A Randomised Trial of Imatinib Alternating With Regorafenib Compared to Imatinib Alone for the First Line Treatment of Advanced Gastrointestinal Stromal Tumour (GIST)

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.