AVAST-M

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:

Absolute neutrophil count (ANC) ≥1.5 x 109/L AND

Platelet count ≥100 x 109/L AND

Haemoglobin ≥9 g/dL (may be transfused to maintain or exceed this level)

Adequate liver function (unless pre-existing abnormality):

Total bilirubin <1.5 x upper limit of normal (ULN) AND

Asparagine aminotransferase (AST), and/or alanine aminotransferase (ALT) <2 x ULN

Adequate renal function:
Serum creatinine ≤1.25 x ULN or calculated creatinine clearance ≥50 mL/min AND
Urine 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

Prothrombin 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:
Women 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.
Men 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.

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