Adjuvant aVAStin Trial in high-risk Melanoma - 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.
The worldwide incidence of melanoma is rising faster than that of any other malignancy, making it a major public health issue. Resection of primary melanomas offers a significant chance of cure. However, melanomas invade and metastasise early and once there is invasion into the dermis, the outlook changes dramatically. The 5-year survival for melanomas greater than 4mm Breslow thickness is around 45%. Macroscopic involvement or regional lymph nodes reduces 5-year survival to as little as 25%, despite full surgical clearance. Once melanoma has spread beyond surgical salvage, life expectancy is extremely poor, with median survival around 6.4 months despite systemic treatment. Thus, effective adjuvant therapy is much needed to improve outcome after resection of melanoma in patients at high risk of disease recurrence.
Doctors usually treat melanoma skin cancer with surgery. After this, you have regular check ups because there is a risk that the melanoma may come back. So far, there is no strong research evidence to show that having any treatment after surgery helped people live longer. So having regular check ups by surgeons is the standard treatment. Bevacizumab (also known as Avastin) is a type of biological therapy called a monoclonal antibody. It seeks out and blocks a particular protein which is needed for the cancer cell to grow. Doctors already use bevacizumab to treat a number of other advanced cancers. But it wasn't known whether it would help stop melanoma coming back after surgery.
AVAST-M is a Randomised Phase III multi-centre prospective clinical trial, with an objective to compare the overall survival of patients with resected melanoma at high risk of recurrence treated with bevacizumab compared with observation only. The aims of the trial are to find out if bevacizumab after surgery could help people with melanoma live longer, or delay melanoma from coming back for longer learn more about the side effects find out if there were ways to predict who would benefit most from bevacizumab.
Main 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:
- 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.
Main 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
Funders and sponsors
Dr Pippa Corrie
Cancer Theme Email: firstname.lastname@example.org