Single arm phase I/II trial to evaluate the safety and efficacy of the combination of bevacizumab, with ipilimumab plus nivolumab, and hypofractionated stereotactic radiotherapy (hSRT) in patients with symptomatic melanoma brain metastases (MBM).
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
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
Single group
Bevacizumab
DrugBevacizumab is a humanised monoclonal antibody with molecular weight 167kD that inhibits all isoforms of the vascular endothelial growth factor (VEGF) and is produced from a Chinese hamster ovary mammalian system. It has high specificity for isoform-A and has a half-life of \~21 days.
Ipilimumab
DrugIpilimumab is an immune checkpoint inhibitor (ICI) that targets anti-tumour immunity. Ipilimumab is a recombinant human immunoglobulin monoclonal antibody that binds CTLA4 and blocks the interaction between CD80/86 and CTLA4.
Nivolumab
DrugNivolumab ia an immune checkpoint inhibitor (ICI) that targets anti-tumour immunity. Nivolumab is a fully human monoclonal IgG4 antibody targeting PD-1 which demonstrates activity across a range of tumours.
Hypofractionated stereotactic radiotherapy
RadiationHypofractionated stereotactic radiotherapy (hSRT) will be delivered to previously untreated brain metastases in eligible participants. hSRT will be delivered to all symptomatic brain metastases, all brain metastases \>1 cm and all brain metastases located in eloquent areas of the brain. hSRT will be commenced after the first cycle of nivolumab plus ipilimumab and completed before the second cycle of nivolumab plus ipilimumab. hSRT should be commenced within 1 week from the planning MRI.
To determine the safety of bevacizumab, in combination with ipilimumab, nivolumab and hSRT
Number of participants with bevacizumab-related SAEs. A dose-limiting toxicity rate of \<33% with a minimum of 3 patients treated will be considered safe.
Determining the magnitude in reduction in prednisolone equivalent dose (relative to baseline dose)
The combination of a strict patient diary of corticosteroid dose, volumetric analysis of oedema on paired MRI samples with Peripheral blood mononuclear cells (PBMCs) to delineate immune cell subsets will allow proof-of-mechanism to be demonstrated. Specifically, if the proposed combination demonstrates preliminary activity, we will be able to demonstrate that this activity corresponds to a decrease in steroid dose (diary) which is permissible due to reduced oedema (volumetric analysis), resulting in augmented antitumour immunity (as evidence by increased peripheral antitumour immune cells). Finally, the inclusion of a health-related quality of life (QoL) analysis in this early phase clinical trial, may demonstrate that the reduction in steroid dose is clinically meaningful to patients.
Intracranial clinical benefit
The rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months after the initiation of treatment, complete response (CR), or partial response (PR)
Response rate
The rate of overall response (defined as the rate of complete or partial response)
Progression-free survival
The rate of intracranial, extracranial (systemic), and global progression-free survival (PFS)
To correlate anti-tumour activity with the detection of putative biomarkers of response/resistance in paired blood samples.
Disease is measured according to the RECIST criteria (version 1.1). Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have been used to assess the anti-tumour effect of a treatment. Overall response rate will be correlated to putative biomarkers.
Rate of cerebral radiation necrosis
To assess the impact of upfront bevacizumab on rates of cerebral radiation necrosis compared to historical controls
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