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b'Written and signed informed consent for all study procedures according to local' |
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b'regulatory requirements prior to beginning of specific protocol procedures.' |
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b'Female (pre- or postmenopausal) or male patients.' |
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b'Age \\u2265 18 years.' |
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b'Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.' |
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b'Confirmed HER2-positive invasive breast cancer by central determination defined by' |
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b'American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP)' |
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b'clinical practice guidelines. (Wolff el al. Arch Pathol Lab Med-Vol 142, November' |
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b'2018;).' |
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b'Known hormone receptor status, as assessed locally, defined by ASCO/CAP clinical' |
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b'practice guidelines. ER/PR positivity is defined as the presence of \\u2265 1% of tumor' |
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b'cells with nuclear staining (Hammond et al. JCO 2010).' |
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b'Histologically confirmed, locally advanced or metastatic adenocarcinoma of the breast.' |
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b'Patients with unresectable locally advanced disease must have recurrent or' |
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b'progressive disease, which must not be amenable to resection with curative' |
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b'intent. Patients with available standard curative options are not eligible.' |
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b'For patients with bilateral breast cancer, HER2-positivity must be demonstrated' |
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b'in both locations or in a metastatic biopsy.' |
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b'Patient must be a candidate to receive maintenance HP after first line treatment for' |
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b'metastatic disease with at least 4 cycles of taxane plus HP.' |
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b'Prior taxane must have been discontinued for a reason other than progressive disease.' |
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b'Patients may or may not have received neo/adjuvant therapy but must have a' |
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b'disease-free interval from completion of anti-HER2 therapy to metastatic diagnosis \\u22656' |
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b'months.' |
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b'PIK3CA mutation identified and confirmed in tumor tissue or plasma ctDNA by central' |
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b'determination.' |
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b'Start of treatment with ipatasertib plus HP no later than 9 weeks after last dose of' |
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b'taxane plus HP (i.e., maximum of 2 HP administrations with no taxane).' |
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b'Willingness and ability to provide archived formalin fixed paraffin embedded (FFPE)' |
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b'tissue block.' |
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b'Measurable or non-measurable (but evaluable) disease, as per RECIST 1.1 criteria.' |
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b'No baseline diarrhea or diarrhea grade \\u22641 within the last 28 days.' |
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b'Adequate hematologic and organ function within 14 days before the first study' |
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b'treatment on Day 1 of Cycle 1, defined by the following:' |
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b'Neutrophils (ANC \\u22651500/\\u03bcL)' |
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b'Hemoglobin \\u22659 g/dL (with no need for transfusions in the last 14 days).' |
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b'Platelet count \\u226575,000/\\u03bcL' |
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b'Serum albumin \\u22653 g/dL' |
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b'Total bilirubin \\u22641.5x the upper limit of normal (ULN), with the exception:' |
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b'patients with known Gilbert syndrome who have serum bilirubin \\u22643x ULN.' |
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b'AST and ALT \\u22642.5x ULN, with the following exception: patients with documented' |
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b'liver or bone metastases who may have AST and ALT \\u22645x ULN.' |
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b'ALP \\u22642x ULN, with the following exceptions:' |
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b'Patients with known liver involvement who may have ALP \\u22645x ULN.' |
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b'Patients with known bone involvement who may have ALP \\u22647x ULN.' |
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b'PTT (or aPTT) and INR \\u22641.5x ULN (except for patients receiving anticoagulation' |
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b'therapy).' |
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b'Patients receiving heparin treatment should have a PTT (or aPTT) between 1.5' |
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b'and 2.5x ULN.' |
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b'Patients receiving coumarin derivatives should have an INR between 2.0 and' |
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b'0 assessed in two consecutive measurements 1 to 4 days apart.' |
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b'Serum creatinine <1.5x ULN or creatinine clearance \\u226550 mL/min based on' |
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b'Cockcroft\\u2212Gault glomerular filtration rate estimation:' |
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b'(140 \\u2212 age) x (weight in Kg) x 0.85 (if female)/72 x (serum creatinine in mg/dL)' |
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b'Fasting total serum glucose \\u2264150mg/dL and glycosylated hemoglobin (HbA1C) \\u22647.5%' |
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b'Life expectancy of at least 6 months.' |
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b'Baseline left ventricular ejection fraction (LVEF) \\u226550% measured by echocardiography' |
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b'(ECHO) or Multiple Gate Acquisition (MUGA) scan.' |
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b'Negative \\u03b2-HCG pregnancy test (serum) for premenopausal women of reproductive capacity' |
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b'(those who are biologically capable of having children) and for women less than 12' |
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b'months after the menopause. All subjects who are biologically capable of having' |
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b'children must agree and commit to the use of a reliable method of birth control from 2' |
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b'weeks before administration of the first dose of investigational product until 28 days' |
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b'after the last dose of investigational product.' |
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b'Absence of any psychological, familial, sociological or geographical condition' |
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b'potentially hampering compliance with the study protocol and follow-up schedule; those' |
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b'conditions should be discussed with the patient before registration in the trial.' |
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b'Last dose of taxane plus HP given more than 9 weeks prior to C1D1.'
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b'Prior malignancy within 3 years prior to randomization, except curatively treated'
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b'non-melanoma skin, carcinoma in situ of the cervix or Stage I uterine cancer.'
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b'Brain metastases that have not been treated previously, are progressive, or require'
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b'any type of therapy (e.g., radiation, surgery, or steroids) to control symptoms within'
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b'30 days prior to the first study treatment dose.'
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b'Radiotherapy for metastatic sites of disease outside of the brain performed within 14'
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b'days prior to study enrollment and/or radiation of >30% of marrow-bearing bone.'
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b'Symptomatic hypercalcemia requiring use of bisphosphonate or RANKL inhibitors therapy'
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b'within 21 days prior to the first study treatment. Patients who receive bisphosphonate'
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b'therapy specifically to prevent skeletal events are eligible if they have been'
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b'initiated prior to the treatment to study.'
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b'Cardiopulmonary dysfunction as defined by:'
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b'Inadequately controlled angina or serious cardiac arrhythmia not controlled by'
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b'adequate medication.'
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b'Inadequate LVEF at baseline, as defined as LVEF <50% by either ECHO or MUGA scan.'
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b'History of symptomatic congestive heart failure (CHF): Grade \\u22653 per NCI CTCAE'
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b'version 4.03 or Class \\u2265II New York Health Association (NYHA) criteria.'
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b'History of a decrease in LVEF to <40% or symptomatic CHF with prior trastuzumab'
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b'or HP treatment.'
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b'History of myocardial infarction within 6 months prior to randomization.'
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b'Current dyspnea at rest due to complications of advanced malignancy, or other'
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b'disease requiring continuous oxygen therapy.'
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b"Congenital long QT syndrome or screening QT interval corrected using Fridericia's"
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b'formula (QTcF) > 480 milliseconds.'
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b'Concurrent, serious, uncontrolled infections or current known infection with HIV'
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b'(testing is not mandatory).'
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b'History of intolerance, including Grade 3-4 infusion reaction or hypersensitivity, to'
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b'trastuzumab or pertuzumab.'
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b'Known hypersensitivity to any of the study drugs, including excipients.'
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b'Known clinically significant history of liver disease consistent with Child-Pugh Class'
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b'B or C, including active viral or other hepatitis (e.g., positive for hepatitis B'
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b'urface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening), current'
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b'drug or alcohol abuse, or cirrhosis.'
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b'Patients with past hepatitis B virus (HBV) infection or resolved HBV infection'
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b'(defined as having a negative HBsAg test and a positive antibody to hepatitis B'
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b'core antigen [HBcAg] antibody test) are eligible.'
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b'Patients positive for HCV antibody are eligible only if polymerase chain reaction'
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b'(PCR) is negative for HCV RNA'
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b'History of Type I or Type II diabetes mellitus requiring insulin. Patients who are on'
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b'table dose of oral diabetes medication > 2 weeks prior to initiation of study'
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b'treatment are eligible for enrollment.'
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b'Grade \\u22652 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia.'
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b"History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative"
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b'colitis) or active bowel inflammation (e.g., diverticulitis).'
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b'Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis,'
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b'cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic'
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b'infections (Pneumocystis pneumonia or Cytomegalovirus pneumonia).'
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b'Need for chronic corticosteroid therapy of >10 mg of prednisone per day or an'
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b'equivalent dose of other anti-inflammatory corticosteroids for a chronic disease.'
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b'Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with'
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b'indwelling catheters (e.g., PleurX\\xae) are allowed.'
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b'Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5'
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b'drug-elimination half-lives, whichever is longer, prior to initiation of study drug.'
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b'Prior treatment with an AKT inhibitor. Prior PI3K or mTOR inhibitors are allowed.'
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b'Current severe, uncontrolled systemic disease (e.g. clinically significant'
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b'cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; bone'
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b'fractures).'
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b'Unresolved, clinically significant toxicity from prior therapy, except for alopecia'
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b'and Grade 1 peripheral neuropathy.'
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b'Major surgical procedure or significant traumatic injury within 28 days prior to'
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b'enrollment.'
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b'Assessment by the investigator to be unable or unwilling to comply with the'
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b'requirements of the protocol.'
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b'History of significant comorbidities that, in the judgment of the investigator, may'
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b'interfere with the conduction of the study, the evaluation of response, or with'
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b'informed consent.'
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