The purpose of this international study is to determine if the combination of regorafenib and
nivolumab is more effective than standard chemotherapy in prolonging overall survival in a
broad group of participants with AGOC, who have progressed after treatment with standard
anti-cancer therapy.
In the INTEGRATE study, regorafenib alone was shown to be effective in prolonging the
progression-free period in people with AGOC following standard anti-cancer therapy (i.e. it
delayed tumour growth), and demonstrated a potential benefit on long term survival. Recent
research has shown the early results from this combination of regorafenib & nivolumab may
improve outcomes for cancer patients. INTEGRATE IIb will investigate this effect further in a
larger group of participants with AGOC.
The study aims to determine:
i. Whether the combination of regorafenib/nivolumab is likely to help patients with AGOC live
longer; ii. The effects of this treatment on progression-free survival; iii. The numbers of
participants responding to the treatment iv. The effects of this treatment on quality of life
v. The side effects and tolerability of this treatment vi. Molecular differences (e.g.
variations in genes or proteins) that may account for the effects of this treatment vii.
Differences in the costs of care for people on this treatment.
The Investigators plan to enrol 450 participants in the study from, but not limited to;
Australia, New Zealand, South Korea, Japan, Taiwan, Canada, USA, Germany, Belgium, Spain,
France, Switzerland, Netherlands and Italy.
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 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.
5. HER2-positive participants must have received trastuzumab
2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix 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. Willing and able to comply with all study requirements, including treatment, timing,
and/or nature of required assessments and follow-up.
8. 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)
9. Signed, written informed consent
Exclusion Criteria:
1. Known allergy to the investigational product drug class or excipients in the
regorafenib and/or nivolumab
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. Any prior use of more than one immune checkpoint inhibitor
6. Treatment with any previous drug therapy within 2 weeks prior to first dose of study
treatment. This includes any investigational therapy.
7. Use of biological response modifiers, such as granulocyte colony stimulating factor
(G-CSF), within 3 weeks prior to randomisation.
8. Concurrent treatment with strong CYP3A4 inhibitors or inducers.
9. 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 V5.0
10. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to randomization
11. Arterial thrombotic or ischaemic events, such as cerebrovascular accident, within 6
months prior to randomization.
12. Venous thrombotic events and pulmonary embolism within 3 months prior to randomization
13. Any haemorrhage or bleeding event ≥ Grade 3 according to CTCAE v5.0 within 4 weeks
prior to randomization.
14. Non-healing wound, ulcer, or bone fracture.
15. Interstitial lung disease with ongoing signs and symptoms
16. 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.
17. Persistent proteinuria of ≥ Grade 3 according to CTCAE v5.0 (equivalent to > 3.5g of
protein over 24 hour measured on either a random specimen or 24 hour collection.
18. Uncontrolled metastatic disease to the central nervous system. To be eligible, known
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.
19. 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
20. 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.
21. Patients with acute coronary syndrome (including myocardial infarction and unstable
angina), and with a history of coronary angioplasty or stent placement performed
within 6 months before enrolment
22. Patients with a ≥ grade 3 active infection according to CTCAE version 5.0
23. Patients with concurrent autoimmune disease, or a history of chronic or recurrent
autoimmune disease
24. Patients who require systemic corticosteroids (excluding temporary usage for tests,
prophylactic administration for allergic reactions, or to alleviate swelling
associated with radiotherapy; if used as replacement therapy e.g. ≤ 10 mg prednisolone
or dexamethasone ≤ 2 mg per day) or immunosuppressants, or who have received such a
therapy < 14 days prior to randomisation
25. Patients with a seizure disorder who require pharmacotherapy
26. Serious medical or psychiatric condition(s) that might limit the ability of the
patient to comply with the protocol.
27. 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.
