AZD6738 Plus Durvalumab in Biliary Tract Cancer

Inclusion Criteria:

1. Written informed consent and any locally-required authorization obtained from thesubject prior to performing any protocol-related procedures, including screeningevaluations
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, extrahepaticbile duct cancer, gallbladder cancer, ampulla of vater cancer
6. Unresectable or recurrent
7. Failed immunotherapy for their advanced BTC (the patient may have also receivedchemotherapy in the 1 or 2L)
8. At least one measurable lesion that can be accurately assessed at baseline by computedtomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated) and issuitable for repeated assessment as per RECIST 1.1.
9. Body weight >30kg
10. Adequate normal organ and marrow function measured within 28 days prior toadministration of study treatment as defined below :

• Haemoglobin ≥9.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count ≥ 100x 109/L
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). (This will notapply to patients with confirmed Gilbert's syndrome (persistent or recurrenthyperbilirubinemia that is predominantly unconjugated in the absence of hemolysisor hepatic pathology), who will be allowed only in consultation with theirphysician.)
• AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless livermetastases are present, in which case it must be ≤5x ULN
• Patients must have creatinine clearance estimated of ≥51 mL/min using theCockcroft-Gault equation or based on a 24 hour urine test : Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a serumcreatinine (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 childbearingpotential: negative urine or serum pregnancy test within 28 days of study treatmentand 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 postmenopausal 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 mustuse a condom during treatment and for 6 months after the last dose of AZD6738 whenhaving sexual intercourse with a pregnant woman or with a woman of childbearingpotential. Female partners of male patients should also use a highly effective form ofcontraception ([see appendix H for acceptable methods]) if they are of childbearingpotential 13. Patient is willing and able to comply with the protocol for the durationof the study including undergoing treatment and scheduled visits and examinationsincluding follow up.

Exclusion Criteria:

1. Participation in another clinical study with an investigational product during thelast 3 weeks
2. Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with absorption of the studymedication.
3. Any previous treatment with ATR inhibitor
4. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study
5. Receipt of the last dose of anti-cancer therapy (chemotherapy, endocrine therapy,targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, otherinvestigational agent) within 21 days of the first dose of study drug .2 The minimumwashout period for immunotherapy is 42 days
6. 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 Fredericiaformula

• Any factors that increase the risk of QTc prolongation or risk of arrhythmic eventssuch as congestive heart failure, unstable angina pectoris, acute myocardialinfarction, hypokalaemia, congenital long QT syndrome, immediate family history oflong QT syndrome or unexplained sudden death under 40 years of age, conductionabnormality not controlled with pacemaker or medication.

7. Current or prior use of immunosuppressive medication within 28 days before the firstdose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids orsystemic corticosteroids at physiological doses, which are not to exceed 10 mg/day ofprednisone, or an equivalent corticosteroid. The following are exceptions to thiscriterion The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)
• Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> ofprednisone or its equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)

8. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria

• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis afterconsultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated bytreatment with durvalumab may be included only after consultation with the StudyPhysician.

9. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormonereplacement therapy) is acceptable.
10. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field ofradiation within 4 weeks of the first dose of study drug
11. Major surgical procedure (as defined by the Investigator) within 28 days prior to thefirst dose of IP. Note: Local surgery of isolated lesions for palliative intent isacceptable. Patients must have recovered from any effects of any major surgery
12. History of allogenic organ transplantation.
13. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoidarthritis, hypophysitis, uveitis, etc]). The following are exceptions to thiscriterion:

• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician
• Patients with celiac disease controlled by diet alone

14. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantially increaserisk of incurring AEs or compromise the ability of the patient to give writteninformed consent
15. History of another primary malignancy except for

• Malignancy treated with curative intent and with no known active disease ≥5 yearsbefore the first dose of IP and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease
• Adequately treated carcinoma in situ without evidence of disease

16. History of leptomeningeal carcinomatosis
17. Brain metastases or spinal cord compression. Patients with symptomatic uncontrolledbrain 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 studyas long as these were started at least 4 weeks prior to treatment. Patients withspinal cord compression unless considered to have received definitive treatment forthis and evidence of clinically stable disease for 28 days.
18. History of active primary immunodeficiency
19. Active infection or immunocompromised patients including tuberculosis (clinicalevaluation that includes clinical history, physical examination and radiographicfindings, and TB testing in line with local practice), hepatitis B , hepatitis C, orhuman immunodeficiency virus (positive HIV 1/2 antibodies). Subjects with simple HBVcarrier, a past or resolved HBV infection (defined as the presence of hepatitis B coreantibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive forhepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negativefor HCV RNA.
20. 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.
21. Female patients who are pregnant or breastfeeding
22. Male or female patients of reproductive potential who are not willing to employeffective birth control from screening to 6 months after the last dose of AZD6738 ordurvalumab monotherapy. (including sperm donation for male patients)
23. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.
24. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which requiredsteroid treatment, or any evidence of clinically active interstitial lung disease. Concomitant use of known potent (eg. phenobarbital, enzalutamide, phenytoin,rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort)inhibitors or CYP3A inducers (eg. bosentan, efavirenz, modafinil). The requiredwashout period prior to starting study treatment is five half-lives, except forSt-Johns' wort, which is 3 weeks.
25. Diagnosis of ataxia telangiectasia.
26. Refractory nausea and vomiting, chronic gastrointestinal diseases or previoussignificant bowel resection, with clinically significant sequelae that would precludeadequate absorption of AZD6738.
27. Haematuria: +++ on microscopy or dipstick.
28. Hypotension (<100/60 mmHg) or clinically relevant orthostatic hypotension, including afall in blood pressure of >20 mmHg.
29. Judgment by the investigator that the patient is unsuitable to participate in thestudy and the patient is unlikely to comply with study procedures, restrictions andrequirements.