PROTOCOL SYNOPSIS 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. 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. 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.~General aim 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.~Design Prospective, randomised, open label phase II trial, stratified by participating site, previous adjuvant therapy (prior vs none), and previous imatinib for metastatic disease for less than 21 days.~Population The target population is adults with histologically confirmed, measurable metastatic GIST, who have received no prior treatment for metastatic disease. Patients who are currently taking, and have had up to 21 days of uninterrupted treatment with 400mg daily of imatinib are eligible to participate in this study.~Study treatments~Patients will be randomised to receive either:~Arm A - imatinib 400mg orally daily continuously (control arm); or Arm B - alternating 28-day periods of imatinib 400mg orally daily for 21 to 25 days followed by a washout (drug free) period of 3 to 7 days, then regorafenib 160mg orally daily for 3 weeks followed by a 7 day washout (drug free) period.~Treatment will continue until disease progression or prohibitive adverse events as detailed in the protocol.~Statistical considerations In order to demonstrate a relative increase in progression free survival at 24 months from the date of randomisation from an expected 78% to 88%, with 80% power and 95% confidence based on A'Hern's adjustment to Fleming's design, approximately 110 evaluable participants will be required in each arm. Thus, it is proposed to enrol 240 participants into the trial, allowing for approximately a 10% drop-out rate. Currently 80% of participants are expected to achieve a clinical benefit at 24 months (CBR - rate of complete or partial response, or stable disease). A secondary outcome would be to determine whether a minimum 25% relative increase of the CBR (from 80% to 85%) in the experimental cohort can be attained. The study will be open to recruitment for 36 months while follow-up will continue until the last enrolled participant has been followed for a minimum of 24 months timed from the date of commencement of treatment.
An open label randomised trial for adults with histologically confirmed measurable metastatic GIST who have received no other treatment for metastatic disease. The study aims to determine if an alternating regimen of imatinib and regorafenib has sufficient activity and safety in comparison to imatinib alone to warrant further evaluation as a first line treatment for metastatic GIST.