Clinical trial NCT03820063: Image-guided De-escalation of Neo-adjuvant Chemotherapy in HER2-positive Breast Cancer: the TRAIN-3 Study
Official title: Image-guided De-escalation of Neo-adjuvant Chemotherapy in HER2-positive Breast Cancer: the TRAIN-3 Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
Keywords: neo adjuvant
HER2 positive
de-escalation
Lead sponsor: Borstkanker Onderzoek Groep
Sponsor class: NETWORK
Collaborators: name: Roche Pharma AG
name: BOOG Study Center
First posted: 2019-01-29
Enrollment: 462
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: neoadjuvant courses PTC-Ptz; adjuvant courses Ptz (pCR) or T-DM1 (non-pCR)
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Event free survival at three years
timeFrame: 3 years
Secondary outcomes:
measure: Overall survival at three years
timeFrame: 3 years
measure: Pathologic complete response in breast and axilla
timeFrame: an average of 6 months
measure: Radiologic complete response
timeFrame: an average of 6 months
measure: Number of neoadjuvant chemotherapy cycles administered
timeFrame: an average of 1 year
measure: Number of radical and non-radical resections
timeFrame: an average of 6 months
measure: Incidence and severity of adverse events
timeFrame: an average of 1 year
measure: Incidence and severity of cardiotoxicity and neuropathy
timeFrame: an average of 1 year
measure: Incidence of symptomatic LVSD (heart failure),
timeFrame: an average of 1 year
measure: Grade ≥3 laboratory test abnormalities
timeFrame: an average of 1 year
measure: Incidence of number of tumor positive Vacuum Assisted Core Biopsy
timeFrame: an average 6 months
Other outcomes:
Locations:
city: Alkmaar
country: Netherlands
facility: Noordwest Ziekenhuisgroep
city: Almelo
country: Netherlands
facility: Ziekenhuisgroep Twente
city: Amersfoort
country: Netherlands
facility: Meander Medisch Centrum
city: Amstelveen
country: Netherlands
facility: Ziekenhuis Amstelland
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Amsterdam
country: Netherlands
facility: NKI-AVL
city: Amsterdam
country: Netherlands
facility: OLVG
city: Apeldoorn
country: Netherlands
facility: Gelre ziekenhuizen
city: Arnhem
country: Netherlands
facility: Rijnstate
city: Beverwijk
country: Netherlands
facility: Rode Kruis Ziekenhuis
city: Bilthoven
country: Netherlands
facility: Alexander Monro ziekenhuis
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Delft
country: Netherlands
facility: Reinier de Graaf Groep
city: Den Bosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Den Haag
country: Netherlands
facility: Haaglanden MC
city: Den Haag
country: Netherlands
facility: Haga Ziekenhuis
city: Deventer
country: Netherlands
facility: Deventer ziekenhuis
city: Dirksland
country: Netherlands
facility: van Weel Bethesda
city: Drachten
country: Netherlands
facility: Nij Smellinghe
city: Ede
country: Netherlands
facility: Ziekenhuisvoorziening Gelderse Vallei
city: Eindhoven
country: Netherlands
facility: Catharina ziekenhuis
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Geldrop
country: Netherlands
facility: Sint Annaziekenhuis
city: Gorinchem
country: Netherlands
facility: RIVAS Beatrixziekenhuis
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
city: Groningen
country: Netherlands
facility: Martini ziekenhuis
city: Harderwijk
country: Netherlands
facility: Ziekenhuis St. Jansdal
city: Heerenveen
country: Netherlands
facility: Tjongerschans
city: Heerlen
country: Netherlands
facility: Zuyderland Medisch Centrum
city: Helmond
country: Netherlands
facility: Elkerliek ziekenhuis
city: Hilversum
country: Netherlands
facility: Tergooi
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Maastricht
country: Netherlands
facility: MUMC
city: Nieuwegein
country: Netherlands
facility: Sint Antonius ziekenhuis
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Ziekenhuis
city: Oss
country: Netherlands
facility: Bernhoven
city: Purmerend
country: Netherlands
facility: Stichting ziekenhuizen West-Friesland en Waterland
city: Roermond
country: Netherlands
facility: Laurentius ziekenhuis
city: Rotterdam
country: Netherlands
facility: Erasmus MC, Universitair Medisch Centrum Rotterdam
city: Rotterdam
country: Netherlands
facility: Franciscus Gasthuis en Vlietland
city: Rotterdam
country: Netherlands
facility: Ikazia Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Maasstadziekenhuis
city: Terneuzen
country: Netherlands
facility: ZorgSaam
city: Tiel
country: Netherlands
facility: Rivierenland Ziekenhuis
city: Tilburg
country: Netherlands
facility: Elisabeth TweeSteden ziekenhuis
city: Utrecht
country: Netherlands
facility: Diakonessenhuis Utrecht
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Venlo
country: Netherlands
facility: VieCurie Medisch Centrum voor Noord-Limburg
city: Winterswijk
country: Netherlands
facility: SKB Ziekenhuis Winterswijk
city: Zaandam
country: Netherlands
facility: Zaans Medisch Centrum
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: NKI-AvL
name: G S Sonke, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: BOOG Study Center
name: A E van Leeuwen- Stok, PhD
role: STUDY_DIRECTOR
References: