Neo Adjuvant Chemotherapy in Triple Negative Breast Cancer (neo-TN)
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| ClinicalTrials.gov Identifier: NCT01057069 |
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Recruitment Status :
Active, not recruiting
First Posted : January 27, 2010
Last Update Posted : January 22, 2021
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| 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 |
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 (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 : | June 2021 |
| Estimated Study Completion Date : | December 2029 |
| Arm | Intervention/treatment |
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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.
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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. |
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Active Comparator: HRD; 3x CP
HRD tumors; any response to 3x ddAC; 3 courses of CP
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Drug: Carboplatin and Paclitaxel
Carboplatin AUC = 6, Q 3 weeks, 3 courses Paclitaxel 80 mg/m2, weekly, 9 administrations
Other Names:
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Active Comparator: non-HRD;3x CP
non-HRD tumors; unfavourable response to 3x ddAC; 3 courses of Carboplatin and Paclitaxel
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Drug: Carboplatin and Paclitaxel
Carboplatin AUC = 6, Q 3 weeks, 3 courses Paclitaxel 80 mg/m2, weekly, 9 administrations
Other Names:
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Active Comparator: non-HRD; response; 3x ddAC
non-HRD tumors; favourable response to 3x ddAC; 3 more courses of ddAC
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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. |
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Active Comparator: non-HRD; response; 3x CP
non-HRD tumors; favourable response to 3x ddAC; 3 courses of Carboplatin and Paclitaxel
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Drug: Carboplatin and Paclitaxel
Carboplatin AUC = 6, Q 3 weeks, 3 courses Paclitaxel 80 mg/m2, weekly, 9 administrations
Other Names:
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- 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 ]
- Recurrence-free survival and overall survival. [ Time Frame: every year ]
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| Ages Eligible for Study: | 18 Years to 59 Years (Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
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
| 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 | |
| Principal Investigator: | Sjoerd Rodenhuis, MD | NKI-AvL |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| 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: | January 22, 2021 |
| Last Verified: | January 2021 |
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Neo adjuvant Triple negative primary tumor over 2 cm and/or positive lymphnodes |
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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 |