To Study Clinical Effectiveness and Safety of Olaparib Monotherapy in Metastatic Breast Cancer Patients.
To Study Clinical Effectiveness and Safety of Olaparib Monotherapy in Metastatic Breast Cancer Patients.
This open-label, multi-centre phase IIIb study will assess the effectiveness, benefits and
 potential harms in the use of olaparib monotherapy treatment for patients with HER2-ve
 metastatic breast cancer associated with germline or somatic breast cancer susceptibility
 gene (gBRCA1/2 or sBRCA1/2) mutations.
The study is a phase IIIb, multicenter, single-arm, open-label study designed to evaluate the
 clinical effectiveness in a real-world setting of olaparib monotherapy in patients with
 confirmed germline or somatic breast cancer susceptibility gene (gBRCA1/2 or sBRCA1/2)
 mutations. This study will generate additional data to support other olaparib studies, which
 may help inform and guide clinical practice. Physician defined the progression-free survival
 (PFS) for gBRCAm patients is the primary outcome measure. Based on the prevalence of gBRCA1/2
 mutations, it is estimated that up to 1400 patients may require screening in order to
 identify 250 gBRCA mutated patients and 20 sBRCA mutated patients. Patients will be
 administered two olaparib 150mg tablets in morning and evening of every day after a light
 meal. Dose reductions may be required for olaparib treatment related toxicities. Patients
 should continue to receive study treatment until documented physician-defined disease
 progression as assessed by the investigator (gBRCA mutated patients), RECIST1.1 disease
 progression (sBRCA mutated patients) or unacceptable toxicity, or for as long as they do not
 meet any other discontinuation criteria. A positive benefit/risk profile is expected and no
 ethical issues are identified from exposing patients to olaparib within the planned clinical
 study.
Inclusion criteria:

 1. Provision of informed consent prior to any study specific procedures. For patients
 aged <20 years and screened in Japan, a written informed consent should be obtained
 from the patient and his or her legally acceptable representative.

 2. Patients must be ≥18 years of age.

 3. Histologically or cytologically confirmed HER2-ve breast cancer with evidence of
 metastatic disease. Patients can have either TNBC (defined as oestrogen receptor and
 progesterone receptor negative [immunohistochemistry nuclear staining <1%] and HER2-ve
 [immunohistochemistry 0, 1+ or 2+ and/or in situ hybridization nonamplified with ratio
 less than 2.0]) or oestrogen receptor / progesterone receptor positive breast cancer
 as long as they are HER2-ve.

 4. Documented BRCA1/2 status

 -  To be regarded as BRCA1/2 (+ve), the patient must have a mutation that is
 predicted to be deleterious or suspected deleterious (known or predicted to be
 detrimental / lead to loss of function). Mutations that are not clearly
 pathogenic may be assessed by a committee of genetic specialists to adjudicate if
 the patient is eligible.

 -  Patients with tBRCA mutations: must be confirmed by a validated method (e.g.
 results from a CLIA-certified laboratory or CE-IVD device)

 5. Prior treatment with a taxane or an anthracycline in either an adjuvant (may include
 neoadjuvant) or metastatic breast cancer treatment setting.

 6. Patients should have received no more than two prior cytotoxic chemotherapy regimens
 in the metastatic setting. If a patient has oestrogen receptor and/or progesterone
 receptor positive HER2 negative metastatic breast cancer and has completed a prior
 line of hormonal treatment, then if the current or currently planned choice of
 treatment for the patient does not include a hormonal treatment then they would be a
 suitable patient to enter the study. Previous endocrine therapy could be in either an
 adjuvant or a metastatic setting and include endocrine therapy in combination with a
 targeted agent such as a CDK4/6 or mTOR inhibitor.

