Clinical Trials Register

Summary
EudraCT Number:	2004-002714-11
Sponsor's Protocol Code Number:	EORTC 22033-26033
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2005-05-02
Trial results	View 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

Austria - BASG

A.2

EudraCT number

2004-002714-11

A.3

Full title of the trial

Primary chemotherapy with temozolomide vs. radiotherapy in patients with low grade gliomas after stratification for genetic 1p loss: a phase III study

A.4.1

Sponsor's protocol code number

EORTC 22033-26033

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	European Organisation for Research and Treatment of Cancer
B.1.3.4	Country	Belgium
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
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	Information not present in EudraCT
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	Temodal
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	SCH#052365
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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.8	Extractive medicinal product	Information not present in EudraCT
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	antineoplastic alkylating agent
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	Information not present in EudraCT
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	Temodal
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	SCH#052365
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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.8	Extractive medicinal product	Information not present in EudraCT
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	antineoplastic alkylating agent
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	Information not present in EudraCT
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	Temodal
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	SCH#052365
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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.8	Extractive medicinal product	Information not present in EudraCT
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	antineoplastic alkylating agent

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

Histologically proven low-grade glioma
♦ Astrocytoma WHO grade II (gemistocytic, fibrillary and protoplasmatic)
♦ Oligoastrocytoma WHO grade II
♦ Oligodendroglioma WHO grade II

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	7.1
E.1.2	Level	LLT
E.1.2	Classification code	10025783

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate a difference in progression-free survival for primary treatment with temozolomide versus primary irradiation.

E.2.2

Secondary objectives of the trial

to assess:
• whether OS can be prolonged by primary chemotherapy with temozolomide
• whether the incidence of late toxicity can be decreased by using primary chemotherapy
• the toxicity profile of the two treatments and the quality of life of the patients

Cytogenetic objective

The impact of 1p deletions in low-grade gliomas: prognostic effect of cytogenetic deletions detected in tumors on PFS overall and by treatment group. Benefit for patients with LGGs and deletions treated with TMZ compared to radiotherapy alone with respect to survival. Interaction between treatment and cytogenetic features.

E.2.3

Trial contains a sub-study

Information not present in EudraCT

E.3

Principal inclusion criteria

At the time of registration
•Histologically proven low-grade glioma
•Astrocytoma WHO grade II (gemistocytic, fibrillary and protoplasmatic)
•Oligoastrocytoma WHO grade II
•Oligodendroglioma WHO grade II
•Supratentorial tumor location only
•WHO performance status <=2
•Age ≥ 18 years

•No previous chemotherapy or radiotherapy for brain tumor
•Absence of known HIV infection, chronic hepatitis B or hepatitis C infection
•Absence of any medical condition, which could interfere with oral medication intake (e.g., frequent vomiting, partial bowel obstruction)
•Availability of histopathologic slides for central pathology review (see chapter 6.1.1, “criteria of evaluation”; and chapter 13 “pathology”)
•Availability of tumor material (paraffin-embedded) and blood for molecular testing*
•Before patient registration, written informed consent for the randomization and for the collection, transfer and analysis of the pathological material, molecular biology testing (1p testing) must be given according ICH GCP, and any applicable local regulations
•For those participating to the translational research, before patient registration, written informed consent for the collection, transfer and analysis of the material for translational research must be given according ICH GCP, and any applicable local regulations

* Patients having had previous 1p testing in a different laboratory than the one specified for this study, will need repeated testing in the central reference laboratory.

At the time of randomization
•Histologically proven low-grade glioma **
** (based on the latest performed histology, if no repeat biopsy has been performed, based on initial histology)
•Astrocytoma WHO grade II (gemistocytic, fibrillary and protoplasmatic)
•Oligoastrocytoma WHO grade II
•Oligodendroglioma WHO grade II;
•Supratentorial tumor location only
•Not candidate for treatment exclusively by surgery
•Requiring treatment as demonstrated by at least one of the following criteria:
•Age ≥ 40 years
•Radiologically proven progressive lesion
•New or worsening neurological symptoms other than seizures only (focal deficits, signs of raised intracranial pressure, mental deficits)
•Intractable seizures defined as:
Suffering from persistent seizures, defined as having both:
• persistent seizures interfering with every day life activities other than driving a car
AND
•failed three lines of anti-epileptic drug regimen, including at least one combination regimen
•WHO performance status <=2
•RTOG Neurological Function 0-3
•1p testing performed (for stratification: 1p deleted versus 1p normal versus undeterminable)
•No previous irradiation to the brain
•No prior chemotherapy
•Patients must have recovered from prior surgery, if applicable
•Adequate hematological, renal and hepatic function according to all of the following laboratory values (to be performed within 14 days, inclusive, prior to randomization):
•Absolute neutrophil count >= 1.5 x109/l
•Platelets >=100x109/l
•Serum creatinine ≤1.5 times upper limit of laboratory normal
•Total serum bilirubin ≤ 1.5 times upper limit of laboratory normal
•ASAT(AST) or ALAT(ALT) ≤ 2.5 times upper limit of laboratory normal
•Alkaline phosphatase of ≤ 2.5 times upper limit of laboratory normal
•Absence of known HIV infection, chronic hepatitis B or hepatitis C infection
•Absence of any other serious medical condition according to the medical judgment of the physician prior to randomization
•Absence of any medical condition, which could interfere with oral medication intake (e.g., frequent vomiting, partial bowel obstruction)
•Absence of previous or concurrent malignancies at other sites with the exception of surgically cured carcinoma in-situ of the cervix and non-melanoma skin cancer
•All patients of reproductive potential (male and female) must use effective contraception for the whole duration of the treatment and until 6 months thereafter. Females must not be pregnant or lactating
•Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule as discussed with the patient before randomization
•Completion of baseline quality of life questionnaires (QLQ-C30 + BN20) must be obtained before randomization (see Appendix D, Appendix H and Appendix I)
•Completion of baseline neuropsychological testing must be obtained before randomization (see Appendix M) for specified centers

E.4

Principal exclusion criteria

See above

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival

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

Information not present in EudraCT

E.6.11

Pharmacogenomic

Yes

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

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Information not present in EudraCT

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Radiotherapy

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.8.5

The trial involves multiple Member States

Yes

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

E.8.7

Trial has a data monitoring committee

Information not present in EudraCT

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

End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis

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

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	Information not present in EudraCT
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	Information not present in EudraCT
F.1.1.3	Newborns (0-27 days)	Information not present in EudraCT
F.1.1.4	Infants and toddlers (28 days-23 months)	Information not present in EudraCT
F.1.1.5	Children (2-11years)	Information not present in EudraCT
F.1.1.6	Adolescents (12-17 years)	Information not present in EudraCT
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
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	Information not present in EudraCT
F.3.3.1	Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2005-05-02.	Yes
F.3.3.2	Women of child-bearing potential using contraception	Information not present in EudraCT
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	100
F.4.2	For a multinational trial
F.4.2.1	In the EEA	550
F.4.2.2	In the whole clinical trial	699

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

2005-06-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2005-06-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-05-01

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