Clinical Trials Register

Summary
EudraCT Number:	2018-000515-24
Sponsor's Protocol Code Number:	RG_17-247
National Competent Authority:	Norway - NOMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-02-11
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Norway - NOMA

A.2

EudraCT number

2018-000515-24

A.3

Full title of the trial

FaR-RMS: An overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma

A.3.1

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

FaR-RMS: An overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma

FaR-RMS: Protokoll for behandling av rhabdomyosarkom hos barn og
voksne

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	Cancer Research UK
B.4.2	Country	United Kingdom
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.5.6	E-mail	farrms@trials.bham.ac.uk
B.Sponsor: 2
B.1.1	Name of Sponsor	Oslo universitetssykehus
B.1.3.4	Country	Norway
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	Oslo universitetssykehus
B.4.2	Country	Norway
B.4.1	Name of organisation providing support	Haukeland universitetssykehus
B.4.2	Country	Norway
B.4.1	Name of organisation providing support	St Olavs hospital
B.4.2	Country	Norway
B.4.1	Name of organisation providing support	Universitetssykehuset i Nord-Norge
B.4.2	Country	Norway
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Oslo universitetssykehus
B.5.2	Functional name of contact point	Barneavdeling for kreft- og blodsyk
B.5.3	Address:
B.5.3.1	Street Address	Sognsvannsveien 20
B.5.3.2	Town/ city	Oslo
B.5.3.3	Post code	0372
B.5.3.4	Country	Norway
B.5.4	Telephone number	4723074593
B.5.5	Fax number	4723074570
B.5.6	E-mail	hglosli@ous-hf.no

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	United Kingdom
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	Actinomycin D
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	dactinomycin
D.3.9.1	CAS number	50-76-0
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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.2.1.2	Country which granted the Marketing Authorisation	Norway
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	Doxorubicin
D.3.4	Pharmaceutical form	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	doxorubicin
D.3.9.1	CAS number	23214-92-8
D.3.9.4	EV Substance Code	AS2
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	2
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.2.1.2	Country which granted the Marketing Authorisation	Norway
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	Ifosfamide
D.3.4	Pharmaceutical form	Powder for concentrate 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	ifosfamide
D.3.9.1	CAS number	3778-73-2
D.3.9.4	EV Substance Code	AS3
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1 to 2
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: 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	Norway
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.3.4	Pharmaceutical form	Concentrate 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	Irinotecan
D.3.9.1	CAS number	97682-44-5
D.3.9.4	EV Substance Code	AS5
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	5 to 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	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: 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	Norway
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	Vincristine
D.3.4	Pharmaceutical form	Solution for injection
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	Vincristine
D.3.9.1	CAS number	57-22-7
D.3.9.4	EV Substance Code	AS6
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.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	Norway
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	Vinorelbine
D.3.4	Pharmaceutical form	Concentrate 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	Vinorelbine
D.3.9.1	CAS number	71486-22-1
D.3.9.4	EV Substance Code	AS4
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	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: 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	Norway
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	Vinorelbine
D.3.4	Pharmaceutical form	Capsule, soft
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	Vinorelbine
D.3.9.1	CAS number	71486-22-1
D.3.9.4	EV Substance Code	AS7
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 80
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: 8
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	Norway
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	Cyclophosphamide
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	Cyclophosphamide
D.3.9.1	CAS number	50-18-0
D.3.9.4	EV Substance Code	AS8
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	500 to 2000
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: 9
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	Norway
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	Cyclophosphamide
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cyclophosphamide
D.3.9.1	CAS number	50-18-0
D.3.9.4	EV Substance Code	AS9
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	500 to 1000
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: 10
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	Norway
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	Cyclophosphamide
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	Cyclophosphamide
D.3.9.1	CAS number	50-18-0
D.3.9.4	EV Substance Code	AS10
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	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: 11
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	European Union
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.3.4	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.3.9.4	EV Substance Code	AS11
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	5 to 250
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

Rhabdomyosarcoma

Rhabdomyosarkom

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.

