Clinical Trials Register

Summary
EudraCT Number:	2007-005802-38
Sponsor's Protocol Code Number:	AP12009-G005
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2009-08-04
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

Germany - BfArM

A.2

EudraCT number

2007-005802-38

A.3

Full title of the trial

Efficacy and Safety of AP 12009 in Adult Patients with Recurrent or Refractory Anaplastic Astrocytoma (WHO grade III) or Secondary Glioblastoma (WHO grade IV) as Compared to Standard Chemotherapy: A Randomized, Actively Controlled, Open Label Clinical Phase III Study.

A.3.1

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

Evaluation of efficacy and safety of the new drug AP 12009 in adult patients suffering from Recurrent or Refractory Anaplastic Astrocytoma (WHO grade III) or Secondary Glioblastoma (WHO grade IV) compared to standard treatment with Temozolomide or Lomustine: A clinical study where patients will be openly and randomly assigned to one of the treatment groups to gain marketing approval for the new drug AP 12009.

A.3.2

Name or abbreviated title of the trial where available

SAPPHIRE

A.4.1

Sponsor's protocol code number

AP12009-G005

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00761280

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	Antisense Pharma GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Antisense Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/02/091
D.3 Description of the IMP
D.3.1	Product name	AP 12009
D.3.2	Product code	AP 12009
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intratumoral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	trabedersen
D.3.9.1	CAS number	92681-61-4
D.3.9.2	Current sponsor code	AP 12009
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	7.37
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	Comparator
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	Temodal, 5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	SP Europe
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.3.4	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	85622931
D.3.9.3	Other descriptive name	TMZ
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	5
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	Comparator
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	Carmubris
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol Myers Squibb
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.3.4	Pharmaceutical form	Powder 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	CARMUSTINE
D.3.9.1	CAS number	154938
D.3.9.3	Other descriptive name	BCNU
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	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	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	Comparator
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	Temodal, 20 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	SP Europe
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.3.4	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	85622931
D.3.9.3	Other descriptive name	TMZ
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	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	Comparator
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	Temodal, 100 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	SP Europe
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.3.4	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	85622931
D.3.9.3	Other descriptive name	TMZ
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	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	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	Comparator
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	Cecenu, 40 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	medac - Gesellschaft fuer klinische Spezialpraeparate mbH
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.3.4	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	LOMUSTINE
D.3.9.1	CAS number	13010-47-4
D.3.9.3	Other descriptive name	CCNU
D.3.9.4	EV Substance Code	SUB08567MIG
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	40
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	Comparator
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	Temodal, 5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	SP Europe
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.3.4	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	85622931
D.3.9.3	Other descriptive name	TMZ
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	5
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	Comparator
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	Temodal, 20 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	SP Europe
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.3.4	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	85622931
D.3.9.3	Other descriptive name	TMZ
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	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: 9
D.1.2 and D.1.3	IMP Role	Comparator
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	Temodal, 100 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	SP Europe
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.3.4	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	85622931
D.3.9.3	Other descriptive name	TMZ
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	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	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	Comparator
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	Cecenu, 40 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	medac - Gesellschaft fuer klinische Spezialpraeparate mbH
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.3.4	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	LOMUSTINE
D.3.9.1	CAS number	13010-47-4
D.3.9.3	Other descriptive name	CCNU
D.3.9.4	EV Substance Code	SUB08567MIG
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	40
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

Recurrent or Refractory Anaplastic Astrocytoma (WHO grade III) or secondary Glioblastoma (WHO grade IV)

E.1.1.1

Medical condition in easily understood language

Anaplastic astrocytoma and glioblastoma are rare malignant brain tumours. They arise from the brain cells themselves (primary tumour), and are therefore not to be confused with brain metastases.

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	14.0
E.1.2	Level	PT
E.1.2	Classification code	10018336
E.1.2	Term	Glioblastoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	PT
E.1.2	Classification code	10002224
E.1.2	Term	Anaplastic astrocytoma
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

To test the efficacy and safety of AP 12009 (concentration 10 μM) in patients with recurrent or refractory anaplastic astrocytoma (AA) or secondary glioblastoma compared to standard chemotherapy treatment.

E.2.2

Secondary objectives of the trial

Secondary objectives with special relevance:

• To compare median overall survival of AP 12009 (10 μM) with standard chemotherapy treatment.
• To compare the 14-month progression rate of AP 12009 (10 μM) with standard chemotherapy
treatment.

In addition, to compare the effect of the different treatments on the following parameters:

• Overall response rate (best response according to Macdonald criteria, PR and CR)
• Tumor control rate (CR, PR and SD)
• Duration of response
• Progression rate at 10, 12, 16, 18, 21, and 24 months
• Time to progression (months)
• Survival rate at 12, 18, 21, 27, and 30 months, and at 3 and 4 years
• Quality of Life (EORTC QLQ-C30, Independent Living Score [ILS])
• Safety and tolerability

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. The patient has provided written informed consent prior to any study-related procedure.
2. The patient is at least 18 years of age and equal to or below 70 years.
3. The patient has a present diagnosis of AA or secondary GBM.
4. The patient has a measurable lesion (> 1 cm3 in volume, central MRI review).
5. The lesion (or sum of lesions) does not exceed 50 cm3 in volume (central MRI review).
6. The tumor is localized supratentorially (central MRI review).
7. All patients have recurrent or refractory disease, i.e. disease has progressed after:
Prior surgery and radiotherapy at any time of the disease course or stage (e.g. prior grade II tumor).
Secondary GBM patients have progressed after a previous diagnosis of A and/or AA.
In case of recent tumor surgery a ≤ 48-hour routine post-surgery MRI (in accordance with study specifications) confirming inclusion criteria 4, 5, and 6 qualifies the patient for study randomization 30 ± 7 days after surgery.
8. The patient has not received more than 2 chemotherapy regimens. Radiation with concomitant
chemotherapy, followed by adjuvant chemotherapy, is considered as one chemotherapy regimen.
9. The patient is eligible for chemotherapy.
10. The patient is on a maximum dose of 4 mg/day dexamethasone or equivalent doses for other corticosteroids, which has been stable or decreasing for at least 3 weeks prior to Screening.
11. The patient is male or a non-pregnant, non-lactating female.
12. Females of childbearing potential must have a negative beta-HCG pregnancy test at Screening. Females of childbearing potential and males must practice strict birth control (see Section 8.2).
13. The patient must have recovered from acute toxicity caused by any previous therapy.
14. The patient has a life expectancy of at least 3 months.
15. The patient has a Karnofsky Performance Status of at least 70%.
16. The patient shows adequate organ functions as assessed by the following screening laboratory values:
a. Adequate renal function determined by serum creatinine and urea < 2 times the upper limit of normal
b. Adequate liver function with ALT, AST and AP < 3 times the upper limit of normal, and bilirubin < 2.5 mg/dL
c. INR < 1.5 and aPTT < 1.5 x ULN
d. Hemoglobin > 9 g/dL
e. Platelet count > 100 x 1 000 000 000/L
f. WBC > 3 x 1 000 000 000/L
g. ANC > 1.5 x 1 000 000 000/L (or WBC > 3.0 x 1 000 000 000/L)

