Intensified IAA With PBPC Support in Breast Tumors With Evidence of a HRD

NCT ID: NCT00448266

Last Updated: 2021-01-22

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-05-31
• Study Completion Date: 2011-02-28

Brief Summary

This phase II/III 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 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.

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

2

1 course ddAc, 2 courses IAA with PBPC support

Group Type: EXPERIMENTAL

Intensified Cyclophophamide, Carboplatin and Thiotepa

Intervention Type: DRUG

2 courses of Intensified Cyclophophamide, Carboplatin and Thiotepa with PBPC support

1

3 courses ddAC

Group Type: ACTIVE_COMPARATOR

dose dense adriamycine and cyclophosphamide

Intervention Type: DRUG

dose dense adriamycine and cyclophosphamide, Q 2 weeks

Interventions

Intensified Cyclophophamide, Carboplatin and Thiotepa

2 courses of Intensified Cyclophophamide, Carboplatin and Thiotepa with PBPC support

Intervention Type: DRUG

dose dense adriamycine and cyclophosphamide

dose dense adriamycine and cyclophosphamide, Q 2 weeks

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• High-risk disease, according to Adjuvant Online version 8.0: the expected 10-year recurrence-free survival without systemic adjuvant therapy according to this program must be 60% or lower.
• 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 test positive for homologous recombination deficiency, as defined by the test of the pathology department of the NKI-AVL (M.J. van de Vijver).
• Age 18 to 59 years; patients older than 59 years may be included when considered 'biologically 59 years or younger'.
• Performance status: WHO 0 or I.
• No previous radiation therapy or chemotherapy.
• No 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.
• 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).
• Adequate renal function (creatinine clearance > 60 ml/min).
• Radionuclide ejection fraction > 0.50.
• Pregnancy or breast feeding must be excluded and patients must use adequate contraceptive protection.
• No 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.
• At randomization, hormone receptor status and HER2/neu receptor status must be known. In case of 2+ HER2/neu expression by immunohistochemistry, FISH or CISH examination is required.
• Informed consent.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 59 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

The Netherlands Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

NKI-AVL

Principal Investigators

Sjoerd Rodenhuis

Role: PRINCIPAL_INVESTIGATOR

The Netherlands Cancer Institute

Locations

NKI-AVL

Amsterdam, , Netherlands

Countries

Netherlands

Other Identifiers

N06IAA

Identifier Type: -

Identifier Source: org_study_id