A series of clinical research activities are associated with this complex disease state, including The Melbourne Melanoma Project, a collaborative project recruiting patients with melanoma from four Victorian hospitals, Peter MacCallum Cancer Centre, The Austin Hospital, The Alfred Hospital and Border Oncology in Albury/Woodonga. The aim of the project is to establish a clinical database with matched tumour specimens as a resource for research projects. To date 1855 patients have been recruited with 537 enrolled at The Alfred.
In June 2014 the Victorian Cancer Agency provided $3,000,000 to fund the Melbourne Melanoma Project for a further 3 years (MMP2). MMP2 will concentrate on enrolling patients with advanced disease (stage 3 or 4) and will aim to understand the links between the molecular characteristics and clinical/pathological features of the disease. MMP2 will also examine the immunological profile of melanoma and link this with clinical outcomes with respect to response to immunotherapies.
Clinical trials for advanced melanoma at the Alfred Hospital
In a new study funded by the Victorian Cancer Agency and the National Health and Medical Research Council, Dr Sashendra Senthi, Radiation Oncologist at Alfred Health Radiation Oncology and Dr Andrew Haydon, Medical Oncologist at The Alfred, will investigate the interaction between radiotherapy and an immune activating drug, Pembrolizumab, in an attempt to improve the survival of patients with metastatic melanoma.
For over a decade the Medical Oncology unit at the Alfred Hospital has been involved in clinical trials in advanced Melanoma. More recently we have been major recruiters for some of the important studies with the newer targeted agents in B-Raf mutant Melanoma. About 40-50% of all melanomas harbour an activating mutation in B-Raf which activates the RAS/RAF/MEK/ERK pathway leading to the phosphorylation of ERK and in turn, increased tumour growth.
The 1st of these studies was “BRIM 4” a phase 1b study with Vemurafenib, with the Alfred recruiting 4 of the 20 patients worldwide to this trial. Vemurafenib is an oral B-Raf inhibitor with activity in B-Raf mutant melanoma and has subsequently been shown in a large phase 3 trial to be superior to DTIC chemotherapy in prolonging both PFS and overall survival. Following this we were involved in the phase 4 “EAP” study of Vemurafenib in metastatic melanoma, screening 29 patients and enrolling 12 patients to the study.
In addition to B-Raf inhibitors, we have also studied the role of MEK inhibitors in B-Raf mutant melanoma. The METRIC study was an international phase 3 trial of the MEK inhibitor Trametinib versus chemotherapy in treatment de novo metastatic melanoma. This was a positive study that showed a significant improvement in both progression free and overall survival. We were in the top 20 sites globally, screening 22 patients and enrolling 5.
Following the METRIC study, interest has moved to comparing single agent B-Raf inhibitor to the combination of a B-raf inhibitor plus a MEK inhibitor. From December 2012 until now the Alfred has opened 3 sequential phase 3 studies addressing this question. COMBI-V, Co-BRIM (which have both closed) and COLUMBUS have all randomised patients to either Vemufarenib or a combination of a B-Raf and a MEK inhibitor. COLUMBUS is expected to remain open until the end of the year, with the Alfred currently the leading Australian site for recruitment.
With the introduction of new active agents in stage 4 disease, two phase 3 trials are currently enrolling patients with resected stage 3 melanoma comparing targeted agents to placebo as adjuvant treatment. The COMBI-AD study compares 12 months of adjuvant Dabrafenib (GSK’s B-Raf inhibitor) plus Trametinib to placebo in a double blinded international study. The Alfred has, to date, screened 36 patients and enrolled 13, making it the 5th highest recruiter worldwide to this pivotal trial.
As a result of our active melanoma trial portfolio, we have been able to offer our patients (and patients from other Monash hospitals) access to new agents that have greatly improved the outcomes for patients with B-Raf mutant advanced melanoma.