Rhabdomyosarkom: kreftsykdom i bløtvev (slik som muskel), bindevev (slik som sener og brusk) eller benvev

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	10039022
E.1.2	Term	Rhabdomyosarcoma
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objectives for this trial are related to each of the trial questions.

For the Phase I Dose Finding Studies, the aim is to determine the recommended phase II dose (RP2D) of new systemic therapy regimens. The first combination to be tested is irinotecan in combination with ifosfamide, vincristine and actinomycin D (IrIVA).

For the frontline chemotherapy questions, the objectives are:
• To compare systemic therapy regimens for patients with Very High Risk (VHR) disease at diagnosis. The first new combination regimens to be compared are IVADo and IrIVA in a dose intense schedule.
•To compare new systemic therapy regimens with standard chemotherapy for patients with High Risk (HR) disease at diagnosis. The standard chemotherapy is ifosfamide, vincristine, actinomycin D (IVA). The first new combination regime to be compared is irinotecan combined with IVA (IrIVA) in a dose intense schedule

For the radiotherapy questions, the objectives are as follows:
•To determine

Hovedhensikten med denne studien er relatert til hvert av studiespørsmålene.
For fase I-studien er målet å bestemme anbefalt dose av medikamentene i de nye systemiske behandlingsregimene i fase II-studien. Den første kombinasjonen som skal testes er irinotekan i kombinasjon med ifosfamid, vinkristin og actinomycin D (IrIVA).
Mht primærbehandlingen er hensikten å sammenligne ulike systemiske behandlingsregimer for pasienter med tumor i hhv veldig høy risk (VHR) og høy risk gruppen ved diagnose. For VHR er de første kombinasjonene som skal sammenlignes IVADo og IrIVA i en doseintensiv behandlingsplan. For HR-gruppen skal man sammenligne nye systemiske behandlingsregimer med standardbehandling. Standardbehandlingen for HR består av ifosfamid, vinkristin og actinomycin D (IVA). Den første kombinasjonen som skal sammenlignes er irinotekan kombinert med IVA (IrIVA) i en doseintensiv behandlingsplan.
Strålebehandling: Er preop strålebehandling like effektiv som postop strålebehandling?

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.

Sekundærhensikten med studien er:
- å validere om bruken av fusjonsstatus (PAX3/PAX7-FOXO1) i stedet for histopatologisk diagnose forbedrer risikostratifiseringen
- å bestemme om bruken av fusjonsstatus er nødvendig i tumorer klassifisert som embryonalt rhabdomyosarkom ved bruk av histopatologi
- å bestemme om et immunhistokjemisk estimat av proteinekspresjon drevet av fusjonsproteinet er en nøyaktig surrogatmarkør for fusjonsstatus
- å bestemme om FDG-PET-CT respons etter induksjonsbehandling med kjemoterapi er en prognostisk biomarkør for lokalt tilbakefall og/eller overlevelse

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Prospective validation of value of FDG-PET response as prognostic biomarker to identify those at highest risk for local failure. This substudy will determine whether FDG PET- CT response assessment following induction chemotherapy is a prognostic biomarker for local failure and/ or survival.

Prospektiv validering av verdien av FDG-PET respons som en prognostisk biomarkør for å identifisere de pasientene som har høyest risiko for lokalt tilbakefall. Denne sub-studien vil bestemme om evaluering med FDG PET-CT etter induksjonsbehandling er en prognostisk biomarkør for lokalt tilbakefall og /eller overlevelse.

