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

Primary Purpose

Breast Cancer

Status
Active
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Carboplatin and Paclitaxel
Doxorubicin, cyclophosphamide
Doxorubicin, cyclophosphamide, carboplatin, thiotepa, cyclophosphamide
Sponsored by
The Netherlands Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring Neo adjuvant, Triple negative, primary tumor over 2 cm and/or positive lymphnodes

Eligibility Criteria

18 Years - 59 Years (Adult)All SexesDoes not accept 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

Sites / Locations

  • Medisch Centrum Alkmaar
  • NKI-AVL
  • OLVG
  • Reinier de Graaf Groep
  • Medisch Centrum Haaglanden
  • Deventer Ziekenhuis
  • Albert Schweitzer ziekenhuis
  • Ziekenhuis Gelderse Vallei
  • Kennemer Gasthuis
  • Atrium Medisch Centrum Parkstad
  • Spaarne Ziekenhuis
  • LUMC
  • Maasstad ziekenhuis
  • Isala Klinieken

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

HRD; 1x ddAC, 2x tCTC

HRD; 3x CP

non-HRD;3x CP

non-HRD; response; 3x ddAC

non-HRD; response; 3x CP

Arm Description

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.

HRD tumors; any response to 3x ddAC; 3 courses of CP

non-HRD tumors; unfavourable response to 3x ddAC; 3 courses of Carboplatin and Paclitaxel

non-HRD tumors; favourable response to 3x ddAC; 3 more courses of ddAC

non-HRD tumors; favourable response to 3x ddAC; 3 courses of Carboplatin and Paclitaxel

Outcomes

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)

Secondary Outcome Measures

Recurrence-free survival and overall survival.

Full Information

First Posted
January 26, 2010
Last Updated
October 11, 2022
Sponsor
The Netherlands Cancer Institute
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1. Study Identification

Unique Protocol Identification Number
NCT01057069
Brief Title
Neo Adjuvant Chemotherapy in Triple Negative Breast Cancer
Acronym
neo-TN
Official Title
Randomized Phase II/III Study of Individualized Neoadjuvant Chemotherapy in ' Triple Negative' Breast Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 2010 (Actual)
Primary Completion Date
June 2023 (Anticipated)
Study Completion Date
December 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Netherlands Cancer Institute

4. Oversight

Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer
Keywords
Neo adjuvant, Triple negative, primary tumor over 2 cm and/or positive lymphnodes

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
310 (Actual)

8. Arms, Groups, and Interventions

Arm Title
HRD; 1x ddAC, 2x tCTC
Arm Type
Experimental
Arm Description
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.
Arm Title
HRD; 3x CP
Arm Type
Active Comparator
Arm Description
HRD tumors; any response to 3x ddAC; 3 courses of CP
Arm Title
non-HRD;3x CP
Arm Type
Active Comparator
Arm Description
non-HRD tumors; unfavourable response to 3x ddAC; 3 courses of Carboplatin and Paclitaxel
Arm Title
non-HRD; response; 3x ddAC
Arm Type
Active Comparator
Arm Description
non-HRD tumors; favourable response to 3x ddAC; 3 more courses of ddAC
Arm Title
non-HRD; response; 3x CP
Arm Type
Active Comparator
Arm Description
non-HRD tumors; favourable response to 3x ddAC; 3 courses of Carboplatin and Paclitaxel
Intervention Type
Drug
Intervention Name(s)
Carboplatin and Paclitaxel
Other Intervention Name(s)
Carboplatin, Paclitaxel
Intervention Description
Carboplatin AUC = 6, Q 3 weeks, 3 courses Paclitaxel 80 mg/m2, weekly, 9 administrations
Intervention Type
Drug
Intervention Name(s)
Doxorubicin, cyclophosphamide
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Doxorubicin, cyclophosphamide, carboplatin, thiotepa, cyclophosphamide
Intervention Description
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.
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
Recurrence-free survival and overall survival.
Time Frame
every year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
59 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sjoerd Rodenhuis, MD
Organizational Affiliation
NKI-AvL
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medisch Centrum Alkmaar
City
Alkmaar
ZIP/Postal Code
1815 JD
Country
Netherlands
Facility Name
NKI-AVL
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands
Facility Name
OLVG
City
Amsterdam
ZIP/Postal Code
1090 HM
Country
Netherlands
Facility Name
Reinier de Graaf Groep
City
Delft
ZIP/Postal Code
2625 AD
Country
Netherlands
Facility Name
Medisch Centrum Haaglanden
City
Den Haag
ZIP/Postal Code
2501 CK
Country
Netherlands
Facility Name
Deventer Ziekenhuis
City
Deventer
ZIP/Postal Code
7400 GC
Country
Netherlands
Facility Name
Albert Schweitzer ziekenhuis
City
Dordrecht
Country
Netherlands
Facility Name
Ziekenhuis Gelderse Vallei
City
Ede
Country
Netherlands
Facility Name
Kennemer Gasthuis
City
Haarlem
ZIP/Postal Code
2000AK
Country
Netherlands
Facility Name
Atrium Medisch Centrum Parkstad
City
Heerlen
ZIP/Postal Code
6401 CX
Country
Netherlands
Facility Name
Spaarne Ziekenhuis
City
Hoofddorp
ZIP/Postal Code
2130 AT
Country
Netherlands
Facility Name
LUMC
City
Leiden
ZIP/Postal Code
2300 RC
Country
Netherlands
Facility Name
Maasstad ziekenhuis
City
Rotterdam
ZIP/Postal Code
3007 AC
Country
Netherlands
Facility Name
Isala Klinieken
City
Zwolle
ZIP/Postal Code
8000 GK
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
19717533
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.
Results Reference
background
PubMed Identifier
27325334
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.
Results Reference
derived
PubMed Identifier
25937263
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.
Results Reference
derived

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Neo Adjuvant Chemotherapy in Triple Negative Breast Cancer

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