Ignite Creation Date:
2024-05-05 @ 5:22 PM
Last Modification Date:
2024-10-26 @ 9:31 AM
Study NCT ID:
NCT00448266
Status:
TERMINATED
Last Update Posted:
2021-01-22
First Post:
2007-03-14
Brief Title:
Intensified IAA With PBPC Support in Breast Tumors With Evidence of a HRD
Sponsor:
The Netherlands Cancer Institute
Organization:
The Netherlands Cancer Institute
Study Overview
Official Title:
Randomized Phase IIIII 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
Status:
TERMINATED
Status Verified Date:
2010-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Activation of a similar multicenter study for same population
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This phase IIIII trial will investigate the ability of chemotherapy with Intensified Aklylating 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 Recomination Deficiency HRD
Detailed Description:
This phase IIIII 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 HER2neu 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 gm2 thiotepa 240 mgm2 and carboplatin 800 mgm2 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
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 HER2neu 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 gm2 thiotepa 240 mgm2 and carboplatin 800 mgm2 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None