Olaparib With Cediranib or AZD6738 for the Treatment of Advanced or Metastatic Germline BRCA Mutated Breast Cancer

Eligibility Criteria

• 1. Provision of informed consent prior to any study specific procedures
• 2. Women age greater than 18 years with advanced/metastatic HER2 negative, BRCA germline positive breast cancer. Estrogen receptor positive (ER+) patients must have progressed on a prior endocrine therapy or are considered inappropriate for any FDA approved endocrine therapies for ER+ breast cancer.
• 3. Eligible patients must agree to a mandatory fresh biopsy (excluding bone) at screening. In addition, if available, an archival tissue sample will also be collected at screening.
• 4. Patients must have normal organ and bone marrow function measured within 28 days (baseline screening) as defined below:
• * Hemoglobin (Hgb) \>/= 10.0 g/dL with no blood transfusion in the past 28 days prior to the administration
• * Absolute neutrophil count (ANC) \>/= 1.5 x 109/L with no GCSF administration within 28 days prior to administration of study treatment
• * Platelet count \>/= 100 x 109/L
• * Total bilirubin \</= 1.5 x institutional upper limit of normal (ULN)
• * Aspartate aminotransferase (AST) / Alanine aminotransferase (ALT) \</=3.0 x institutional upper limit of normal unless liver metastases are present in which case they must be \</=5x ULN
• 1. Patients who have had chemotherapy or RT within 3 weeks ( or less than 1 week if on weekly chemotherapy) prior to start of the study agents. or persisting \>/= Grade 2 CTCAE toxicity (except alopecia and Grade 2 peripheral neuropathy) from previous anti-cancer treatment(s), or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier. No washout time period is needed for PARP inhibitors.
• 2. Patients received any other investigational agents within the past 4 weeks.
• 3. Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or magnetic resonance imaging (MRI) scans should be excluded from this clinical trial. Patient with known and treated brain metastases is allowed in this study if they fulfil the following criteria: The lesions have improved or remained stable radiographically and clinically for at least 6 weeks after completion of brain irradiation or stereotactic brain radiosurgery. Patients can be on steroids not more than 10 mg/day if started 4 weeks prior to initiation of study drug).
• 4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Olaparib or ceralasertib.
• 5. Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 (See Appendix A) are ineligible, unless discontinues within the washout period (2 weeks for CYP3A4 inhibitors and 4weeks for CYP3A4 inducers) as described in Appendix A. Dihydropyridine calcium-channel blockers are permitted for management of hypertension. Other medications described in Appendix A should be discontinued within the washout period prior to the initiation of study drugs. In addition, patients enrolled in Olaparib+ ceralasertib arm, co-administration of study drug with substrates of OATP1B1 and Pgp (P-glycoprotein) inhibitor or inducer is prohibited.
• 6. Current use of natural herbal products (see Appendix A) or other complementary alternative medications (CAM) or "folk remedies" should be discontinued 7 days prior to the initiation of study drugs.
• * 4cm in diameter, all the following criteria must be met:
• * An ultrasound (US) within the last 6 months will be required to document that it is \</= 5cm
• * Patient must be asymptomatic from the aneurysm.
• * Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation \>450 milli-second, or patients with congenital long QT syndrome or family history of unexplained sudden death under 40 years of age
• * Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block).