Clinical Trials Register

Summary
EudraCT Number:	2012-003138-17
Sponsor's Protocol Code Number:	MO28347
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-06-04
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

Portugal - INFARMED

A.2

EudraCT number

2012-003138-17

A.3

Full title of the trial

A double-blind, placebo-controlled, randomised, Phase II study
evaluating the efficacy and safety of addition of continuous multiple line bevacizumab treatment to lomustine in second (2nd)-line followed by standard of care (SOC) in third (3rd)-line and beyond compared to addition of placebo, following first progression of disease (PD1) in patients with glioblastoma (GBM) after first (1st)-line treatment with radiotherapy, temozolomide and bevacizumab

A.3.1

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

Clinical study evaluating if the patient is better and lives longer if bevacizumab is continued to be added to the standard treatment for worsening brain cancer

A.4.1

Sponsor's protocol code number

MO28347

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01860638

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	F. Hoffmann-La Roche Ltd
B.1.3.4	Country	Switzerland
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	F. Hoffmann-La Roche Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F.Hoffmann-La Roche Ltd
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.6	E-mail	global.rochegenentechtrials@roche.com

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.3.1	Product name	Bevacizumab
D.3.2	Product code	RO4876646/F02
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	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.2	Current sponsor code	RO4876646
D.3.9.4	EV Substance Code	SUB16402MIG
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)	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	Yes
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 humanised monoclonal antibody
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.2.1.1.1	Trade name	Cecenu®
D.2.1.1.2	Name of the Marketing Authorisation holder	MEDAC, Germany
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
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.3.9.2	Current sponsor code	Ro 021-6173
D.3.9.3	Other descriptive name	LOMUSTINE
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Glioblastoma

E.1.1.1

Medical condition in easily understood language

Brain tumour

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	10018336
E.1.2	Term	Glioblastoma
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of addition of continuous multiple line bevacizumab treatment to lomustine in 2nd-line followed by standard of care (SOC) in 3rd-line and beyond compared to addition of bevacizumabplacebo, as measured by overall survival (OS) from randomisation at
first progression of disease (PD1).

E.2.2

Secondary objectives of the trial

To assess:
• overall survival as measured from randomization at PD1.
• progression free survival from randomization at PD1, to 2nd PD (PD2) (PFS2), and to 3rd PD (PD3) (PFS3).
• response rates (RRs), disease control rates (DCRs), and durations of response at PD2 and PD3.
• the safety of bevacizumab treatment across multiple lines of treatment and from randomization at PD1.
• HRQoL, neurocognitive function (NCF) and resource utilization

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Are currently enrolled in Study MO28347 and have provided additional consent following amendment 6 to the protocol, which changed the study from a Phase IIIb to a Phase II study
• Age ≥ 18 years .
• Karnofsky performance status (KPS) ≥ 60.
• Newly diagnosed, histologically confirmed glioblastoma not previously treated with chemotherypy or radiotherapy
• If female and not postmenopausal (< 12 months of amenorrhea) or surgically sterile, must agree to use a highly effective contraceptive method during the treatment period and for at least 6 months after the
last dose of study drug
• Mandatory tissue collection during pre-study surgery or biopsy for confirmation of the diagnosis and pathology.
• Craniotomy or intracranial biopsy site must be adequately healed. Study treatment should be initiated > 28 days following the last surgical
procedure.

Principal eligibility criteria at the time of randomisation (following PD1):
• Documented disease progression (PD1)
• Eligibility for 2nd-line treatment with lomustine and bevacizumab as investigational medicinal products.
• Patients for whom operation or re-operation is indicated before 2nd line starts, tissue submission is mandatory
• Eastern Cooperative Oncology Group (ECOG) performance status is 0-2 when starting 2nd-line treatment
• Bevacizumab was well tolerated and treatment interruption lasted not more than 60 days

E.4

Principal exclusion criteria

• Any prior chemotherapy for GBM and low grade astrocytomas.
• Any prior radiotherapy to the brain or prior radiotherapy resulting in a potential overlap in the radiation field.
• Prior or current anti-angiogenic treatment
•Treatment with any other investigational drug within 28 days or 2 investigational agent half-lives (whichever is longer) prior to first study treatment
• Inadequate hematological, renal or liver function
• Inadequately controlled hypertension
• Prior history of gastrointestinal perforation or abscess
• Clinically significant cardiovascular disease, NYHA >/= Grade II congestive heart failure, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment
• History or evidence of central nervous system disease unrelated to cancer unless adequately treated with standard medical therapy
• History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding
• Serious non-healing wound, active ulcer, or untreated bone fracture
• Known hypersensitivity to any component of Avastin/placebo or any of the study drugs
• Active infection requiring intravenous antibiotics at start of study treatment
• Other malignancy within 5 years prior to study enrollment, except for carcinoma in situ of the cervix, basal or squamous cell skin cancer,
localized prostate cancer or ductal carcinoma in situ treated with curative intent
• Pregnant or lactating women
• Participation in any other study

E.5 End points

E.5.1

Primary end point(s)

Overall survival (OS)

E.5.1.1

Timepoint(s) of evaluation of this end point

When 130 events have been observed

E.5.2

Secondary end point(s)

- 2nd and 3rd line progression free survival (PFS)
- Response, duration of response and disease control rates in 2nd and 3rd line
- Safety
- Neurocognitive function, Health Related QoL, resource utilization

E.5.2.1

Timepoint(s) of evaluation of this end point

at the time of the primary endpoint (when 130 events have been observed)

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

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Health related Quality of Life, Neurocognitive function

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

Austria

Bulgaria

Croatia

Estonia

France

Greece

Italy

Latvia

Portugal

Romania

Spain

Sweden

Turkey

United Kingdom

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

The end of the study is defined as the date when the LPLV occurs. LPLV is planned 30 days after the 130th OS event is reported which is estimated approximately 36 months after the first patient is enrolled.

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.1.2.1

Number of subjects for this age range:

234

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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.4.2.1

In the EEA

284

F.4.2.2

In the whole clinical trial

300

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)

Patients benefiting from treatment with bevacizumab in any line of therapy at the study end will be offered to continue bevacizumab (provided by the sponsor) by consenting to participate in another separate bevacizumab study (AVALTE MO25757). This step will be possible only if the period from last Avastin dose in TAMIGA to first dose of Avastin in AVALTE is less than 42 days and all other eligibility criteria for AVALTE study are met.

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

2013-06-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2017-01-06

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