Trastuzumab & Pertuzumab Followed by T-DM1 in MBC

OBJECTIVES:

Primary

-To evaluate the efficacy in terms of overall survival (OS) at 24 months of a chemotherapy-free dual HER2-inhibition with trastuzumab and pertuzumab (first-line) followed by T-DM1 (second-line) and of a chemotherapy-containing dual HER2-inhibition with trastuzumab and pertuzumab (first-line) followed by T-DM1 (second-line) in patients with HER2-positive metastatic breast cancer.

Secondary

• To evaluate other efficacy parameter
• To evaluate the safety and tolerability profile of the two treatment strategies
• To evaluate the Quality of Life (QoL)
• To learn how patients are treated after trial treatment

OUTLINE: This is a multicenter study. Patients are stratified according to hormone receptor status (positive vs negative), prior trastuzumab (never or >12 months vs ≤12 months after last infusion), visceral metastases (present vs absent) and site. Patients are randomized to 1 of 2 treatment arms.

SELECTION OF PATIENTS (MOST IMPORTANT CRITERIA)

Inclusion criteria

for first-line therapy

• Histologically confirmed breast cancer with distant metastases

Note:

• A biopsy from the primary tumor or a metastasis can be used for diagnosis.
• Patients with non-measurable lesions are eligible.
• Patients with inoperable, locally advanced breast cancer with lymph node metastases other than ipsilateral locoregional (axillary, infraclavicular, parasternal) or other distant metastases are eligible.
• Patients with bone metastases with or without bone targeted therapy (bisphosphonates, denosumab) are eligible.
• Patients with de-novo Stage IV disease are eligible.

• HER2-positive tumor according to central pathology testing for HER2

Note:

• 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.
• 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 MUGA
• 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, ALT ≤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

Note:

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 randomization.

• Re-exposure to vinorelbine is permitted, if the last dose of vinorelbine was given at least 1 year before randomization.
• Prior anti-HER2 treatment for metastatic or inoperable breast cancer

Note:

Prior neoadjuvant/adjuvant anti-HER2 treatment with trastuzumab and/or lapatinib is allowed.

• More than one endocrine treatment line for metastatic or inoperable breast cancer exceeding a duration of 1 month

Note:

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• Adjuvant endocrine treatment is not counted as one line.
• Patients progressing on endocrine treatment: this specific endocrine treatment must have been stopped at least 2 weeks prior to randomization.

• Prior treatment with pertuzumab and/or T-DM1

• Known leptomeningeal or CNS metastases

Note:

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 or radiotherapy of a bone metastasis

Notes:

First new parenchymal CNS metastases only do not count as progression requiring the initiation of second line trial treatment. Radiotherapy of a single area only for pain control is allowed and will not count as PD.

• 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
• Interstitial lung disease (ILD) or pneumonitis grade ≥3
• Any other adverse event which has not recovered to CTCAE grade ≤1 (except alopecia)