Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT00496795 |
| Other study ID # |
Ethics committee 079.06 |
| Secondary ID |
NSD 1491814918 |
| Status |
Active, not recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
September 2007 |
| Est. completion date |
May 2026 |
Study information
| Verified date |
June 2022 |
| Source |
University of Bergen |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Molecular markers predicting response to dose dense chemotherapy with epirubicin and
docetaxel in sequence for locally advanced breast cancer
Protocol summary.
Principal Investigator Hans P. Eikesdal, Professor, Dept. of Oncology, Haukeland University
Hospital & Dept. of Clinical Science, University of Bergen
Project leader: Professor Per Eystein Lønning, Dept. of Oncology, Haukeland University
Hospital & Dept. of Clinical Science, University of Bergen
Collaborators. Dept of Surgery - Responsible: Turid Aas, Consultant Surgeon
Participants. Dept of Oncology Stephanie Geisler, Consultant Oncologist Jurgen Geisler,
Consultant Oncologist
Type of Study Phase II, Translational research
Scientific aims: Addressing factors predicting response to dose intensive epirubicin followed
by docetaxel sequential therapy
Treatment regimen: epirubicin 60 mg/m2 on a 2 weekly basis x 4 followed by docetaxel 100
mg/m2 2-weekly x 4.
Patients: Breast cancer patients below 65 years of age suffering from large (>4 cm largest
diameter, non-inflammatory and / or N2-N3) primary breast cancer.
.
Clinical aim: Assessing responsiveness to this dose intensive regimen.
Number of patients to be enrolled: 60 - 100
Description:
Aim The scientific aim of this study is to explore mechanisms of resistance to chemotherapy
in breast cancer. To do so, we explore molecular parameters predicting response to
chemotherapy administered prior to local therapy in large, primary breast cancers.
Background Neoadjuvant (primary medical) therapy has got wide acceptance as primary therapy
in breast cancer. In addition, this treatment provides an optimal setting studying the
mechanisms of drug resistance in human cancers.
Considering chemotherapy for primary breast cancer treatment, contemporary trend has been to
treat these tumors more aggressively. High-dose therapy involving stem cell support is not
advocated, as this has not been shown to improve long-term survival in early breast cancer.
However, the attitude in general has been toward a more aggressive approach within the frame
of "conventional" therapy.
Based on theoretical modeling, an alternative approach, "dose-dense" therapy, has been
advocated. Recently, that concept was brought to the test in two adjuvant trials. Thus,
Citron et al applying doxorubicin, paclitaxel and cyclofosfamide revealed an improved outcome
for dose-dense (2-weekly) administration compared to regular 3-weekly scheduling. In
contrast, the German GEPARDUO study reported doxorubicin plus cyclophosphamide and docetaxel,
given in sequence on a 3-weekly basis (8 cycles), to be superior to doxorubicin and docetaxel
given in concert on a 2-weekly basis for 4 cycles. However, the doses administered
(doxorubicin 50 versus 60 mg/m2; docetaxel 75 versus 100 mg/m2) was unequal, meaning total
drug dose exposure differed between the two treatment arms. While more data are warranted, a
reasonable interpretation of available data suggest sequential administration of different
compounds in a dose-density approach to be a suitable regimen provided adequate total doses
are given.
Rationale for regimen Considering anthracyclines, most regimens today combine either
epirubicin or doxorubicin in concert with 5-fluorouracil and cyclophosphamide. However, based
on the evidence in the literature, it is not clear what the contribution of 5-FU or
cyclophosphamide is to the effectiveness of such regimens, in particular not when a taxane is
administered in sequence or concert. Thus, the NSABP-group has abandoned use of 5-FU from
their adjuvant regimen. Considering cyclophosphamide, this compound seems to add to the
carcinogenetic effect of anthracyclines enhancing the risk of secondary leukemia, while the
contribution to the antitumor efficacy of the regimen remains uncertain. The taxanes are
known to have significant antitumor effects in breast cancer when administered as
monotherapy. Considering docetaxel, the dose generally advocated for monotherapy is 100
mg/m2, while a dose of 75mg/m2 is recommended for combined use. Thus, the potential exists
that the dose for combined use may be sub-optimal in some patients.
Justification for a sequential approach is further supported by studies in metastatic breast
cancer.
Scientific aims While many mechanisms of resistance have been identified in experimental
systems, we have little knowledge what may be the cause of drug resistance in human cancers.
The factors so far identified that have been found associated with resistance to chemotherapy
in breast cancer are amplification of HER-2 / Topo-II and mutations affecting TP53.
Recently, several groups have explored responsiveness to chemotherapy using mRNA microarrays.
While these studies consistently identified different gene profiles correlating to
responsiveness to different regimens, the predictive value was too low for clinical
application. Moreover, the results did not add to our understanding of the biological
mechanisms causing drug resistance. In contrast, studies exploring different forms of cancer
have started to reveal specific gene alterations, in particular affecting pathways of DNA
damage repair or apoptosis in relation to drug resistance. Thus, our primary aim is to
explore potential gene disturbances based on functional hypotheses.
A major issue identifying mechanisms of drug resistance is to explore different compounds on
a monodrug basis. Clinically, the major reason for combining or administering sequentially an
anthracycline and a taxane is the efficacy of each compound combined with a significant lack
of cross-resistance. Administered as a combined schedule, this limits the possibility of
identifying the mechanisms of resistance / sensitivity to each compound individually.
