo di sopravvivenza libera da guasti locali (LFFS) è definito come il tempo dalla randomizzazione al primo evento di guasto locale. Un evento di fallimento locale è la ricaduta o la progressione del tumore nel sito primario in qualsiasi momento, anche se si è verificato un precedente fallimento concomitante locale, regionale o distante.

E.5.2

Secondary end point(s)

• Best Response for randomisation CT3
• Dose Limiting Toxicity for registration phase 1b
• Event Free Survival for all patients, randomisations RT1a, RT1b, RT1c and also the PET sub-study
• Local failure free survival for the PET sub-study
• Loco-regional failure-free survival for randomisations RT1a, RT1b, RT1c and RT2
• Health Related Quality of Life for randomisations RT1a and RT2
• Maximum Tolerated Dose for registration phase 1b
• Overall Survival for all patients, randomisations CT1a, CT1b, CT2, CT3, RT1a, RT1b, RT1c and also RT2
• Response for registration phase 1b and also randomisations CT1a, CT1b, and CT3
• Recommended Phase II Dose for registration phase 1b
• Toxicity for registration phase 1b and also randomisations CT1a, CT1b, and CT3
• Duration of response for randomisation CT3
• Acute post-radiotherapy complications for randomisations RT1a, RT1b, RT1c and RT2
• Late complications for randomisations RT1a, RT1b and RT1c
• Acute post-operative complications for randomisations RT1a and RT1b
• Wound complications for randomisations RT1a and RT1b
• PET response for the PET sub-study

• Migliore risposta per la randomizzazione CT3
• Tossicità limitante la dose per la fase di registrazione 1b
• Sopravvivenza libera da eventi per tutti i pazienti, randomizzazioni RT1a, RT1b, RT1c e anche il sottostudio PET
• Sopravvivenza libera da guasti locali per il sottostudio PET
• Sopravvivenza libera da guasti loco-regionali per le randomizzazioni RT1a, RT1b, RT1c e RT2
• Qualità della vita correlata alla salute per le randomizzazioni RT1a e RT2
• Dose massima tollerata per la fase di registrazione 1b
• Sopravvivenza globale per tutti i pazienti, randomizzazioni CT1a, CT1b, CT2, CT3, RT1a, RT1b, RT1c e anche RT2
• Risposta per la fase di registrazione 1b e anche randomizzazioni CT1a, CT1b e CT3
• Dose di Fase II raccomandata per la fase di registrazione 1b
• Tossicità per la fase di registrazione 1b e anche per randomizzazioni CT1a, CT1b e CT3
• Durata della risposta per la randomizzazione CT3
• Complicanze acute post-radioterapia per randomizzazioni RT1a, RT1b, RT1c e RT2
• Complicazioni tardive per randomizzazioni RT1a, RT1b e RT1c
• Complicanze post-operatorie acute per randomizzazioni RT1a e RT1b
• Complicazioni della ferita per randomizzazioni RT1a e RT1b
• Risposta PET per il sottostudio PET
Ulteriori informazioni su questo testo di origine

E.5.2.1

Timepoint(s) of evaluation of this end point

first failure event
death from any cause
first local failure event
first local or regional failure event.
30 days after the last treatment
within 120 days from surgery
completion of radiotherapy
Progression
Relapse
after 120 days from last local therapy.
at the start of radiotherapy,
At completion of radiotherapy,
3 months following the end of radiotherapy,
24 months following radiotherapy
after course 2 and 6 for the newly diagnosed chemotherapy
after course 2 and 4 for the relapse randomisation.
End of any Phase 1b study
time point at which no or one participant experiences a DLT when at least two of three to six participants experience a DLT at the next highest dose
3 cycles of induction chemotherapy

primo evento di fallimento
morte per qualsiasi causa
primo evento di fallimento locale
primo evento di fallimento locale o regionale.
30 giorni dopo l'ultimo trattamento
entro 120 giorni dall'intervento
completamento della radioterapia
Progressione
Ricaduta
dopo 120 giorni dall'ultima terapia locale.
all'inizio della radioterapia,
Al termine della radioterapia,
3 mesi dopo la fine della radioterapia,
24 mesi dopo la radioterapia
dopo il corso 2 e 6 per la chemioterapia di nuova diagnosi
dopo il corso 2 e 4 per la randomizzazione della ricaduta.
Fine di qualsiasi studio di fase 1b
punto temporale in cui nessuno o uno dei partecipanti sperimenta una DLT quando almeno due dei tre-sei partecipanti sperimentano una DLT alla dose più alta successiva
3 cicli di chemioterapia di induzione

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Dose finding study of combination with unknown safety profile, suggested evidence of activity

Studio di determinazione della dose di combinazione con profilo di sicurezza sconosciuto, ha suggeri

E.7.2

Therapeutic exploratory (Phase II)

Yes

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

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

Yes

E.8.2.3.1

Comparator description

dose di radioterapia

radiotherapy dose

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

118

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

Information not present in EudraCT

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

Australia

New Zealand

Belgium

Denmark

France

Ireland

Italy

Netherlands

Norway

Slovakia

Spain

United Kingdom

Czechia

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

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

Yes

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

157

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)

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

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

children

Bambini

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

250

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1251

F.4.2.2

In the whole clinical trial

1672

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)

On completing protocol defined treatment, their treating physician will discuss further treatment options with them and their family as per standard care

Al termine del trattamento definito dal protocollo, il medico curante discuterà ulteriori opzioni di trattamento con loro e con la loro famiglia secondo le cure standard

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

2021-12-06

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status

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