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…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint (HRD tumors):
Average Neoadjuvant Response Index (NRI) after intensified alkylating therapy
in comparison to that after *standard* neoadjuvant chemotherapy. The NRI
incorporates the frequently employed (and widely accepted) endpoint of
pathologic Complete Remission (pCR).
Primary endpoint (non-HRD tumors):
Average Neoadjuvant Response Index (NRI) of the *regimen switching* policy
(*standard treatment*) versus the conditional switching policy. This part of
the study will collect preliminary data required to plan for a larger
(adequately powered) study.
Secondary outcome
Secondary endpoint (HRD tumors):
Recurrence-free survival and overall survival after intensified alkylating
therapy in comparison to that after *standard* neoadjuvant chemotherapy.
Secondary endpoint (non-HRD tumors):
Recurrence-free survival and overall survival.
Background summary
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.
Study objective
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 design
Patients with triple-negative breast cancer of 2 cm or more in diameter and/or
with a clinically tumor-positive axilla will receive 3 courses of standard
preoperative chemotherapy with dose-dense Doxorubicin and Cyclophosphamide
(ddAC). Before and following these 3 courses, contrast-enhanced MRI studies of
the breast (CE-MRI) will be done, and each patient will be classified as either
having a *favorable response* or as having a *less-than favorable* response. In
addition, all tumors will be classified as having or not having HRD
characteristics. Patients with HRD tumors will be randomized to continue
treatment with either intensified alkylator therapy or with conventional
chemotherapy (3 x ddAC in case of a favorable response and 3 x Carboplatin /
Paclitaxel (CP) in case of a less-than-favorable response). Patients with
tumors lacking HRD will switch to CP in case of a less-than-favorable response
and will be randomized to continue with either ddAC or with CP in case of a
favorable response.
Tumors in which the HRD status cannot be determined for technical or other
reasons will be regarded as ' tumors without HRD' for all study purposes.
Intervention
All patients will recieve 3 cycles of dose dense AC
(doxorubicin-cyclophosphamide), given every 2 weeks with PEG-filgrastim
support. After this induction chemotherapy the MRI evaluation of the tumor will
be repeated en the rsult of the HRD analysis will be known.
Based on the MRI evaluation and the HRD result the continuation of the
treatment will be either 3 cycles of dose dense AC, 3 cycles of CP or 1 cycle
of dose dense AC followed by peripheral blood progenitor cell mobilisation and
harvest. After harvest patients will receive 2 cycles of intensified alkylating
chemotherapy (CTC) where each chemotherapy cycle is followed by peripheral
blood progenitor cell reinfusions to ensure and hasten bone marrow recovery
(See protocol for the schedule)
Patients who refuse randomization because they do not wish to undergo intensive
chemotherapy may be transfered to the non-HRD part of the study and are
eligible for the non-HRD randomization.
Study burden and risks
Patients who receive the intensified alkylating chemotherapy will receive 2
non-standard courses of chemotherapy (CTC) which are clearly more toxic than
the corresponding chemotherapy courses in the other arms. Each of the CTC
courses will take 3 weeks of recovery rather than 2, and 2 nights of hospital
stay per course versus nil in the conventional arm. Side effects such as nausea
and vomiting, fatique, allergic reactions, bone marrow suppression and
neutropenic fever are more frequent in the CTC arm. There may be a small risk
of toxic death, although this is probably (and considerably) below 1%.
Previous experience with an earlier CTC regimen (high-dose chemotherapy with
CTC) has shown a significant benefit for patients with HER2-negative breast
cancer when employed in the adjuvant setting. A meta-analysis of the Early
Breast Cancer Trialists' Collaborative Group has shown that high- dose
chemotherapy in the adjuvant treatment of breast cancer is associated with a
significant (albeit small) reduction in recurrence and in breast cancer death
rate. It is therefore reasonable to expect that patients in the CTC arm will
have increased disease-free cancer survival.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. 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.
2. Patients with 'locally advanced breast cancer' are consequently eligible,
including those with ipsilateral supraclavicular lymph node metastases.
3. 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).
4. 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.
5. 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).
6. Performance status: WHO 0 or I.
7. Informed consent.
8. Adequate bone marrow function (W.B.C. count > 3.0 x 109/l, platelets > 100 x
109/l).
9. 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).
10. Adequate renal function (creatinine clearance > 60 ml/min).
Exclusion criteria
1. Previous radiation therapy or chemotherapy.
2. 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.
3. Pregnancy or breast feeding must be excluded and patients must use adequate
contraceptive protection.
4. 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-015238-31-NL |
| ClinicalTrials.gov | NCT01057069,ClinicalTrials.gov |
| CCMO | NL29425.031.09 |