Back to resultsNeoadjuvant Response-guided Treatment of HER2 Positive Breast Cancer (PREDIX HER2)
Primary Purpose
Early-Stage Breast Carcinoma, HER-2 Positive Breast Cancer
Status
Active
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
docetaxel + trastuzumab sc + pertuzumab
trastuzumab emtansin
Sponsored by
About this trial
This is an interventional treatment trial for Early-Stage Breast Carcinoma focused on measuring Neoadjuvant therapy
Eligibility Criteria
Inclusion Criteria:
- Written informed consent
- Patients with breast cancer confirmed by histology, characterized by immunohistochemistry for ER, PR, HER2 and proliferation marker
- Tumor and blood samples available. HER2 type confirmed by ISH
- Age 18 years or older. Elderly patients in condition adequate for planned therapy
- Primary breast cancer >20mm in diameter and/or verified lymph node metastases
- Adequate bone marrow, renal, hepatic and cardiac functions and no other uncontrolled medical or psychiatric disorders
- LVEF ≥55%
- ECOG performance status 0-1
- Primary breast cancer as defined in p. 5 plus at most 2 morphologically characterized well-defined distant metastases accessible for stereotactic radiotherapy, provided that this treatment is available
Exclusion Criteria:
- Distant metastases, including node metastases in the contralateral thoracic region or in the mediastinum
- Other malignancy diagnosed within the last five years, except for radically treated basal or squamous cell carcinoma of the skin or CIS of the cervix
- Patients in child-bearing age without adequate contraception
- Pregnancy or lactation
- Uncontrolled hypertension, heart, liver, kidney related or other medical or psychiatric disorders
Sites / Locations
- Dept. of Oncology, Örebro University Hospital
- Dept. of Oncology, Sahlgrenska University Hospital
- Dept. of Oncology, Skåne University Hospital
- Dept. of Oncology, Karolinska University Hospital
- Dept. of Oncology, Sundsvall Hospital
- Dept. of Oncology, University Hospital of Umeå
- Dept. of Oncology, Uppsala University Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Experimental
Arm Label
A standard treatment
B experimental treatment
Arm Description
docetaxel + trastuzumab sc + pertuzumab. Treatment with all three drugs is given on day 1, repeated every three weeks. Six courses of preoperative treatment. Response evaluations after every 2nd course. In case of no change (NC), treatment is switched to arm B. Postoperatively, patients receive 2 courses of treatment with the combination epirubicin + cyclophosphamide (EC), followed by adjuvant trastuzumab, radiotherapy, eventually endocrine treatment.
trastuzumab emtansine. Treatment is given on day 1, repeated every three weeks. Six courses of preoperative treatment. Response evaluations after every 2nd course. In case of no change (NC), treatment is switched to arm A. Postoperatively, patients receive 4 courses of treatment with the combination epirubicin + cyclophosphamide (EC), followed by adjuvant trastuzumab, radiotherapy, eventually endocrine treatment.
Outcomes
Primary Outcome Measures
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
Secondary Outcome Measures
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
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
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
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
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
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
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
Frequency of breast-conserving surgery
Type of surgery is recorded at the time of surgery
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02568839
Brief Title
Neoadjuvant Response-guided Treatment of HER2 Positive Breast Cancer
Acronym
PREDIX HER2
Official Title
PREDIX HER2 - Neoadjuvant Response-guided Treatment of HER2 Positive Breast Cancer. Part of a Platform of Translational Phase II Trials Based on Molecular Subtypes
Study Type
Interventional
2. Study Status
Record Verification Date
August 2020
Overall Recruitment Status
Active, not recruiting
Study Start Date
November 2014 (undefined)
Primary Completion Date
February 2019 (Actual)
Study Completion Date
February 2029 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Thomas Hatschek
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
Detailed Description
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:
PET-CT using FDG, confined to the chest, is performed before start, and after the 2nd and 6th course (functional imaging, optional).
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
Blood samples are collected repeatedly during the ongoing treatment and yearly follow-up
FNAs from metastases in case of recurrence during follow-up
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Early-Stage Breast Carcinoma, HER-2 Positive Breast Cancer
Keywords
Neoadjuvant therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
202 (Actual)
8. Arms, Groups, and Interventions
Arm Title
A standard treatment
Arm Type
Active Comparator
Arm Description
docetaxel + trastuzumab sc + pertuzumab. Treatment with all three drugs is given on day 1, repeated every three weeks. Six courses of preoperative treatment. Response evaluations after every 2nd course. In case of no change (NC), treatment is switched to arm B.
Postoperatively, patients receive 2 courses of treatment with the combination epirubicin + cyclophosphamide (EC), followed by adjuvant trastuzumab, radiotherapy, eventually endocrine treatment.
Arm Title
B experimental treatment
Arm Type
Experimental
Arm Description
trastuzumab emtansine. Treatment is given on day 1, repeated every three weeks. Six courses of preoperative treatment. Response evaluations after every 2nd course. In case of no change (NC), treatment is switched to arm A.