Provided that a sequential regimen provides the same efficacy as a combined schedule, such an
approach is justified ethically. Thus, for a patient given 2 and 3 drugs in concert, the
potential may be they respond to one drug only, while having the toxicity of the other
compounds. In case of non-responsiveness to a single compound, this may be exchanged for an
alternative treatment option. This contrasts the possibilities provided in the adjuvant
setting. In adjuvant therapy, there is no way by which we may assess the response to
individual drugs; thus the different compounds have to administer in concert.
Based on what is said above, we consider sequential dose-dense treatment using epirubicin and
docetaxel sequentially to be a feasible treatment option.
Treatment regimen Each patient will receive 4 cycles of epirubicin 60 mg/m2 given at 2 weekly
intervals together with G-CSF. Thereafter, docetaxel 100 mg/ m2 will be given at 2 weekly
intervals for 4 cycles. Patients revealing positivity for HER2 status will have trastuzumab
(Herceptin) implemented together with docetaxel but not during anthracycline treatment.
Staging at baseline
After given informed consent, patients will be staged as follows:
- MRI of both breasts
- Chest X-ray
- Liver ultrasound (in case metastases are suspected or verified; to be followed by CT and
/ or MRI confirmation)
- Skeletal scintigram. Any positive findings to be confirmed by subsequent X-ray / CT and
/ or MRI
- ECG
- LVEF (Left Ventricular Ejection Fraction)
Response evaluation Response will be evaluated based on clinical examination and MRI, each
assessment to be done separately.
Clinical examination will be performed prior to commencing therapy (before surgical biopsy)
and subsequently at 4, 6 and 8 weeks on therapy. Response will be classified according to the
common "RECIST" criteria. An important exception is to be made. As argued in a previous
protocol, we consider the RECIST definition of "progressive disease" as a 20% increase in the
sum of the largest tumor diameters to be too liberal with respect to large primary tumors.
Based on experience in our clinic, we believe the definition of progressive disease as an
increase of > 25% in the product of the largest tumor diameter and its perpendicular (the
previous common UICC criteria) to be a more suitable definition, protecting patients from
undergoing deterioration of their clinical condition. This is in accordance to our previous
experience.
In case of "progressive disease" at any stage during epirubicin treatment, the patient will
terminate epirubicin immediately and go ahead with docetaxel treatment. In case of
progressive disease on docetaxel treatment, further therapy is left to the physician's
discretion.
Considering MRI assessment, this should be performed prior to commencing therapy, in the
interval following the 4th cycle of epirubicin (prior to commencing docetaxel) and after the
4th cycle of docetaxel, prior to surgery.
Tissue sampling
1. Each patient will undergo a surgical biopsy prior to commencing treatment.
2. A Tru-cut biopsy should be obtained 24 hours after administration of the first
epirubicin cycle to assess "immediate" alterations in response to cytotoxic damage.
3. Immediately prior to commencing treatment with docetaxel, a third sample (this time a
Tru-Cut biopsy) is obtained for snap-freezing.
4. A Tru-cut biopsy should be obtained 24 hours after administration of the first docetaxel
cycle to assess "immediate" alterations in response to cytotoxic damage.
5. Finally, tumor tissue is collected and snap-frozen at surgery following docetaxel
therapy.
Bone marrow aspiration A single unilateral bone marrow aspiration is performed prior to
commencing chemotherapy treatment.
Study Endpoint
- Primary endpoint is to correlate molecular parameters to objective response to each of
the 2 regimens applied.
- Secondary endpoint are
: - to correlate molecular parameters to relapse-free and overall survival
- to identify and explore characteristics of epithelial and mesenchymal stem cells
isolated in tumor tissue and bone marrow
Surgery While many centers practice breast conservative surgery for tumors successfully
downstaged by primary medical treatment, in general we have applied a conservative approach,
advocating mastectomy. However, downstaging for limited surgery is not a primary or secondary
endpoint of this study. In general, we will advocate mastectomy also for patients with a
clinical complete response. However, this practice may change based on contemporary results
from other centers, and the protocol allow limited surgery at the physicians discretion in
individual patients.
Laboratory Investigations The area of molecular biology is rapidly developing with respect to
biological knowledge as well as technical analytical methods. Thus, it is not possible to
predict upfront which genes may be of particular interest in 5 years from know; neither is it
possible to foresee completely which laboratory methods will be available. Our aim is to
explore potential genetic alterations explaining the mechanisms of drug resistance. While it
is not possible to predict in detail, the aim of the study and all analysis to be conducted
should aim at this major goal.
Number of patients to be enrolled The study is an exploratory translational study. Thus, we
do not know the number of patients expected to achieve a clinical or pathological complete
response. Currently, on average 20 patients are referred to our Department for a diagnosis of
locally advanced breast cancer on an annual basis; including patients with tumors measuring
between 4 and 5 cm in diameter, we estimate the total number may be somewhere between 30 and
40 patients per year. From this cohort, we estimate an average number of 20 patients to be
enrolled in the study on an annual basis. Our aim is to recruit 100 patients with a minimum
of 60.
Publication Our aim is to publish the results from this study in peer-reviewed international
journals with contributors from the clinic and laboratory as authors.
References; from the Trial Administrator upon request.