E.4

Principal exclusion criteria

1. Patient unable or not willing to comply with the protocol regulations.
2. The investigator deems it necessary to surgically (re-)resect the present tumor (NOTE: the patient might still be eligible for randomization at a later timepoint, see inclusion criterion 7 and exclusion criterion 3).
3. Tumor surgery, tumor debulking, or other neurosurgery within 3 months prior to randomization. If a ≤ 48-hour routine post-surgery MRI (in accordance with study specifications) qualifies the patient for study participation (see inclusion criterion 7), the patient can be randomized 30 ± 7 days post-surgery.
4. Radiotherapy or stereotactic (gamma knife) radiosurgery within 3 months prior to randomization.
5. Prior interstitial brachytherapy of the brain with permanent implants. Prior interstitial brachytherapy of the brain with removable implants within 3 months prior to randomization.
6. Chemotherapy, hormone therapy, or any other therapy with established or suggested anti-tumor effects within 4 weeks (nitrosoureas: 6 weeks) prior to randomization.
7. Prior anti-TGF-beta 2 targeted therapy.
8. Screening MRI shows a mass effect caused by the tumor defined as significant compression of the ventricular system and/or a midline shift ( ≥ 3 mm, central MRI review). Compression of the ventricular
system and/or a midline shift ≥ 3 mm only due to the presence of (a) cyst(s) or scarring processes does not exclude an individual from the study.
9. Participation in another clinical study with another investigational medicinal product within 30 days prior to randomization.
10. History of a second independent malignant disorder within 5 years, except for carcinoma in situ of the cervix and basal cell carcinoma.
11. Presence of poorly controlled seizures, defined as:
a. Seizures, which require frequent hospitalizations or other medical interventions because of their serial nature and/or clinical symptoms.
b. Seizure symptoms, which significantly interfere with normal life and restrict medical treatments that are necessary for patient care.
12. Clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure, unstable angina, or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to randomization.
13. HIV, HBV or HCV infection.
14. Acute viral, bacterial, or fungal infection.
15. Acute medical problems that may be considered to become an unacceptable risk, or any conditions, which might be contraindications for starting study treatment.
16.Presence of high risk for pulmonary toxicities, defined as:
a. Lung function: vital capacity ≤ 70%
b. Status following sequential or concomitant thoracic irradiation
c. Increased risk for a pulmonary toxicity induced by BCNU (Carmustine) or CCNU (Lomustine). Risk
factors include smoking, presence of a respiratory condition, pre-existing radiographic pulmonary
abnormalities, exposure to agents that cause lung damage.18. Drug abuse or extensive use of alcohol.
17. History of allergies to reagents used in this study, history of coeliac disease (gluten intolerance).
18. Drug abuse or extensive use of alcohol.
19. Clinically relevant psychiatric disorders/legal incapacity or a limited legal capacity.
20. Concomitant treatment with yellow fever vaccine.

E.5 End points

E.5.1

Primary end point(s)

• Survival rate at 24 months

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary objective of the study is to compare the overall survival (OS) at 24 months of patients treated with AP 12009 at a concentration of 10 μM over a 7-day period every other week versus standard chemotherapy treatment. Consequently, the primary efficacy endpoint is the proportion of patients showing survival 24 months after randomization for the ITT population.

(see Protocol, e.g. Synopsis)

E.5.2

Secondary end point(s)

Secondary endpoints with special relevance:

• Median overall survival (mOS)
• 14-month progression rate

Secondary efficacy endpoints:

• Overall response rate (best response according to Macdonald criteria, PR and CR)
• Tumor control rate (CR, PR, and SD)
• Duration of response
• Progression rate at 10, 12, 16, 18, 21, and 24 months
• Time to progression (months)
• Survival rate at 12, 18, 21, 27, and 30 months, and at 3 and 4 years
• Quality of Life (EORTC QLQ-C30, Independent Living Score [ILS])

E.5.2.1

Timepoint(s) of evaluation of this end point

In the final analysis the primary endpoint as well as the secondary endpoints with special relevance will be tested hierarchically. A closed test procedure with the following sort order will be used for the final analysis: 1) 24-month survival rate, 2) Median overall survival (Kaplan-Meier), 3) 14-month progression rate.
Special emphasis will be given to the interim analysis of progression rates at 14 months.
Similar statistical methods to those planned for the primary endpoint will also be used to analyze progression rates at 10, 12, 16, 18, 21, and 24 months, survival rates at 12, 18, 21, 27, and 30 months, and at 3 and 4 years, and for the analysis of overall response rates, and tumor control rate.

(see Protocol, e.g. Synopsis)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

European Union

Argentina

Brazil

Canada

India

Israel

Korea, Republic of

Mexico

Russian Federation

Taiwan

Ukraine

United States

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

Please refer to section 8.12 of the study protocol.

OR

The end of the study is defined as the moment when 80% of all randomized patients have either died or are lost to follow-up.

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	117
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	63
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	17
F.4.2	For a multinational trial
F.4.2.1	In the EEA	40
F.4.2.2	In the whole clinical trial	180

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	NIHR CRN Coordinating Centre
G.4.3.4	Network Country	United Kingdom

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2008-08-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-05-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2012-01-10

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