Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II, Randomised, Multi-Centre Study Evaluating Lapatinib in Combination With Vinorelbine or Capecitabine in Women With ErbB2 Overexpressing Metastatic Breast Cancer
Brief Summary: This is a randomized, parallel-arm, open-label, multi-centre, Phase II study to determine the efficacy and safety of lapatinib in combination with vinorelbine or capecitabine in women with ErbB2 overexpressing metastatic breast cancer (MBC) who have received no more than one chemotherapeutic regimen in the metastatic setting.


Options:
A: Inclusion Criteria :

* Signed informed consent prior to registration.
* Considered by the investigator to have a life expectancy of ≥12 weeks.
* Subjects must be female and have histologically - confirmed invasive breast cancer with Stage IV disease at primary diagnosis or at relapse after curative - intent surgery.
* Documented overexpression of ErbB2
* Subjects should have progressive disease following prior therapy which may include anthracyclines, taxanes, and trastuzumab.
* Females aged ≥18 years
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1.
* Subjects must have adequate organ and marrow function
* Subjects must have a cardiac ejection fraction of at least 50% and within the institutional range of normal.
* Radiotherapy prior to initiation of study medication is allowed to a limited area ( e . g . , palliative therapy ) , if it is not the sole site of disease.
* Subjects with stable central nervous system (CNS) metastases are permitted.
* Subject must be free of gastrointestinal diseases or any other conditions that impede swallowing, retaining, and absorption of oral medications.
* Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of study medication. Prophylactic use of bisphosphonates in subjects without bone disease, except for the treatment of osteoporosis, is not permitted.

Exclusion Criteria:

* Subjects taking prohibited medications are not eligible for the study.
* Therapy with lapatinib, vinorelbine, or capecitabine prior to randomization into this study.
* Prior therapy with more than one chemotherapeutic regimen for metastatic breast cancer.
* Concurrent anticancer or concomitant radiotherapy treatment.
* History of uncontrolled or symptomatic angina; history of arrhythmias requiring medications ; clinically significant myocardial infarction \< 6 months from study entry; uncontrolled or symptomatic congestive heart failure; ejection fraction below the institutional normal limit; or any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.
* Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).
* Use of an investigational drug within 30 days or 5 half - lives, whichever is longer, preceding the first dose of investigational treatment, or, concurrent treatment with an investigational agent or participation in another clinical trial involving investigational agents.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the agents used in this study or their excipients that in the opinion of the investigator or GSK Medical Monitor contraindicates their participation.
* Known deficiency for the enzyme dihydropyrimidine dehydrogenase (DPD).
* Known history of uncontrolled inter - current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness / social situations that would limit compliance with study requirements.
* Concurrent disease or condition that would make the subject inappropriate for study participation , or any serious medical disorder that would interfere with the subject's safety.
* Pregnant or lactating females at any time during the study (due to the potential teratogenic or abortifacient effects of lapatinib and breastfeeding).
* Subjects with diseases affecting gastrointestinal function resulting in an inability to take oral medication , including ; malabsorption syndrome, disease significantly affecting gastrointestinal function , or resection of the stomach , small bowel , or colon. Subjects with inflammatory bowel disease or ulcerative colitis are also excluded.
* Peripheral neuropathy of Grade 2 or greater.
* Unresolved or unstable, serious toxicity from prior administration of another investigational drug and / or of prior cancer treatment.
* Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
B: Inclusion Criteria:

To be eligible for inclusion in the study, each patient must fulfill each of the criteria below.

* Have provided written informed consent prior to study-specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.
* Be female and 18 years of age or older.
* Have histologically confirmed invasive breast cancer.
* High risk of breast cancer recurrence (\> 25% within the first 5 years without adjuvant therapy, \> 35% within the first 10 years) with one of the following:

  * Regional node positive disease (pN+; tumor cells or tumor cell clusters \< 0.2 mm in diameter are not counted as metastases);
  * Pathological N0 and PgR- and tumor size \> 20 mm.

Exclusion Criteria:

Patients who fulfill any of the following criteria will be excluded:

* \> 65 years of age.
* "Special type" histology (mucinous, papillary, medullary, or tubular breast cancer), when pN0.
* ER, PgR and HER-2 status (via in situ hybridization or immunohistochemistry) not determined.
* Presence of distant metastases.
* Previous chemotherapy in the neoadjuvant setting.
* Non-ambulatory or WHO performance status \> 1.
* Pregnant or lactating women. Women of childbearing potential (menstruating within 6 months of study entry or with no hysterectomy and age \< 55) with either a positive or no pregnancy test at baseline.
* Women of childbearing potential unless using a reliable and appropriate contraceptive method. (Post-menopausal women must have been amenorrheic for at least 6 months to be considered of non-childbearing potential).
* More than 12 weeks between breast surgery and date of randomization.
* Organ allografts with immunosuppressive therapy required.
* Major surgery (except breast surgery) within 4 weeks prior to study treatment start, or lack of complete recovery from the effects of major surgery.
* Participation in any investigational drug study within 4 weeks preceding treatment start.
* Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant precluding informed consent or interfering with compliance for oral drug intake.
* History of another malignancy within the last five years except cured basal cell carcinoma of skin or carcinoma in situ of the uterine cervix.
* Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmia not well controlled with medication) or myocardial infarction within the last 12 months.
* Abnormal laboratory values:

