Inclusion Criteria:

1. Histologically confirmed metastatic renal cell carcinoma of predominant clear cell
histology

2. Unsuitable for nephrectomy

3. Unsuitable for 'watch and wait' policy

4. No prior systemic therapy for renal cell carcinoma

5. Measurable metastatic disease using RECIST v1.1

6. Life expectancy 12 weeks or greater

7. ECOG performance status 0 or 1

8. Adequate organ function as defined by serum aspartate transaminase (AST) and serum
alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN), or AST and ALT ≤5 x
ULN if liver function abnormalities are due to liver metastases; total serum
bilirubin ≤1.5 x ULN

9. Adequate haematological function as defined by absolute neutrophil count (ANC)
≥1500/μL, platelets ≥75,000/μL, haemoglobin ≥9.0 g/dL and prothrombin time (PT) ≤1.5
x ULN

10. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min;

11. Urinary protein <2+ by urine dipstick.

12. No evidence of pre-existing uncontrolled hypertension

13. Women of childbearing potential must have a negative serum or urine pregnancy test
within 3 days prior to treatment.

14. Willingness and ability to comply with study procedures, including tumour biopsies.

15. Written informed consent

Exclusion Criteria:

1. The presence of intracranial disease, unless stable >6 months. In the case of a
solitary brain metastasis which has been resected, there must be evidence of a
disease-free interval of at least 3 months post-surgery. All patients previously
treated for brain metastases must be stable off corticosteroid therapy for at least
28 days.

2. The presence of active second malignancy.

3. Women who are pregnant or are breastfeeding. Female patients must be surgically
sterile, be postmenopausal, or must agree to use effective contraception during the
period of therapy.

4. Male patients must be surgically sterile or must agree to use effective contraception
during the period of therapy.

5. Current signs or symptoms of severe progressive or uncontrolled hepatic, endocrine,
pulmonary disease other than directly related to RCC.

6. Gastrointestinal abnormalities including:

1. inability to take oral medication;

2. requirement for intravenous alimentation;

3. prior surgical procedures affecting absorption including total gastric
resection;

4. treatment for active peptic ulcer disease in the past 6 months;

5. active gastrointestinal bleeding, unrelated to cancer, as evidenced by
hematemesis, hematochezia or melena in the past 3 months without evidence of
resolution documented by endoscopy or colonoscopy;

6. malabsorption syndromes.

7. Current use or anticipated need for treatment with drugs that are known potent CYP3A4
inhibitors (see section 8.12, concomitant therapy).

8. Current use or anticipated need for treatment with drugs that are known CYP3A4 or
CYP1A2 inducers (see section 8.12, concomitant therapy).

9. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose
anticoagulants for maintenance of patency of central venous access device or
prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular
weight heparin is allowed.

10. Active seizure disorder, spinal cord compression, or carcinomatous meningitis.

11. Any of the following within 12 months prior to study entry: myocardial infarction,
uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive
heart failure, cerebrovascular accident or transient ischemic attack.

12. Deep vein thrombosis or pulmonary embolism within 6 months prior to study entry.

13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS)-related illness.