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

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ClinicalTrials.gov Identifier: NCT01057069
Recruitment Status : Active, not recruiting
First Posted : January 27, 2010
Last Update Posted : April 17, 2017
Sponsor:
Information provided by (Responsible Party):
The Netherlands Cancer Institute

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
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 : January 2010
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2029

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arms and Interventions
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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
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Primary Outcome Measures :
  1. 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 Measures :
  1. Recurrence-free survival and overall survival. [ Time Frame: every year ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 59 Years   (Adult)
Sexes Eligible for Study:   All
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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01057069


Locations
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Netherlands
Medisch Centrum Alkmaar
Alkmaar, Netherlands, 1815 JD
NKI-AVL
Amsterdam, Netherlands, 1066 CX
OLVG
Amsterdam, Netherlands, 1090 HM
Reinier de Graaf Groep
Delft, Netherlands, 2625 AD
Medisch Centrum Haaglanden
Den Haag, Netherlands, 2501 CK
Deventer Ziekenhuis
Deventer, Netherlands, 7400 GC
Albert Schweitzer ziekenhuis
Dordrecht, Netherlands
Ziekenhuis Gelderse Vallei
Ede, Netherlands
Kennemer Gasthuis
Haarlem, Netherlands, 2000AK
Atrium Medisch Centrum Parkstad
Heerlen, Netherlands, 6401 CX
Spaarne Ziekenhuis
Hoofddorp, Netherlands, 2130 AT
LUMC
Leiden, Netherlands, 2300 RC
Maasstad ziekenhuis
Rotterdam, Netherlands, 3007 AC
Isala Klinieken
Zwolle, Netherlands, 8000 GK
Sponsors and Collaborators
The Netherlands Cancer Institute
Investigators
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Principal Investigator: Sjoerd Rodenhuis, MD NKI-AvL
More Information
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Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT01057069    
Other Study ID Numbers: M09TNM
2009-015238-31 ( EudraCT Number )
First Posted: January 27, 2010    Key Record Dates
Last Update Posted: April 17, 2017
Last Verified: April 2017
Keywords provided by The Netherlands Cancer Institute:
Neo adjuvant
Triple negative
primary tumor over 2 cm and/or positive lymphnodes
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Cyclophosphamide
Carboplatin
Doxorubicin
Liposomal doxorubicin
Thiotepa
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
 Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors