Breast CancerPhase 2/3NCT00448266
Intensified IAA With PBPC Support in Breast Tumors With Evidence of a HRD
A Phase 2/3 study testing Intensified Cyclophophamide, Carboplatin and Thiotepa and dose dense adriamycine and cyclophosphamide in people with Breast Cancer, run by The Netherlands Cancer Institute at 1 site in Netherlands.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 59 years, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Intensified Cyclophophamide, Carboplatin and Thiotepa and dose dense adriamycine and cyclophosphamide
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteNetherlands
- Study dates
- May 2007to Feb 2011
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 59 years
- Women only
- No healthy volunteers
- Adult
- Proven infiltrating breast cancer with either a primary tumor over 3 cm in size (clinical examination) or cytologically proven spread to the axillary lymph nodes.
- Stage II or stage III disease (revised AJCC staging system 2001). Patients with 'locally advanced breast cancer' are consequently eligible, including those with ipsilateral supraclavicular lymph node metastases. In stage II patients with T1N1 disease, N1 status must have been demonstrated by either fine needle aspiration from an axillary lymph node or by a metastasis of over 2 mm in diameter in a sentinel node biopsy. Stage IIA patients without lymph node metastases are only eligible if the tumor is over 3 cms in diameter.
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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.
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).
Read the 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
- Being tested
- Intensified Cyclophophamide, Carboplatin and Thiotepa, dose dense adriamycine and cyclophosphamide
- Keywords
- Breast cancer, high-dose chemotherapy, Homologous Recombination Deficiency, Alkylator therapy, Peripheral Blood Progenitor Cell Support
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Intensified Cyclophophamide, Carboplatin and ThiotepaDrug
2 courses of Intensified Cyclophophamide, Carboplatin and Thiotepa with PBPC support
dose dense adriamycine and cyclophosphamideDrug
dose dense adriamycine and cyclophosphamide, Q 2 weeks
| Study group | Role | What they receive |
|---|---|---|
| 2 | Experimental | 1 course ddAc, 2 courses IAA with PBPC support Receives: Drug: Intensified Cyclophophamide, Carboplatin and Thiotepa |
| 1 | Active comparator | 3 courses ddAC Receives: Drug: dose dense adriamycine and cyclophosphamide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of tumors with HRD (phase II part)
pCR rate
Secondary outcomes (3)
Comparison of extramedullary toxicity between the treatment arms.
Need for hospitalization.
Recurrence-free survival and overall survival (phase III part).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Mar 2007 (estimated)
- Study startMay 2007
- Primary completionFeb 2010
- Study completionFeb 2011
Why it stopped: Activation of a similar multicenter study for same population
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by The Netherlands Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Netherlands Cancer Institute
- Sponsor type
- University, hospital or other
- Investigators
- Sjoerd Rodenhuis, Principal investigator, The Netherlands Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00448266
- Sponsor's protocol ID
- N06IAA
- Status last verified
- Oct 2010
- First submitted
- 14 Mar 2007
- Last updated
- 22 Jan 2021
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT00448266
- Acronym / sponsor ID
- N06IAA
- Conditions
- Breast Cancer
- Keywords
- Breast cancer, high-dose chemotherapy, Homologous Recombination Deficiency, Alkylator therapy, Peripheral Blood Progenitor Cell Support
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Activation of a similar multicenter study for same population
- Enrolment
- 12 participants (actual)
- Lead sponsor
- The Netherlands Cancer InstituteUniversity, hospital or other
- Study start
- May 2007
- Primary completion
- Feb 2010 (actual)
- Study completion
- Feb 2011 (actual)
- First posted
- 16 Mar 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 2 | Experimental | Drug: Intensified Cyclophophamide, Carboplatin and Thiotepa1 course ddAc, 2 courses IAA with PBPC support |
| 1 | Active comparator | Drug: dose dense adriamycine and cyclophosphamide3 courses ddAC |
Who may qualify
- Ages
- 18 to 59 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Intensified Cyclophophamide, Carboplatin and Thiotepa2 courses of Intensified Cyclophophamide, Carboplatin and Thiotepa with PBPC support | Drug | 2 |
| dose dense adriamycine and cyclophosphamidedose dense adriamycine and cyclophosphamide, Q 2 weeks | Drug | 1 |
Primary outcome
Percentage of tumors with HRD (phase II part)
pCR rate
3 secondary outcomes
Comparison of extramedullary toxicity between the treatment arms.
Need for hospitalization.
Recurrence-free survival and overall survival (phase III part).
Results and safety
The study was stopped early (reason given: Activation of a similar multicenter study for same population). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jan 2021.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sjoerd Rodenhuis principal investigator
The Netherlands Cancer Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Intensified Cyclophophamide, Carboplatin and Thiotepa and dose dense adriamycine and cyclophosphamide in people with Breast Cancer, run by The Netherlands Cancer Institute at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 22 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Activation of a similar multicenter study for same population). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of tumors with HRD (phase II part). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jan 2021.