| Eligibility |
Inclusion Criteria - All Patients
- Histologically verified inoperable locally advanced or metastatic adenocarcinoma of
the oesophagus, oesophago-gastric junction, or stomach.
- Completion of 18 weeks of first-line chemotherapy with either CX/ CAPOX or FOLFOX
(HER2 negative) or CX/ CF + trastuzumab (HER2 positive) for locally advanced /
metastatic disease with > stable disease on the end of treatment CT scan (HER2
positive patients must have received at least one cycle of trastuzumab alongside first
line chemotherapy; patients receiving chemotherapy delivered on a 3-weekly basis eg
CX/ CAPOX should have received 6 cycles and on a two weekly basis e.g. FOLFOX should
have received 9 cycles).
- Disease which, following first-line chemotherapy, remains inoperable and unsuitable
for definitive chemoradiotherapy.
- Able to proceed with maintenance treatment within 28 days of the last day of the last
cycle of chemotherapy.
- Formalin fixed paraffin embedded (FFPE) blocks of diagnostic tissue available for
biomarker analysis.
- Any prior chemotherapy or radiotherapy in the adjuvant setting must have been
completed at least 6 months prior to the first occurrence of metastatic disease.
- No prior radiotherapy in the advanced disease setting. Patients receiving palliative
radiotherapy to sites of disease that are not measurable may be eligible and should be
discussed with the Chief Investigator.
- Male/female patients aged =18 years.
- WHO Performance status 0, 1 or 2.
- Patients should have a projected life expectancy of at least 3 months.
- Adequate bone marrow function: absolute neutrophil count (ANC) =1.5x109/l; white blood
cell count = 3x109/l; platelets = 100x109/l; haemoglobin (Hb) = 9g/dl (can be
post-transfusion).
- Adequate renal function: calculated creatinine clearance =50ml/minute.
- Adequate liver function: serum bilirubin =1.5x ULN; aspartate aminotransferase (AST),
alanine aminotransferase (ALT), and alkaline phosphatase =2.5 x ULN (5 × ULN is
acceptable for ALT, AST and ALP if liver metastases are present).
- Women of childbearing potential as well as fertile men and their partners must agree
to abstain from sexual intercourse or to use an effective form of contraception during
the study and for 7 months following the last dose of assigned study drug(s).
- Written informed consent must be obtained from the patient before any study-specific
procedures are performed.
Exclusion Criteria - All Patients
- Concurrent enrolment in another clinical trial unless it is an observational
(non-interventional) clinical study.
- Tumours of squamous histology.
- Documented brain metastases, central nervous system metastases or leptomeningeal
disease.
- Patients who have not recovered from clinically significant effects of any prior
surgery, radiotherapy or any other anti-neoplastic therapies. All toxicities must have
resolved to grade 1 or less, with the exception of peripheral neuropathy which must be
less than or equal to grade 2 according to NCI CTCAE version 4.0.
- Any major surgery within 4 weeks prior to the start of study treatment.
- Uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood
pressure >100 mm Hg).
- Clinically significant (i.e. active) cardiac disease e.g. symptomatic coronary artery
disease, symptomatic congestive heart failure, uncontrolled cardiac dysrhythmia, or
myocardial infarction within the last 12 months. Patients with any prior history of
clinically significant cardiac failure are excluded from study entry.
- History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or
evidence of interstitial lung disease on baseline chest CT scan.
- Lack of physical integrity of the upper gastro-intestinal tract, malabsorption
syndrome, or inability to take oral medication.
- Patients who are pregnant or lactating.
- Known positive tests for human immunodeficiency virus (HIV) infection, hepatitis A or
C virus, acute or chronic active hepatitis B infection.
- Other clinically significant disease or co-morbidity which may adversely affect the
safe delivery of treatment within this trial.
- Any other malignancies within the last 3 years (other than curatively treated basal
cell carcinoma of the skin and/or in situ carcinoma of the cervix).
- Treatment with another investigational agent within 30 days of commencing study
treatment.
Additional Inclusion / Exclusion Criteria - HER-2 Negative Patients (Arm A)
- Patients must have histologically or cytologically confirmed HER-2 negative disease
(HER-2 0-2 by IHC; note if ISH testing is performed this must not demonstrate evidence
of gene amplification).
- Patients with known capecitabine intolerance are excluded. This includes patients with
previous coronary artery spasm or chest pain deemed to be capecitabine-related.
- Patients with homozygous DPYD gene mutations are excluded. Patients with heterozygous
DPYD gene mutations who have tolerated dose-reduced fluoropyrimidines during
first-line chemotherapy as per local guidelines are eligible.
- Prior treatment with a PARP inhibitor is excluded (only applicable for A4 & A5
patients).
- Any Grade 3 or 4 GI bleeding within 3 months prior to enrollment are excluded
- Any Grade 3 or 4 venous thromboembolic event (VTE) that is considered by the
investigator to be life threatening or that is symptomatic and not adequately treated
by anticoagulation therapy, within 3 months prior to randomization are excluded.
- History of GI perforation within 6 months of randomisation are excluded
- History of hepatic encephalopathy or cirrhosis (level Child-Pugh B or worse) are
excluded
- Patients must have adequate coagulation function as defined by International
Normalised Ratio (INR) =1.5 and a partial thromboplastin time/activated partial
thromboplastin time (PTT or aPTT) = 5 seconds above the ULN (unless receiving
anticoagulation therapy. Patients receiving warfarin must be switched to low molecular
weight heparin prior to randomisation.
- Patients with a serious or non-healing wound, ulcer or bone fracture within 28 days
prior to randomisation are excluded.
- The patient's urinary protein is =1+ on dipstick or routine urinalysis (if urine
dipstick is
- 2+, a 24 hour urine collection for protein must demonstrate < 1000mg of protein
in 24 hours.
- Patients experiencing thromboembolic events, including but not limited to myocardial
infarction, transient ischaemic attack, cerebrovascular accident, unstable angina,
within 6 months prior to first dose of protocol therapy are excluded.
- Patients who have undergone major surgery within 28 days prior to first dose of
protocol therapy, or minor surgery/ subcutaneous venous access device placement within
7 days prior to first dose of protocol therapy are excluded.
- Patients receiving chronic anti-platelet therapy or NSAIDS including ibuprofen,
naproxen, dipyridamole or clopidogrel, or similar agents are excluded. Once daily
aspirin use (up to 325mg/day) is permitted.
Additional Inclusion / Exclusion Criteria - HER-2 Positive Patients (Arm B)
- Patients must have histologically or cytologically confirmed HER-2 positive disease
(HER-2 3+ by IHC or HER-2 2+ by IHC and HER-2 gene amplified by ISH).
- Patients must have left ventricular ejection fraction (LVEF) >50% as measured by
echocardiogram or >45% measured by MUGA (must also be greater than lower limit of
normal at institution).
- Patients with active or prior history of New York Heart Association (NYHA) congestive
heart failure are excluded.
- Patients with a known history of hypersensitivity to trastuzumab or any of its
components are excluded.
|
