To Study Clinical Effectiveness and Safety of Olaparib Monotherapy in Metastatic Breast Cancer Patients.
Condition: HER2-ve Metastatic Breast Cancer; Germline BRCA1/2 Mutations; Somatic BRCA1/2 Mutations
MeSH terms: Breast Neoplasms
Intervention: Olaparib
Intervention description: Patients will be administered olaparib orally, twice daily at 300 mg. Two (2) 150 mg olaparib tablets should be taken at the same time each morning and evening of every day, approximately 12 hours apart.
Intervention MeSH terms: Olaparib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 256.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: HER2-ve metastatic breast cancer; Germline BRCA1/2 mutations; Somatic BRCA1/2 mutations; BRCA1; BRCA2

Summary:

      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.
    

Eligibility criteria:

        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.