E.3

Principal inclusion criteria

Inclusion Criteria for study entry
1. Histologically confirmed diagnosis of RMS (except pleomorphic RMS)
2. Written informed consent from the patient and/or the parent/legal guardian
Inclusion criteria for all randomisations and registrations:
• Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months
after last trial treatment (males), where patient is sexually active
• Written informed consent from the patient and/or the parent/legal guardian
• Medically fit to receive treatment
Frontline chemotherapy specific inclusion:
• Entered in to the FaR-RMS study at diagnosis
• No prior treatment for RMS other than surgery
• Documented negative pregnancy test for female patients of childbearing potential
• Adequate hepatic function: Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert’s syndrome
Phase 1b Specific Inclusion
• VHR disease
• Age >12 months and ≤25 years
• Adequate hepatic function: ALT or AST < 2.5 X ULN for age
• Adequate renal function: estimated or measured creatinine clearance ≥60 ml/min/1.73 m2
• Absolute neutrophil count ≥1.0x 10^9/L
• Platelets ≥ 80 x 10^9/L

CT1a specific inclusion
• VHR disease
• Age ≥ 6 months
• Available for randomisation ≤60 days after diagnostic biopsy/surgery
• Fractional Shortening ≥ 28%
• Absolute neutrophil count ≥1.0x 10^9/L (except in patients with documented bone marrow disease)
• Platelets ≥ 80 x 109/L (except in patients with documented bone marrow disease)

CT1b specific inclusion
• HR disease
• Age ≥ 6 months
• Available for randomisation ≤60 days after diagnostic biopsy/surgery
• Absolute neutrophil count ≥1.0x 10^9/L
• Platelets ≥ 80 x 10^9/L

Radiotherapy Inclusion
• Entered in to the FaR-RMS study (at diagnosis or prior to radiotherapy randomisation)
• VHR, HR and SR disease
• ≥ 2 years of age
• Receiving frontline induction treatment as part of the FaR-RMS trial or with a IVA/IVADo based chemotherapy regimen
• patients for whom. Note that patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible
• Documented negative pregnancy test for female patients of childbearing potential
• RT1a and RT1b Specific Inclusion
• Primary tumour deemed resectable (predicted R0/ R1 resection feasible) after 3 cycles of induction chemotherapy
• (6 cycles for metastatic disease)
• Adjuvant radiotherapy required in addition to surgical resection (local decision).
• Available for randomisation after cycle 3 and prior to the start of cycle 6 of induction chemotherapy for localised
• disease, or after cycle 6 and prior to the start of cycle 9 for metastatic disease

RT1b and RT1c Specific Inclusion
• Higher Local Failure Risk (HLFR) based on presence of either of the following criteria:
• Unfavourable site
• Age ≥ 18yrs

RT1c Specific Inclusion
• Primary radiotherapy indicated (local decision)
• Available for randomisation after cycle 3 and prior to the start of cycle 6 of induction chemotherapy for localised disease, or after cycle 6 and prior to the start of cycle 9 for metastatic disease

RT2 Specific Inclusion
• Available for randomisation after cycle 6 and before the start of cycle 9 of induction chemotherapy.
• Unfavourable metastatic disease, defined as Modified Oberlin Prognostic Score 2-4

Maintenance specific Inclusion
• Received frontline induction chemotherapy as part of the FaR-RMS trial or with a IVA/IVADo based chemotherapy
• regimen
• Patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible
• No evidence of progressive disease
• Absence of severe vincristine neuropathy – i.e requiring discontinuation of vincristine treatment)

CT2a specific inclusion
• VHR disease
• Completed 11 cycles of VnC maintenance treatment (either oral or IV regimens)

CT2b specific Inclusion
• HR disease
• Completed 5 cycles of VnC maintenance treatment

Relapse CT3 specific Inclusion
• Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point including at relapse)
• Age ≥ 6 months
• First or subsequent relapse of RMS
• No cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous two weeks
• Documented negative pregnancy test for female patients of childbearing potential

Inklusjonskriterier for å delta i FaR-RMS
1. Histologisk bekreftet RMS-diagnose (unntak: pleomorft RMS)
2. Skriftlig informert samtykke fra pasienten og/eller foreldre/verge
Inklusjonskriterier for alle randomiseringer og registreringer:
• Pasienten samtykker til å bruke prevensjonsmidler under behandling og i 12 måneder etter avsluttet behandling (kvinner) eller 6 måneder etter avsluttet behandling (menn), så lenge pasienten er seksuelt aktiv
• Skriftlig informert samtykke fra pasient og/eller foreldre/verge
• Medisinsk skikket til å motta behandling

Spesifikke inklusjonskriterier for primærbehandling:
• Inkludert i FaR-RMS studien ved diagnose
• Ingen tidligere behandling for RMS annet enn kirurgi
• Dokumenter negativ graviditetstest for kvinnelige pasienter i fertil alder
• Adekvat leverfunksjon: Total bilirubin ≤ 1.5 ganger øvre normalverdi (ULN) for alder, unntatt pasienter med kjent Gilbert’s syndrom

Spesifikke inklusjonskriterier for Fase 1b:
• VHR RMS
• Alder >12 måneder og ≤25 års
• Adekvat leverfunksjon: ALAT eller ASAT < 2.5 x ULN for alder
• Adekvat nyrefunksjon: beregnet eller målt kreatinin clearance ≥60 ml/min/1.73 m2
• Absolutt neutrophil antall ≥1.0x 10^9/L
• Trombocytter ≥ 80 x 10^9/L

Spesifikke inklusjonskriterier for CT1a:
• VHR RMS
• Alder ≥ 6 måneder
• Tilgjengelig for randomisering ≤60 dager etter diagnostisk biopsi/kirurgi
• Adekvat hjertefunksjon med forkortningsfraksjon ≥ 28%
• Absolutt neutrophil antall ≥1.0x 10^9/L (unntatt i pasienter med dokumentert benmargssvikt)
• Trombocytter ≥ 80 x 109/L (unntatt i pasienter med dokumentert benmargssvikt)

Spesifikke inklusjonskriterier for CT1b
• HR RMS
• Alder ≥ 6 måneder
• Tilgjengelig for randomisering ≤60 dager etter diagnostisk biopsi/kirurgi
• Absolutt neutrophil antall ≥1.0x 10^9/L
• Trombocytter ≥ 80 x 10^9/L

Inklusjonskriterier for strålebehandling
• Inkludert i FaR-RMS studien (ved diagnose eller før strålebehandlingsrandomisering)
• VHR, HR og SR (standard risk) RMS
• ≥ 2 års alder
• Mottar primærbehandling som del av FaR-RMS studien eller får behandling med et IVA/IVADo basert kjemoterapi regime
• Legg merke til at pasienter som får behandling der ifosfamid er erstattet med cyclofosfamid er fremdeles inkluderbare
• Dokumentert negativ graviditetstest for kvinnelige pasienter i fertil alder

Spesifikke inklusjonskriterier for RT1a og RT1b:
• Primærtumor er vurdert å være operabel (forventer at R0/ R1 reseksjon er mulig) etter 3 kurer med induksjonskjemoterapi (6 kurer ved metastatisk sykdom)
• Behov for adjuvant strålebehandling i tillegg til kirurgisk reseksjon (lokal beslutning).
• Tilgjengelig for randomisering etter 3. syklus og før oppstart av 6. syklus med induksjonskjemoterapi for lokalisert sykdom, eller etter 6. syklus og før oppstart av 9. syklus for metastatisk sykdom

Spesifikke inklusjonskriterier for RT1b og RT1c:
• Høyere risiko for lokalt tilbakefall (HLFR) basert på tilstedeværelse av følgende kriterier:
• Ugunstig lokalisasjon
• Alder ≥ 18 år

Spesifikke inklusjonskriterier for RT1c:
• Indikasjon for primær strålebehandling (lokal beslutning)
• Tilgjengelig for randomisering etter 3. syklus og før oppstart av 6. syklus av induksjonsbehandlingen for lokalisert sykdom, eller etter 6. syklus og før oppstart av 9. syklus for metastatisk sykdom

