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

• 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.
• 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 the Cockcroft-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 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.
• Able to swallow pills and capsules

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.