Postoperatively, patients receive 4 courses of treatment with the combination epirubicin + cyclophosphamide (EC), followed by adjuvant trastuzumab, radiotherapy, eventually endocrine treatment.
Intervention Type
Drug
Intervention Name(s)
docetaxel + trastuzumab sc + pertuzumab
Other Intervention Name(s)
Herceptin SC, Perjeta
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
trastuzumab emtansin
Other Intervention Name(s)
Kadcyla
Intervention Description
trastuzumab emtansine 3.6 mg/kg IV, repeated every 3 weeks, 6 courses
Primary Outcome Measure Information:
Title
Pathological objective response to primary medical treatment
Description
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
Secondary Outcome Measure Information:
Title
Clinical/radiological objective response during neoadjuvant treatment
Description
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
Title
Event-free survival
Description
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
Title
Disease-free survival
Description
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
Title
Breast cancer specific survival
Description
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
Title
Overall survival
Description
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
Title
Incidence of treatment-emergent adverse events [Safety and Tolerability]
Description
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
Title
Health Related Quality of life
Description
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
Title
Frequency of breast-conserving surgery
Description
Type of surgery is recorded at the time of surgery
Time Frame
At surgery
Other Pre-specified Outcome Measures:
Title
Changes of morphological, functional and biological characteristics of early breast cancer before and after exposure to cytotoxic and targeted treatment
Description
Includes genomics, proteomics and other biomarker-related analyses on core biopsies and blood samples before start and after two courses of treatment, collection of tumor samples from the surgical specimen at the date of operation, blood samples in connection with annual follow-up visits and FNA and blood samples in case of recurrence. Time frame for collection of biological samples from start of preoperative treatment until 60 months of follow-up post surgery. Functional imaging using 18F-FDG PET-CT is performed at baseline and after the 2nd and 6th treatment course.
Time Frame
5 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Written informed consent
Patients with breast cancer confirmed by histology, characterized by immunohistochemistry for ER, PR, HER2 and proliferation marker
Tumor and blood samples available. HER2 type confirmed by ISH
Age 18 years or older. Elderly patients in condition adequate for planned therapy
Primary breast cancer >20mm in diameter and/or verified lymph node metastases
Adequate bone marrow, renal, hepatic and cardiac functions and no other uncontrolled medical or psychiatric disorders
LVEF ≥55%
ECOG performance status 0-1
Primary breast cancer as defined in p. 5 plus at most 2 morphologically characterized well-defined distant metastases accessible for stereotactic radiotherapy, provided that this treatment is available
Exclusion Criteria:
Distant metastases, including node metastases in the contralateral thoracic region or in the mediastinum
Other malignancy diagnosed within the last five years, except for radically treated basal or squamous cell carcinoma of the skin or CIS of the cervix
Patients in child-bearing age without adequate contraception
Pregnancy or lactation
Uncontrolled hypertension, heart, liver, kidney related or other medical or psychiatric disorders
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thomas Hatschek, Assoc prof
Organizational Affiliation
Breast-sarcoma unit, Dept. of Oncology, Karolinska university hospital
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Jonas Bergh, Professor
Organizational Affiliation
Dept. of Oncology-Pathology, Karolinska Institutet
Official's Role
Study Director
Facility Information:
Facility Name
Dept. of Oncology, Örebro University Hospital
City
Örebro
State/Province
Närke
Country
Sweden
Facility Name
Dept. of Oncology, Sahlgrenska University Hospital
City
Göteborg
ZIP/Postal Code
413 45
Country
Sweden
Facility Name
Dept. of Oncology, Skåne University Hospital
City
Lund
Country
Sweden
Facility Name
Dept. of Oncology, Karolinska University Hospital
City
Stockholm
ZIP/Postal Code
17176
Country
Sweden
Facility Name
Dept. of Oncology, Sundsvall Hospital
City
Sundsvall
ZIP/Postal Code
851 86
Country
Sweden
Facility Name
Dept. of Oncology, University Hospital of Umeå
City
Umeå
Country
Sweden
Facility Name
Dept. of Oncology, Uppsala University Hospital
City
Uppsala
Country
Sweden
12. IPD Sharing Statement
Citations:
PubMed Identifier
34165503
Citation
Hatschek T, Foukakis T, Bjohle J, Lekberg T, Fredholm H, Elinder E, Bosch A, Pekar G, Lindman H, Schiza A, Einbeigi Z, Adra J, Andersson A, Carlsson L, Dreifaldt AC, Isaksson-Friman E, Agartz S, Azavedo E, Gryback P, Hellstrom M, Johansson H, Maes C, Zerdes I, Hartman J, Brandberg Y, Bergh J. Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-Positive Breast Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2021 Sep 1;7(9):1360-1367. doi: 10.1001/jamaoncol.2021.1932. Erratum In: JAMA Oncol. 2021 Sep 1;7(9):1405-1406.
Results Reference
derived
Links:
URL
http://esmo.org
Description
Oral presentation, #97O, at ESMO Breast conference 2020.
Learn more about this trial
Neoadjuvant Response-guided Treatment of HER2 Positive Breast Cancer
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