A Study of Regorafenib in Refractory Advanced Gastro-Oesophageal Cancer

Inclusion Criteria

1. Adults (18 years or over) with metastatic or locally recurrent gastro-oesophageal
cancer which:

1. has arisen in any primary gastro-oesophageal site (oesophago-gastric junction
(GOJ) or stomach); and

2. is of adenocarcinoma or undifferentiated carcinoma histology , and

3. is evaluable according to Response Evaluation Criteria in Solid Tumours (RECIST
Version 1.1) by computed tomography (CT) scan performed within 21 days prior to
randomisation. 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 enrolment; and

4. has failed or been intolerant to a minimum of 2 and a maximum of 3 lines of prior
anti-cancer therapy for recurrent/metastatic disease which must have included at
least one platinum agent and one fluoropyrimidine analogue.

Note: Neoadjuvant or adjuvant chemotherapy or chemoradiotherapy will be considered as
first line treatment where people have relapsed or progressed within 6 months of
completing treatment; Radiosensitising chemotherapy given solely for this purpose
concurrent with palliative radiation will not be considered as a line of treatment.
Ramucirumab monotherapy, or immunotherapy with a checkpoint inhibitor, will be
considered a line of treatment.

2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

3. Ability to swallow oral medication.

4. Adequate bone marrow function (Platelets ≥100x109/L; Absolute Neutrophil Count (ANC)
≥1.5x109/L and Haemoglobin ≥ 9.0g/dL).

5. Adequate renal function (Creatinine clearance >50 ml/min) based on either the
Cockcroft-Gault formula (Appendix 2), 24-hour urine or Glomerular Filtration Rate
(GFR) scan; and serum creatinine ≤1.5 x Upper Limit of Normal (ULN).

6. Adequate liver function (Serum total bilirubin ≤1.5 x ULN, and INR ≤ 1.5 x ULN, and
Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase
(ALP) ≤2.5 x ULN (≤ 5 x ULN for participants with liver metastases)). Participants
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.

7. Adequate cardiac function (Left Ventricular Ejection Fraction (LVEF) ≥ 50% or above
the lower limit of normal (LLN) for the Institution (whichever is lower). Cardiac
function should be assessed within 3 months prior to randomisation, but after
completion of any anthracycline-containing chemotherapy.

8. Willing and able to comply with all study requirements, including treatment, timing,
and/or nature of required assessments and follow-up.

9. Study treatment both planned and able to start within 7 days after randomisation
(note: subjects randomised on a Friday should commence treatment no earlier than the
following Monday).

10. Signed, written informed consent.

Exclusion Criteria

1. Known allergy to the investigational product drug class or excipients in the
regorafenib.

2. Poorly-controlled hypertension (systolic blood pressure >140mmHg or diastolic
pressure> 90mmHg despite optimal medical management).

3. Participants with known, uncontrolled malabsorption syndromes.

4. Any prior anti-VEGF targeted therapy using small molecule VEGF TKIs (e.g. apatinib).
Prior anti-VEGF targeted monoclonal antibody therapies (e.g. bevacizumab and
ramucirumab) are permitted.

5. Treatment with any previous drug therapy within 3 weeks prior to randomization. This
includes any investigational therapy.

6. Use of biological response modifiers, such as granulocyte colony stimulating factor
(G-CSF), within 3 weeks prior to randomisation.

7. Concurrent treatment with strong CYP3A4 inhibitors or inducers.

8. Palliative radiotherapy, unless more than 14 days have elapsed between completion of
radiation and the date of registration, and adverse events resulting from radiation
have resolved to< Grade 2 according to CTCAE V4.03.

9. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to randomization.

10. Arterial thrombotic or ischaemic events, such as cerebrovascular accident, within 6
months prior to randomization.

11. Venous thrombotic events and pulmonary embolism within 3 months prior to
randomization.

12. Any haemorrhage or bleeding event ≥ Grade 3 according to CTCAE v4.03 within 4 weeks
prior to randomization.

13. Non-healing wound, ulcer, or bone fracture.

14. Interstitial lung disease with ongoing signs and symptoms.

15. Clinical hyperthyroidism or hypothyroidism. Note: non-clinically significant abnormal
TFTs (abnormal TSH and abnormal T3 and/or abnormal T4) considered to be due to sick
euthyroid syndrome is allowed.

16. Persistent proteinuria of ≥ Grade 3 according to CTCAE v4.03 (equivalent to > 3.5g of
protein over 24 hours, measured on either a random specimen or 24 hour collection).

17. Uncontrolled metastatic disease to the central nervous system. To be eligible, CNS
metastases should have been treated with surgery and/or radiotherapy and the patient
should have been receiving a stable dose of steroids for at least 2 weeks prior to
randomization, with no deterioration in neurological symptoms during this time.

18. History of another malignancy within 2 years prior to randomization. Participants with
the following are eligible for this study:

1. curatively treated cervical carcinoma in situ,

2. non-melanomatous carcinoma of the skin,

3. superficial bladder tumours (T1a [Non-invasive tumour], and Tis[Carcinoma in
situ]),

4. treated thyroid papillary cancer

19. Any significant active infection, including chronic active hepatitis B, hepatitis C,
or HIV. Testing for these is not mandatory unless clinically indicated. Participants
with known Hepatitis B/C infection will be allowed to participate providing evidence
of viral suppression has been documented and the patient remains on appropriate
anti-viral therapy.

20. Serious medical or psychiatric condition(s) that might limit the ability of the
patient to comply with the protocol.

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 randomization. Men
must have been surgically sterilized or use a barrier method of contraception.