A Translational Study of Single Agent Olaparib in the Treatment of Advanced Oesophagogastric Cancer

Inclusion Criteria:

1. Locally advanced or metastatic oesophageal, gastro-oesophageal junction or gastricadenocarcinoma that has progressed during or within 6 months of first or subsequentline treatment

2. Patients with HER2-positive oesophageal, gastro-oesophageal, or gastric adenocarcinomamust have received previous treatment with trastuzumab

3. Male and female patients ≥18 years of age

4. Availability of tissue sample (resection or biopsy) confirming oesophageal,gastro-oesophageal junction, or gastric adenocarcinoma. If the patient does not haveprior histological diagnosis, then the planned baseline fresh tumour biopsy may beused for both the purpose of confirming the histological diagnosis and subsequentbiomarker analysis. All patients must be willing to have a fresh tumour biopsy toobtain tumour tissue for biomarker analysis at baseline and on progression

5. Disease amenable to safe biopsy

6. At least one lesion, not previously irradiated, that can be accurately measured as perRECIST criteria 1.1

7. Able to give informed consent

8. Adequate organ and bone marrow function measured within 28 days prior toadministration of study treatment as defined below: Hb 10.0 g/dL independent of bloodtransfusions for 28 days, Absolute neutrophil count (ANC) 1.5 x 109/L, Platelet count ≥ 100 x 109/L, INR < 1.5, Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN), AST/ ALT ≤ 2.5 x institutional ULN (unless liver metastases are present inwhich case it must be ≤ 5x ULN), Serum creatinine ≤ 1.5 x institutional upper limit ofnormal (ULN) or a calculated creatinine clearance >51 mL/min for patients withcreatinine levels above institutional normal. For GFR estimation, the Cockcroft andGault equation should be used: GFR = CrCl (ml/min) = (140 - age [years]) × weight (kg) (xF)a /(serum creatinine [mg/dL]× 72)awhere F =0.85 for females and F=1 for males,Albumin >33 g/L

9. WHO ECOG performance status 0-1

10. Life expectancy of 16 weeks or more

11. Negative urine or serum pregnancy test within 28 days of study treatment and confirmedprior to treatment on day 1) or postmenopausal status Postmenopausal status is definedas: Amenorrhoeic for 1 year or more following cessation of exogenous hormonaltreatments, LH and FSH levels in the postmenopausal range for women under 50,Radiation induced oophorectomy with last menses >1 year ago, Chemotherapy-inducedmenopause with >1 year interval since last menses, Or surgical sterilisation (bilateral oophorectomy or hysterectomy)

12. Patient is willing and able to comply with the protocol for the duration of the studyincluding having examinations, undergoing treatment, and attending scheduled visits (including follow up)

13. Patients of child bearing potential and their partners, who are sexually active, mustagree to the use of TWO acceptable effective birth control methods in combinationthroughout their participation in the study and for at least 1 month after the lastdose of study drug. For example, condom with spermicide and oralcontraceptive/hormonal therapy or condom with spermicide and placement of anintra-uterine device.

Exclusion Criteria:

1. Any previous treatment with a PARP inhibitor, including olaparib

2. Any second primary cancer (except adequately treated non-melanoma skin cancer,curatively treated cervical carcinoma-in-situ and curatively treated other solidtumours with no evidence of disease for 5 years or more)

3. Patients receiving any systemic chemotherapy, radiotherapy (except for palliativereasons) or investigational product within 4 weeks from the last dose prior tostarting treatment (or a longer period depending on the defined characteristics of theagents used). A stable dose of bisphosphonates is permitted for bone metastases beforeand during the study as long as they were started at least 4 weeks prior to startingtreatment

4. Clinically significant heart disease such as uncontrolled symptomatic arrhythmias,congestive heart failure, or myocardial infarction within the previous 3 months ofscreening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined bythe New York Heart Association Functional Classification

5. Interstitial pneumonia or symptomatic fibrosis of the lungs

6. Active brain or leptomeningeal metastases. A scan to confirm the absence of brainmetastases is not required. Patients with known brain metastases are eligible if theyhave been treated and there is no evidence of progression for at least 4 weeks aftertreatment is complete and within 28 days prior to first dose of study drugadministration. Patients can take a stable dose of corticosteroids before and duringthe study as long as these were started 4 or more weeks prior to treatment

7. Major surgery within 2 weeks of starting study treatment and patients must haverecovered from any previous major surgery

8. Pregnant and breastfeeding women

9. Patients considered a poor medical risk due to a serious uncontrolled medicaldisorder, non-malignant systemic disease or active uncontrolled infection. Examplesinclude, but are not limited to, uncontrolled major seizure disorder, unstable spinalcord compression (untreated and unstable for at least 28 days prior to study entry),superior vena cava syndrome, extensive bilateral lung disease on HRCT scan or anypsychiatric disorder that prohibits obtaining informed consent

10. Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with study medication absorption

11. Persistent toxicities (of CTCAE grade 2 or above) with the exception of alopecia,caused by previous cancer therapy

12. Immunocompromised patients e.g. patients who are known to be serologically positivefor human immunodeficiency virus (HIV)

13. Patients with known active hepatic disease (i.e. Hepatitis B or C)

14. Patients with intestinal obstruction or patients with CTCAE grade ≥ 3 upper GIbleeding within 4 weeks of study entry

15. Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washoutperiod prior to starting olaparib is 2 weeks.

16. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) ormoderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washoutperiod prior to starting study treatment is 5 weeks for enzalutamide or phenobarbitaland 3 weeks for other agents

17. Involvement in the planning and/or conduct of the study (applies to both AstraZenecastaff and/or staff at the study site)

18. Previous enrolment in the present study

19. Resting ECG with QTc of over 500 msec on 2 or more time points within a 24 hour periodor a family history of long QT syndrome.

20. Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or featuressuggestive of MDS/AML

21. Patients with known hypersensitivity to olaparib or any of the excipients of theproducts

22. Vaccinated with live, attenuated vaccines within 4 weeks of enrolment

23. Previous allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUBCT)