A randomised phase II trial of imatinib alternating with;regorafenib compared to imatinib alone for the first line ;treatment of advanced gastrointestinal stromal tumour (GIST)

1. 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., 2.
Unresectable, metastatic disease., 3. 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., 4. 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., 5. ECOG performance status 0*2, 6. 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)., 7. Adequate bone marrow
function (Haemoglobin >= 9.0g/dL, platelet count >= 100 x 109/L, and absolute
neutrophil count >= 1.5 x 109/L)., 8. 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., 9.
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., 10. Tumour tissue available for
central review., 11. Willing and able to comply with all study requirements,
including treatment timing and/or nature of required assessments., 12. Study
treatment both planned and able to start within 14 days of randomisation., 13.
Signed, written informed consent.

1. 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., 2. Use of other investigational drugs within
4 weeks prior to enrolment., 3. Known sensitivity to any of the study drugs,
study drug classes, or excipients in the formulation., 4. Participants
receiving therapeutic doses of warfarin., 5. Presence of brain metastases., 6.
The presence of PDGFR D842V mutation or other mutation known to cause imatinib
resistance., 7. Inability to swallow tablets., 8. 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., 9. Poorly controlled hypertension (systolic blood pressure >
140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).,
10. Major surgical procedure, open biopsy, or significant traumatic injury
within 28 days prior to randomisation, or non healing wound, ulcer or
fracture., 11. 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 antiarrhythmic, therapy (beta blockers or
digoxin are permitted)., 12. Haemorrhage or bleeding event >= Grade 3 according
to CTCAE v4.0 within 4 weeks prior to randomisation., 13. Ongoing infection of
> Grade 2 according to CTCAE v4.0., 14. 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., 15. Interstitial lung
disease with ongoing signs and symptoms., 16. Persistent proteinuria of >= Grade
3 (>3.5g/24 hours) according to CTCAE v4.0, 17. Other significant medical or
psychiatric condition judged by the investigator to interfere with protocol
requirements., 18. Use of biological response modifiers such as granulocyte
colony stimulating factor (G*CSF), within 3 weeks prior to randomisation., 19.
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)., 20.
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. , 21.
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.