AIMS  - To determine if an alternating regimen of imatinib and regorafenib has sufficient activity and safety to warrant further evaluation as a first line treatment for metastatic GIST.

§  Primary endpoint: PFS at 24 months as calculated from the commencement of treatment  to the date of progression as determined by RECIST v1.1

§  Secondary endpoints:

o    Objective tumour response rate following 2 cycles of treatment

o    Clinical benefit rate (SD + PR + CR) following 2 cycles of treatment

o    CR rate

o    Time-to-treatment failure

o    Safety/toxicity/tolerability

o    Overall survival

BACKGROUND – Despite highly active current treatment for metastatic gastrointestinal stromal tumour(GIST) with the use of imatinib, most people will ultimately relapse and die of multifocal metastatic disease. Regorafenib, a multi-targeted tyrosine kinase inhibitor (TKI) with activity against angiogenic, stromal and oncogenic receptor tyrosine kinases, has demonstrated activity in the treatment of GIST and is FDA approved for third line therapy of advanced GIST. Using an alternating regimen of imatinib and regorafenib with brief drug free intervals may allow tumour stem cells to re-enter the cell cycle and become susceptible once more to drug therapy. 

STUDY DESIGN – Prospective, randomised 1:1, open label phase II trial, stratified by site, receipt of previous adjuvant therapy (prior adjuvant therapy vs no prior adjuvant therapy), and receipt of imatinib for metastatic disease for less than 21 days (yes or no). Proposed to enrol 240 patients.

STUDY PROGRESS – EORTC and Scandinavian Sarcoma Group participation confirmed. Financial support from Bayer confirmed. Protocol being finalised.

TRANSLATIONAL RESEARCH – Collection of FFPE diagnostic tumour tissue and blood for research at multiple timepoints. Determination of exon mutation profile of primary tumour and protein expression relating to EGFR and PDGFR signalling pathways. Planned research into circulating serum plasma growth factor and cytokine levels, plasma drug levels and circulating tumour cells and free circulating DNA load.