Clinical trial NCT01057069: Neo Adjuvant Chemotherapy in Triple Negative Breast Cancer
Official title: Randomized Phase II/III Study of Individualized Neoadjuvant Chemotherapy in ' Triple Negative' Breast Tumors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Breast Cancer
Keywords: Neo adjuvant
Triple negative
primary tumor over 2 cm and/or positive lymphnodes
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
First posted: 2010-01-27
Enrollment: 310
Sex: ALL
Minimum age (years): 18
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study aims to compare the response of triple-negative breast cancer with deficient homologous recombination to intensified alkylating chemotherapy versus standard chemotherapy with dose dense AC and/or Docetaxel-Capecitabine.

Detailed description: Homologous Recombination (HR) is a DNA repair mechanism that can repair double-strand DNA breaks. It is the only reliable repair mechanism that can repair the consequences of DNA adducts caused by bifunctional alkylating agents (such as cyclophosphamide, thiotepa or carboplatin). Alternative DNA repair mechanisms exist, but these unavoidably induce DNA mutations, deletions and chromosome aberrations, giving give rise to genetic instability. HRD may be a consequence of inactivation of the BRCA-1 or BRCA-2 genes (as in hereditary breast cancer), but it may also be caused by defects in the Fanconi anemia pathway or by amplification of the EMSY gene. HRD is present in breast cancer cells but not in healthy cells of BRCA-1 or BRCA-2 mutation carriers, and also in about half of the sporadic triple-negative breast cancers.

This phase II/III controlled multicenter trial will investigate the ability of individualized chemotherapy to improve the objective response rate of 'triple-negative' breast cancer (estrogen receptor and progesterone receptor-negative, no HER2 amplification) to preoperative (neoadjuvant) chemotherapy. It will answer the question whether intensified alkylating chemotherapy improves the response rate of tumors with a Homologous Recombination Defect (HRD) and it will gather data required for the design of a phase III study documenting the efficacy of response monitoring by contrast-enhanced MRI in TN breast cancer without HRD.

Eligibility criteria: Inclusion Criteria:

* Proven infiltrating breast cancer with either a primary tumor over 2 cm in size (MRI or ultrasound examination) and/or cytologically proven spread to the axillary lymph nodes.
* Patients with 'locally advanced breast cancer' are consequently eligible, including those with ipsilateral supraclavicular lymph node metastases.
* The tumor must be HER2/neu-negative (either score 0 or 1 at immunohistochemistry or negative at in situ hybridization \[CISH or FISH\] in case of score 2 or 3 at immunohistochemistry).
* The tumor must be Estrogen receptor (ER) -negative (\< 10% nuclear staining at IHC) and Progesterone receptor (PR) -negative (\< 10% nuclear staining at IHC). However, the rare tumors that are ER-negative and PR-positive will be eligible, if this pattern of hormone receptor expression can be verified in the NKI-AVL reference pathology lab.
* Age 18 to 59 years; patients older than 59 years may be included when considered 'biologically 59 years or younger' (as judged by the investigator).
* Performance status: WHO 0 or I.
* Adequate bone marrow function (W.B.C. count \> 3.0 x 109/l, platelets \> 100 x 109/l).
* Adequate hepatic function (ALAT, ASAT and bilirubin \< 2 x upper limit of normal, or minor abnormalities of these tests judged to be of no consequence by the study coordinator).
* Adequate renal function (creatinine clearance \> 60 ml/min).
* Informed consent

Exclusion Criteria:

* Previous radiation therapy or chemotherapy.
* Other malignancy except carcinoma in situ, unless the other malignancy was treated 5 or more years ago with curative intent without the use of chemotherapy or radiation therapy.
* Pregnancy or breast feeding.
* Evidence of distant metastases. Staging examinations must have included a chest roentgenogram, an ultrasound examination of the liver and an isotope bone scan. Abnormal uptake on the isotope bone scan can only be accepted if bone metastases were excluded by MRI

Primary outcomes:
measure: Primary endpoint (HRD tumors): Average Neoadjuvant Response Index (NRI) after intensified alkylating therapy in comparison to that after 'standard' neoadjuvant chemotherapy. Primary endpoint (non-HRD tumors): Average Neoadjuvant Response Index (NRI)
timeFrame: end of neo adjuvant chemotherapy
Secondary outcomes:
measure: Recurrence-free survival and overall survival.
timeFrame: every year
Other outcomes:
Locations:
city: Alkmaar
country: Netherlands
facility: Medisch Centrum Alkmaar
city: Amsterdam
country: Netherlands
facility: NKI-AVL
city: Amsterdam
country: Netherlands
facility: OLVG
city: Delft
country: Netherlands
facility: Reinier de Graaf Groep
city: Den Haag
country: Netherlands
facility: Medisch Centrum Haaglanden
city: Deventer
country: Netherlands
facility: Deventer Ziekenhuis
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer ziekenhuis
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Haarlem
country: Netherlands
facility: Kennemer Gasthuis
city: Heerlen
country: Netherlands
facility: Atrium Medisch Centrum Parkstad
city: Hoofddorp
country: Netherlands
facility: Spaarne Ziekenhuis
city: Leiden
country: Netherlands
facility: LUMC
city: Rotterdam
country: Netherlands
facility: Maasstad ziekenhuis
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: NKI-AvL
name: Sjoerd Rodenhuis, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rodenhuis S, Mandjes IAM, Wesseling J, van de Vijver MJ, Peeters MTDFV, Sonke GS, Linn SC. A simple system for grading the response of breast cancer to neoadjuvant chemotherapy. Ann Oncol. 2010 Mar;21(3):481-487. doi: 10.1093/annonc/mdp348. Epub 2009 Aug 28.
citation: Miquel-Cases A, Retel VP, van Harten WH, Steuten LM. Decisions on Further Research for Predictive Biomarkers of High-Dose Alkylating Chemotherapy in Triple-Negative Breast Cancer: A Value of Information Analysis. Value Health. 2016 Jun;19(4):419-30. doi: 10.1016/j.jval.2016.01.015. Epub 2016 Apr 6.
citation: Miquel-Cases A, Steuten LM, Retel VP, van Harten WH. Early stage cost-effectiveness analysis of a BRCA1-like test to detect triple negative breast cancers responsive to high dose alkylating chemotherapy. Breast. 2015 Aug;24(4):397-405. doi: 10.1016/j.breast.2015.03.002. Epub 2015 Apr 28.