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

Phase 2

Active, not recruiting

• Conditions: Breast Cancer
• Interventions: Drug: PTC-Pz

• Registration Number: NCT03820063
• Lead Sponsor: Borstkanker Onderzoek Groep

Brief Summary

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.

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 Timeline

• Study First Submitted: 2019-01-25
• Study First Submitted QC: 2019-01-25
• Study First Posted: 2019-01-29
• Study Start: 2019-02-27
• Primary Completion: 2022-11-15
• Status Verified: 2023-02
• Last Update Submitted: 2023-02-21
• Last Update Posted: 2023-02-22
• Study Completion: 2032-05-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 462

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)

Read More

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

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PTC-Pz	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.

Primary Outcome Measures

Name	Time	Method
Event free survival at three years	3 years	Number of patients without progression of disease recurrence, second primary or death

Secondary Outcome Measures

Name	Time	Method
Overall survival at three years	3 years	Number of patients alive at three years
Pathologic complete response in breast and axilla	an average of 6 months	Number of patients with absence of invasive tumor cells in breast and axilla at surgery
Radiologic complete response	an average of 6 months	Number of patients with absence of pathologic enhancement on MRI
Number of neoadjuvant chemotherapy cycles administered	an average of 1 year	Number of neoadjuvant chemotherapy cycles administered per patient
Number of radical and non-radical resections	an average of 6 months	Number of patients with radical and non-radical resections
Incidence and severity of adverse events	an average of 1 year	Number of patients with toxicity grade \>= 3 (CTCAE v5.0) until 30 days after last adjuvant administration
Incidence of symptomatic LVSD (heart failure),	an average of 1 year	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%
Grade ≥3 laboratory test abnormalities	an average of 1 year	Number of patients with Grade ≥3 laboratory test abnormalities
Incidence and severity of cardiotoxicity and neuropathy	an average of 1 year	Number of patients with cardiotoxicity and neuropathy grade \>= 2 (CTCAE v5.0) until 30 days after last adjuvant administration
Incidence of number of tumor positive Vacuum Assisted Core Biopsy	an average 6 months	Number of patients with tumor present at Vacuum Assisted Core Biopsy at the moment of radiological complete response on MRI

Trial Locations

Locations (52)

Ziekenhuis St. Jansdal; 🇳🇱 Harderwijk, Netherlands

Zuyderland Medisch Centrum; 🇳🇱 Heerlen, Netherlands

Ikazia Ziekenhuis; 🇳🇱 Rotterdam, Netherlands

VieCurie Medisch Centrum voor Noord-Limburg; 🇳🇱 Venlo, Netherlands

Noordwest Ziekenhuisgroep; 🇳🇱 Alkmaar, Netherlands

OLVG; 🇳🇱 Amsterdam, Netherlands

Gelre ziekenhuizen; 🇳🇱 Apeldoorn, Netherlands

Groene Hart Ziekenhuis; 🇳🇱 Gouda, Netherlands

Amsterdam UMC; 🇳🇱 Amsterdam, Netherlands

Reinier de Graaf Groep; 🇳🇱 Delft, Netherlands

Haaglanden MC; 🇳🇱 Den Haag, Netherlands

Deventer ziekenhuis; 🇳🇱 Deventer, Netherlands

Nij Smellinghe; 🇳🇱 Drachten, Netherlands

Ziekenhuisvoorziening Gelderse Vallei; 🇳🇱 Ede, Netherlands

Catharina ziekenhuis; 🇳🇱 Eindhoven, Netherlands

Maxima Medisch Centrum; 🇳🇱 Eindhoven, Netherlands

MUMC; 🇳🇱 Maastricht, Netherlands

Martini ziekenhuis; 🇳🇱 Groningen, Netherlands

Elkerliek ziekenhuis; 🇳🇱 Helmond, Netherlands

Tergooi; 🇳🇱 Hilversum, Netherlands

Laurentius ziekenhuis; 🇳🇱 Roermond, Netherlands

Medisch Centrum Leeuwarden; 🇳🇱 Leeuwarden, Netherlands

Erasmus MC, Universitair Medisch Centrum Rotterdam; 🇳🇱 Rotterdam, Netherlands

Franciscus Gasthuis en Vlietland; 🇳🇱 Rotterdam, Netherlands

Universitair Medisch Centrum Utrecht; 🇳🇱 Utrecht, Netherlands

Ziekenhuisgroep Twente; 🇳🇱 Almelo, Netherlands

Meander Medisch Centrum; 🇳🇱 Amersfoort, Netherlands

Rijnstate; 🇳🇱 Arnhem, Netherlands

Ziekenhuis Amstelland; 🇳🇱 Amstelveen, Netherlands

NKI-AVL; 🇳🇱 Amsterdam, Netherlands

Rode Kruis Ziekenhuis; 🇳🇱 Beverwijk, Netherlands

Amphia Ziekenhuis; 🇳🇱 Breda, Netherlands

Alexander Monro ziekenhuis; 🇳🇱 Bilthoven, Netherlands

Jeroen Bosch Ziekenhuis; 🇳🇱 Den Bosch, Netherlands

Haga Ziekenhuis; 🇳🇱 Den Haag, Netherlands

van Weel Bethesda; 🇳🇱 Dirksland, Netherlands

Tjongerschans; 🇳🇱 Heerenveen, Netherlands

RIVAS Beatrixziekenhuis; 🇳🇱 Gorinchem, Netherlands

Spaarne Gasthuis; 🇳🇱 Hoofddorp, Netherlands

Sint Antonius ziekenhuis; 🇳🇱 Nieuwegein, Netherlands

Bernhoven; 🇳🇱 Oss, Netherlands

Stichting ziekenhuizen West-Friesland en Waterland; 🇳🇱 Purmerend, Netherlands

Maasstadziekenhuis; 🇳🇱 Rotterdam, Netherlands

ZorgSaam; 🇳🇱 Terneuzen, Netherlands

Rivierenland Ziekenhuis; 🇳🇱 Tiel, Netherlands

Diakonessenhuis Utrecht; 🇳🇱 Utrecht, Netherlands

Elisabeth TweeSteden ziekenhuis; 🇳🇱 Tilburg, Netherlands

Zaans Medisch Centrum; 🇳🇱 Zaandam, Netherlands

Isala Klinieken; 🇳🇱 Zwolle, Netherlands

Sint Annaziekenhuis; 🇳🇱 Geldrop, Netherlands

Canisius Wilhelmina Ziekenhuis; 🇳🇱 Nijmegen, Netherlands

SKB Ziekenhuis Winterswijk; 🇳🇱 Winterswijk, Netherlands