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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by The Netherlands Cancer Institute
Sponsor:
Information provided by (Responsible Party):
The Netherlands Cancer Institute
ClinicalTrials.gov Identifier:
NCT01057069
First received: January 26, 2010
Last updated: November 18, 2013
Last verified: November 2013
  Purpose

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 Intervention Phase
Breast Cancer
Drug: Docetaxel, Capecitabine
Drug: Doxorubicin, cyclophosphamide
Drug: Doxorubicin, cyclophosphamide, carboplatin, thiotepa, cyclophosphamide
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II/III Study of Individualized Neoadjuvant Chemotherapy in ' Triple Negative' Breast Tumors

Resource links provided by NLM:


Further study details as provided by The Netherlands Cancer Institute:

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) [ Time Frame: end of neo adjuvant chemotherapy ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Recurrence-free survival and overall survival. [ Time Frame: every year ] [ Designated as safety issue: No ]

Estimated Enrollment: 270
Study Start Date: January 2010
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 ddAC
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: HRD; 3x CD
HRD tumors; unfavourable response to 3x ddAC; 3 courses of Docetaxel and Capecitabine
Drug: Docetaxel, Capecitabine
Docetaxel 75 mg/m2 on day 1 and Capecitabine 1000 mg/m2 twice daily on days 1-14, q 3 weeks
Active Comparator: non-HRD;3x CD
non-HRD tumors; unfavourable response to 3x ddAC; 3 courses of Docetaxel and Capecitabine
Drug: Docetaxel, Capecitabine
Docetaxel 75 mg/m2 on day 1 and Capecitabine 1000 mg/m2 twice daily on days 1-14, q 3 weeks
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 CD
non-HRD tumors; favourable response to 3x ddAC; 3 courses of Docetaxel and Capecitabine
Drug: Docetaxel, Capecitabine
Docetaxel 75 mg/m2 on day 1 and Capecitabine 1000 mg/m2 twice daily on days 1-14, q 3 weeks

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

Ages Eligible for Study:   18 Years to 59 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01057069

Contacts
Contact: Sjoerd Rodenhuis, Prof. MD +31205129111 ext 2870 s.rodenhuis@nki.nl

Locations
Netherlands
Medisch Centrum Alkmaar Recruiting
Alkmaar, Netherlands, 1815 JD
Contact: Carolina Smorenburg, MD         
Principal Investigator: Carolina Smorenburg, MD         
NKI-AVL Recruiting
Amsterdam, Netherlands, 1066 CX
Contact: Sjoerd Rodenhuis, Prof. MD         
Principal Investigator: Sjoerd Rodenhuis, Prof. MD         
OLVG Recruiting
Amsterdam, Netherlands, 1090 HM
Contact: O Leeksma, MD         
Principal Investigator: O C Leeksma, MD         
Reinier de Graaf Groep Recruiting
Delft, Netherlands, 2625 AD
Contact: M Bos, MD         
Principal Investigator: M Bos, MD         
Medisch Centrum Haaglanden Not yet recruiting
Den Haag, Netherlands, 2501 CK
Contact: Rianne Oosterkamp, MD         
Principal Investigator: Rianne Oosterkamp, MD         
Deventer Ziekenhuis Recruiting
Deventer, Netherlands, 7400 GC
Contact: Alex Imholz, MD         
Principal Investigator: Alex Imholz, MD         
Kennemer Gasthuis Not yet recruiting
Haarlem, Netherlands, 2000AK
Contact: Philomeen Kuijer, MD         
Principal Investigator: Philomeen Kuijer, MD         
Atrium Medisch Centrum Parkstad Recruiting
Heerlen, Netherlands, 6401 CX
Contact: Jacob Wals, MD         
Principal Investigator: Jacob Wals, MD         
Spaarne Ziekenhuis Recruiting
Hoofddorp, Netherlands, 2130 AT
Contact: Jolanda Schrama, MD         
Principal Investigator: Jolanda Schrama, MD         
LUMC Recruiting
Leiden, Netherlands, 2300 RC
Contact: Judith Kroep, MD         
Principal Investigator: Judith Kroep, MD         
Maasstad ziekenhuis Active, not recruiting
Rotterdam, Netherlands, 3007 AC
Isala Klinieken Recruiting
Zwolle, Netherlands, 8000 GK
Contact: Aafke H Honkoop, MD       h.a.honkoop@isala.nl   
Principal Investigator: Aafke H Honkoop, MD         
Sponsors and Collaborators
The Netherlands Cancer Institute
Investigators
Principal Investigator: Sjoerd Rodenhuis, MD NKI-AvL
  More Information

Publications:
Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT01057069     History of Changes
Other Study ID Numbers: M09TNM, 2009-015238-31
Study First Received: January 26, 2010
Last Updated: November 18, 2013
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by The Netherlands Cancer Institute:
Neo adjuvant
Triple negative
primary tumor over 2 cm and/or positive lymphnodes

Additional relevant MeSH terms:
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
Thiotepa
Liposomal doxorubicin
Docetaxel
Capecitabine
Doxorubicin
Carboplatin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Tubulin Modulators
Antimitotic Agents

ClinicalTrials.gov processed this record on August 25, 2014