Planning Treatment for Oesophago-gastric Cancer: a Maintenance Therapy Trial
Planning Treatment for Oesophago-gastric Cancer: a Maintenance Therapy Trial
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.