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.

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.

Inclusion Criteria:

• Adults (over 18 yrs) with histologically confirmed GIST. In CD-117-negative cases DOG-1 must be positive or a KIT/PDGFRA mutation must be present.
• Unresectable, metastatic disease.
• No prior TKI for metastatic disease, with the exception of those patients who have had up to 21 days of uninterrupted treatment on 400mg daily of imatinib.
• Imatinib therapy given as an adjuvant treatment and completed at least 3 months prior to entry into this trial is permitted. Patients who have progression of GIST while on adjuvant therapy are not eligible for this trial.
• ECOG performance status 0-2
• Measurable disease by RECIST version 1.1. (Note: Participants with only peritoneal disease will be eligible only if they have lesions measurable in two dimensions and have at least 1 lesion which is ≥ 2 cm in size).
• Adequate bone marrow function (Haemoglobin ≥ 9.0g/dL, platelet count ≥ 100 x 109/L, and absolute neutrophil count ≥ 1.5 x 109/L).
• Adequate liver function (Serum total bilirubin ≤1.5 x ULN, INR ≤ 1.5, and ALT, AST, ALP ≤2.5 x ULN (≤ 5 x ULN for participants with liver metastases). Lipase level must be ≤ 1.5 x ULN.
• Adequate renal function (Creatinine clearance > 50ml/min) based on either the Cockcroft Gault formula, 24 hour urine or Glomerular Filtration Rate (GFR scan); and serum creatinine ≤ 1.5 x ULN.
• Tumour tissue available for central review.
• Willing and able to comply with all study requirements, including treatment timing and/or nature of required assessments.
• Study treatment both planned and able to start within 14 days of randomisation.
• Signed, written informed consent.

Exclusion Criteria:

• Concurrent GI illness which may prevent absorption of imatinib or regorafenib - please note that prior gastrectomy or bowel resection does not exclude patients from this study.
• Use of other investigational drugs within 4 weeks prior to enrolment.
• Known sensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
• Participants receiving therapeutic doses of warfarin.
• Presence of brain metastases.
• The presence of PDGFR D842V mutation or other mutation known to cause imatinib resistance.
• Inability to swallow tablets.
• Arterial thrombotic or ischaemic events, such as cerebrovascular accident or pulmonary embolism within 6 months prior to randomisation; or major venous thrombotic events requiring use of an anticoagulant such as warfarin within 6 months prior to randomisation.
• Poorly controlled hypertension (systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomisation, or non healing wound, ulcer or fracture.
• Congestive cardiac failure (NYHA ≥ grade 2), unstable angina or new onset angina within the previous 3 months, or AMI within the previous 6 months. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
• Haemorrhage or bleeding event ≥ Grade 3 according to CTCAE v4.0 within 4 weeks prior to randomisation.
• Ongoing infection of > Grade 2 according to CTCAE v4.0.
• Active hepatitis B or C or HIV, or chronic hepatitis B or C requiring treatment with antiviral therapy. Testing for these is not mandatory unless clinically indicated.
• Interstitial lung disease with ongoing signs and symptoms.
• Persistent proteinuria of ≥ Grade 3 (>3.5g/24 hours) according to CTCAE v4.0
• Other significant medical or psychiatric condition judged by the investigator to interfere with protocol requirements.
• Use of biological response modifiers such as granulocyte colony stimulating factor (G-CSF), within 3 weeks prior to randomisation.
• Patients taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinovir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg carbamazepine, phenobarbitol, phenytoin, rifampicin, St John's wort).
• History of another malignancy within 5 years prior to registration. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 5 years after definitive primary treatment.
• Pregnancy, lactation, or inadequate contraception. Women must be post menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Women of childbearing potential and men must agree to use adequate contraception before entering the trial until at least 8 weeks after the last study drug administration.