Intensified IAA With PBPC Support in Breast Tumors With Evidence of a HRD
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|ClinicalTrials.gov Identifier: NCT00448266|
Recruitment Status : Terminated (Activation of a similar multicenter study for same population)
First Posted : March 16, 2007
Last Update Posted : October 26, 2010
|Condition or disease||Intervention/treatment||Phase|
|Breast Cancer||Drug: Intensified Cyclophophamide, Carboplatin and Thiotepa Drug: dose dense adriamycine and cyclophosphamide||Phase 2 Phase 3|
This phase II/III trial will investigate the ability of chemotherapy with 'Intensified Alkylating Agents' (IAA) to achieve a high pathological complete response (pCR) rate when employed in the preoperative chemotherapy of breast cancer with evidence of a Homologous Recombination Deficiency (HRD).
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 agensts (such as cyclophosphamide, thiotepa or carboplatin). Alternative DNA repair mechanisms are available in case of HRD, but these induce DNA mutations and chromosome aberrations and thus give rise to major genetic instability. HRD is a consequence of inactivation of BRCA-1 or BRCA-2, but 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 up to 30% of sporadic breast cancers.
Patients under 60 years of age with intermediate or high risk breast cancer, whose tumors show evidence of HRD and do not contain a HER2/neu amplification are eligible. All patients will receive 3 courses of standard preoperative chemotherapy with dose-dense Doxorubicin and Cyclophosphamide (ddAC). Patients with a favorable response according to repeat MRI, will be randomized to undergo either a further 3 courses of ddAC prior to local therapy and endocrine adjuvant therapy (standard arm) or 1 course of ddAC followed by peripheral blood progenitor cell (PBPC) harvest and 2 courses of IAA with Cyclophosphamide (3 g/m2), thiotepa (240 mg/m2) and carboplatin (800 mg/m2) (experimental arm). IAA is administered during a 1 or 2-night hospital stay, the bone marrow aplasia phase is managed on an out-patient basis and the second course will be started on day 22 of the first one. Patients who do not achieve a favorable response as determined by their MRI after 3 cycles of ddAC will be offered treatment according to the experimental arm as salvage therapy.
The primary endpoint of the study is the pCR rate of the breast. The phase II part of the study will serve to further develop the pathology tests for HRD and to estimate the pCR rates of HRD-breast cancers to both the conventional and the experimental treatments. The phase III part of the study will be initiated when the test for HRD is sufficiently standardized to be employed in a multi-center setting and when the preliminary information collected at that point continues to be consistent with the assumption that HRD renders tumor cells highly sensitive to IAA. If breast cancer is indeed exquisitely sensitive to IAA, the pCR rate in the experimental arm could rise from 10% to 30% in luminal tumor types and from 50% to 80% in basal-like tumor types. For 80% power to detect such a response-improvement, 186 patients with HRD must be included in the phase III part of the study.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||237 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Randomized Phase II/III Study of Intensified Alkylating Agent Chemotherapy With Peripheral Blood Progenitor Cell Support in the Preoperative Chemotherapy of Breast Tumors That Are Deficient for Homologous Recombination.|
|Study Start Date :||May 2007|
|Actual Primary Completion Date :||February 2010|
1 course ddAc, 2 courses IAA with PBPC support
Drug: Intensified Cyclophophamide, Carboplatin and Thiotepa
2 courses of Intensified Cyclophophamide, Carboplatin and Thiotepa with PBPC support
Active Comparator: 1
3 courses ddAC
Drug: dose dense adriamycine and cyclophosphamide
dose dense adriamycine and cyclophosphamide, Q 2 weeks
- Percentage of tumors with HRD (phase II part)
- pCR rate
- Comparison of extramedullary toxicity between the treatment arms.
- Need for hospitalization.
- Recurrence-free survival and overall survival (phase III part).
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): NCT00448266
|Amsterdam, Netherlands, 1066 CX|
|Principal Investigator:||Sjoerd Rodenhuis||The Netherlands Cancer Institute|