Neoadjuvant Response-guided Treatment of HER2 Positive Breast Cancer (PREDIX HER2)

• ClinicalTrials.gov Identifier: NCT02568839
• Recruitment Status: Active, not recruiting
• First Posted: October 6, 2015
• Last Update Posted: August 13, 2020
• Sponsor: Thomas Hatschek
• Information provided by (Responsible Party): Thomas Hatschek, Karolinska University Hospital

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.

Condition or disease	Intervention/treatment	Phase
Early-Stage Breast Carcinoma; HER-2 Positive Breast Cancer	Drug: docetaxel + trastuzumab sc + pertuzumab; Drug: trastuzumab emtansin	Phase 2; Phase 3

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:

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 202 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: November 2014
• Actual Primary Completion Date: February 2019
• Estimated Study Completion Date: February 2029

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: A standard treatment; 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.	Drug: docetaxel + trastuzumab sc + pertuzumab; 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; Other Names: Herceptin SC; Perjeta
Experimental: B experimental 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.	Drug: trastuzumab emtansin; trastuzumab emtansine 3.6 mg/kg IV, repeated every 3 weeks, 6 courses; Other Name: Kadcyla

Outcome Measures

Primary Outcome Measures :

1. Pathological objective response to primary medical treatment [ Time Frame: At surgery ]
   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 :

1. Clinical/radiological objective response during neoadjuvant treatment [ Time Frame: During the 18-week treatment period before surgery ]
   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
2. Event-free survival [ Time Frame: All events from date of randomization until follow-up to 10 years ]
   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
3. Disease-free survival [ Time Frame: During the follow-up to 10 years ]
   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
4. Breast cancer specific survival [ Time Frame: During the follow-up to 10 years ]
   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
5. Overall survival [ Time Frame: During the follow-up to 10 years ]
   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
6. Incidence of treatment-emergent adverse events [Safety and Tolerability] [ 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 ]
   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
7. Health Related Quality of life [ Time Frame: From date of randomisation until follow-up to 5 years ]
   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
8. Frequency of breast-conserving surgery [ Time Frame: At surgery ]
   Type of surgery is recorded at the time of surgery

Other Outcome Measures:

1. Changes of morphological, functional and biological characteristics of early breast cancer before and after exposure to cytotoxic and targeted treatment [ Time Frame: 5 years ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Written informed consent
2. Patients with breast cancer confirmed by histology, characterized by immunohistochemistry for ER, PR, HER2 and proliferation marker
3. Tumor and blood samples available. HER2 type confirmed by ISH
4. Age 18 years or older. Elderly patients in condition adequate for planned therapy
5. Primary breast cancer >20mm in diameter and/or verified lymph node metastases
6. Adequate bone marrow, renal, hepatic and cardiac functions and no other uncontrolled medical or psychiatric disorders
7. LVEF ≥55%
8. ECOG performance status 0-1
9. 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:

1. Distant metastases, including node metastases in the contralateral thoracic region or in the mediastinum
2. 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
3. Patients in child-bearing age without adequate contraception
4. Pregnancy or lactation
5. Uncontrolled hypertension, heart, liver, kidney related or other medical or psychiatric disorders

Contacts and Locations

Locations

Sweden

Dept. of Oncology, Örebro University Hospital

Örebro, Närke, Sweden

Dept. of Oncology, Sahlgrenska University Hospital

Göteborg, Sweden, 413 45

Dept. of Oncology, Skåne University Hospital

Lund, Sweden

Dept. of Oncology, Karolinska University Hospital

Stockholm, Sweden, 17176

Dept. of Oncology, Sundsvall Hospital

Sundsvall, Sweden, 851 86

Dept. of Oncology, University Hospital of Umeå

Umeå, Sweden

Dept. of Oncology, Uppsala University Hospital

Uppsala, Sweden

Sponsors and Collaborators

Thomas Hatschek

Investigators

• Study Chair: Thomas Hatschek, Assoc prof; Breast-sarcoma unit, Dept. of Oncology, Karolinska university hospital
• Study Director: Jonas Bergh, Professor; Dept. of Oncology-Pathology, Karolinska Institutet

More Information

Additional Information:

Oral presentation at ASCO 2019 

Poster presentation, #583, of Health Related Quality of Life 

Oral presentation, #97O, at ESMO Breast conference 2020. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hatschek T, Foukakis T, Bjöhle 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, Grybäck P, Hellström 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.

• Responsible Party: Thomas Hatschek, Sen. Consultant, MD, PhD, Assoc. professor, Karolinska University Hospital
• ClinicalTrials.gov Identifier: NCT02568839
• Other Study ID Numbers: PREDIX HER2
• First Posted: October 6, 2015
• Last Update Posted: August 13, 2020
• Last Verified: August 2020

Keywords provided by Thomas Hatschek, Karolinska University Hospital:

Neoadjuvant therapy

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Docetaxel; Trastuzumab; Pertuzumab; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological