<Objectives>
Primary Objectives:
To assess the effect of AZD6738 and Durvalumab combination / AZD6738 and olaparib combination on DCR (disease control rate) in biliary tract cancer patients who have failed to 1st-line chemotherapy. 
-Disease control rate (based on RECIST v1.1)

Secondary Objective(s):
To see the efficacy and safety of AZD6738 and Durvalumab combination / AZD6738 and olaparib combination in biliary tract cancer patients who have failed to 1st-line chemotherapy.
 -Efficacy: overall response rate (RECIST 1.1, ir response), progression-free survival, duration of response, overall survival, EORTC QLQ-C30,
-Safety: toxicity (CTCAE V5.0), irAE

<Background>
DNA damage repair pathways, which include BAP1, MSH6, BRCA1, ATM, MLH1, and MSH2, are altered in about 20% of BTC cases. A faulty DDR generally affects the response to chemotherapeutic drugs, and there is growing evidence that tumors with defective DNA damage repair could be sensitive to certain DDR-targeted agents . In addition, the frequent occurrence of these mutations often leads to microsatellite instability (MSI), and the MSI status has an important role in the pathogenesis of cancers. Notably, previous studies showed that MSI-High was present in about 25% of BTC cases. Furthermore, the occurrence of TP53 gene mutations was observed in 33.9% of BTC cases. TP53 is one of the most widely found tumor suppressor genes, and acts as the guardian of genomic P53 signaling pathways that control DNA damage repair, cell cycle progression, or apoptosis. Therefore, various researchers have employed TP53-deficient cancer cells in DDR-targeted therapeutic studies. Taken together, BTC has the potential to respond well to DDR-targeted agents.

<Hypothesis>
• Hypothesis 1:
Dual targeting DNA-damage response (DDR) and Immune checkpoint (I-O) is synergistic and enhance antitumor effects in biliary tract cancer (BTC) patients. The dynamics of immune environment by ATR inhibition and its changes by combination with immune-oncology agents will be uncovered in BTC patients. The combination of AZD6738 with Durvalumab is tolerable and efficacious in BTC patients.
• Hypothesis 2:
Dual targeting DDRs using ATR inhibitor (AZD6738) and PARP inhibitor (Olaparib) is synergistic and effective in BTC patients. The combination of AZD6738 with olaparib is tolerable and efficacious in BTC patients.

<Study Design>Open-label, phase II, 
This is the umbrella study enrolling advanced BTC patients who have failed to 1st-line chemotherapy, which is composed of 2 cohorts. Based on the new emerging therapies, cohorts can be added into existing protocol.
One cycle consists of 4weeks. Response evaluation will be done every 8 weeks (every 2 cycles) of treatment 
1) tumor biopsy is mandatory : screening, after 8weeks (1st-response evaluation), at disease progression (PD)
2) blood sampling for biomarker study is mandatory: every cycles
3) To evaluate the metabolic changes by AZD6738 and Durvalumab combination

Treatment

In AZD6738+Durvalumab cohort, the dosage of AZD6738 and durvalumab is following:
•	Durvalumab  1500 mg iv on D1
•	AZD6738 240 mg bid on D15-D28
Every 4 weeks
Durvalumab 1500 mg will be dosed at C1D1, and AZD6738 240 mg bid will be dosed D15-D28 of cycle.

In AZD6738+ Olaparib cohort, the dosage of AZD6738 and olaparib is following:
•	AZD6738 160 mg qd on D1-7
•	Olaparib 300 mg bid on D1-28
 Every 4 weeks
In every cycle which consists of 28 days, AZD6738 160 mg qd will be administered on D1-D7 and olaparib 300mg bid will be administered on D1-D28.

Arm Label

Target Number of Participant

Arm Type

Arm Description

•	Durvalumab  1500 mg iv on D1
•	AZD6738 240 mg bid on D15-D28
Every 4 weeks
Durvalumab 1500 mg will be dosed at C1D1, and AZD6738 240 mg bid will be dosed D15-D28 of cycle.

Arm Label

Target Number of Participant

Arm Type

Arm Description

•	제1-7일에 AZD6738 160 mg 1일 1회
•	제1-28일에 Olaparib 300 mg 1일 2회
매 4주마다 반복 투여한다.

각 치료 주기의 단위 기간은 4주로 구성된다. 각 주기마다 제1-7일에 AZD6738을 160 mg 1일 1회 용법용량으로 투여한다. 제1-28일에 olaparib을 300 mg 1일 2회 용법용량으로 투여한다.

