Olaparib in Combination with Vorinostat in Patients with Relapsed/Refractory And/or Metastatic Breast Cancer

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 metastaticbreast 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 toadministration of the study treatment.

• White blood cell (WBC) count >2,500/microL and <15,000/microL

• Lymphocyte count ≥500/microL

• Total bilirubin (TBL) ≤1.5 × institutional ULN

• Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤2.5 ×institutional ULN (patients with liver metastases ≤5 × ULN) and alkaline phosphatase (ALP) ≤2.5 × institutional ULN (patients with liver metastases ≤5 × ULN).

• Serum creatinine ≤1.5 × ULN and creatinine clearance (CrCl) estimated using theCockcroft-Gault equation of ≥51 mL/min

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

• Life expectancy ≥6 months.

• Postmenopausal or evidence of non-childbearing status for women of childbearingpotential (WOCBP): negative serum (beta-human chorionic gonadotropin) pregnancy testwithin 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 thecourse of the study through 1 month after the last treatment dose.

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

• Willing and able to comply with the protocol for the duration of the study includingundergoing treatment and scheduled visits and examinations.

• Willing to undergo biopsy as required by the study.

• Able to swallow pills and capsules

Exclusion Criteria:

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

• Previous allogenic bone marrow transplant or double umbilical cord bloodtransplantation.

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

• Unable to swallow orally administered medication and patients with gastrointestinaldisorders 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, excludingalopecia.

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

• Known hypersensitivity to olaparib or vorinostat or any of their excipients oranalogues (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 formore 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 thelast 3 months.

• Any previous treatment with PARP inhibitor including olaparib or HDAC inhibitorincluding 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 sustainedventricular tachycardia, ventricular fibrillation, clinically significantbradycardia, advanced heart block (Mobitz II or higher atrioventricular nodalblock), prolonged corrected QT interval (mean >470 milliseconds), or history ofacute myocardial infarction.

• Risk factors for torsades de pointes such as hypokalemia, hypomagnesemia, cardiacfailure, clinically significant/symptomatic bradycardia, or high-gradeatrioventricular 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 drugfor 2 weeks to be eligible).

• Presence of active or suspected acute or chronic uncontrolled infection or historyof immunocompromise, including participants who are known to be serologicallypositive for HIV.

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