Clinical Trials Register

Summary
EudraCT Number:	2007-005017-19
Sponsor's Protocol Code Number:	BO20924
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-04-21
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2007-005017-19

A.3

Full title of the trial

Open-label, multi-center, randomized, two stage adaptive design study of the combination of bevacizumab with standard chemotherapy in minor patients with metastatic rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma or Ewing’s sarcoma/soft-tissue primitive neuroectodermal tumors

A.3.2

Name or abbreviated title of the trial where available

BERNIE

A.4.1

Sponsor's protocol code number

BO20924

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

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	ROCHE
B.1.3.4	Country	Italy
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
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	United Kingdom
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	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.3.10	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	Non Applicabile

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

childhood and adolescent patients, with metastatic rhabdomyosarcoma (RMS), nonrhabdomyosarcoma soft-tissue sarcoma (NRSTS), or Ewing’s sarcoma(ES)/soft-tissue primitive neuroectodermal tumor (PNET)

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10039026

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10016635

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10015562

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10029274

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 evaluate the feasibility and efficacy of the combination of bevacizumab with standard chemotherapy as compared with standard chemotherapy alone in childhood and adolescent patients in the indication specified above, as assessed by: Incidence rate of patients with dose discontinuation or dose modification/delay. Event-free survival (EFS) (2nd stage only).

E.2.2

Secondary objectives of the trial

To determine the safety, tolerability and efficacy of the combination of bevacizumab with standard chemotherapy as compared with standard chemotherapy alone in the indication specified above, as assessed by : Adverse event profile. Response rate (according to RECIST). Overall survival (OS). Duration of response (DR)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent of patient/parent/legally acceptable representative (latest approved version by the Independent Ethics Committee [IEC]/Institutional Review Board [IRB]), obtained prior to any study-specific procedures. 2. Age prior to treatment start &#8805; 2 years and &#8804; 17 years. 3. Newly diagnosed, histologically documented, patients with one of the following diseases: Metastatic Rhabdomyosarcoma (RMS). Risk factors:Bone or bone marrow involvement (considered as 1 site). More than two different organs with metastatic disease. Unfavorable primary sites: extremities (including buttocks and shoulder) and trunk. At least two of the RMS specific risk factors are required for the 1st stage of the study. Metastatic non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS). Metastatic Ewing’s sarcoma (ES)/soft-tissue primitive neuroectodermal tumor (PNET) Risk factors: Bone metastases. Bone marrow metastases. At least one of these ES/PNET specific risk factors is required for the 1st stage of the study. 4. Age-adapted performance status and life expectancy adequate for chemotherapy according to the protocol. 5. Adequate bone marrow function: Absolute neutrophil count (ANC) &#8805; 1.0 x 109/L and WBC &#8805; 2.0 x 109/L. Platelet count &#8805; 100 x 109/L (in case of bone marrow involvement &#8805; 75 x 109/L). Hb > 7.5 g/dL (75 g/L - including after transfusion). 6. Adequate blood clotting: PT-INR &#8804; 1.5 and aPTT &#8804; 1.5 x upper limit of normal (ULN) within 7 days prior to treatment start. 7. Adequate liver function: Serum (total) bilirubin &#8804; 1.5 x ULN. AST and ALT &#8804; 2.5 x ULN in patients without liver metastases, &#8804; 5 x ULN in patients with liver metastases. 8. Adequate renal function: Serum creatinine < 1.5 x ULN for age; If serum creatinine is > 1.5 x ULN for age, the creatinine clearance (or radioisotope GFR) must be > 70 mL/min/1.73 m2. Urine dipstick < 2+ for proteinuria. Patients who have &#8805; 2+ of proteinuria on dipstick urinalysis should undergo a 24 hour urine collection; children and adolescents &#8804; 12 years must have &#8804; 500 mg of protein/24 hours and patients > 12 years must have &#8804; 1 g of protein/24 hours. No clinical evidence of nephrotic syndrome. 9. Adequate cardiac function (Shortening Fraction (SF) &#8805; 28%) at screening, as determined by echocardiography; no evident and clinically significant symptoms of CHF (must be < class II of classification for heart failure (New York Heart Association (NYHA) or Ross scale).

