A new alternative treatment caused the decrease in the rhythm of recruitment.

Eligible patients must receive vinorelbine plus capecitabine, with or without trastuzumab, until disease progression or unbearable toxicity. Cycles will be administered every 3 weeks.Human epidermal growth factor receptor 2 (HER2) status must be locally assessed by immunohistochemistry (IHC). All 3+ patients are eligible. In 2+ patients, HER2 status must be confirmed by fluorescence in situ hybridization (FISH).

Principal outcome is clinical benefit (complete + partial responses + stable disease). Sample size in each arm has been estimated with the Fleming method. Previous data show a clinical benefit rate of vinorelbine plus capecitabine around 50%. The researchers assume trastuzumab can increase it by 20%. With an alpha error of 0.05 and 80% power, 37 patients per arm are needed.

This is a randomised phase II trial. With a minimum expected benefit rate of 50%, at least 36 patients are needed to choose, with a 90% of probability to be right, the best treatment arm, providing it increases benefit rate at least by 15%.

Assuming a drop-out rate of 10%, the total number of patients needed is 82, 41 per treatment arm.

Patients will be stratified as per investigational site, and presence of visceral metastatic lesion (liver, lung, pleura, heart, peritoneum, suprarenal glands). All patients must receive 2 cycles. If no disease progression is detected, treatment must continue until progression or unbearable toxicity.

Inclusion Criteria:

• Written informed consent.

• Women older than 18 years old.

• HER2 positive breast cancer with histological diagnoses.

• Non-operable locally advanced or metastatic disease, previously treated with trastuzumab and taxanes.

• Measurable or non-measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST).

• Disease progression during or after treatment with trastuzumab and taxanes.

• Maximum of 1 previous chemotherapy line for advanced or metastatic disease.

• Previous radiotherapy is allowed if radiated area is not the only documented lesion.

• At least 4 weeks since the last administration of antineoplastic treatment and all toxicities resolved.

• Performance status Eastern Cooperative Oncology Group (ECOG) >=2.

• Life expectancy of at least 12 weeks.

• Left Ventricular Ejection Fraction (LVEF) evaluation (>=50%) in previous 4 weeks.

• Hematology:

  • neutrophils >=1.5 x 10e9/l;
  • platelets >= 100 x 10e9/l;
  • hemoglobin >= 10 mg/dl

• Hepatic function:

  • total bilirubin <= 1.5 x under normal limit (UNL);
  • Aspartate aminotransferase (SGOT) and Alanine aminotransferase (SGPT) and alkaline phosphatase <= 2.5 x UNL, or <=5 x UNL if hepatic lesions present

• Renal function:

  • creatinine <= 175 µmol/l (2 mg/dl);
  • creatinine clearance >= 60 ml/min.

• Patients able to comply with treatment and follow-up.

• Negative pregnancy test in the previous 14 days. Adequate contraceptive method during treatment and up to 3 months after finalised.

• Brain metastatic lesions are allowed provided all other criteria are met.

• Male who met inclusion criteria are eligible.

Exclusion Criteria:

• History of hypersensitivity to vinorelbine, trastuzumab, rat proteins or trastuzumab components.
• History of dyspnea at rest, or chronic oxygen therapy required.
• Active infection.
• Second malignancy, except for cervical in situ carcinoma, basal skin carcinoma, adequately treated. Previous malignancies with a 5 year disease free survival are allowed.
• Pregnant or lactating women.
• Any other serious medical pathology, such as congestive heart failure, unstable angina, history of myocardial infarction during the previous year, uncontrolled hypertension or high risk arrhythmias.
• History of neurological or psychiatric disorders, which could preclude the patients to free informed consent.
• Active uncontrolled infection.
• Active peptic ulcer, unstable diabetes mellitus.
• Concomitant treatment with other investigational products. Participation in other clinical trials with a non-marketed drug in the 30 previous days before randomization.
• Concomitant treatment with other therapy for cancer.