neo-TN: Neo Adjuvant Chemotherapy in Triple Negative Breast Cancer

Sponsor

The Netherlands Cancer Institute (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01057069

Collaborator

(none)

310

Enrollment

Locations

Arms

239

Duration (Months)

22.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Carboplatin and Paclitaxel Drug: Doxorubicin, cyclophosphamide Drug: Doxorubicin, cyclophosphamide, carboplatin, thiotepa, cyclophosphamide	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

310 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jan 1, 2010

Anticipated Primary Completion Date :

Jun 1, 2022

Anticipated Study Completion Date :

Dec 1, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: HRD; 1x ddAC, 2x tCTC HRD positive tumors; irrespective of response; - a fourth course of AC 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.	Drug: 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.
Active Comparator: HRD; 3x CP HRD tumors; any response to 3x ddAC; 3 courses of CP	Drug: Carboplatin and Paclitaxel Carboplatin AUC = 6, Q 3 weeks, 3 courses Paclitaxel 80 mg/m2, weekly, 9 administrations Other Names: Carboplatin Paclitaxel
Active Comparator: non-HRD;3x CP non-HRD tumors; unfavourable response to 3x ddAC; 3 courses of Carboplatin and Paclitaxel	Drug: Carboplatin and Paclitaxel Carboplatin AUC = 6, Q 3 weeks, 3 courses Paclitaxel 80 mg/m2, weekly, 9 administrations Other Names: Carboplatin Paclitaxel
Active Comparator: non-HRD; response; 3x ddAC non-HRD tumors; favourable response to 3x ddAC; 3 more courses of ddAC	Drug: 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.
Active Comparator: non-HRD; response; 3x CP non-HRD tumors; favourable response to 3x ddAC; 3 courses of Carboplatin and Paclitaxel	Drug: Carboplatin and Paclitaxel Carboplatin AUC = 6, Q 3 weeks, 3 courses Paclitaxel 80 mg/m2, weekly, 9 administrations Other Names: Carboplatin Paclitaxel

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

Recurrence-free survival and overall survival. [every year]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 59 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Medisch Centrum Alkmaar	Alkmaar	Netherlands	1815 JD
2	NKI-AVL	Amsterdam	Netherlands	1066 CX
3	OLVG	Amsterdam	Netherlands	1090 HM
4	Reinier de Graaf Groep	Delft	Netherlands	2625 AD
5	Medisch Centrum Haaglanden	Den Haag	Netherlands	2501 CK
6	Deventer Ziekenhuis	Deventer	Netherlands	7400 GC
7	Albert Schweitzer ziekenhuis	Dordrecht	Netherlands
8	Ziekenhuis Gelderse Vallei	Ede	Netherlands
9	Kennemer Gasthuis	Haarlem	Netherlands	2000AK
10	Atrium Medisch Centrum Parkstad	Heerlen	Netherlands	6401 CX
11	Spaarne Ziekenhuis	Hoofddorp	Netherlands	2130 AT
12	LUMC	Leiden	Netherlands	2300 RC
13	Maasstad ziekenhuis	Rotterdam	Netherlands	3007 AC
14	Isala Klinieken	Zwolle	Netherlands	8000 GK