A randomized, double-blind, placebo-controlled phase III study of regorafenib plus best supportive care versus placebo plus best supportive care for subjects with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) whose disease has progressed despite prior treatment with at least imatinib and sunitinib

1. Signed informed consent obtained before any study specific procedures.
Subjects must be able to understand and willing to sign a written informed
consent.
2. Male or female subjects >=18 years of age.
3. Subjects with histologically confirmed metastatic and/or unresectable
GIST.
4. At least imatinib and sunitinib as prior treatment regimens, with objective
disease progression or intolerance to imatinib, as well as disease
progression while on sunitinib therapy. Additionally, disease progression
or intolerance to other systemic therapies, as well as investigational new
agents, is allowed, except prior treatment with any other vascular
endothelial growth factor receptor (VEGFR) inhibitor.
5. Subjects must have at least one measurable lesion according to RECIST,
version 1.1. A lesion in a previously irradiated area is eligible to be
considered as measurable disease as long as there is objective evidence of
progression of the lesion prior to study enrollment.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or
1.
7. Adequate bone marrow, liver, and renal function as assessed by the
following laboratory requirements conducted within 7 days of starting
study treatment:
- Total bilirubin <= 1.5 x the upper limit of normal (ULN). Documented
Gilbert syndrome is allowed if total bilirubin is mildly elevated
(< 6 mg/dL).
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
<=3.0 x ULN (<= 5 x ULN for subjects with liver involvement of their
GIST).
- Lipase <= 1.5 x the ULN
- Serum creatinine <= 1.5 x the ULN.
- Glomerular filtration rate (GFR) >= 30 ml/min/1.73 m2 according to the
Modified Diet in Renal Disease (MDRD) abbreviated formula.
- International normalized ratio (INR) <= 1.5 x ULN and partial
thromboplastin time (PTT) or activated partial thromboplastin time
(aPTT) <= 1.5 x ULN.
Subjects who are being treated with an anti-coagulant, such as warfarin
or heparin, will be allowed to participate provided that no prior
evidence of an underlying abnormality in these parameters exists.
Close monitoring of at least weekly evaluations will be performed until
INR and PTT are stable based on a pre-dose measurement as defined
by the local standard of care.
- Platelet count >= 100000/mm3, hemoglobin (Hb) >= 9.0 g/dl, absolute
neutrophil count (ANC) >= 1500/mm3. Transfusion of subjects to meet
the inclusion criteria will not be allowed.
- Alkaline phosphatase limit <= 2.5 x ULN (<= 5 x ULN for subjects
whose cancer involves their liver).
8. Recovery to NCI-CTCAE v4.0 Grade 0 or 1 level or recovery to baseline
preceding the prior treatment from any previous drug/procedure-related
toxicity (except alopecia, anemia, and hypothyroidism).

1. Prior treatment with regorafenib. Subjects permanently withdrawn from
study participation will not be allowed to re-enter the study.
2. Prior treatment with any vascular endothelial growth factor receptor
(VEGFR) inhibitor except sunitinib.
3. Use of any approved tyrosine kinase inhibitors or investigational agents
within 1 week or 6 half-lives of the agent, whichever is shorter, prior to
receiving study drug.
4. Cancer other than GIST within 5 years prior to randomization EXCEPT for
curatively treated cervical cancer in situ, non-melanoma skin cancer, and
superficial bladder tumors (Ta [Non-invasive tumor], and Tis [Carcinoma
in situ]).
5. Major surgical procedure, open biopsy, or significant traumatic injury
within 28 days before start of study medication.
6. Pregnant or breast-feeding subjects. Women of childbearing potential not
employing adequate contraception. Women of childbearing potential must
have a pregnancy test performed a maximum of 7 days before start of study
medication and a negative result must be documented before start of study
medication.
Women of childbearing potential and men must agree to use adequate
contraception (barrier method of birth control) since signing of the
informed consent form until at least 3 months after the last study drug
administration. The definition of adequate contraception will be based on
the judgment of the treating investigator or a designated associate.
7. Congestive heart failure New York Heart Association (NYHA) >= class 2.
8. Unstable angina (angina symptoms at rest, new-onset angina, ie, within the
last 3 months) or myocardial infarction (MI) within the past 6 months
before start of study medication.
9. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or
digoxin are permitted).
10. Uncontrolled hypertension (systolic blood pressure > 140 mmHg or
diastolic pressure > 90 mmHg despite optimal medical management).
11. Subjects with pheochromocytoma.
12. Arterial thrombotic or embolic events such as cerebrovascular accident
(including transient ischemic attacks), or pulmonary embolism within the 6
months before start of study drug.
13. Venous thrombotic events such as deep vein thrombosis within the 3
months before start of study drug
14. Ongoing infection > grade 2 National Cancer Institute-Common
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0.
15. Known history of human immunodeficiency virus (HIV) infection.
16. Subjects with seizure disorder requiring medication.
17. Symptomatic metastatic brain or meningeal tumors
18. History of organ allograft.
19. Subjects with evidence or history of bleeding diathesis. Any hemorrhage
or bleeding event * NCI-CTCAE version 4.0 grade 3 or higher within
4 weeks prior to the start of study drug.
20. Non-healing wound, ulcer, or bone fracture.
21. Renal failure requiring hemo- or peritoneal dialysis.
22. Dehydration NCI-CTCAE version 4.0 grade >= 1.
23. Substance abuse or medical, psychological, or social conditions that may
interfere with the subject*s participation in the study or evaluation of the
study results.
24. Known hypersensitivity to the study drug, study drug class, or excipients in
the formulation.
25. Any illness or medical conditions that are unstable or could jeopardize the
safety of the subject and his/her compliance in the study.
26. Interstitial lung disease with ongoing signs and symptoms at the time of
screening.
27. Subjects unable to swallow oral medications.
28. Persistent proteinuria of NCI-CTCAE version 4.0 grade 3 or higher
(> 3.5 g/24 hrs, measured by urine protein:creatinine ratio on a random
urine sample).
29. Any malabsorption condition.
30. Close affiliation with the investigational site, eg, a close relative of the
investigator or dependent person (eg, employee of or student at the
investigational site who would have access to study records and case report
form [CRF] data).
31. Unresolved toxicity higher than NCI-CTCAE version 4.0 grade 1
(excluding alopecia, anemia, and hypothyroidism) attributed to any prior
therapy/procedure.
32. Concomitant participation in another clinical study.
33. Left ventricular ejection fraction (LVEF) < 50% or below the LLN for the
institution (whichever is higher).
34. Pleural effusion or ascites that causes respiratory compromise (>= NCICTCAE
version 4.0 Grade 2 dyspnea).