Gender

Age

Description

1.	Written informed consent and any locally-required authorization obtained from the subject prior to performing any protocol-related procedures, including screening evaluations 
2.	Age > 20 years at time of study entry 
3.	Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4.	Life expectancy of > 16weeks
5.	Histologically proven BTC, including intrahepatic cholangiocarcinoma, extrahepatic bile duct cancer, gallbladder cancer, ampulla of vater cancer
6.	Unresectable or recurrent 
7.	Failed to 1st-line chemotherapy for their advanced BTC (IO is not allowed)
8.	At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1.
9.	Body weight >30kg (for durvalumab cohort) 
10.	Adequate normal organ and marrow function measured within 28 days prior to administration of study treatment as defined below: 
	Haemoglobin ≥9.0 g/dL (>10 for olaparib cohort with no transfusion within the previous 28 days)
	Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
	Platelet count ≥ 100 x 109/L 
	Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). (This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.)
	AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
	Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test :
Estimated creatinine clearance =	(140-age [years]) x weight (kg)    (x F)a
serum creatinine (mg/dL) x 72
	a where F=0.85 for females and F=1 for males.
11.	Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1. 
Postmenopausal is defined as:
-Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
-Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
-radiation-induced oophorectomy with last menses >1 year ago
-chemotherapy-induced menopause with >1 year interval since last menses
-surgical sterilisation (bilateral oophorectomy or hysterectomy)
12.	Male patients must use a condom during treatment and for 6 months after the last dose of study drug when having sexual intercourse with a pregnant woman or with a woman of childbearing potential.  Female partners of male patients should also use a highly effective form of contraception ([see appendix H for acceptable methods]) if they are of childbearing potential
13.	Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

1.	Participation in another clinical study with an investigational product during the last 3 weeks
2.	Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
3.	Any previous treatment with Immune check point inhibitor, ATR or PARP inhibitor, including Olaparib.
4.	Whole blood transfusions in the last 120 days prior to entry to the study in olaparib cohort (packed red blood cells and platelet transfusions are acceptable outside of 28 days prior to treatment
5.	Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
6.	Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) within 21 days of the first dose of study drug .2 The minimum washout period for immunotherapy is 42 days
7.	Mean QT interval:
Mean resting corrected QT interval (QTc) >470 msec for females and >450 for men, obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart using the Fredericia formula
-	Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as congestive heart failure, unstable angina pectoris, acute myocardial infarction, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age, conduction abnormality not controlled with pacemaker or medication.
8.	In AZD6738+Durvalumab cohort, current or prior use of immunosuppressive medication within 14days (use 28 days if combining durvalumab with a novel agent) before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. The following are exceptions to this criterion
The following are exceptions to this criterion:
-	Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
-	Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
Also, Any of the following cardiac diseases currently or within the last 6 months (by New York Heart Association (NYHA) ≥ Class 2 where applicable):
-	Unstable angina pectoris
-	Congestive heart failure or known reduced LVEF < 55%
-	Acute myocardial infarction
-	Conduction abnormality not controlled with pacemaker or medication e.g. complete left bundle branch block, third degree heart block
-	Significant ventricular or supraventricular arrhythmias e.g. (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
-	Patients at risk of brain perfusion problems, e.g., medical history of carotid stenosis or pre-syncopal or syncopal episodes, history of TIAs  
Uncontrolled hypertension (grade 2 or above) requiring clinical intervention.
9.	Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria 
	Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
	Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician. 
10.	Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable. 
11.	Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
12.	Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. Patients must have recovered from any effects of any major surgery
13.	History of allogenic organ transplantation.
14.	Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
	Patients with vitiligo or alopecia
	Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement 
	Any chronic skin condition that does not require systemic therapy
	Patients without active disease in the last 5 years may be included but only after consultation with the study physician
	Patients with celiac disease controlled by diet alone
15.	Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
16.	History of another primary malignancy except for
	Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
	Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
	Adequately treated carcinoma in situ without evidence of disease
17.	History of leptomeningeal carcinomatosis
18.	Brain metastases or spinal cord compression. Patients with symptomatic uncontrolled brain metastases.  A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment.  Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
19.	History of active primary immunodeficiency 
20.	Active infection or immunocompromised patients including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B , hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Subjects with simple HBV carrier, a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
21.	Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
22.	Female patients who are pregnant or breastfeeding. 
23.	Male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 6 months after the study drug. (including sperm donation for male patients) 
24.	Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
25.	Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
26.	Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML for olaparib cohort 
27.	For olaparib cohort, concomitant use of known potent (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting study treatment is five half-lives, except for St-Johns’ wort, which is 3 weeks. 
28.	For olaparib cohort, previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
29.	For AZD6738 cohort, diagnosis of ataxia telangiectasia.
30.	Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection, with clinically significant sequelae that would preclude adequate absorption of AZD6738.
31.	For AZD6738 cohort, haematuria: +++ on microscopy or dipstick.
32.	For AZD6738 cohort, Patients with relative hypotension (<100/60 mmHg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of >20 mmHg.
33.	Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.
34.	Involvement in the planning and/or conduct of the study
35. Previous enrolment <<or randomisation>> in the present study

Disease control rate

every 8weeks

overall response rate

every 8weeks

progression-free survival

every 8weeks

duration of response

every 8weeks

overall survival

every 2months

Quality of life (EORTC QLQ-C30)

every 4weeks

toxicity(CTCAE V5.0)

every 4weeks

immune-related adverse event

every 4weeks