The purpose of this trial is to evaluate efficacy and toxicity of either the combination of docetaxel, trastuzumab sc and pertuzumab (arm A) or trastuzumab emtansin (arm B). Switch of therapy to the opposite treatment alternative is applicable in case of lack of response after two courses of treatment, or for medical reasons under exceptional circumstances (drug reaction, other medical conditions) at any point. After termination of the primary treatment follow-up for five years. A translational subprotocol is a mandatory part of the study protocol, with exception for the use of PET-CT evaluations.
Patients with HER2-positive tumors \>20 mm or verfied regional lymph node metastases are randomized to either arm A, the combination of docetaxel, trastuzumab sc (Herceptin SC®) and pertuzumab (Perjeta®) or arm B, trastuzumab emtansin (Kadcyla®). Switch to the opposite treatment is performed in case of lack of response after evaluations with mammography and ultrasound, alternatively MRI breast after the 2nd, 4th and 6th course of treatment. Postoperative treatment, trastuzumab, radiotherapy, eventual endocrine treatment) according to standard guidelines. Structured follow-up visits yearly for five years, including reporting of persistent treatment-related toxicity, HRQoL, recurrence and death. The trial contains also a translational subprotocol: 1. PET-CT using FDG, confined to the chest, is performed before start, and after the 2nd and 6th course (functional imaging, optional). 2. Core biopsies from the tumor are collected before start and after the 2nd course of treatment. If residual tissue is available, samples are collected from the surgical sample 3. Blood samples are collected repeatedly during the ongoing treatment and yearly follow-up 4. FNAs from metastases in case of recurrence during follow-up
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
202
docetaxel 75-100 mg IV + trastuzumab sc 5 ml (600 mg) SC + pertuzumab 840 mg IV starting dose, subsequently 420 mg IV, repeated every 3 weeks, 6 courses
trastuzumab emtansine 3.6 mg/kg IV, repeated every 3 weeks, 6 courses
Dept. of Oncology, Örebro University Hospital
Örebro, Närke, Sweden
Dept. of Oncology, Sahlgrenska University Hospital
Gothenburg, Sweden
Dept. of Oncology, Skåne University Hospital
Lund, Sweden
Dept. of Oncology, Karolinska University Hospital
Stockholm, Sweden
Dept. of Oncology, Sundsvall Hospital
Sundsvall, Sweden
Dept. of Oncology, University Hospital of Umeå
Umeå, Sweden
Dept. of Oncology, Uppsala University Hospital
Uppsala, Sweden
Pathological objective response to primary medical treatment
Efficacy measure after 18 weeks of preoperative treatment, starting from the start of preoperative medical treatment until the date of surgery. Outcome should be received within not more than 4 weeks post surgery
Time frame: At surgery
Clinical/radiological objective response during neoadjuvant treatment
Clinical measurements with caliper, radiological evaluations with mammography and ultrasound, alternately MRI, within 6 weeks before start, and 14 days after 3-weekly courses 2, 4 and 6; PET-CT within 2 weeks before start, and 16 days after courses 2 and 6. Time frame for these response evaluations is between between week 4 and week 18 of preoperative treatment
Time frame: During the 18-week treatment period before surgery
Event-free survival
Time frame for reporting is from date of randomization until first reported event, including disease progression, documented first recurrence, first contralateral breast cancer, first cancer of other origin, or death of any cause, whatever occurs first
Time frame: All events from date of randomization until follow-up to 10 years
Disease-free survival
Time frame for reporting is between date of surgery and 10 years follow-up. Date of detection of metastasis will be reported within 12 months after occurence
Time frame: During the follow-up to 10 years
Breast cancer specific survival
Time frame for reporting is between date of surgery and 60 months follow-up. Date and cause of death will be reported within 12 months after occurence
Time frame: During the follow-up to 10 years
Overall survival
Time frame for reporting is between date of surgery and 10 years follow-up. Date of death will be reported within 12 months after occurence
Time frame: During the follow-up to 10 years
Incidence of treatment-emergent adverse events [Safety and Tolerability]
Time frame for reporting of acute side effects is from start of treatment until 30 days after termination of the treatment, totally 22 weeks. Late side effects are reported within 60 months post surgery. Cardiac toxicity is given special attention during the entire period. Echocardiograms and ECGs are performed within 6 weeks before start of treatment, after 16 weeks of treatment before surgery, and then every 3 months during postoperative treatment with trastuzumab the 1st postoperative year; thereafter every 12 months until 10 years of follow-up after surgery
Time frame: During the 18-week period of treatment and until 30 days after termination and during the follow-up period up to 10 years
Health Related Quality of life
Repeated assessments using EOTC QLQ-C30 and BR23 during the treatment period, before randomization and after courses 2, 4 and 6, 3 months post surgery and annually during the follow-up period up to 10 years. Time frame covers the 18-week period of preoperative treatment and 10 years follow-up period after surgery
Time frame: From date of randomisation until follow-up to 5 years
Frequency of breast-conserving surgery
Type of surgery is recorded at the time of surgery
Time frame: At surgery
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