Clinical Trials Register

Summary
EudraCT Number:	2006-005505-64
Sponsor's Protocol Code Number:	AVAST-M
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2008-02-22
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

UK - MHRA

A.2

EudraCT number

2006-005505-64

A.3

Full title of the trial

A Randomised Trial Evaluating the VEGF Inhibitor, Bevacizumab (Avastin), as Adjuvant Therapy following Resection of AJCC Stage IIB (T3bN0M0 & T4aN0M0), IIC (T4bN0M0) and III (TxN1-3M0) Cutaneous Melanoma

A.3.1

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

A trial looking at bevacizumab after surgery for melanoma skin cancer (AVAST-M)

A.3.2

Name or abbreviated title of the trial where available

AVAST-M

A.4.1

Sponsor's protocol code number

AVAST-M

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN81261306

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	Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital
B.1.3.4	Country	United Kingdom
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	Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital
B.5.2	Functional name of contact point	Sabine Klager
B.5.3	Address:
B.5.3.1	Street Address	Clinical Trials Office, Addenbrooke's Hospital
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	CB2 0QQ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+4401223348179
B.5.5	Fax number	+4401223348071
B.5.6	E-mail	sabine.klager@addenbrookes.nhs.uk

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
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.3.10	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	100mg/4ml
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	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
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.3.10	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	400mg/16ml
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

Patients at high risk of recurrence after resection of cutaneous melanoma:
those patients with histological confirmation of completely resected AJCC stage IIB (T3bN0M0 & T4aN0M0), IIC (T4bN0M0) and III (TxN1-3M0) cutaneous melanoma

E.1.1.1

Medical condition in easily understood language

A type of skin cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 determine the overall survival of patients treated with bevacizumab, compared with standard observation after resection of high risk melanoma

E.2.2

Secondary objectives of the trial

The study will also compare the two arms of the study in terms of the following parameters:
• Disease free interval
• Distant metastatis-free interval
• Safety and toxicity
• Quality of life
• Measurement of angiogenesis biomarkers in tissue and peripheral blood to identify potential prognostic and predictive indicators

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Written informed consent
•Age ≥16 years
•Able to comply with the protocol
•Patients with histological confirmation of completely resected AJCC stage IIB (T3bN0M0 & T4aN0M0), IIC (T4bN0M0) and III (TxN1-3M0) cutaneous melanoma
•Patients may or may not have undergone sentinel lymph node dissection and/or elective lymph node dissection
•Patients must be randomised within 12 weeks of completing latest surgery for melanoma
•For patients with resected stage IIB or IIC disease, when wide local excision is undertaken after resection of primary melanoma, the interval between the two procedures must be ≤ 12 weeks.
•For patients where sentinel lymph node biopsy followed by complete lymph node dissection is the latest surgery for melanoma, the time between the two procedures must be ≤ 12 weeks.
•Eastern Cooperative Oncology Group (ECOG) performance status 0-1
•Life expectancy ≥ 6 months
•Blood pressure systolic ≤150 and diastolic ≤100 mmHg.
•Adequate haematological function:
oAbsolute neutrophil count (ANC) ≥1.5 x 109/L AND
oPlatelet count ≥100 x 109/L AND
oHaemoglobin ≥9 g/dL (may be transfused to maintain or exceed this level)
•Adequate liver function (unless pre-existing abnormality):
oTotal bilirubin <1.5 x upper limit of normal (ULN) AND
oAsparagine aminotransferase (AST), and/or alanine aminotransferase (ALT) <2 x ULN
•Adequate renal function:
oSerum creatinine ≤1.25 x ULN or calculated creatinine clearance ≥50 mL/min AND
oUrine dipstick for proteinuria <2+. Patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤1 g of protein in 24 hours AND
oProthrombin time (PT) and Partial thromboplastin time (PTT/aPTT) ≤1.5 x ULN
•Negative pregnancy test (serum or urine dipstick) for women of child bearing potential (WOCBP)
•Adequate contraception:
oWomen of child bearing potential (WOCBP) must agree to use, effective non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) if randomised to the treatment arm and for a period of 6 months following the last administration of bevacizumab.
oMen must agree to use effective contraception if randomised to the treatment arm and for a period of 90 days following the last administration of bevacizumab.

E.4

Principal exclusion criteria

•Non-cutaneous melanoma as the primary disease site
•Any evidence of distant or non-regional lymph node metastases
•Evidence of CNS metastases.
•Incomplete surgical resection of the disease
•Adjuvant radiotherapy ongoing at randomisation
•Prior chemotherapy, immunotherapy, or hormonal therapy for melanoma within 12 weeks of randomisation
•Any surgery (including open biopsy, but excluding insertion of an indwelling catheter), or significant traumatic injury within 28 days prior to randomisation, or anticipation of the need for surgery during study treatment including invasive dental surgery
•Current or recent (within 7 days of randomisation) use of aspirin (> 300 mg/day) or clopidogrel (> 75 mg/day)
•Current or recent (within 7 days of randomisation) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes. Prophylactic use of anticoagulants is allowed
•History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding
•Clinically significant (i.e. active) cardiovascular disease for example CVA (≤6 months before randomisation), myocardial infarction (≤6 months before randomisation), unstable angina, congestive heart failure NYHA Class ≥II, serious cardiac arrhythmia requiring medication during the study and might interfere with regularity of the study treatment, or not controlled by medication
•Unhealed wound, active peptic ulcer or bone fracture
•History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of randomisation
•Pregnant or breast-feeding females.
•Treatment with any other investigational agent within 28 days prior to randomisation
•Known hypersensitivity to bevacizumab or any of its excipients
•Evidence of any other disease, neurological or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
•Any condition, which, in the opinion of the investigator, might interfere with the safety of the patient or evaluation of the study objectives
•Previous malignancy in the last 5 years (patients must have been continuously disease free for 5 years prior to the time of randomisation) except for curatively treated basal or squamous cell skin cancers or in situ malignancies

E.5 End points

E.5.1

Primary end point(s)

To determine the overall survival of patients treated with bevacizumab, compared with standard observation after resection of high risk melanoma

E.5.1.1

Timepoint(s) of evaluation of this end point

March 2017 - Anticipated analysis with a minimum follow-up of 5 years

E.5.2

Secondary end point(s)

The study will also compare the two arms of the study in terms of the following parameters:
• Disease free interval
• Distant metastasis-free interval
• Safety and toxicity
• Quality of life (QoL)
• Measurement of angiogenesis biomarkers in tissue and peripheral blood to identify potential prognostic and predictive indicators

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

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

Yes

E.6.13.1

Other scope of the trial description

Quality of life

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

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

Standard observation

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.8.5.1

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

End of trial is defined by the last visit of the last patient undergoing the trial

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

Information not present in EudraCT

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

F.3.3.3

Pregnant women

Information not present in EudraCT

F.3.3.4

Nursing women

Information not present in EudraCT

F.3.3.5

Emergency situation

Information not present in EudraCT

F.3.3.6

Subjects incapable of giving consent personally

Information not present in EudraCT

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

1320

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

1320

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)

Expected normal treatment of that condition

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

2007-02-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-03-16

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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