Clinical Trials Register

Summary
EudraCT Number:	2009-012186-63
Sponsor's Protocol Code Number:	LWNO 0901
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2009-07-13
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

Netherlands - Competent Authority

A.2

EudraCT number

2009-012186-63

A.3

Full title of the trial

Landelijke Werkgroep voor Neuro-Oncologie trial (LWNO 0901)
Randomized phase II study of Bevacizumab versus Bevacizumab plus Lomustine in patients with recurrent Glioblastoma: the BELOB trial

A.3.2

Name or abbreviated title of the trial where available

BELOB trial

A.4.1

Sponsor's protocol code number

LWNO 0901

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	Erasmus MC, more specifically for and on behalf of the department of Neurology/Neuro-Oncology
B.1.3.4	Country	Netherlands
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	Yes
D.2.1.1.1	Trade name	Avastin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
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	Intravenous infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.3	Other descriptive name	Avastin
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	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	No
D.3.11.8	Extractive medicinal product	No
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	Recombinant humanized monoclonal antibody
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	Belustine
D.2.1.1.2	Name of the Marketing Authorisation holder	Prostrakan
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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*
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	LOMUSTINE
D.3.9.1	CAS number	13010474
D.3.9.3	Other descriptive name	CCNU
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)	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	No
D.3.11.8	Extractive medicinal product	No
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	Alkylating oncolyticum (nitrosureumderivate)

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

Patients with recurrent glioblastoma multiforme who failed combined chemo-irradiation with temozolomide.

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	12.0
E.1.2	Level	LLT
E.1.2	Classification code	10018336
E.1.2	Term	Glioblastoma

E.1.2 Medical condition or disease under investigation

E.1.2	Version	12.0
E.1.2	Level	LLT
E.1.2	Classification code	10018337
E.1.2	Term	Glioblastoma multiforme

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to assess the therapeutic activity of Bevacizumab in combination with Lomustine and of Bevacizumab given as single agent in patients with recurrent GBM who failed combined chemo-irradiation with temozolomide.
The primary end-point will be 6 months PFS.

E.2.2

Secondary objectives of the trial

Secondary endpoints are median PFS, PFS at and 12 months, median Overall Survival (OS), OS at 6 and 12 months, response rate, neurological deterioration free survival, Quality of Life and steroid use. Response will only be assessed in patients with measurable disease.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age ≥ 18 years
• WHO Performance status 0 - 2
• Histologically or biopsy proven glioblastoma multiforme including patients with anaplastic oligoastrocytomas with necrosis (which meets WHO 2007 criteria for glioblastoma)
• First relapse after prior treatment with combined chemo-irradiation with temozolomide
• Patient may have undergone surgery for the recurrence. If operated, residual and measurable disease after surgery is not required but surgery must have confirmed the recurrence. In case of operation, post-operative MRI must be made within 48 hours following surgery. Minimum interval of at least 4 weeks between surgery and the start of Bevacizumab treatment, and patients should have fully recovered from the surgery.
• For non operated patients, recurrent disease must be at least one bidimensionally measurable target lesion (contrast enhancing lesion) with one diameter of at least 2cm, based on MRI scan done within two weeks prior to start of treatment.
• Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan.
• No prior treatment with Lomustine or other nitrosourea’s.
• No prior treatment with Bevacizumab or other VEGF-R signalling inhibitors
• No radiotherapy within the three months prior to the diagnosis of progression
• No chemotherapy in the past four weeks
• No radiotherapy with a dose over 65 Gy, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven
• Normal hematological functions: neutrophils ≥ 1.5 x 109 cells/l, platelets ≥100 x 109 cells/l, Hb ≥ 6.2 mmol/l.
• Normal liver function: bilirubin < 1.5 x upper limit of the normal range (ULN), alkaline phosphatase and transaminases (ASAT/ALAT) < 2.5 x ULN, INR < 1.5.
• Normal renal function:
o calculated (Cockcroft-Gault) or measured creatinine clearance > 30 mL/min
o Urine dipstick for proteinuria < 2+. Patients with >2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine collection and must demonstrate ≤1 g of protein/24 hr.
• Women of reproductive potential, female patients within one year of entering the menopause as well as males must agree to use an effective non-hormonal method of contraception during the treatment period and for at least 6 months after the last dose of Bevacizumab.
• No other diseases, interfering with follow up.
• No geographical, psychological or other non-medical conditions interfering with follow-up
• Written informed consent.

E.4

Principal exclusion criteria

• History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
• Arterial or venous thrombosis ≤ 12 months prior to registration
• History of myocardial infarction (≤ 6 months prior to inclusion), unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication.
• Uncontrolled hypertension defined by a systolic pressure > 150 mm Hg and/or diastolic pressure > 100 mm Hg, with or without anti-hypertensive medication. Patients with initial blood pressure elevation are eligible if initiation or adjustment of anti-hypertensive medication lowers pressure to meet the entry criteria.
• Current or recent (within 10 days of first dose of Bevacizumab) use of aspirin (> 325 mg/day) or other NSAID with anti-platelet activity or treatment with dipyramidole, ticlopidine, clopidogrel and cilostaz.
• Use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic (as opposed to prophylactic) purposes.
• Clinically serious (as judged by the investigator) non-healing wounds, active skin ulcers or incompletely healed bone fracture.
• History of active gastroduodenal ulcer(s).
• History of abdominal fistula as well as non-GI fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to inclusion.
• Evidence of any active infection requiring hospitalization or antibiotics, within 2 weeks prior to day 1 of cycle 1.
• Invasive procedures (major surgical procedure, open biopsy or significant traumatic injury) within 4 weeks prior to randomization, or anticipation of the need for major surgery during the course of the study treatment. Placement of a vascular access device is not considered as a major surgical procedure if performed more than 24 hours prior to Bevacizumab administration.
• Current or recent (within 4 weeks of enrollment) treatment with another investigational drug or participation in another investigational study.
• Known hypersensitivity to any part of the Bevacizumab formulation.
• Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibody.
• Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to randomization.

E.5 End points

E.5.1

Primary end point(s)

The primary end-point will be 6 months PFS.

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

End of study occurs when all of the following criteria have been satisfied:
1 - The trial is mature for the analysis of the primary endpoint
2 - The database has been fully cleaned and locked 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

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

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

The treatment or care will not be different from normal treatment

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

2009-07-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-11-05

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

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