BRAFV600 mutations occur in 40-50% of melanomas and cause upregulation of the MAPK pathway, predisposing to tumourigenesis and uncontrolled cell proliferation. BRAF and MEK inhibitors, including encorafenib and binimetinib, inhibit this pathway and significantly improve survival in patients with BRAF-mutant metastatic melanoma. However, resistance to this treatment combination eventually develops in the majority of patients and therefore novel strategies to overcome this are required.
Up to 90% of melanomas also exhibit dysregulation of the CDK4/6 pathway. Preclinical data combining BRAF inhibition with palbociclib, a CDK4/6 inhibitor, showed cell cycle arrest and cell death in vitro, with rapid and sustained tumour regression in human tumour xenograft models. There is also increasing recognition of the immunomodulatory activity of CDK4/6 inhibitors.
No dedicated phase II trials with this triplet combination have been conducted to date. Several early phase trials have demonstrated the combination is feasible warranting more robust exploration in a larger dedicated study.
CELEBRATE is an investigator initiated multicentre phase 1b dose-escalation and dose-expansion study to determine the maximum tolerated dose, dose-limiting toxicities, and recommended phase 2 dose of palbociclib in combination with encorafenib and binimetinib. Secondary endpoints include further evaluation of safety and clinical efficacy. Both treatment naïve patients and those demonstrating resistance to BRAF/MEK inhibitors are eligible. CELEBRATE will also explore the association between early FDG-PET response and progression free survival, as well as changes within the tumour microenvironment, circulating DNA and faecal microbiome. Recruitment began in December 2019 and is ongoing.
There are plans to introduce a teletrial component, which has become increasingly relevant given the COVID-19 pandemic. Collaboration with American investigators running a parallel trial evaluating dabrafenib, trametinib and ribociclib will allow learnings from both studies to be applied in determining the optimal dose and schedule of combination BRAF, MEK and CDK4/6 inhibition in BRAF-mutant melanoma.