Spesifikke inklusjonskriterier for RT2
• Tilgjengelig for randomisering etter 6. syklus og før oppstart av 9. syklus av induksjonsbehandlingen
• Ugunstig metastatisk sykdom, definert i henhold til modifisert Oberlin Prognostisk Score 2-4

Spesifikke inklusjonskriterier for vedlikeholdsbehandlingen:
• Har mottatt primærbehandling som ledd i FaR-RMS studien eller fått behandling med IVA/IVADo basert kjemoterapiregime
• Pasienter som har fått behandling der ifosfamid er erstattet av cyclofosfamid er inkluderbare
• Ingen tegn på progressiv sykdom
• Fravær av alvorlig vinkristin nevropati – f.eks ha behov for pauser i vinkristinbehandlingen

Spesifikke inklusjonskriterier for CT2a:
• VHR RMS
• Har fullført 11 sykluser med Vinorelbin-Cyklofosfamid (VnC) vedlikeholdsbehandling (enten peroralt eller intravenøst regime)

Spesifikke inklusjonskriterier for CT2b:
• HR RMS
• Har fullført 5 sykluser med VnC vedlikeholdsbehandling

Spesifikke inklusjonskriterier for Relapse (tilbakefall) CT3
• Inkludert i FaR-RMS studien (ved diagnose eller på et senere tidspunkt grunnet et tilbakefall)
• Alder ≥ 6 måneder
• Første eller senere tilbakefall av RMS
• Har ikke fått behandling med cytotoksisk kjemoterapi eller andre utprøvende medikamenter (IMP) i løpet av de siste 2 ukene
• Dokumentert negativ graviditetstest for kvinnelige pasienter i fertil alder

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

Spesifikke eksklusjonskriterier for Phase 1b:
• Vekt <10kg
• Aktiv > grad 2 diaré
• Tidligere allo- eller autolog stamcelletransplantasjon
• Ukontrollert interkurrent sykdom eller aktiv infeksjon
• Tilstedeværelse av medisinsk tilstand som ødelegger for kreftbehandlingen
• Kjent hypersensitivitet for noen av medikamentene eller tilsetningsstoffene
• Sekundær malignitet
• Gravide eller ammende kvinner
• Obstruksjon av urinveiene som ikke kan heves før oppstart av behandling
• Aktiv inflammasjon i urinblæren (cystitt)

Spesifikke eksklusjonskriterier for CT1a and CT1b:
• Aktiv > grad 2 diaré
• Tidligere allo- eller autolog stamcelletranplantasjon
• Ukontrollert interkurrent sykdom eller aktiv infeksjon
• Tilstedeværelse av medisinsk tilstand som ødelegger for kreftbehandlingen
• Kjent hypersensitivitet for noen av medikamentene eller tilsetningsstoffene
• Sekundær malignitet
• Gravide eller ammende kvinner
• Obstruksjon av urinveiene som ikke kan heves før oppstart av behandling
• Aktiv inflammasjon i urinblæren (cystitt)

Spesifikke eksklusjonskriterier for strålebehandling
• Tidligere allo- eller autolog stamcelletranplantasjon
• Sekundær malignitet
• Gravide eller ammende kvinner
• Får strålebehandling som brachyterapi

Spesifikke eksklusjonskriterier for CT2a and CT2b
• Tidligere allo- eller autolog stamcelletranplantasjon
• Ukontrollert interkurrent sykdom eller aktiv infeksjon
• Sekundær malignitet
• Gravide eller ammende kvinner
• Obstruksjon av urinveiene som ikke kan heves før oppstart av behandling
• Aktiv inflammasjon i urinblæren (cystitt)

Spesifikke eksklusjonskriterier for CT3:
• Aktiv > grad 2 diaré
• Tidligere allo- eller autolog stamcelletranplantasjon
• Ukontrollert interkurrent sykdom eller aktiv infeksjon
• Tilstedeværelse av medisinsk tilstand som ødelegger for kreftbehandlingen
• Kjent hypersensitivitet for noen av medikamentene eller tilsetningsstoffene
• Sekundær malignitet
• Gravide eller ammende kvinner

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

De primære endepunktene for denne studien:

Anbefalt fase 2 Dose (RP2D) - fase 1b
Hendelsesfri overlevelse (EFS) for randomiseringene CT1a, CT1b, CT2, RT2 og CT3.
Lokal hendelsesfri overlevelse for randomiseringene RT1a, RT1b og 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.

