MEtronomic TrEatment Option in Advanced bReast cAncer

This is a multi-center, randomized phase II trial that will randomise women with ER-positive, HER2-negative (Human Epidermal Growth factor Receptor 2-negative) metastatic or locally relapsed breast cancer in a ratio of 1:1 to receive a metronomic regimen of vinorelbine plus cyclophosphamide and capecitabine, or the conventional paclitaxel monotherapy.

The prognosis for patients with locally advanced or metastatic disease (ABC) remains poor, with a median survival of 2-4 years. About 10% of newly diagnosed BC patients present with ABC, and 30% to 50% of patients diagnosed at earlier stages will subsequently develop metastatic disease.

In the first-line treatment of HER2 (Human Epidermal Growth factor Receptor 2) negative ABC patients, various chemotherapy regimens can be used including taxanes, which are among the most active agents in BC. Single agent response rates range from 20 to 50%. However, eventually all patients will progress with a median time to progression of 5 to 7 months. A weekly (qw) over a three-weekly (q3w) administration schedule of paclitaxel has been shown to be more effective in the metastatic as well as in the adjuvant setting after standard chemotherapy

The VEX regimen was recently investigated within a phase II trial currently ongoing at the European Institute of Oncology (IEO) (IEO number IEOS582/111; EudraCT Number: 2010-024266-21; title: "A phase II study of metronomic oral chemotherapy with cyclophosphamide plus capecitabine and vinorelbine in metastatic breast cancer patients"). Patients received vinorelbine 40 mg orally on days 1, 3 and 5 every week, cyclophosphamide 50 mg daily and capecitabine 500 mg 3 times a day.

Given the promising activity of the VEX regimen in a pre-treated population of advanced breast cancer patients and the good tolerability, the aim of the present trial is to investigate whether the VEX schedule may improve efficacy and tolerability as compared to standard paclitaxel treatment in advanced or metastatic ER-positive/HER2-negative breast cancer patients.

The concept of the VEX metronomic treatment is to administer the combination for as long as the patient has the possibility of deriving a benefit from it. The time to treatment failure (TTF) has been chosen as primary endpoint for this trial. TTF is defined as time from the date of randomization to the date when the final dose of trial treatment is administered. Chemotherapy may need to be stopped due to lack of tolerability, lack of efficacy or patient preference through subjective symptom assessment. TTF is a composite endpoint combining all these feasibility aspects of a treatment. It is therefore uniquely suited to the research question of the current trial. The secondary endpoints progression-free survival, disease control and safety will allow further assessment of the feasibility of the VEX metronomic treatment versus the paclitaxel monotherapy regimen.

Eligibility Criteria:
Inclusion Criteria:

* Histologically or cytologically confirmed HER2-negative locally advanced or metastatic (stage IV) breast cancer.
* Maximum of one prior line of chemotherapy for advanced or metastatic breast cancer.
* Measurable or non-measurable, but radiologically evaluable (except for skin lesions), disease according to RECIST 1.1 criteria.
* Female aged 18 years or older.
* Life expectancy \> 3 months.
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
* ER-positive disease by local laboratory, determined on most recent available tissue (latest biopsy of metastatic lesion, otherwise prior biopsy or surgical specimen).
* If previously treated with a taxane in the neoadjuvant or adjuvant setting, the period from end of treatment to disease recurrence must have been \> 12 months (\> 365 days).
* Radiation therapy, if given and regardless of site, must be completed at least 2 weeks prior to randomization.
* Normal hematologic status,
* Absolute neutrophil count ≥1000/mm3 (1.0 × 109/L),
* Platelets ≥ 100 × 109/L,
* Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
* Normal renal function: serum creatinine ≤ 1.5 ULN or calculated creatinine clearance ≥ 50 mL/min according to the Cockcroft-Gault formula.
* Normal liver function:
* Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (\< 3 × ULN) is allowed.
* Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 3 × ULN; if the patient has liver metastases, ALT and AST must be ≤ 5 × ULN.
* Women of child bearing potential must have documented negative pregnancy test within 2 weeks prior to randomization and agree to acceptable birth control (non-hormonal) during and up to 6 months after trial therapy.
* Written Informed Consent (IC) must be signed and dated by the patient and the Investigator prior to starting screening procedures and randomization.
* The patient has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines.

Exclusion Criteria:

* More than one prior line of chemotherapy for advanced or metastatic breast cancer
* Previous treatment for advanced or metastatic disease with taxanes, or capecitabine or vinorelbine or oral cyclophosphamide.
* More than 2 lines of previous endocrine therapy for locally advanced or metastatic breast cancer.
* Known active central nervous system metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth (patients with history of Central Nervous System (CNS) metastases or spinal cord compression are eligible if they are clinically and radiologically stable for at least 4 weeks before first dose of trial treatment and have not required high-dose steroid treatment in the last 4 weeks).
* Peripheral neuropathy grade 2 or higher (CTCAE version 4.0).
* Significant uncontrolled cardiac disease (i.e. unstable angina, myocardial infarction within prior 6 months), patients classified as having a New York Heart Association (NYHA) class III or IV congestive heart failure.
* Pregnant or lactating.
* Prior history of non-breast malignancy (except for adequately controlled basal cell carcinoma of the skin, carcinoma in situ of the cervix, in situ carcinoma of the bladder).
* Any concurrent condition which in the Investigator's opinion makes it inappropriate for the patient to participate in the trial or which would jeopardize compliance with the protocol.
* Contraindications or known hypersensitivity to the trial medication or excipients.
* The use of any anti-cancer investigational agents within 30 days prior to expected start of trial treatment.