Combining bevacizumab with immunotherapy and targeted radiotherapy for melanoma brain metastases

Inclusion Criteria:

* 1\. Histologically (or cytologically) proven metastatic melanoma, with radiologically confirmed brain metastases.
* 2\. Symptomatic from brain metastases at the time of study enrolment, or brain metastases that requires corticosteroids for the management of neurological symptoms.
* 3\. Intracranial lesions amenable to hypofractionated stereotactic radiotherapy. These are defined as all intracranial melanoma lesions greater or equal to 5 mm in diameter, all intracranial lesions that are causing symptoms, and all intracranial lesions located in the eloquent areas of the brain.
* 4\. World Health Organisation (WHO) performance status of 0 - 2
* 5\. At least one brain metastasis has to be symptomatic.
* 6\. Laboratory tests required: Haemoglobin (Hb) ≥ 9.0 g/dL Absolute neutrophil count ≥ 1 x 109/L Platelet count ≥ 100 x 109/L Either: Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (Patients with isolated hyperbilirubinaemia due to Gilbert's syndrome are allowed.) Or: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x (ULN) unless raised due to tumour in which case up to 5 x ULN is permissible Creatinine clearance ≥ 40 mL/min (Cockcroft-Gault or MDRD are acceptable)
* 7\. Age ≥ 18 years
* 8\. Able to provide informed written consent (signed and dated), attend trial site for study visits and be capable of co-operating with treatment and follow-up

Exclusion Criteria:

* 1\. Prior radiotherapy to the brain
* 2\. Active concurrent malignancy requiring systemic anti-cancer therapy within the last 2 years. Patients with any malignancy treated with curative intent and no evidence of disease will be eligible for this trial.
* 3\. Prior systemic therapy for melanoma, unless given in the neoadjuvant or adjuvant setting for extracranial disease only, completed more than \>6 months prior to enrolment in this trial and if administered with radiological proof of the absence of brain metastases
* 4\. Inability to undergo MRI of the brain
* 5\. Definitive leptomeningeal disease. Patients with equivocal leptomeningeal disease may be included on the trial after discussion with CPI.
* 6\. Female patients who are pregnant or lactating. Patients who are able to become pregnant, must return a negative serum or urine pregnancy test before enrolment and agree to use two forms of contraception (one effective form plus a barrier method) \[oral, injected or implanted hormonal contraception and condom; intra-uterine device and condom; diaphragm with spermicidal gel and condom\] or agree to sexual abstinence, effective from signing the consent form, throughout the trial and for six months after any treatment for melanoma, radiotherapy or immunotherapy, are considered eligible.
* 7\. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using a barrier method of contraception or to sexual abstinence effective from the first administration of bevacizumab, throughout the trial and for six months afterwards after treatment the end-of-trial visit. Men with partners of child-bearing potential must also be willing to ensure that their partner uses an effective method of contraception for the same duration for example, hormonal contraception, intrauterine device, diaphragm with spermicidal gel or sexual abstinence). Men with pregnant or lactating partners must be advised to use barrier method contraception to prevent exposure of the foetus or neonate. Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
* 8\. Haemorrhage encompassing \>50% of any lesion that is \>10 mm in diameter (excluding surrounding oedema). A modern susceptibility-sensitive MRI sequence such as SWI is mandatory.
* 9\. Brain metastases greater than 5 cm in maximal diameter
* 10\. Increasing corticosteroid dose for 48 hours prior to initiation of study therapy OR current dexamethasone-equivalent dose of \>8 mg per day
* 11\. Major thoracic or abdominal surgery within 28 days prior to initiation of trial treatment
* 12\. Neurosurgery within 14 days prior to initiation of trial treatment
* 13\. Active or history of severe auto-immune disease requiring systemic anti-inflammatory therapy. Patients with well-controlled auto-immune diseases not requiring systemic anti-inflammatory therapy may be included after consultation with the CPI. Severe auto-immune respiratory disease will be excluded from the trial.
* 14\. History of inflammatory bowel disease
* 15\. Requirement for ongoing concurrent systemic immunosuppressive therapy (other than corticosteroids).
* 16\. History of intra-abdominal inflammatory process within 6 months prior to initiation of trial treatment, including but not limited to peptic ulcer disease, diverticular disease or colitis.
* 17\. History of abdominal or trachea-oesophageal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to initiation of trial treatment
* 18\. History of intestinal obstruction and/or clinical signs or symptoms of gastrointestinal obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration, parenteral nutrition or tube feeding within 6 months prior to initiation of trial treatment
* 19\. Any Grade ≥3 haemorrhage or bleeding event within 28 days of trial treatment initiation. Patients presenting with haemorrhagic brain metastases that have been adequately treated with neurosurgery are not excluded under this criterion but remain subject to criterion 12 pertaining to timing of neurosurgery.
* 20\. Current use of full-dose anticoagulation or thrombolytic therapy within 10 days of initiation of trial treatment
* 21\. Evidence of bleeding diatheses or significant coagulopathy
* 22\. History of inadequately controlled arterial hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg despite maximal medical therapy); prior history of hypertensive crises or hypertensive encephalopathy
* 23\. Concurrent congestive heart failure, prior history of NYHA class III/ IV cardiac disease, prior history of cardiac ischaemia or prior history of cardiac arrhythmia
* 24\. Concurrent participation in another interventional clinical trial or intention to do so. Concurrent participation in an observational trial is acceptable.
* 25\. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.