Varighet av hendelsesfri overlevelse (EFS) er definert som tid fra hver enkelt relevant randomisering til første hendelse .
Hendelser er definert som:
• Tilbakefall eller progresjon av aktuell kreftsykdom, elle forekomst av kreftsykdom på nye steder,
• Død, uansett årsak uten tegn til progresjon av kreftsykdom,
• Sekundær kreftsykdom

Varighet av hendelsesfri lokal overlevelse (LFFS) er definert som tid fra randomisering til forekomst av den første lokale hendelsen. En lokal hendelse er et hvilket som helst tilbakefall eller progresjon av kreftsykdom på primærlokalisasjonen, selv om det tidligere har vært en samtidig lokal, regional eller fjerntliggende hendelse.

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

Beste behandlingseffekt for randomisering CT3
• Dosbegrensende toksisitet (DLT) for fase 1b
• Hendelsesfri overlevelse (EFS) for alle pasienter, randomiseringene RT1a, RT1b, RT1c og PET substudien
• Lokal hendelsesfri overlevelse (LFFS) for PET substudien
• Lokal og regional hendelsesfri overlevelse for randomiseringene RT1a, RT1b, RT1c og RT2
• Helserelatert livskvalitet for randomiseringene RT1a og RT2
• Maksimal tolererbar dose (MTD) for fase 1b
• Total overlevelse (OS) for alle pasienter, randomiseringene CT1a, CT1b, CT2, CT3, RT1a, RT1b, RT1c og RT2
• Vurdering av behandlingseffekt for fase 1b og for randomiseringene CT1a, CT1b, og CT3
• Anbefalt fase II Dose for fase 1b
• Toksisitet for fase 1b og randomiseringene CT1a, CT1b, og CT3
• Varighet av behandlingseffekt for randomisering CT3
• Akutt post-strålebehandlings komplikasjoner for randomiseringene RT1a, RT1b, RT1c og RT2
• Seneffekter/komplikasjoner for randomiseringene RT1a, RT1b og RT1c
• Akutte postoperative komplikasjoner for randomiseringene RT1a og RT1b
• Sårkomplikasjoner for randomiseringene RT1a og RT1b
• PET respons for PET substudien

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

første hendelse
død, uansett årsak
første lokale hendelse
første lokale eller regionale hendelse
30 dager etter siste behandling
innen 120 dager etter kirurgi
fullføring av strålebehandling
progresjon
tilbakefall
etter 120 dager etter siste lokalbehandling
ved start av strålebehandling
ved fullføring av strålebehandling
3 måneder etter avsluttet strålebehandling
24 måneder etter strålebehandling
etter cellegiftkur 2 og 6 for nydiagnostiserte
etter cellegiftkur 2 og 4 for de med tilbakefall som skal randomiseres
ved slutten av en hver fase 1b studie
når ingen eller 1 deltager opplever DLT
når minst 2/3-6 deltagere opplever DLT ved nest høyeste dose
3 sykluser av cellegidt i induksjon

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

Studie for å bestemme korrekt dose i kombinasjon, ukjent sikkerhetsprofil, forventet effekt

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

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

stråledose

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

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

Belgium

Czech Republic

Denmark

France

Ireland

Italy

Netherlands

New Zealand

Norway

Slovakia

Spain

United Kingdom

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

LVLS (siste besøk for siste pasient)

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