Studieoverzicht - 2018-01 TRAIN-3

 
Number 2018-01 TRAIN-3
Nickname TRAIN-3
Status Open Date: 27-02-2019
Inclusion closed
Other study number(s)
Participating parties/groups
Full title Image-guided de-escalation of neoadjuvant chemotherapy in HER2-positive breast cancer: the TRAIN-3 study
Phase and type single arm
Age ≥18 woman / man
Menopausal status Not applicable
Indication Neoadjuvant
Subindication HER2+, any HR
Target sample size 462
Actual accrual 6 Date: 01-04-2019
Estimated study completion date 31-12-2022
CCMO approval Yes Date: 08-01-2019 Nr: NL66887.038.18
EudraCT nr. 2018-003275-35
Trial Register NCT03820063
METC approval Yes Date: 07-02-2019 METC: Nederlands Kanker Instituut Nr: M18TRD
Amendments Yes Date: 19-03-2019
KWF-CKS approval Not applicable Date: Nr:
News item
Website
Sponsor BOOG Study Center
Principal Investigator(s) Dr. G.S. Sonke MD PhD (The Netherlands Cancer Institute)
Study manager Dr. A.E. van Leeuwen-Stok (BOOG Study Center)

Studycoördinator:
A. van der Voort, MD
T 020-5126169

Central datamanagement and randomization Randomization: Authorized persons at the site, through ALEA

Central contact Data Centre:
T. Westphal MSc
NKI Data Center
Phone +31 20 512 9050
E-mail t.westphal@nki.nl
Monitoring NKI Data Center
Phone +31 20 512 2655
E-mail e.v.schaffelaar@nki.nl; r.vd.wiel@nki.nl
Local datamanagement Centrum zelf of IKNL
E-mail trialbureau@iknl.nl
Phone +31 88 234 6500
Funding
Extra Contracts & finances: BOOG Study Center (info@boogstudycenter.nl)

Design:

Objectives:

Primary efficacy objective 

To evaluate efficacy of image-guided de-escalating chemotherapy in the presence of dual HER2-blockade with Herceptin® and pertuzumab in HER2-positive breast cancer, as measured by three-year event-free survival.
 
Secondary efficacy objectives

o To evaluate 3-year overall survival

o To evaluate pCR rate in breast and axilla o To evaluate 5-year, and 10-year overall and event-free survival rate

o To evaluate the association between pCR and long-term outcome

o To evaluate the association between radiologic complete response (rCR) and pCR

o To compare short-term and long-term efficacy by number of chemotherapy cycles received

o To compare non-radical resection percentages between rCR and no rCR
 
Safety objectives

o Incidence and severity of adverse events grade ≥3 (CTCAE v5.0)

o Incidence and severity of cardiotoxicity and neuropathy grade ≥2

o Incidence of symptomatic LVSD (heart failure), and incidence of asymptomatic decrease in LVEF, defined as 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%

o Grade ≥3 laboratory test abnormalities
 
Exploratory objectives

o To explore mechanisms of resistance to treatment based on immunohistochemistry and whole exome sequencing plus proteomics of pre-treatment and on-treatment biopsies, comparison of pre-treatment biopsies with residual tumor after treatment, sequential cfDNA and tumor-educated platelets. 

o To evaluate the effect of in vivo biotransformation of trastuzumab and pertuzumab on the treatment response 
 

Endpoints:

Primary efficacy outcome measure:

o Event-free survival (EFS), defined as the interval from registration to the earliest occurrence of disease progression resulting in inoperability, invasive loco regional recurrence, distant metastases, or death from any cause, whichever comes first
 
Secondary efficacy outcome measures:

o Overall survival (OS), defined as the time from registration to death from any cause

o Pathologic complete response in breast and axilla, defined as the absence of invasive tumor cells, irrespective of the presence of in-situ lesions

o Radiologic complete response defined as the absence of pathologic enhancement on MRI and normalization of possible lymph node involvement at ultrasound and FNA examination

o Number of neoadjuvant chemotherapy cycles administered

o Number of radical and non-radical resections
 
Safety outcome measures:

o Incidence and severity of adverse events grade ≥3 (CTCAE v5.0) until 30 days after last adjuvant treatment administration

o Incidence and severity of cardiotoxicity and neuropathy grade ≥2

o Incidence of symptomatic LVSD (heart failure), and incidence of asymptomatic decrease in LVEF, defined as 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%

o Grade ≥3 laboratory test abnormalities
 
Exploratory outcome measures:

o PCR rate, 3-year EFS and OS stratified by the identified potential biomarkers

o PCR rate, 3-year EFS and OS stratified by degree of biotransformation of trastuzumab and pertuzumab
 

Main eligibility criteria:

Eligible patients must meet all of the following criteria:

o Signed written informed consent

o Histologically confirmed infiltrating breast cancer

o Stage II or III disease according to TNM-staging (8th edition, AJCC). 

o Overexpression and/or amplification of HER2 in an invasive component of the core biopsy, according to ASCO/CAP 2013 guideline (locally assessed)

o Known estrogen- and progesteron-receptor expression of the invasive tumor

o Age ≥18

o WHO performance status ≤1

o Visible breast tumor on contrast enhanced MRI and/or the presence of malignant lymph node(s) 

o Adequate bone marrow function,  hepatic function, renal function

o LVEF ≥50% measured by echocardiography, MUGA, or MRI

o Women of childbearing potential and men must agree to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods (failure rate of <1% per year,) during treatment and for at least seven months after the last dose of pertuzumab/Herceptin®.

o Women who are not postmenopausal (≥12 months of non−therapy-induced amenorrhea) or surgically sterile must have a negative β-HCG serum or urine pregnancy test result.
 
Exclusion criteria

A subject who meets any of the following criteria will be excluded from participation in this study:

o Concurrent breastfeeding

o Evidence of distant metastases on FDG-PET

o Concurrent contralateral or ipsilateral second primary infiltrating breast cancer

o Concurrent anti-cancer treatment or another investigational drug

o Contra-indication for neoadjuvant chemotherapy

o Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

o Other invasive malignancy unless treated without chemotherapy more than five years ago and without evidence of recurrence. Patients with prior adequately treated basal cell or squamous cell skin cancer are also eligible.

o Peripheral neuropathy ≥grade 2 CTCAE v5.0

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