Clinical Trials Register

Summary
EudraCT Number:	2009-011400-33
Sponsor's Protocol Code Number:	MO22224
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-06-24
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

Sweden - MPA

A.2

EudraCT number

2009-011400-33

A.3

Full title of the trial

A multi-centre, open-label, randomised, two-arm Phase III trial of bevacizumab plus chemotherapy versus chemotherapy alone in patients with platinum-resistant, epithelial ovarian, fallopian tube or primary
peritoneal cancer.

A.3.1

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

A study of bevacizumab plus chemotherapy versus chemotherapy alone in patients with ovarian cancer.

A.3.2

Name or abbreviated title of the trial where available

AURELIA

A.4.1

Sponsor's protocol code number

MO22224

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00976911

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.3.4	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.3.9.3	Other descriptive name	rhuMAb VEGF, anti-VEGF
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.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

Platinum-resistant, epithelial ovarian, fallopian tube or primary peritoneal cancer

E.1.1.1

Medical condition in easily understood language

ovarian cancer

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	16.1
E.1.2	Level	PT
E.1.2	Classification code	10061344
E.1.2	Term	Peritoneal neoplasm
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	16.1
E.1.2	Level	PT
E.1.2	Classification code	10016180
E.1.2	Term	Fallopian tube cancer
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	16.1
E.1.2	Level	PT
E.1.2	Classification code	10033128
E.1.2	Term	Ovarian cancer
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 compare progression-free survival (PFS) of patients randomised to selected chemotherapy only or to selected chemotherapy plus bevacizumab

E.2.2

Secondary objectives of the trial

• Objective response rate (ORR)
- by RECIST and CA-125 response criteria (“responders”)
- by RECIST only (“RECIST responders”)
- by CA-125 response criteria only (“CA-125 responders”).
• Biological progression-free interval (PFIBIO)
- by serum CA-125 and assessed according to the GCIG criteria
• Overall survival (OS)
• Quality of life (QOL)
- QOL and symptom control will be assessed using EORTC QLQ-C30, QLQ-OV28,
Hospital Anxiety Depression Scale (HADS), FACT/NCCN Ovarian Symptom Index
(FOSI) and symptom questionnaires.
• Safety and tolerability

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent obtained prior to initiation of any study-specific procedures and treatment as confirmation of the patient’s awareness and willingness to comply with the study requirements.
2. Patients ≥18 years of age with histologically confirmed and documented disease. The following histological types are eligible:
• adenocarcinoma NOS
• clear cell adenocarcinoma
• endometriod adenocarcinoma
• malignant Brenner's tumour
• mixed epithelial carcinoma
• mucinous adenocarcinoma
• serous adenocarcinoma
• transitional cell carcinoma
• undifferentiated carcinoma.
3. Patients must have platinum-resistant disease (defined as progression within <6
months from completion of a minimum of 4 platinum therapy cycles. The date should be calculated from the last administered dose of platinum therapy).
4. Patients must have disease that is measurable according to RECIST or assessable according to the GCIG CA-125 criteria and require chemotherapy treatment.
5. ECOG PS 0–2.
6. Life expectancy of greater than or equal to 12 weeks.

E.4

Principal exclusion criteria

1. Patients whose disease was refractory to their previous platinum treatment.
2. Non-epithelial, including malignant mixed Müllerian tumours.
3. Ovarian tumours with low malignant potential.
4. History of other clinically active malignancy within 5 years of enrollment
5. Previous treatment with >2 anticancer regimens.
6. Any prior radiotherapy to the pelvis or abdomen.
7. Surgery (incl. open biopsy) within 4 wks prior to the start of study, or anticipation of the need for major surgery during study treatment.
8. Minor surgical procedures within 24 hours prior to first study treatment.
9. Previous exposure to murine CA-125 Ab (only applicable to those patients with non-measurable disease by RECIST).
10. Current or recent chronic daily treatment with aspirin (>325 mg/day).
11. Current or recent treatment with another investigational drug within 30 days of first study treatment dosing or earlier participation in this study.
12. Chronic daily treatment with corticosteroids, excluding inhaled steroids.
13. Inadequate bone marrow function: ANC: <1.5x10E9/l, or platelet count <100x10E9/l, or haemoglobin <9 g/dl. Patients may be transfused to maintain haemoglobin values >9 g/dl.
14. Inadequate coagulation parameters: aPTT >1.5 x ULN (patients on heparin treatment must have an aPTT between 1.5 - 2.5 x ULN), or INR >1.5.
15. Inadequate liver function, defined as: serum (total) bilirubin >1.5 x ULN for the
institution; alkaline phosphatase, AST/SGOT or ALT/SGPT >2.5 x ULN (or 5 x ULN in the presence of liver metastases).
16. Inadequate renal function, defined as serum creatinine >2.0mg/dl or >177μmol/l or calculated creatinine clearance <40ml/min for patients intended to be treated with topotecan. urine dipstick for proteinuria >2+. Patients with ≥2+ proteinuria on baseline dipstick analysis should undergo a 24-hour urine collection and must demonstrate ≤1 g of protein in the 24-hour urine. Alternatively, proteinuria testing can be performed according to local
standards.
17. History or evidence upon physical/ neurological examination of CNS disease unrelated to cancer, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).
18. Symptomatic CNS metastasis
19. Pre-existing peripheral neuropathy ≥CTC grade 2 for those patients planned to receive paclitaxel.
20. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start, or within 14 days (with a confirmatory urine pregnancy test within 7 days prior to study treatment start).
21. Women of childbearing potential not using highly-effective, hormonal or nonhormonal means of contraception (i.e. intrauterine contraceptive device) during
the study and for 6 months after the last dose of study medication.
22. History or evidence of thrombotic or hemorrhagic disorders; including CVA/stroke or TIA or sub-arachnoid haemorrhage within ≤6 months prior to the first study treatment.
23. Uncontrolled hypertension (sustained systolic >150 mmHg and/or diastolic >100
mmHg despite antihypertensive therapy) or clinically significant (i.e. active cardiovascular disease, including: myocardial infarction or unstable angina within ≤6 months prior to the first study treatment; NYHA grade II or greater CHF;
serious cardiac arrhythmia requiring medication (with the exception of atrial
fibrillation or paroxysmal supraventricular tachycardia); peripheral vascular disease >grade 3.
24. LVEF defined by MUGA/ECHO below the institutional lower limit of normal (only
applicable for patients intended to be treated with PLD).
25. History of bowel obstruction, including sub-occlusive disease, related to the
underlying disease and history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess. Evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction.
26. Non-healing wound, ulcer or bone fracture.
27. Serious active infection requiring i.v. antibiotics and/or hospitalisation at study
entry.
28. Known hypersensitivity to any of the study drugs or excipients.
29. Evidence of any other medical conditions, physical examination or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment-related complications.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable is progression-free survival (PFS). It is defined as the time from the date of randomisation to the first documented disease progression or death, whichever occurs first.

E.5.1.1

Timepoint(s) of evaluation of this end point

Disease progression, death, or 6 month after the first dose of study treatment, whichever occurs first.

E.5.2

Secondary end point(s)

• Objective response rate (ORR)
• Overall survival (OS)

E.5.2.1

Timepoint(s) of evaluation of this end point

For Objective response rate, the timepoint is disease progression, death, or 6 month after the first dose of study treatment, whichever occurs first.
For overall survival, the timepoint is death or 12 month after the last patient last dose of study treatment, whichever occurs first

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability; Biomarker (CA-125) analysis; QoL

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

selected standard chemotherapy

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

Belgium

Denmark

France

Greece

Italy

Netherlands

Norway

Portugal

Sweden

Bosnia and Herzegovina

Finland

Germany

Spain

Turkey

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

LPLV. The study will be closed as soon as the protocol amendment 5 is approved by CAs and ECs. The primary analysis will be performed once at least 247 events of disease progression or death have been observed, or at the end of study which ever occurs first. Patients are anticipated to be followed for a minimum of 6 months for PFS. Survival follow-up will continue until protocol amendment 5 is approved by Competent Authorities and Ethics Committees.

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:

228

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

133

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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

341

F.4.2.2

In the whole clinical trial

361

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 receiving bevacizumab at the time of study end will be offered participation in the Avastin Long Term Extension study (MO25757). In countries where MO25757 protocol is not approved, patients may be offered continued bevacizumab treatment with sponsored commercial drug until PD, toxicity or patient request for discontinuation.

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	PAREXEL International GmbH
G.4.3.4	Network Country	Germany

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2009-07-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-08-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-07-09

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