This is an institutional, monocentric, open-label, phase II study of oral "metronomic"
Vinorelbine plus Capecitabine and Cyclophosphamide (VEX) in patients with advanced breast
Patients will receive the combination regimen as follow:
Cyclophosphamide 50 mg daily Capecitabine 500 mg, thrice daily Vinorelbine 40 mg orally
thrice a week
Four independent cohorts of patients will be evaluated in the study:
1. Untreated (naïve) patients with endocrine responsive disease
2. Pretreated patients with endocrine responsive disease
3. Untreated (naïve) patients with triple negative disease
4. Pretreated patients with triple negative disease Combination will be administered until
disease progression or unacceptable toxicity.
The primary endpoint will be to assess the Time to progression (TTP) of VEX combination in
the four different cohorts
1. Pre- or post-menopausal women (age ≥18 years) with histologically or cytologically
(cell block) proven, locally advanced (inoperable) or metastatic breast carcinoma.
Immunohistochemical evaluation of estrogen receptor (ER), progesterone receptor (PgR),
human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor
(EGFR) according to European Institute of Oncology guidelines is mandatory.
2. Patients with HER2 overexpressed tumors, are eligible if they had received previous
trastuzumab therapy for advanced disease, and/or a treatment with anti HER2 targeted
3. Patients fulfilling one of the following criteria:
- Patients with measurable disease as per RECIST 1.1 criteria. This is defined as
at least one lesion that can be accurately measured in at least one dimension
(longest diameter to be recorded) as 20 mm with conventional techniques or as 10
mm with spiral CT scan
- Patients with bone lesions, lytic or mixed (lytic + sclerotic), in the absence of
measurable disease as defined by RECIST 1.1 criteria. Bone lesions must be
evaluable by plain CT or MRI. Patients with lesions identified only on
radionucleotide bone scan are not eligible.
4. Patients may have received any primary and/or adjuvant therapies, as any previous
lines of chemotherapy and endocrine therapy for advanced disease. Patients may have
received metronomic capecitabine, methotrexate and cyclophosphamide in adjuvant
setting at least 12 months before study entry
5. Previous treatment with capecitabine, cyclophosphamide and vinorelbine not in
metronomic schedule for advanced disease is allowed, provided that the patient has
progressive disease at study entry and the patients should not be defined as
"refractory" to treatments (Pathological Response or Complete Response or Stable
Disease > 6 months).
6. Patients may have had previous hormonal therapy as treatment of metastatic disease
provided that the patient has progressive disease at study entry. Hormonal therapy
must be discontinued prior to study entry, excluding Luteinizing Hormone-Releasing
Hormone (LHRH) analogue.
7. Life expectancy greater than 6 months.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status performance status <2
9. Patients must have normal organ and marrow function as defined below:
- leukocytes ≥ 3,000/μL
- absolute neutrophil count ≥ 1,000/μL
- platelets ≥ 100,000/μL
- Haemoglobin ≥ 10 g/dl
- total bilirubin within normal institutional limits
- Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) ≤ 2 X
institutional upper limit of normal
- creatinine within normal institutional limits OR
- creatinine clearance ≥ 60 mL/min/1.73 m for patients with creatinine levels above
10. Geographically accessible for follow up.
11. Ability to understand and the willingness to sign a written informed consent document.
1. Previous metronomic chemotherapy for advanced disease with capecitabine,
cyclophosphamide and vinorelbine
2. Patients defined as "refractory" to capecitabine, cyclophosphamide and vinorelbine
(Progression Disease or Stable Disease < 6 months).
3. Presence of symptomatic cerebral or leptomeningeal involvement.
4. Previous or concomitant other malignancy except basal or squamous cell carcinoma of
the skin or adequately treated in situ carcinoma of the cervix.
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
6. Malabsorption syndrome or disease affecting significantly gastrointestinal function or
major resection of the stomach or proximal small bowel that could affect absorption of
7. Concurrent treatment with any other anti-cancer therapy except LHRH analogue.
8. Patients with pre-existing motor or sensory peripheral neuropathy grade 2 according to