Neo Adjuvant Chemotherapy in Triple Negative Breast Cancer (neo-TN)

October 11, 2022 updated by: The Netherlands Cancer Institute

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

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

310

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Alkmaar, Netherlands, 1815 JD
        • Medisch Centrum Alkmaar
      • Amsterdam, Netherlands, 1090 HM
        • OLVG
      • Amsterdam, Netherlands, 1066 CX
        • NKI-AVL
      • Delft, Netherlands, 2625 AD
        • Reinier de Graaf Groep
      • Den Haag, Netherlands, 2501 CK
        • Medisch Centrum Haaglanden
      • Deventer, Netherlands, 7400 GC
        • Deventer Ziekenhuis
      • Dordrecht, Netherlands
        • Albert Schweitzer Ziekenhuis
      • Ede, Netherlands
        • Ziekenhuis Gelderse Vallei
      • Haarlem, Netherlands, 2000AK
        • Kennemer Gasthuis
      • Heerlen, Netherlands, 6401 CX
        • Atrium Medisch Centrum Parkstad
      • Hoofddorp, Netherlands, 2130 AT
        • Spaarne Ziekenhuis
      • Leiden, Netherlands, 2300 RC
        • LUMC
      • Rotterdam, Netherlands, 3007 AC
        • Maasstad Ziekenhuis
      • Zwolle, Netherlands, 8000 GK
        • Isala Klinieken

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 59 years (ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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)
Time Frame: end of neo adjuvant chemotherapy
end of neo adjuvant chemotherapy

Secondary Outcome Measures

Outcome Measure
Time Frame
Recurrence-free survival and overall survival.
Time Frame: every year
every year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Netherlands Cancer Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

January 1, 2010

Primary Completion (ANTICIPATED)

June 1, 2023

Study Completion (ANTICIPATED)

December 1, 2029

Study Registration Dates

First Submitted

January 26, 2010

First Submitted That Met QC Criteria

January 26, 2010

First Posted (ESTIMATE)

January 27, 2010

Study Record Updates

Last Update Posted (ACTUAL)

October 12, 2022

Last Update Submitted That Met QC Criteria

October 11, 2022

Last Verified

October 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • M09TNM
  • 2009-015238-31 (EUDRACT_NUMBER)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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