Phase II Multicenter Study of Durvalumab and Olaparib in Platinum tReated Advanced Triple Negative Breast Cancer (DORA)

Subjects suitable for enrollment into this trial are adult subjects with histologically
documented triple negative adenocarcinoma of the breast that is inoperable, locally advanced,
or metastatic, and is not amenable to resection with curative intent, and who have received
at least 4 cycles of platinum-based chemotherapy in the 1st or 2nd line setting AND derived
clinical benefit (CR / PR / SD) per RECIST 1.1 with platinum-based therapy as determined by
the treating physician.

Eligible subjects will be randomized to either olaparib or olaparib in combination with
durvalumab. Study treatment will continue until disease progression, intolerable toxicity,
elective withdrawal from the study, or study completion or termination. Upon treatment
discontinuation, subjects will be followed every 2 months for survival.

Although randomization will be used to allocate subjects to either the olaparib or olaparib
in combination with durvalumab arm, no comparisons between treatment regimens are planned.
The purpose of randomization was to reduce bias due to subject selection into either
treatment arm.

Inclusion Criteria:

1. Prior treatment of 4 cycles of platinum chemotherapy with documented stable disease
(SD), partial response (PR) or complete response (CR) per RECIST 1.1 to the platinum
therapy.

2. Has received no more than 2 prior chemotherapy regimens for metastatic breast cancer
including current platinum based chemotherapy.

3. Able to provide a representative formalin-fixed, paraffin embedded tumour specimen
archival or fresh tissue for correlative studies and biomarker analysis

4. Hemoglobin ≥ 10.0 g/dL and no blood transfusions in the 28 days prior to study entry.
White blood cells (WBC) >3 x 10^9/L.

5. Platelet count >100 x 10^9/L.

6. Total bilirubin <1.5 x the upper limit of normal (ULN) with the following exception:
subjects with known Gilbert's disease who have serum bilirubin <3 x ULN may be
enrolled.

7. Aspartate transaminase (AST) and alanine transaminase (ALT) <2.5 x ULN with the
following exceptions: subjects with documented liver or bone metastases may have AST
and ALT <5 x ULN.

8. Alkaline phosphatase (ALP) <2 x ULN (<5 x ULN in subjects with known liver involvement
and <7 ULN in subjects with known bone involvement).

9. Serum creatinine <1.5 x ULN or creatinine clearance >51 mL/min by the Cockcroft-Gault
formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of
creatinine clearance.

10. For subjects of childbearing potential, agreement (by both subject and partner) to use
an effective form of contraception, including surgical sterilization, reliable barrier
method, birth control pills, contraceptive hormone implants, or true abstinence and to
continue its use for the duration of the study and for 6 months after last dose of
study treatment.

11. Subjects of childbearing potential should have a negative urine or serum pregnancy
test within 72 hours prior to receiving the first dose of study medication. If the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required.

12. Subjects willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examination.

13. For inclusion in genetic research, subjects must provide informed consent for genetic
research.

Exclusion Criteria:

1. Currently participating and receiving study therapy or has participated in a study of
an investigational agent and received study therapy or used an investigation device
within 4 weeks of first dose of treatment. Subjects who have entered the follow-up
phase of an investigational study may participate as long as it has been 4 weeks since
last dose of the previous investigational agent of device.

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

3. Active autoimmune disease that has required systemic treatment in past 2 years (ie,
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency, or similar treatment) is not
considered a form of systemic treatment.

4. Current or prior use of immunosuppressive medication within 28 days before the first
dose of investigational drug(s), 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.

5. Previous treatment with PARP inhibitors including olaparib.

6. Received prior therapy with an anti-PD-1, anti-PD-L1 (including durvalumab) or an
anti-PD-L2 agent.

7. Known active central nervous system metastasis and / or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate, provided they have:

1. Stable brain metastases [without evidence of progression by imaging (confirmed by
computerized tomography {CT} scan if CT used at prior imaging) for at least four
weeks prior to the first dose of trial treatment**,

2. No evidence of new or enlarging brain metastases; any neurologic symptoms should
have returned to baseline,

3. Not used steroids for brain metastases in the 28 days prior to trial initiation.

- This exception does not include carcinomatous meningitis, as subjects with
carcinomatous meningitis are excluded regardless of clinical stability.

8. History and/or confirmed pneumonitis, or extensive bilateral lung disease on high
resolution/spiral CT scan. Patients with suspected or confirmed myelodysplastic
syndrome/acute myeloid leukemia.

9. History of another primary malignancy except for:

1. Malignancy treated with curative intent and with no known active disease ≥5 years
before the first dose of study drug and of low potential risk for recurrence.

2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.

3. Adequately treated carcinoma in situ without evidence of disease eg, cervical
cancer in situ.

10. Major surgery within 2 weeks of starting the study, and subjects must have recovered
from any effects of any major surgery.

11. Receipt of radiation therapy within 4 weeks prior to starting study drug(s). Limited
field of radiation for palliation within 2 weeks of the first dose of study treatment
is allowed provided:

1. The lung is not in the radiation field

2. Irradiated lesion(s) cannot be used as target lesions

12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, active peptic ulcer disease, active bleeding
diatheses including any subjects known to have evidence of acute or chronic hepatitis
B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness / social
situations that would limit compliance with study requirements or compromise the
ability of the subject to give written informed consent.

13. Subjects unable to swallow orally administered medication, and subjects with
gastrointestinal disorders likely to interfere with absorption of the study
medication.

14. Subjects requiring treatment with potent inhibitors or inducers of CYP3A4.

15. Pregnant or breast-feeding women. If breastfeeding can be stopped prior to study
enrollment until 1 month after the last study dose, then the patient could be allowed
to enter the study.

16. Immunodeficient subjects, eg, receiving systemic steroid therapy or any other form of
immunosuppressive therapy within 7 days prior to the first dose of trial treatment,
and subjects who are known to be serologically positive for human immunodeficiency
virus (HIV).

17. Received a live vaccine within 30 days of planned start of study therapy.

18. Subjects with a known hypersensitivity to olaparib or durvalumab, or any of the
excipients of the product.

19. Active or prior documented inflammatory bowel disease (eg, Crohn's disease, ulcerative
colitis)

20. History of allogeneic organ transplant

21. Active bleeding diatheses

22. Patients with known active hepatic disease (ie, Hepatitis B or C)

23. Known history of previous clinical diagnosis of tuberculosis.