Image-guided De-escalation of Neo-adjuvant Chemotherapy in HER2-positive Breast Cancer: the TRAIN-3 Study (TRAIN-3)

This is a multicenter, single arm, phase II study evaluating the efficacy of image-guided de-escalating neoadjuvant treatment with paclitaxel, Herceptin® (trastuzumab), carboplatin, and pertuzumab (PTC-Ptz) in stage II-Ill HER2-positive breast cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: PTC-Pz

Detailed Description

High pathological complete response (pCR)-rates are seen using different neoadjuvant chemotherapy schedules with trastuzumab and pertuzumab in HER2-positive stage II - III breast cancer patients. Total pCR rates in breast and axilla have been described as high as 64%, and with an even higher rate of >80% in patients with HER2-positive and hormone receptor (HR) negative tumors. PCR is associated with better long-term outcomes in patients with HER2-positive breast cancer. Three year progression-free survival ranges between 85-90%. Neoadjuvant treatment of HER2-positive breast cancer typically consists of six to nine cycles of treatment. Longer duration of treatment is associated with higher pCR-rates but gives more toxicity. Pathological complete responses are sometimes seen after only 10-12 days of neoadjuvant treatment. It is therefore important to investigate which patients can safely be treated with less than six cycles of chemotherapy and who requires more than six cycles for maximum activity.

The radiologic response of a breast tumor after neoadjuvant therapy is predictive of the pathologic response, although the accuracy differs between breast cancer subtypes. It is hypothesized that patients with an early complete radiologic response may not benefit from additional chemotherapy and can be referred for early surgery. Patients who have not achieved pCR after early surgery despite radiologic complete response (rCR) are candidates for further adjuvant chemotherapy to complete the initially planned number of treatment cycles and maintain maximum treatment activity. Imaged guided de-escalation in which the number of treatment cycles is determined by the radiologic response could thus reduce toxicity in neoadjuvant treatment while maintaining activity.

This study will evaluate the efficacy of image-guided de-escalation of neoadjuvant chemotherapy in patients with HER2-positive breast cancer.

To maintain efficacy, patients who do not achieve pCR will complete a total of nine cycles taxane-containing chemotherapy followed by 14 cycles of treatment with adjuvant T-DM1. Patients who achieve early pCR will continue treatment with Herceptin® and pertuzumab to complete one full year of treatment.

• Study Type: Interventional
• Enrollment (Estimated): 462
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • 's-Hertogenbosch, Netherlands
    • Jeroen Bosch Ziekenhuis
  • Alkmaar, Netherlands
    • Noordwest Ziekenhuisgroep
  • Almelo, Netherlands
    • Ziekenhuisgroep Twente
  • Amersfoort, Netherlands
    • Meander Medisch Centrum
  • Amstelveen, Netherlands
    • Ziekenhuis Amstelland
  • Amsterdam, Netherlands
    • OLVG
  • Amsterdam, Netherlands
    • Amsterdam UMC
  • Amsterdam, Netherlands
    • NKI-AvL
  • Apeldoorn, Netherlands
    • Gelre Ziekenhuizen
  • Arnhem, Netherlands
    • Rijnstate
  • Beverwijk, Netherlands
    • Rode Kruis Ziekenhuis
  • Bilthoven, Netherlands
    • Alexander Monro Ziekenhuis
  • Breda, Netherlands
    • Amphia Ziekenhuis
  • Delft, Netherlands
    • Reinier de Graaf Groep
  • Deventer, Netherlands
    • Deventer Ziekenhuis
  • Dirksland, Netherlands
    • Van Weel Bethesda
  • Drachten, Netherlands
    • Nij Smellinghe
  • Ede, Netherlands
    • Ziekenhuisvoorziening Gelderse Vallei
  • Eindhoven, Netherlands
    • Catharina Ziekenhuis
  • Eindhoven, Netherlands
    • Maxima Medisch Centrum
  • Geldrop, Netherlands
    • Sint Annaziekenhuis
  • Gorinchem, Netherlands
    • Rivas Beatrixziekenhuis
  • Gouda, Netherlands
    • Groene Hart Ziekenhuis
  • Groningen, Netherlands
    • Martini Ziekenhuis
  • Harderwijk, Netherlands
    • Ziekenhuis St. Jansdal
  • Heerenveen, Netherlands
    • Tjongerschans
  • Heerlen, Netherlands
    • Zuyderland Medisch Centrum
  • Helmond, Netherlands
    • Elkerliek Ziekenhuis
  • Hilversum, Netherlands
    • Tergooi
  • Hoofddorp, Netherlands
    • Spaarne Gasthuis
  • Leeuwarden, Netherlands
    • Medisch Centrum Leeuwarden
  • Maastricht, Netherlands
    • MUMC
  • Nieuwegein, Netherlands
    • Sint Antonius Ziekenhuis
  • Nijmegen, Netherlands
    • Canisius Wilhelmina Ziekenhuis
  • Oss, Netherlands
    • Bernhoven
  • Purmerend, Netherlands
    • Stichting ziekenhuizen West-Friesland en Waterland
  • Roermond, Netherlands
    • Laurentius Ziekenhuis
  • Rotterdam, Netherlands
    • Franciscus Gasthuis en Vlietland
  • Rotterdam, Netherlands
    • Erasmus MC, Universitair Medisch Centrum Rotterdam
  • Rotterdam, Netherlands
    • Ikazia Ziekenhuis
  • Rotterdam, Netherlands
    • Maasstadziekenhuis
  • Terneuzen, Netherlands
    • ZorgSaam
  • The Hague, Netherlands
    • Haga ziekenhuis
  • The Hague, Netherlands
    • Haaglanden MC
  • Tiel, Netherlands
    • Rivierenland Ziekenhuis
  • Tilburg, Netherlands
    • Elisabeth Tweesteden Ziekenhuis
  • Utrecht, Netherlands
    • Diakonessenhuis Utrecht
  • Utrecht, Netherlands
    • Universitair Medisch Centrum Utrecht
  • Venlo, Netherlands
    • VieCurie Medisch Centrum voor Noord-Limburg
  • Winterswijk, Netherlands
    • SKB Ziekenhuis Winterswijk
  • Zaandam, Netherlands
    • Zaans Medisch Centrum
  • Zwolle, Netherlands
    • Isala Klinieken