E.4

Principal exclusion criteria

1. Previous malignant tumors. 2. Prior systemic anti-tumor treatment. 3. Evidence of symptomatic spinal cord compression, CNS or brain metastases; patients must undergo a MRI or CT scan of the brain and/or spine in case of suspected brain metastatic disease. 4. Tumor invading major blood vessels (CT scan based evidence); the investigator or radiologist must excludeor extending into the lumen of a major blood vessel (e.g. pulmonary artery or superior vena cava). 5. Major surgical procedures or anticipation of the need for major surgery (other than the standard per protocol surgery) between screening and the first safety follow-up visit is considered incompatible with the use of bevacizumab; minor surgical procedures, including biopsy similar to and including central venous access device placement, within less than 7 days prior to randomization, or anticipated treatment start before the wound has healed. 6. Documentation of clinically evident non-healing wound (as determined by the investigator), peptic ulcer or bone fracture. 7. Current or recent (within 30 days prior to study start) treatment with another investigational drug or participation in another investigational study. 8. Increased risk of gastrointestinal, renal, bone marrow, or congenital bleeding disorders. 9. History or evidence of severe uncontrolled intercurrent illness at study entry, e.g. Uncontrolled seizures. Any bleeding or clotting diathesis, e.g. venous or arterial thromboembolic events (VTE, ATE), pulmonary embolism (PE). Any clinically significant (i.e. active) cardiovascular disease, e.g. cerebrovascular accidents (CVAs)/stroke, myocardial infarction (MI), transient ischemic attacks (TIAs), unstable angina, or severe cardiac arrhythmia; clinical evidence of arterial hypertension, specified as systolic and diastolic BP &#8805; 95th percentile for age, gender and height (see Appendix 7). Any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or places the patient at unacceptable risk from treatment complications. General or peripheral neuropathy &#8805; grade 2 which is not induced by the underlying malignant disease. Uncontrolled infection. 10. Known hypersensitivity to: Any component of study drugs or ingredients. Chinese hamster ovary products or other recombinant human or humanized antibodies. 11. Ongoing (for &#8805; 10 days prior to the 1st dose of study treatment) antithrombotic treatment, i.e. with aspirin or other platelet inhibitors, anticoagulants including thrombolytic agents, unfractionated or low-molecular-weight heparins, or coumarin-derived anticoagulants; well-controlled anticoagulation is permitted as primary prophylaxis against thromboembolic events (TEs) and/or for maintenance of patency of a central access venous device (CVAD). 12. Pregnancy and/or lactation: a negative serum pregnancy test in all female patients aged &#8805; 12 years (to be confirmed by urine test if serum test was performed more than 7 days prior to treatment start) must be obtained before treatment start;fertile patients with potential to bear or father a child must use an effective method of contraception. et al.....

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint – 1st stage of the study: The primary endpoint of the 1st stage of the study is the incidence rate of patients with dose discontinuation or dose modification/delay of any component of study treatment. A summary of incidence rates will be produced. Primary endpoint – 2nd stage of the study: The primary endpoint of the 2nd stage of the study is an exploratory analysis of the event free survival defined as time between randomization and insufficient therapeutic response or death due to any cause. Patients without an event will be censored at the date of last follow up for progression. Patients with no post baseline follow up for progression will be censored at the day of randomization.

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

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

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

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

fase I / II in pediatria

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

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

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

L`analisi finale (fine della fase II) sara` effettuata a circa 19 mesi dalla data di randomizzazione dell`ultimo paziente

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	Yes
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)	Yes
F.1.1.6	Adolescents (12-17 years)	Yes
F.1.2	Adults (18-64 years)	No
F.1.3	Elderly (>=65 years)	No
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 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 2009-04-21.	Yes
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	12
F.4.2	For a multinational trial
F.4.2.1	In the EEA	150
F.4.2.2	In the whole clinical trial	150

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

2008-12-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-02-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-04-30

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials