Olaparib with or Without Durvalumab for DDR Gene Mutated Biliary Tract Cancer Following Platinum-based Chemotherapy

Inclusion Criteria:

Inclusion Criteria:

• Capable of giving signed informed consent which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol.

• Age 19 years and older

• Eastern Cooperative Oncology Group (ECOG) performance status 0 ~ 1

• Patients must have a life expectancy ≥ 16 weeks.

• Histologically confirmed adenocarcinoma of biliary tract (intrahepatic, extrahepaticcholangiocarcinoma, or gallbladder carcinoma).

• Locally advanced unresectable, recurrence after curative surgery or metastaticdisease

• At least 16 weeks of continuous first-line platinum-based chemotherapy forunresectable or metastatic disease

• Somatic or germline mutation of at least one the DNA damage repair gene includingATM, ATR, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, GEN1, FANCA, FANCD2,POLE, MLH1, MSH2, MSH6, MRE11A, NBN, PALB2, PMS2, RAD50, RAD51, RAD51C, RAD51D, andXRCC2 confirmed by targeted exome sequencing

• Measurable disease is not necessarily needed for enrollment.

• No active uncontrolled infection, except chronic viral hepatitis under antiviraltherapy.

• Normal organ and bone marrow function measured within 28 days prior toadministration of study treatment including haemoglobin ≥10.0 g/dL with no bloodtransfusion in the past 28 days, platelets ≥ 100 x 109/L, neutrophils ≥ 1.5 x 109/L,creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation orbased on a 24 hour urine test ,serum total bilirubin ≤ 1.5 x ULN and alanineaminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 x ULN

• No other malignant disease apart from adequately treated non-melanotic skin cancer,curatively treated carcinoma in situ of the uterine cervix, localized prostate orpapillary thyroid cancer, or any other cancer where treated with curative intent > 5years previously without evidence of relapse

• Written, informed consent to the study

• Body weight >30kg

• Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up.

Exclusion Criteria:

Exclusion Criteria:

• Participation in another clinical study with an investigational product during thelast 6 months.

• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study.

• Medical or psychiatric conditions that compromise the patient's ability to giveinformed consent or to complete the protocol or a history of non-compliance

• Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The requiredwashout period prior to starting study treatment is 2 weeks.

• Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort )or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The requiredwashout period prior to starting study treatment is 5 weeks for enzalutamide orphenobarbital and 3 weeks for other agents.

• Obstruction of gastrointestinal tract

• Active gastrointestinal bleeding

• Myocardial infarction within 6 months prior to the study medication, and otherclinically significant heart disease (e.g., unstable angina, congestive heartfailure or uncontrolled hypertension)

• Evidence of severe or uncontrolled systemic disease or any concurrent conditionwhich in the investigator's opinion makes it undesirable for the patient toparticipate in the study or which would jeopardise compliance with the protocol

• Combined hepatocellular carcinoma/cholangiocarcinoma is excluded.

• ECG abnormalities including mean QT interval corrected for heart rate usingFridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5minutes apart), resting ECG indicating uncontrolled, potentially reversible cardiacconditions, as judged by the investigator (eg., unstable ischemia, uncontrolledsymptomatic arrhythmia, congestive heart failure, electrolyte disturbances, etc.),or patients with congenital long QT syndrome.

• Patients with myelodysplastic syndrome/acute myeloid leukaemia or with featuressuggestive of MDS/AML.

• Patients with leptomeningeal carcinomatosis or symptomatic uncontrolled brainmetastases.

• Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with absorption of the studymedication.

• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia and vitiligo

• Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of IP. Note: Local surgery of isolated lesions for palliative intentis acceptable.

• History of allogenic organ transplantation or double umbilical cord bloodtransplantation.

• Active or prior documented autoimmune or inflammatory disorders.

• History of active primary immunodeficiency.

• Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and TB testing in line withlocal practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),hepatitis C.

• Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab.

• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.

• Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 90 days after the last dose of durvalumab monotherapy.

• Concomitant use of known strong or moderate CYP3A inhibitors/inducers, unless withadequate washout period prior to starting olaparib.