Clinical trial NCT01996267: Neoadjuvant Chemotherapy in HER2 Positive Breast Cancer, TRAIN-2
Official title: Optimizing Neoadjuvant Systemic Treatment for HER2 Positive Breast Cancer - the TRAIN-2 Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Breast Cancer
HER2 Positive
Keywords: neoadjuvant
breast cancer
HER2 positive
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
name: Borstkanker Onderzoek Groep
First posted: 2013-11-27
Enrollment: 437
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study compares two schedules of upfront chemotherapy in HER positive breast cancer.

Detailed description: Upfront trastuzumab treatment is beneficial to patients with HER2 positive breast cancer. The potential synergistic cardiotoxicity of trastuzumab and anthracyclines has led to the development of non-anthracycline containing regimens, which have shown high pathologic complete response rates. Anthracyclines remain very active in HER2 positive breast cancer, however, and increasing evidence now supports safe combination of trastuzumab and epirubicin. Therefore, the addition of epirubicin to a non-anthracycline containing regimen may further improve outcome for patients with HER2 positive breast cancer.

Several reports confirmed benefit of dual HER2 blockade by adding pertuzumab to a trastuzumab containing neoadjuvant regimen. The results of the combined treatment in the Neosphere study, however, are similar to what we found in a phase II trial using a weekly paclitaxel, trastuzumab, carboplatin combination with pCR rates of approximately 44%. Adding pertuzumab to this regimen is likely to also increase the high pCR rate and to add substantial benefit to patients.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed infiltrating breast cancer
* Stage II or stage III disease. Nodal status must be examined by ultrasound, fine needle aspiration, sentinel node biopsy, or FDG-PET scan.
* Overexpression and/or amplification of HER2 in an invasive component of the core biopsy, according to one of the following definitions:

  •\>30% of invasive tumor cells showing strong complete circumferential membrane staining (score 3+)

  •HER2 gene amplification defined as \>6 HER2 gene copies per nucleus by in situ hybridization.
* Age ≥18
* Eastern Cooperative Oncology Group performance status ≤1
* Adequate bone marrow function (ANC \>1.5 x 109/l, platelets \>100 x 109/l)
* Adequate hepatic function (ALAT, ASAT and bilirubin \<2.5 times upper limit of normal)
* Adequate renal function (creatinine clearance \>50 ml/min)
* LVEF ≥50% measured by echocardiography or MUGA
* Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
* Absence of any medical condition that would place the patient at unusual risk.
* Signed written informed consent

Exclusion Criteria:

* previous radiation therapy or chemotherapy
* other malignancy except carcinoma in situ, unless the other malignancy was treated ≥5 years ago with curative intent without the use of chemotherapy or radiation therapy.
* current pregnancy or breastfeeding. Women of childbearing potential must use adequate contraceptive protection
* evidence of distant metastases. Evaluation of the presence of distant metastases may include chest X-ray, liver ultrasound, isotope bone-scan, CT-scan of chest and abdomen and/or FDG-PET scan, according to local procedures.
* evidence of bilateral infiltrating breast cancer. Evaluation of the presence of bilateral infiltrating breast cancer may include mammography, breast ultrasound and/or MRI breast.
* concurrent anti-cancer treatment or another investigational drug.

Primary outcomes:
measure: Number of patients with pathological complete response
timeFrame: at week 30
Secondary outcomes:
measure: Number of patients with grade >2 adverse events as a measure of safety and tolerability
timeFrame: up to week 35
measure: identify prognostic and predictive biomarkers for pCR
timeFrame: within one year after end of treatment
Other outcomes:
Locations:
city: Alkmaar
country: Netherlands
facility: MCA
city: Almelo
country: Netherlands
facility: ZGT
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek
city: Amsterdam
country: Netherlands
facility: AZVU
city: Amsterdam
country: Netherlands
facility: OLVG
city: Beverwijk
country: Netherlands
facility: Rode Kruis 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 Hospital
city: Den Haag
country: Netherlands
facility: Haga
city: den Haag
country: Netherlands
facility: Bronovo Ziekenhuis
city: Deventer
country: Netherlands
facility: Deventer ziekenhuis
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Geldrop
country: Netherlands
facility: St Anna Geldrop
city: Geleen
country: Netherlands
facility: Orbis Medisch Centrum
city: Gouda
country: Netherlands
facility: Groene Hart
city: Haarlem
country: Netherlands
facility: Kennemer Gasthuis
city: Heerlen
country: Netherlands
facility: Atrium Medisch Centrum Parkstad
city: Hoofddorp
country: Netherlands
facility: Spaarne ziekenhuis
city: Hoorn
country: Netherlands
facility: Westfries Gasthuis
city: Leeuwarden
country: Netherlands
facility: MCL
city: Leiden
country: Netherlands
facility: LUMC
city: Meppel
country: Netherlands
facility: Diaconessenhuis Meppel
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Hospital
city: Purmerend
country: Netherlands
facility: Waterlandziekenhuis
city: Schiedam
country: Netherlands
facility: Vlietland Ziekenhuis
city: Tilburg
country: Netherlands
facility: St. Elisabeth
city: Utrecht
country: Netherlands
facility: Diaconessenhuis Utrecht
city: Venlo
country: Netherlands
facility: VieCuri Medisch Centrum voor Noord-Limburg
city: Zaandam
country: Netherlands
facility: Zaans Medisch Centrum
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: Antoni van Leeuwenhoek, Amsterdam
name: Gabe S Sonke, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: van der Voort A, van Ramshorst MS, van Werkhoven ED, Mandjes IA, Kemper I, Vulink AJ, Oving IM, Honkoop AH, Tick LW, van de Wouw AJ, Mandigers CM, van Warmerdam LJ, Wesseling J, Vrancken Peeters MT, Linn SC, Sonke GS. Three-Year Follow-up of Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual ERBB2 Blockade in Patients With ERBB2-Positive Breast Cancer: A Secondary Analysis of the TRAIN-2 Randomized, Phase 3 Trial. JAMA Oncol. 2021 Jul 1;7(7):978-984. doi: 10.1001/jamaoncol.2021.1371.
citation: van Ramshorst MS, van der Voort A, van Werkhoven ED, Mandjes IA, Kemper I, Dezentje VO, Oving IM, Honkoop AH, Tick LW, van de Wouw AJ, Mandigers CM, van Warmerdam LJ, Wesseling J, Vrancken Peeters MT, Linn SC, Sonke GS; Dutch Breast Cancer Research Group (BOOG). Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018 Dec;19(12):1630-1640. doi: 10.1016/S1470-2045(18)30570-9. Epub 2018 Nov 6.