Neo Adjuvant Chemotherapy in Triple Negative Breast Cancer

Breast Cancer Clinical Trial

— neo-TN  

Official title:

Randomized Phase II/III Study of Individualized Neoadjuvant Chemotherapy in ' Triple Negative' Breast Tumors

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01057069
• Other study ID #: M09TNM
• Secondary ID: 2009-015238-31
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: January 2010
• Est. completion date: December 2029

Study information

• Verified date: October 2022
• Source: The Netherlands Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 310
• Est. completion date: December 2029
• Est. primary completion date: June 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 59 Years

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Carboplatin and Paclitaxel
Carboplatin AUC = 6, Q 3 weeks, 3 courses Paclitaxel 80 mg/m2, weekly, 9 administrations
• Doxorubicin, cyclophosphamide
Two-weekly administrations of 600 mg/m2 cyclophosphamide and 60 mg/m2 doxorubicin PEG-filgrastim (Neulasta(r)) will be administered on the day following chemotherapy.
• Doxorubicin, cyclophosphamide, carboplatin, thiotepa, cyclophosphamide
One course of of 600 mg/m2 cyclophosphamide and 60 mg/m2 doxorubicin. PEG-filgrastim (Neulasta(r)) will be administered on the day following chemotherapy. This course is followed by Peripheral Blood Progenitor Cell (PBPC) harvest and tandem intermediate-dose alkylating therapy (miniCTC, carboplatin 800 mg/m2, thiotepa 250 mg/m2, and cyclophosphamide 3000 mg/m2) with PBPC-reinfusion.

Locations

Country	Name	City	State
Netherlands	Medisch Centrum Alkmaar	Alkmaar
Netherlands	NKI-AVL	Amsterdam
Netherlands	OLVG	Amsterdam
Netherlands	Reinier de Graaf Groep	Delft
Netherlands	Medisch Centrum Haaglanden	Den Haag
Netherlands	Deventer Ziekenhuis	Deventer
Netherlands	Albert Schweitzer ziekenhuis	Dordrecht
Netherlands	Ziekenhuis Gelderse Vallei	Ede
Netherlands	Kennemer Gasthuis	Haarlem
Netherlands	Atrium Medisch Centrum Parkstad	Heerlen
Netherlands	Spaarne Ziekenhuis	Hoofddorp
Netherlands	LUMC	Leiden
Netherlands	Maasstad ziekenhuis	Rotterdam
Netherlands	Isala Klinieken	Zwolle

Sponsors (1)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)		end of neo adjuvant chemotherapy
Secondary	Recurrence-free survival and overall survival.		every year