  * Hemoglobin \< 10.0 g/dL, neutrophils \< 1.5 x 10\^9/L, platelet count \< 120 x 10\^9/L;
  * Serum creatinine \> 1.5 x Upper Limit of Normal (ULN);
  * Creatinine clearance (calculated per Cockroft and Gault) \< 50 mL/min;
  * Serum bilirubin \> ULN;
  * ALAT \> 1.5 x ULN;
  * Alkaline phosphatase \> 2.5 x ULN.
* Serious uncontrolled intercurrent infections or other serious uncontrolled concomitant disease.
* Lack of physical integrity of the upper gastrointestinal tract or those who have clinically significant malabsorption syndrome.
* Inability to swallow tablets.
* Life expectancy of less than 3 months.
* Unwilling or unable to comply with the protocol for the duration of the study.
* Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine.
C: Key Inclusion Criteria:

- Women with locally advanced, recurrent, or metastatic breast cancer along with confirmation of estrogen-receptor positive (ER+). Measurable disease defined as at least one lesion ≥ 10 mm by CT or MRI that can be accurately measured in at least one dimension (CT scan slice thickness ≤ 5 mm) OR • Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable disease as defined above.

Key Exclusion Criteria:

- Patients who received more than one chemotherapy line. Patients with only non-measurable lesions other than lytic or mixed (lytic and blastic) bone metastasis.Previous treatment with exemestane, mTOR inhibitors, PI3K inhibitors or AKT inhibitors.
D: Inclusion Criteria:

* Female patients with histologically proven, core-biopsied, invasive breast cancer of any clinical and/or radiological T-stage (except for T4d)
* Age 18-70 years
* WHO performance status ≤ 2
* No prior or current neoplasm except for curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix
* No distant disease / secondary carcinoma judged clinically and at least by chest X-ray, liver sonography, and bone scan upon randomization
* No medical and/or cardiologic contraindication to receive an anthracycline- and taxane-containing chemotherapy regimen. Normal cardiac function must be confirmed by LVEF (echocardiography or Muga scan). The result must be above 50% or above the institution's ULN
* Results of the following assessments at the time of randomization must be available:

  1. chest wall CT, abdomen CT, bilateral mammography: within 4 weeks before enrolment;
  2. laboratory requirements: within 2 weeks before enrolment
  3. hematology: neutrophils ≥ 4.0 x 109/l, platelets ≥ 150 x 109/l, haemoglobin ≥ 13 g/dl
  4. hepatic function: total bilirubin \< 1 x ULN, ASAT (SGOT) and ALAT (SGPT) \< 1x ULN, alkaline phosphatase \< 1 x ULN. In case of abnormal values, liver function tests have to be repeated within 3 days before study treatment.
  5. renal function: creatinine ≤ 1 x ULN,
  6. histology, grading, hormone receptor status, HER-2/neu status
* Signed and dated informed consent before the start of specific protocol procedures
* Negative pregnancy test in the presence of childbearing potential

Exclusion Criteria:

* Stage T4d / inflammatory breast cancer
* Pregnant or lactating patients; patients of childbearing potential must implement adequate contraceptive measures during study participation
* Pre-existing motor or sensory neurotoxicity of a severity ≥ WHO grade 2
* Preoperative local treatment for breast cancer (i.e. incomplete surgery, radiotherapy)
* Prior or concomitant systemic antitumor therapy
* Other serious illness or medical condition

  1. congestive heart failure or unstable angina pectoris, even if medically controlled.

     Previous history of myocardial infarction within 1 year from study entry, uncontrolled hypertension or high-risk uncontrolled arrythmias
  2. history of significant neurologic or psychiatric disorders, including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent
  3. active uncontrolled infection
  4. unstable peptic ulcer, unstable diabetes mellitus or other contraindication for the use of corticosteroids
* Concurrent treatment with corticosteroids except as use for the prophylactic regimen, inhalational use, treatment of acute hypersensitivity reactions, treatment of nausea/vomiting or chronic treatment (initiated \> 6 months prior to study entry) at low dose (≤ 20 mg methylprednisolone or equivalent)
* Known hypersensitivity against taxanes and/or epirubicin and/or fluorouracil/capecitabine
* Known dihydropyrimidine-dehydrogenase (DPD) deficit
* Treatment with an investigational drug within 30 days prior to study entry
* Legally incapacitated and/or other circumstances which make it unfeasible for the subject to understand the nature, meaning and consequences of the clinical study
* Concurrent psychiatric illness according to ICD (alcohol addiction) at the time of study entry

Answer: A