 7. Be considered suitable, by the Investigator, for further treatment with single-agent
 chemotherapy for the metastatic disease

 8. Patients must have normal organ and bone marrow function measured within 14 days prior
 to administration of study treatment as defined below:

 -  Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days

 -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

 -  Platelet count ≥ 100 x 109/L

 -  Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless the
 patient has documented Gilbert's Syndrome

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT))
 / alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase (SGPT)) ≤
 2.5 x institutional ULN unless liver metastases are present in which case they
 must be ≤ 5x ULN

 -  Patients must have creatinine clearance (CrCl) estimated using the Cockcroft-
 Gault equation of ≥ 51 mL/min or 24 hour urine test may be done if standard of
 care:

 Estimated CrCl = (140-age [years]) x weight (kg) (x F)a serum creatinine (mg/dL) x 72

 a- where F=0.85 for females and F=1 for males

 9. Patients must have a life expectancy ≥ 16 weeks

 10. Postmenopausal or evidence of non-childbearing status for women of childbearing
 potential: negative urine or serum pregnancy test within 28 days of study treatment
 and confirmed prior to treatment on Day 1

 Postmenopausal is defined as (at least one criterion met):

 -  amenorrhoeic for 1 year or more following cessation of exogenous hormonal
 treatments

 -  luteinizing hormone and follicle stimulating hormone levels in the postmenopausal
 range for women under 50

 -  radiation-induced oophorectomy with last menses >1 year ago

 -  chemotherapy-induced menopause with >1 year interval since last menses

 -  surgical sterilisation (bilateral oophorectomy or hysterectomy).

 11. Women of childbearing potential, who are sexually active, must agree to the use of one
 highly effective form of contraception and their male partners must use a condom from
 the signing of the informed consent, throughout the period of taking study treatment
 and for at least 1 month after last dose of study drug, or they must totally/truly
 abstain from any form of sexual intercourse.

 12. Male patients must use a condom during treatment and for 3 months after the last dose
 of olaparib when having sexual intercourse with a pregnant woman or with a woman of
 childbearing potential. Female partners of male patients should also use one highly
 effective form of contraception if they are of childbearing potential.

 13. Patient is willing and able to comply with the protocol for the duration of the study
 including undergoing treatment and scheduled visits and examinations for greater than
 6 months.

 Exclusion criteria:

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

 2. Previous enrolment in the present study

 3. Exposure to an investigational product (IP) during the last 1 month or 5 half-lives
 (whichever is longer) prior to enrolment

 4. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
 reasons) within 3 weeks prior to study treatment

 5. Any previous treatment with a PARP inhibitor, including olaparib

 6. Other malignancy unless curatively treated with no evidence of disease for ≥5 years
 except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer
 of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial
 carcinoma.

 7. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as
 judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic
 arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte
 disturbances, etc.), or patients with congenital long QT syndrome.

 8. Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin,
 clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
 saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.,
 ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
 period prior to starting olaparib is 2 weeks.

 9. Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin,
 rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
 moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout
 period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
 weeks for other agents.

 10. Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2)
 caused by previous cancer therapy, excluding alopecia.

 11. Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with
 features suggestive of MDS/AML

 12. Patients with symptomatic uncontrolled brain metastases.

 - Exception: Patients with adequately treated brain metastases documented by baseline
 CT or MRI scan that has not progressed since previous scans and that does not require
 corticosteroids (except ≤10 mg/day prednisone or equivalent for at least 14 continuous
 days prior to dosing) for management of CNS symptoms are eligible, provided that a
 repeat CT or MRI following the identification of CNS metastases (obtained at least 2
 weeks after definitive therapy) must document adequately treated brain metastases.

 13. Major surgery within 2 weeks of starting study treatment and patients must have
 recovered from any effects of any major surgery.

 14. Patients considered a poor medical risk due to a serious, uncontrolled medical
 disorder, non-malignant systemic disease or active, uncontrolled infection.

 Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent
 (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable
 spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral
 lung disease on high resolution computed tomography (HRCT) scan or any psychiatric
 disorder that prohibits obtaining informed consent.

 15. Patients unable to swallow orally administered medication and patients with
 gastrointestinal disorders likely to interfere with absorption of the study medication

 16. Breastfeeding women

 17. Immunocompromised patients, e.g., patients who are known to be serologically positive
 for human immunodeficiency virus (HIV)

 18. Patients with a known hypersensitivity to olaparib or any of the excipients of the
 product

 19. Patients with known active hepatitis (i.e., hepatitis B or C)

 20. Whole blood transfusions in the last 28 days prior to entry to the study.