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Pathologically confirmed advanced high grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer |
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Female, aged at least 18 years |
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Documented mutation in BRCA1 or BRCA2 germline and/or somatic that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function) |
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FIGO stages III-IV primary ovarian, primary peritoneal, or fallopian tube cancers not suitable of primary cytoreductive surgery (Criteria for Neoadjuvant Chemotherapy despite to Primary Surgery: clinical conditions; Fagotti's score > 10, small bowel carcinosis, mesenteric retraction) |
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Measurable disease according to RECIST criteria 1.1 |
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Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 |
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Left Ventricular Ejection Fraction (LVEF) institutional lower limit of normal |
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Patients must have a life expectancy of >16 weeks |
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Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below |
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Haemoglobin 10.0 g/dL and no blood transfusions in the 28 days prior to entry/randomisation (choose whichever is most applicable to the study) |
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Absolute neutrophil count (ANC) 1.5 x 109/L |
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No features suggestive of MDS/AML on peripheral blood smear |
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White blood cells (WBC) > 3x109/L |
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Platelets count 100 x 109/L |
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Total bilirubin 1.5 x institutional upper limit of normal (ULN) |
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AST (Aspartate Aminotransferase)/ALT (Alanine aminotransferase) 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be 5x ULN |
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Creatinine clearance estimated using the Cockcroft-Gault equation of 51 mL/min using the Cockcroft-Gault equation |
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Estimated creatinine clearance =[ (140-age [years]) x weight (kg) (x F)] |
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[serum creatinine (mg/dL) x 72]; where F=0.85 for females |
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\. No other invasive malignancy within the past 3 years except non-melanoma |
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skin cancer or in situ cervical cancer (patients with previous cancers may be |
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enrolled providing that no recurrences have be reported in the last 3 years) |
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\. Written Informed Consent |
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\. Postmenopausal status defined as |
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Amenorrheic for 1 year or more following cessation of exogenous hormonal |
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treatments Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) |
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levels in the post menopausal range for women under 50 Radiation-induced |
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oophorectomy with last menses >1 year ago Chemotherapy-induced menopause with |
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>1 year interval since last menses Surgical sterilisation (bilateral |
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oophorectomy or hysterectomy) or evidence of non-childbearing status for women |
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of childbearing potential: negative urine or serum pregnancy test prior to |
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Myriad BRCA test during screening part 1, within 28 days of study treatment |
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and confirmed prior to treatment on day 1 |
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\. Patient is willing and able to comply with the protocol for the duration |
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of the study including undergoing treatment and scheduled visits and |
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examinations |
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\. For inclusion in the optional exploratory genetic and the optional |
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biomarker research, patients must provide informed consent for genetic and for |
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biomarker research |
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History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for 5 years or longer
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Other serious illnesses, such as
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Congestive heart failure or angina pectoris; myocardial infarction within 3
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months before enrolment; uncontrolled arterial hypertension or arrhythmias
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Psychiatric disorder that prevents compliance with protocol Uncontrolled
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seizures Active viral hepatitis; or chronic liver disease Active infection Any
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other unstable medical conditions
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\. Involvement in the planning and/or conduct of the study (applies to both
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AstraZeneca staff and/or staff at the study site)
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\. Non defective BRCA status or BRCA 1 and/or BRCA2 mutations that are
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considered to be non detrimental (e.g."Variants of uncertain clinical
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significance" or "Variant of unknown significance"or "Variant, favor
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polymorphism" or "benign polymorphism" etc)
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\. Patients with early stage disease (FIGO Stage I, IIA, IIB or IIC)
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\. Patients who have previously received chemotherapy or radiotherapy for any
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abdominal or pelvic tumour, including treatment for prior diagnosis at an
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earlier stage for their ovarian, fallopian tube or primary peritoneal cancer
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(Patients who have received prior adjuvant chemotherapy for localised breast
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cancer may be eligible, provided that it was completed more than three years
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prior to registration, and that the patient remains free of recurrent or
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metastatic disease)
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\. Patients with synchronous primary endometrial cancer, or a past history of
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primary endometrial cancer, unless all of the following conditions are met
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Stage not greater than I-A; no more than superficial myometrial invasion
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without vascular or lymphatic invasion; no poorly differentiated subtypes
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including papillary serous, clear cell or other FIGO Grade 3 lesions
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\. Participation in another clinical study with an investigational product
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\. Any previous treatment with PARP inhibitor, including olaparib
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\. Resting ECG with QTc (corrected QT interval) > 470 msec on 2 or more time
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points within a 24 hour period or family history of long QT syndrome
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\. Concomitant use of known potent CYP3A4 (Cytochrome P450 3A4)inhibitors
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such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir
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telithromycin, clarithromycin and nelfinavir. The required washout period
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prior to starting olaparib is 2 weeks
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\. Persistent toxicities (>Common Terminology Criteria for Adverse Event
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(CTCAE) grade 2 caused by previous cancer therapy, excluding alopecia
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\. Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia
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(AML) or with features suggestive of MDS/AML
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\. Patients with symptomatic uncontrolled brain metastases. A scan to
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confirm the absence of brain metastases is not required. The patient can
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receive a stable dose of corticosteroids before and during the study as long
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as these were started at least 4 weeks prior to treatment. Patients with
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spinal cord compression unless considered to have received definitive
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treatment for this and evidence of clinically stable disease for 28 days
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\. Major surgery within 2 weeks of starting study treatment and patients
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must have recovered from any effects of any major surgery
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\. Patients unable to swallow orally administered medication and patients
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with gastrointestinal disorders likely to interfere with absorption of the
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study medication, including gastrectomy
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\. Breast feeding women
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\. Immunocompromised patients, e.g., patients who are known to be
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serologically positive for human immunodeficiency virus (HIV)
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\. Patients with a known hypersensitivity to olaparib or any of the
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excipients of the product
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\. Patients with a known hypersensitivity to Paclitaxel or Carboplatin, or
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any of the excipients of these agents
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\. Previous allogeneic bone marrow transplant, or double umbilical cord
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blood transplantation
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\. Previous enrolment in the present study
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\. Patients receiving any systemic chemotherapy or radiotherapy (except for
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palliative reasons) within 3 weeks prior to study treatment
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\. Concomitant use of known strong (eg. phenobarbital, enzalutamide
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phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and
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St John's Wort ) or moderate CYP3A inducers (eg. bosentan, efavirenz
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modafinil). The required washout period prior to starting olaparib is 5 weeks
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for phenobarbital and 3 weeks for other agents
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\. Whole blood transfusions in the last 120 days prior to entry to the
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study
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