A Randomised Phase III Double-Blind Placebo-Controlled Study of regorafenib in Refractory Advanced Gastro-Oesophageal Cancer (AGOC)

Exclusion Criteria27

• Known allergy to the investigational product drug class or excipients in the regorafenib
• Poorly controlled hypertension (systolic blood pressure greater than 140mmHg or diastolic pressure greater than 90mmHg despite optimal medical management).
• Participants with known uncontrolled malabsorption syndromes
• 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.
• Treatment with any previous drug therapy within 2 weeks prior to first dose of study treatment. This includes any investigational therapy.
• Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks prior to randomisation.
• Concurrent treatment with strong CYP3A4 inhibitors or inducers.
• 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 less than Grade 2 according to CTCAE V4.03
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization
• Arterial thrombotic or ischaemic events, such as cerebrovascular accident within 6 months prior to randomization.
• Venous thrombotic events and pulmonary embolism within 3 months prior to randomization
• Any haemorrhage or bleeding event greater than or equal to Grade 3 according to CTCAE v4.03 within 4 weeks prior to randomization.
• Non-healing wound, ulcer, or bone fracture.
• Interstitial lung disease with ongoing signs and symptoms
• 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.
• Persistent proteinuria of greater than or equal to Grade 3 according to CTCAE v4.03
• (Equivalent to greater than or equal to 3.5g of protein over 24 hours, measured on either a random specimen of 24 hour collection).
• 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.
• History of another malignancy within 2 years prior to randomization. Participants with the following are eligible for this study:
• a) curatively treated cervical carcinoma in situ,
• b) non-melanomatous carcinoma of the skin,
• c) superficial bladder tumours (T1a [Non-invasive tumour], and Tis[Carcinoma in situ]),
• d) treated thyroid papillary cancer
• 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.
• Serious medical or psychiatric condition(s) that might limit the ability of the patient to comply with the protocol.
• 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.