Olaparib in Combination With Vorinostat in Patients With Relapsed/Refractory and/or Metastatic Breast Cancer

This is a Phase I/Ib study testing the safety and preliminary efficacy of olaparib and
vorinostat when used together in participants with relapsed/refractory and or metastatic
breast cancer. Cancer cells grow in an uncontrolled manner and this causes damage to their
DNA (genetic makeup). Cancer cells that cannot repair this damage will not survive and die.
Unfortunately, cancer cells contain certain proteins whose job is to repair DNA damage. Poly
(adenosine 5' diphosphoribose) polymerase (PARP) and histone deacetylase (HDAC) are two such
proteins. Olaparib stops PARP from working, and vorinostat stops histone deacetylase from
working. The use of olaparib and vorinostat together may better block the ability of cancer
cells to repair their DNA damage. This may lead to even better killing of cancer cells.

The study will be done in two parts. In part one of the study, different dose levels of
olaparib and vorinostat will be tested in several study participants. This part of the study
will allow us to see the doses of olaparib and vorinostat that can be used safely together in
participants with relapsed/refractory and/or metastatic breast cancer. Up to 4 different dose
levels will be studied. In part two of the study, the dose level of olaparib and vorinostat
found to be the safest in the first part of the study will be tested. This part of the study
will allow us to see how well relapsed/refractory and/or metastatic breast cancer responds to
treatment with olaparib and vorinostat. Participants who received the dose level of olaparib
and vorinostat found to be the safest in the first part of the study will also take part in
part two of the study.

Inclusion Criteria:

- Provision of informed consent prior to any study-specific procedures.

- Female or male ≥18 years of age.

- Histologically or cytologically confirmed relapsed/refractory and/or metastatic breast
cancer with the exception of human epidermal growth factor receptor 2-positive breast
cancer.

- Evaluable or measurable disease as per the RECIST 1:1.

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

- Eastern Cooperative Oncology Group performance status of 0 or 1.

- Life expectancy ≤6 months.

- Postmenopausal or evidence of non-childbearing status for women of childbearing
potential (WOCBP): negative serum (beta-human chorionic gonadotropin) pregnancy test
within 28 days of study treatment and confirmed prior to treatment on Day 1.

- WOCBP must be willing to use 2 highly effective methods of contraception for the
course of the study through 1 month after the last treatment dose.

- Male patients must be willing to use condom contraception for the course of the study
through 3 months after the last treatment dose.

- Willing and able to comply with the protocol for the duration of the study including
undergoing treatment and scheduled visits and examinations.

- Willing to undergo biopsy as required by the study.

Exclusion Criteria:

- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).

- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation.

- Whole blood transfusions in the last 120 days prior to study entry.

- Unable to swallow orally administered medication and patients with gastrointestinal
disorders likely to interfere with absorption of the study treatment.

- Concomitant use of known strong or moderate cytochrome P450 (CYP)3A inhibitors.

- Concomitant use of known strong or moderate CYP3A inducers.

- Persistent toxicities (CTCAE Grade 2) caused by previous cancer therapy, excluding
alopecia.

- Participants with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with
features suggestive of MDS/AML.

- Known hypersensitivity to olaparib or vorinostat or any of their excipients or
analogues (PARP/HDAC inhibitors).

- Breastfeeding women.

- No active malignancy except for non-melanoma skin cancer, in situ cervical cancer, or
a treated cancer from which the patient has been continuously disease free for more
than 5 years.

- Pneumonitis or at risk of pneumonitis.

- Uncontrolled brain or leptomeningeal metastases.

- Any systemic chemotherapy or radiation therapy within 4 weeks prior to study entry.

- Major surgery within 4 weeks of starting the study treatment.

- Participation in another clinical study with an investigational product during the
last 3 months.

- Any previous treatment with PARP inhibitor including olaparib or HDAC inhibitor
including vorinostat.

- New York Heart Association Class III or IV heart failure or unstable angina.

- History of liver disease, such as cirrhosis or active/chronic hepatitis B or C.

- Sustained or clinically significant cardiac arrhythmias including sustained
ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia,
advanced heart block (Mobitz II or higher atrioventricular nodal block), prolonged
corrected QT interval (mean >470 milliseconds), or history of acute myocardial
infarction.

- Risk factors for torsades de pointes such as hypokalemia, hypomagnesemia, cardiac
failure, clinically significant/symptomatic bradycardia, or high-grade
atrioventricular nodal block.

- Concomitant disease(s) that could prolong QT interval such as autonomic neuropathy
(caused by diabetes or Parkinson's disease), human immunodeficiency virus (HIV),
cirrhosis, uncontrolled hypothyroidism, or cardiac failure.

- Concomitant medication(s) known to prolong QT interval (patient must be off the drug
for 2 weeks to be eligible).

- Presence of active or suspected acute or chronic uncontrolled infection or history of
immunocompromise, including participants who are known to be serologically positive
for HIV.

- Any severe and/or uncontrolled medical conditions or other conditions that could
affect study participation, such as severely impaired lung function; any active (acute
or chronic) or uncontrolled infection/disorders; or non-malignant medical illnesses
that are uncontrolled or whose control may be jeopardized by the study treatment.