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Histologically confirmed primairy infiltrating breast cancer.
2. Stage II or Ill disease.
3. Overexpression and/or amplification of HER2 in an invasive component of the core biopsy.
4. Age <:18
5. ECOG Group performance status
6. LVEF >50% measured by echocardiography, MRI or MUGA
7. Known HR-status ( in percentages)

Exclusion Criteria:

1. Previous radiation therapy of chemotherapy
2. Pregnancy or breastfeeding
3. Evidence of distant metastases
4. Evidence of bilateral infiltrating breast cancer
5. Concurrent anti-cancer treatment or another investigational drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: PTC-Pz; Paclitaxel 80mg/m2 administered intravenously on day 1 and day 8; Herceptin® 6mg/kg administered intravenously on day 1 (loading dose 8mg/kg) or Herceptin® administered subcutaneously 600mg on day 1; Carboplatin AUC 6mg•ml/min administered intravenously on day 1; Pertuzumab 420mg administered intravenously on day 1 (loading dose 840mg); Treatment cycles are repeated on day 22 Patients who do not achieve pCR will complete a total of nine cycles taxane-containing chemotherapy followed by 14 cycles of treatment with adjuvant T-DM1.

Drug: PTC-Pz; Paclitaxel 80mg/m2 administered intravenously on day 1 and day 8; Herceptin® 6mg/kg administered intravenously on day 1 (loading dose 8mg/kg) or Herceptin® administered subcutaneously 600mg on day 1; Carboplatin AUC 6mg•ml/min administered intravenously on day 1; Pertuzumab 420mg administered intravenously on day 1 (loading dose 840mg); Treatment cycles are repeated on day 22 In case of non pCR; Adjuvant T-DM1, 3.6mg/kg Q 22 days, for 14 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event free survival at three years	Number of patients without progression of disease recurrence, second primary or death	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival at three years	Number of patients alive at three years	3 years
Pathologic complete response in breast and axilla	Number of patients with absence of invasive tumor cells in breast and axilla at surgery	an average of 6 months
Radiologic complete response	Number of patients with absence of pathologic enhancement on MRI	an average of 6 months
Number of neoadjuvant chemotherapy cycles administered	Number of neoadjuvant chemotherapy cycles administered per patient	an average of 1 year
Number of radical and non-radical resections	Number of patients with radical and non-radical resections	an average of 6 months
Incidence and severity of adverse events	Number of patients with toxicity grade >= 3 (CTCAE v5.0) until 30 days after last adjuvant administration	an average of 1 year
Incidence and severity of cardiotoxicity and neuropathy	Number of patients with cardiotoxicity and neuropathy grade >= 2 (CTCAE v5.0) until 30 days after last adjuvant administration	an average of 1 year
Incidence of symptomatic LVSD (heart failure),	Number of patients with an asymptomatic decline in LVEF requiring treatment or leading to discontinuation of pertuzumab and Herceptin, or a decrease ≥10 percentage points from baseline to a LVEF <50%	an average of 1 year
Grade ≥3 laboratory test abnormalities	Number of patients with Grade ≥3 laboratory test abnormalities	an average of 1 year
Incidence of number of tumor positive Vacuum Assisted Core Biopsy	Number of patients with tumor present at Vacuum Assisted Core Biopsy at the moment of radiological complete response on MRI	an average 6 months

Collaborators and Investigators

• Sponsor: Borstkanker Onderzoek Groep
• Collaborators: Roche Pharma AG; BOOG Study Center
• Investigators: Principal Investigator: G S Sonke, MD, NKI-AvL; Study Director: A E van Leeuwen- Stok, PhD, BOOG Study Center

Publications and helpful links

General Publications

• van der Voort A, Louis FM, van Ramshorst MS, Kessels R, Mandjes IA, Kemper I, Agterof MJ, van der Steeg WA, Heijns JB, van Bekkum ML, Siemerink EJ, Kuijer PM, Scholten A, Wesseling J, Vrancken Peeters MTFD, Mann RM, Sonke GS; Dutch Breast Cancer Research Group. MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II-III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2024 May;25(5):603-613. doi: 10.1016/S1470-2045(24)00104-9. Epub 2024 Apr 5.

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2019
• Primary Completion (Actual): November 15, 2022
• Study Completion (Estimated): May 1, 2032

Study Registration Dates

• First Submitted: January 25, 2019
• First Submitted That Met QC Criteria: January 25, 2019
• First Posted (Actual): January 29, 2019

Study Record Updates

• Last Update Posted (Estimated): September 19, 2025
• Last Update Submitted That Met QC Criteria: September 18, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: HER2 positive; neo adjuvant; de-escalation
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms
• Other Study ID Numbers: BOOG 2018-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No