A multicenter randomized phase III study to compare the combination trastuzumab and capecitabine, with or without pertuzumab, in patients with HER2-positive metastatic breast cancer that have progressed after one line of trastuzumab-based therapy in the metastatic setting (PHEREXA)

Disease-Specific:
1.Pathologically confirmed breast cancer and documented metastatic disease.
2.HER2-positive (FISH/CISH-positive or IHC 3+*) MBC confirmed by a Sponsor-designated central laboratory. Availability of a FFPE tumor tissue sample from primary tumor for eligibility testing (HER2-status) is mandatory (minimum 6 slides). Additional tumor tissue material for biomarker assessment is requested (if available).
3.Disease progression during or following a trastuzumab-based treatment for first-line metastatic breast cancer.
4.Trastuzumab must have been part of the last prior treatment regimen.
5.Prior treatment with a taxane-containing regimen.;General:
6.Female patients, age *18 years.
7.LVEF * 50% at baseline (assessed within 42 days prior to randomization) as determined by either 2D echocardiogram (ECHO) or MUGA (ECHO is the preferred method). If the patient is randomized, the same method of LVEF assessment, ECHO or MUGA, must be used throughout the study, and to the extent possible, be obtained at the same institution.
8.Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
9.For women of childbearing potential agreement to use highly effective form of contraception (patient and/or partner, e.g., surgical sterilization, or true abstinence) or two effective forms of contraception, a reliable barrier method, condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and an intrauterine device (IUD) or intrauterine system (IUS) and to continue its use for the duration of study treatment and for at least 7 months after the last dose of study treatment. Periodic abstinence (e.g., calendar ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception. Postmenopausal is defined as * 12 months of amenorrhea.
10.Written and signed informed consent (approved by the Independent Ethics Committee) obtained prior to beginning any protocol-specific procedures.

Cancer-Related:
1.Prior therapy with pertuzumab or capecitabine.
2.Concurrent immunotherapy or anticancer hormonal therapy.
3.Existing acute reversible effects of prior treatment. This generally means at least 3 weeks should have elapsed since prior chemotherapy and at least 4 weeks since prior (radical) radiotherapy or major surgery.
4.History of another malignancy which could affect compliance with the protocol or interpretation of results. Patients treated with curative intent and disease-free for at least 5 years are generally eligible, as are patients treated curatively for carcinoma in situ of the cervix or non melanomatous skin cancer.
5.CNS metastases which are not well controlled. Eligible patients must be asymptomatic, can not be receiving steroids, and must be enrolled at least 1 month after the end of the radiotherapy treatment. Note: CT or MRI scan of the brain is mandatory (within 4 weeks prior to randomization) in case of clinical suspicion of CNS metastases.
6.History of exposure to at least one of the following cumulative doses of anthracyclines:
*doxorubicin or liposomal doxorubicin > 360 mg/m2
*epirubicin > 720 mg/m2
*mitoxantrone > 120 mg/m2
*idarubicin > 90 mg/m2
*Other (e.g. liposomal doxorubicin or other anthracycline > the equivalent of 360 mg/m2 of doxorubicin)
*If more than 1 anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin.
Hematological, Biochemical and Organ Function:
7.Current uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mmHg) or unstable angina.
8.History of CHF of any New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (except for atrial fibrillation and/or paroxysmal supraventricular tachycardia).
9.History of myocardial infarction within 6 months of randomization.
10.History of LVEF decline to below 50% during or after prior trastuzumab therapy or other cardiac toxicity during previous trastuzumab treatment that necessitated discontinuation of trastuzumab.
11.Current dyspnoea at rest requiring supportive oxygen therapy or with significant pleural effusions.
General Exclusion Criteria
12.Inadequate organ function, evidenced by the following laboratory results within 28 days prior to randomization:
*absolute neutrophil count (ANC) < 1.5 x 109/L
*platelet count < 100 x 109/L
*hemoglobin < 9 g/dL
*serum (total) bilirubin > 1.5 x the upper limit of normal (ULN) (unless the patient has documented Gilbert*s syndrome)
*AST/SGOT or ALT/SGPT >2.5 x ULN (> 5 x ULN in patients with liver metastases)
*Alkaline phosphatase levels > 2.5 times the ULN at screening/baseline (> 5 x ULN in patients with liver metastases, or > 10 x ULN in patients with bone metastases)
*Moderate or severe renal impairment [creatinine clearance equal to or below 50ml/min (calculated according to Cockroft and Gault, see Appendix 2)], or serum creatinine > upper limit of normal (ULN)
*International normalized ratio (INR) and activated partial thromboplastin time (aPTT) >1.5 x ULN (unless on therapeutic coagulation)
13.Current severe, uncontrolled systemic disease (e.g. clinical significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures).
14.Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, or that may affect patient compliance with study routines, or place the patient at high risk from treatment complications.
15.Patients with insulin-dependent diabetes.
16.Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start or anticipation of the need for major surgery during the course of study treatment with full recovery.
17.Pregnant or lactating females.
18.Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study screening.
19.Current known infection with HIV, HBV, or HCV.
20.Active infection requiring antibiotics within 14 days of randomization.
21.Current chronic daily treatment with corticosteroids (dose of >10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
22.Known hypersensitivity to any of the study drugs or excipients. History of severe and unexpected reactions to fluoropyrimidine therapy.
23.Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or ulcerative colitis.
24.Psychiatric disability judged by the Investigator to be interfering with compliance for oral drug intake.
25.Known deficiency or family history of deficiency of dihydropyrimidine dehydrogenase.
26.Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or chemically related analogues, such as brivudine.
27.Life expectancy <12 weeks.
28.Inaccessible for treatment and/or follow-up or unwilling to comply with the requirements of the protocol.