A Phase I, Open-Label, 2 Part Multicentre Study to Assess the Safety and Efficacy of Olaparib in Combination With Carboplatin in Patients With Advanced HER-2 Negative Breast Cancer

In Part A up to 36 evaluable patients with advanced breast cancer will be enrolled across 6
cohorts. The total number of patients will depend on the number of dose escalations necessary
to enable a decision to be made on the recommended dose to take forward into Part B of the
study.

The planned dose escalation will start with cohort 1, where patients will receive carboplatin
(AUC5) on day 1 of cycle 1, and will start dosing with olaparib tablets at the dose of 50 mg
twice daily (bd) on day 4 until day 19 of cycle 1 inclusive (a total of 16 days per cycle).
Patients will receive carboplatin on day 1 of each 3 weeks cycle in combination with olaparib
for a total of 4 cycles. Provided that there are no safety concerns after assessment of 6
evaluable patients in the first cohort, patients in subsequent cohorts may be dosed following
Safety Review Committee (SRC) approval. Dose escalation scheme may be adjusted during the
study on the basis of emerging safety, efficacy and pharmacokinetic data. Those patients in
Part A who tolerate the combination up to and including cycle 4 may remain on treatment,
either continuing with the combination, with carboplatin alone at the same AUC or with
olaparib alone at the dose of 300 mg bd, if in the opinion of the treating Investigator, a
patient is deemed to be deriving clinical benefit from treatment. In these cases, a patient
may remain on treatment until progression, unacceptable toxicity or until other
discontinuation criteria are met. Beyond cycle 4, patients will undergo assessments in line
with the clinical protocol. Once the maximum tolerated dose (MTD) and/or recommended dose
(RD) has been defined in Part A, a dose expansion phase, Part B will begin and this will
include up to 21 patients with HER2 negative breast cancer, with a deleterious or suspected
deleterious germlineBRCA1/2 (gBRCA1/2) mutation, who are deemed eligible for neoadjuvant
therapy.

Part B will explore the safety, tolerability and efficacy of the combination of olaparib and
carboplatin in terms of pathological complete response (pCR) rate. Neoadjuvant systemic
therapy will consist of the following anti-cancer drugs for a total of 8 cycles of treatment:

- The first 4 cycles (cycle 1 to cycle 4: 12 weeks) will be based on combination of
olaparib, at the defined RD and schedule from Part A, with carboplatin. It is expected
that a cycle of treatment would be 3 weeks.

- Another 4 cycles (cycle 5 to cycle 8) will be based on a combination of an anthracycline
and cyclophosphamide (AC). The choice of the AC regimen will be up to local Investigator
following international guidelines (National Comprehensive Cancer Network (NCCN),
European Society for Medical Oncology (ESMO), and St Gallen).

The tumour response will be assessed through careful clinical examination and also with
radiological examinations between cycle 4 and 5 and at the end of neoadjuvant part, before
surgery. Additionally, tumour biopsy will be performed within 7 days before cycle 5 day 1,
after completion of carboplatin and olaparib combination therapy and early pathological
response assessed by local pathologist. Curative-intent surgery should be performed following
completion of neoadjuvant treatment in all patients, 3 to 5 weeks after day 1 of the last
cycle of neoadjuvant treatment.

A decision has been made to stop recruitment after Part A cohort 2, and to not start Part B
of the study. The protocol has been amended to define that the collection of clinical data
will stop once the final patient from cohort 2 of Part A has completed 4 cycles or all
patients from cohort 2 of Part A discontinue prior to end of cycle 4 to enable data analysis
and reporting. The database would close at this time point, however AstraZeneca commits to
providing study treatment to ongoing patients that continue to receive clinical benefit, in
Investigator's judgment. Patients who remain on study treatment after this time point will be
monitored according to routine clinical practice as defined by the Investigator and no
clinical data will be collected, other than SAEs and drug dispensing/accountability.

Inclusion criteria

- Male or female aged ≥18 years

- Normal organ and bone marrow function, measured within 28 days prior to administration
of study treatment

- Eastern Cooperative Oncology Group performance status of 0-1

- Postmenopausal or evidence of non-childbearing status for women of childbearing
potential.

Additional for patients participating in Part A only

- Advanced or metastatic breast cancer that is HER-2 negative (HR positive or HR
negative)

- Between 0 and 2 lines of prior cytotoxic chemotherapy. Additional for patients
participating in Part B only

- Patients with operable breast adenocarcinoma and no evidence of metastatic disease are
allowed.

- Patient must meet at least one of the following criteria: Clinical primary tumour size
defined as T2 or above, clinical or patho-histological evidence of regional lymph
nodes involvement (N+), grade 2-3 disease

- Availability of formalin fixed, paraffin embedded tumour sample from diagnostic
biopsies (Not Applicable for patients at sites in Israel)

- Histological confirmation of HER-2 negative breast cancer

- Documented germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or
suspected deleterious

- Eligible for neo-adjuvant chemotherapy, but have not yet received neoadjuvant
chemotherapy for breast cancer (chemo-naive) Exclusion criteria

- Exposure to an investigational product within 30 days or 5 half-lives (whichever is
the longer) prior to enrolment

- Prior use of Poly ADP Ribose Polymerase (PARP) inhibitors

- Patients with a known hypersensitivity to olaparib or carboplatin

- Concurrent treatment with an ovarian hormonal replacement therapy or with hormonal
agents such as raloxifene, tamoxifen or other selective estrogen receptor modulator.
Patient must have discontinued use of such agents 3 weeks prior to beginning study
treatment. Luteinising hormone-Releasing hormone (LHRH) analogues are allowed for all
patients in Part A.

- Concomitant use of known potent Cytochrome P450 3A4 (CYP3A4) inhibitors and inducers

- Persistent toxicities (Common Terminology Criteria for Adverse Event (CTCAE) grade ≥2
and neuropathy CTCAE > grade 1) caused by previous cancer therapy, excluding alopecia
- Patient with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with
features suggestive of MDS/AML

- Patient must have recovered from any effects of any major surgery

- Patient considered at poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled seizures or active
uncontrolled infection

- Patient with known active Hepatitis B or C, or Human immunodeficiency virus (HIV)

- Other malignancy within the last 5 years (few exceptions apply). Additional for
patients participating in Part A only

- Prior chemotherapy within 3 weeks of study entry

- Other anti-cancer therapy (eg, targeted biotherapy of hormonal agents) within 3 weeks
of study entry

- Radiation therapy within 4 weeks or radionuclide treatment within 6 weeks of treatment
start

- Prior use of platinum compound in the advanced or metastatic setting. Previous
exposure to platinum compounds is allowed only if they were used in early adjuvant or
neoadjuvant setting with relapse occurring >6 months after the last platinum
administration and if there is no residual toxicity

- Patient with a history of treated Central Nervous System (CNS) metastases are
eligible, provided they meet certain protocol-specified criteria.

Additional for patients participating in Part B only

- Prior treatment (local or systemic) of their breast tumour. Sentinel lymph node biopsy
is considered as diagnostic procedure and therefore is authorized before neoadjuvant
treatment in part B

- Patients with inflammatory breast cancer or patients with inoperable locally advanced
breast cancer (including T4 lesions) at the time of enrolment.