Phase II Study of the Combination of Durvalumab (MEDI4736) (PDL1 Inhibitor) and Olaparib (PARP Inhibitor) in Advanced Cholangiocarcinoma After Initial Chemotherapy and Durvalumab (BIL-PPP)

Inclusion Criteria:

1. Age ≥18 years, and life expectancy>12 weeks

2. Weight: >30kg

3. Histologically proven locally advanced or metastatic/unresectable cholangiocarcinoma

4. Documentation of RECISTv1.1 measurable disease

5. Must not have had radiologic progression after 6-8 cycles of gemcitabine andcisplatin and durvalumab

6. Adequate haematological and end-organ function as defined by the followingparameters:

7. Haemoglobin ≥ 90g/L (without a transfusion in the past two weeks)

8. Platelets ≥100 x 109/L (without a transfusion in the past two weeks)

9. Neutrophils ≥ 1.0 x 109/L (without the use of G-CSF in the 4 weeks prior tofirst dose)

10. ALT/AST <3x ULN irrespective of presence of liver metastases

11. Serum bilirubin ≤ 1.5x ULN except in cases of known Gilbert's Syndrome wheretotal bilirubin must be <4x ULN

12. Albumin ≥ 25 g/L

13. Serum Creatinine ≤1.5 x ULN or eGFR ≥ 30mL/min/1.73m2 as calculated byCockcroft Gault Equation

14. Able to swallow oral medications without any difficulties or medical historyassociated with malabsorption or any conditions that may impact on compliance orabsorption of the study treatment.

15. Women of Childbearing potential must be either totally abstinent or agree to use atleast one highly effective method of birth control (e.g., oral contraceptive pill,barrier method) for the duration of the study and for at least 6 months after thefinal dose of study medication. They must also have a negative serum beta-hCG in the 7 days prior to first dose of study drug.

16. Non-sterile males and their female partners must also either be totally abstinent oragree to use at least one highly effective method of birth control (e.g., oralcontraceptive pill, barrier method) for the duration of the study and for at least 6months after the final dose of study medication.

17. Patient is willing and able to comply with the protocol for the duration of thestudy, including undergoing treatment and scheduled visits and examinationsincluding follow up.

18. Capable of giving signed informed consent, which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol. Written informed consent and any locally required authorization obtainedfrom the patient/legal representative prior to performing any protocol-relatedprocedures, including screening evaluations.

Exclusion Criteria:

1. Previous use of a PARP inhibitor.

2. All prior treatment-related AEs must have resolved to a CTCAE v5 Grade 1 or lessprior to commencement of study medication, with the exception of alopecia andperipheral neuropathy which can be grade 2 or less. i. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis afterconsultation with the Study Physician. ii. Patients with irreversible toxicity not reasonably expected to be exacerbated bytreatment with durvalumab or olaparib may be included only after consultation withthe Study Chairs.

3. Known symptomatic or progressive CNS metastases or leptomeningeal disease. Patientswith treated brain metastases are eligible for inclusion in the study if they hadreceived treatment >4 weeks prior to commencement of study medication, and have arepeat MRI scan demonstrating stability in disease.

4. Patients with severe chronic or active infections requiring systemic antibiotics orantifungals in the two weeks prior to starting trial treatment.

5. Any of the following cardiovascular risk factors:

6. Acute myocardial infarction (MI) ≤6 months prior to study registration

7. New York Heart Association (NYHA) Heart Failure Class III-IV within ≤6 monthsof registration

8. History of cerebral vascular accident (CVA) within 6 months of first dose

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

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 tothe first dose of IP. Note: Local surgery of isolated lesions for palliative intentis acceptable.

12. History of allogeneic 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, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions tothis criterion:

14. Patients with vitiligo or alopecia.

15. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement.

16. Any chronic skin condition that does not require systemic therapy.

17. Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician.

18. Patients with celiac disease controlled by diet alone.

19. 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 diarrhoea, or psychiatric illness/socialsituations that would limit compliance with study requirements, substantiallyincrease risk of incurring AEs, or compromise the ability of the patient to givewritten informed consent.

20. History of another primary malignancy except for:

21. Malignancy treated with curative intent and with no known active disease ≥2years before the first dose of IP and of low potential risk for recurrence.

22. Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease.

23. Adequately treated carcinoma in situ without evidence of disease.

24. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 mscalculated from 3 ECGs (within 15 minutes at 5 minutes apart).

25. History of active primary immunodeficiency.

26. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody,hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), atscreening. Participants with a past or resolved HBV infection (defined as thepresence of anti HBc and absence of HBsAg) are eligible. Participants positive forHCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

27. Participants co-infected with HBV and HCV, or co-infected with HBV and HDV,namely: HBV positive (presence of HBsAg and/or anti HBcAb with detectable HBVDNA); AND

28. HCV positive (presence of anti-HCV antibodies); OR

29. HDV positive (presence of anti-HDV antibodies).

30. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that mayinclude clinical history, physical examination and radiographic findings, ortuberculosis testing in line with local practice). Known HIV infection that is notwell controlled. All of the following criteria are required to define an HIVinfection that is well controlled: undetectable viral RNA load for 6 months prior,CD4+ count of >500, no history of AIDS-defining opportunistic infection within thepast 12 months, and stable for at least 6 months on the same anti-HIV medications.

31. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab. The following are exceptions to this criterion:

32. Intranasal, inhaled, topical steroids, or local steroid injections (e.g.,intra-articular injection)

33. Systemic corticosteroids at physiologic doses that do not exceed 10 mg/day ofprednisolone or its equivalent.

34. Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)

35. 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 andup to 90days after the last dose of IP.19. Female patients who are pregnant orbreastfeeding, or male or female patients of reproductive potential who are notwilling to employ effective birth control from screening to 90 days after the lastdose of durvalumab monotherapy.

36. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.

37. 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.