A Randomized Phase II Trial of Pertuzumab in Combination With Trastuzumab With or Without Chemotherapy, Both Followed by T-DM1 in Case of Progression, in Patients With HER2-positive Metastatic Breast Cancer
SELECTION OF PATIENTS (MOST IMPORTANT CRITERIA)
Inclusion criteria for first-line therapy
• Histologically confirmed breast cancer with distant metastases
1. A biopsy from the primary tumor or a metastasis can be used for diagnosis.
2. Patients with non-measurable lesions are eligible.
3. Patients with inoperable, locally advanced breast cancer with lymph node metastases
other than ipsilateral locoregional (axillary, infraclavicular, parasternal) or other
distant metastases are eligible.
4. Patients with bone metastases with or without bone targeted therapy (bisphosphonates,
denosumab) are eligible.
5. Patients with de-novo Stage IV disease are eligible. • HER2-positive tumor according
to central pathology testing for HER2
1. A formalin-fixed paraffin-embedded (FFPE) biopsy from the primary tumor or a
metastasis has to be used for HER2 status determination. If a biopsy is available
from a metastasis, the HER2 testing should be performed using the metastasis.
2. Fine needle aspiration is not acceptable for HER 2 testing. • Women aged ≥18 years
• WHO performance status 0 to 2
- Left Ventricular Ejection Fraction (LVEF) ≥50% as determined by either ECHO or
- Adequate organ function, evidenced by the following laboratory results:
Neutrophils >1.5x109/L, platelets >100x109/L, hemoglobin ≥90g/L, total bilirubin
≤1.5xULN (unless the patients has documented Gilbert's disease), AST≤3xULN, AP
≤2.5xULN (except in patients with bone metastases: AP ≤5xULN), creatinine ≤1.5xULN
Exclusion criteria for first-line therapy
• Prior chemotherapy for inoperable locally advanced or metastatic breast cancer
Prior neoadjuvant/adjuvant chemotherapy is allowed if doses for anthracyclines have
not exceeded 720mg/m2 and 240mg/m2 for epirubicin and doxorubicin, respectively.
- Re-exposure to paclitaxel is permitted, if the last dose of taxane was given at
least 1 year before randomisation.
- Re-exposure to vinorelbine is permitted, if the last dose of vinorelbine was given
at least 1 year before randomisation.
• Prior anti-HER2 treatment for metastatic or inoperable breast cancer
Prior neoadjuvant/adjuvant anti-HER2 treatment with trastuzumab and/or lapatinib is
- More than one endocrine treatment line for metastatic or inoperable breast
cancer exceeding a duration of 1 month
1. Adjuvant endocrine treatment is not counted as one line.
2. All endocrine treatment must have been stopped prior to randomization.
• Prior treatment with pertuzumab and/or T-DM1
• Known leptomeningeal or CNS metastases
A brain MRI or CT scan is mandatory in case of clinical suspicion of CNS metastases.
• Single bone metastasis treated with radiotherapy (if the bone metastasis is the
only tumor lesion)
Inclusion criteria for second-line therapy
• At least one dose of trial therapy in the first-line treatment phase of this trial
• Proven disease progression on first-line therapy
First new parenchymal CNS metastases only do not count as progression requiring the
initiation of second line trial treatment • Adequate organ function, evidenced by the
following laboratory results: Neutrophils >1.5x109/L, platelets >100x109/L,
hemoglobin ≥90g/L, total bilirubin ≤1.5xULN (unless the patients has documented
Gilbert's disease), AST ≤3xULN, AP ≤2.5xULN (except in patients with bone metastases:
AP ≤5xULN), creatinine ≤1.5ULN
• LVEF ≥50% as determined by either ECHO or MUGA
- QoL questionnaire has been completed.
Exclusion criteria for second-line therapy
• Termination of first-line therapy with trastuzumab/pertuzumab due to unacceptable
toxicity without objective evidence of disease progression
- CNS metastases that are untreated, symptomatic, or require therapy to control
symptoms, as well as a history of radiation, surgery, or other therapy,
including steroids, to control symptoms from CNS metastases within 2 months (60
days) before registration
- Peripheral neuropathy of CTCAE grade ≥3
- Any other adverse event which has not recovered to CTCAE grade ≤1 (except