To evaluate the efficacy of maintenance therapies following completion of standard first-line
chemotherapy in patients with locally advanced or metastatic HER-2 positive or HER-2 negative
oesophago-gastric adenocarcinomas.
This is a prospective, open label, multicentre, randomised phase II clinical trial. An
adaptive trial design is proposed to allow ineffective treatments to be discontinued early,
and to potentially add novel treatment arms as the trial progresses.
Patients will initially receive standard chemotherapy for their locally advanced or
metastatic oesophago-gastric adenocarcinoma, according to local practice based upon their
HER-2 status (tested locally). In order to be eligible for trial entry, HER-2 negative
patients should have received a platinum-fluoropyrimidine based chemotherapy doublet or
triplet (Arm A), whilst HER-2 positive patients (IHC 3+ or IHC 2+ and FISH positive) should
have received cisplatin in combination with either capecitabine or 5-FU (CX or CF) plus
trastuzumab chemotherapy (Arm B). Potentially eligible patients will be registered with the
trials office whilst undergoing first line chemotherapy.
Patients will then become eligible for trial recruitment and randomization following
completion of at least 6 cycles of standard chemotherapy with ≥SD (stable disease) or better
on the end-of-treatment CT scan. Eligible patients will then be randomised according to HER-2
status as follows:
- HER-2 positive patients (~20%) will be currently not be randomised and will be assigned
maintenance single-agent trastuzumab (current UK standard), a comparator arm is in
development.
- HER-2 negative patients (~80%) will be randomised in a 1:1:1 fashion between
surveillance only (current UK standard), maintenance capecitabine, or maintenance
immuno-modulatory therapy (anti-PD-L1 antibody)
Patients will be stratified according to: locally advanced disease versus metastatic disease,
and performance status (0 versus 1 versus 2).
Review of patients will occur every 4 weeks in the observation only arm. In maintenance
therapy arms, patients will be reviewed every 3 or every 4 weeks depending upon the treatment
strategy. CT assessments of response will occur every 12 weeks (3 months) in all arms of the
trial. Treatment will be continued indefinitely until the occurrence of either disease
progression, unacceptable toxicity, or patient withdrawal for another reason.
The trial is being run from the RMH GI clinical trials unit with Professor David Cunningham
as the over-arching CI. Effective arms in the phase II portion of the trial may be taken
forward into a phase III maintenance trial powered for overall survival. It is also hoped
that, as more robust data becomes available for other biomarker-selected populations (e.g.
MET-positive, FGFR-amplified), it may be possible to amend the overall trial design to
incorporate these biomarker-targeted maintenance therapies in the HER-2 negative population.
Inclusion Criteria - All Patients
- Histologically verified inoperable locally advanced or metastatic adenocarcinoma of
the oesophagus, oesophago-gastric junction, or stomach.
- Completion of 6 cycles of first-line chemotherapy for locally advanced / metastatic
disease (this must have included a platinum and fluoropyrimidine in all cases; HER-2
positive patients must have received trastuzumab alongside chemotherapy) with > stable
disease on the end of treatment CT scan. If your patient has received first line
therapy, delivered on a two weekly basis e.g. FOLFOX they should have received 8
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
< 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 or 1 by IHC or HER-2 2+ by IHC and no HER-2 gene amplification by ISH).
- Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency or known
capecitabine intolerance are excluded. This includes patients with previous coronary
artery spasm or chest pain deemed to be capecitabine-related.
- Patients with known allergy or reaction to any component of the MEDI4736 formulation
are excluded.
- Patients with current or prior use of immunosuppressive medication within 4 weeks are
excluded, with the exceptions of intranasal and inhaled corticosteroids or systemic
corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or
equivalent.
- Patients with active or prior documented autoimmune disease within the past 2 years
are excluded. Subjects with vitiligo, Grave's disease, and psoriasis not requiring
systemic treatment within the past 2 years are eligible.
- Patients with active or prior documented inflammatory bowel disease (e.g. Crohn's
disease, ulcerative colitis) are excluded.
- Patients with a history of primary immunodeficiency are excluded.
- Patients with a history of organ transplant requiring use of immunosuppressives are
excluded.
- Patients with known history of tuberculosis are excluded.
- Patients who have received a live attenuated vaccination within 30 days prior to study
entry are excluded.
- Prior treatment with a PARP inhibitor is excluded.
- Any Grade 3 or 4 GI bleeding within 3 months prior to enrollment are excluded
- Any significant history of DVT or PE within 3 months of randomisation (catheter
associated or superficial venous thrombosis are not considered significant) 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 thime (PTT) ≤ 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.
