A Phase III Trial to Compare ETC vs, EC-TX and Ibandronate vs. Observation in Patients With Node-positive Primary Breast Cancer (GAIN)
18 Years
65 Years
Female
Breast Cancer
Trial Information
A Phase III Trial to Compare ETC vs, EC-TX and Ibandronate vs. Observation in Patients With Node-positive Primary Breast Cancer (GAIN)
Currently several strategies are under investigation to further improve adjuvant treatment
of early node-positive breast cancer. These are combination treatment of drugs with
synergistic mode of action, dose-dense application of cytotoxic drugs, dose-intensification
and the use of new, non-cytotoxic approaches.
In the recent AGO-study, a dose-dense and dose-intensified sequence of Epirubicin -
Paclitaxel - Cyclophosphamide has shown superior efficacy compared to a conventionally dosed
sequence of Epirubicin / Cyclophosphamid and Paclitaxel and was therefore chosen as standard
treatment in this study.
The experimental arm of EC-TX combines several of the above mentioned strategies: the
combination of EC will be administered every 2 weeks as a dose-dense regimen, the
combination of TX can also be considered as dose-dense due to the weekly application of
paclitaxel. Furthermore there is clinical evidence, that a combination of capecitabine and
Paclitaxel provide synergistic effects with improved tumour response. A randomized phase III
study could demonstrate a survival benefit of a combination of capecitabine with Docetaxel
in patients with metastatic breast cancer. This synergistic effect is probably based on the
preclinical observed taxane-mediated up-regulation of thymidine phosphorylase in the tumour
cell, which give drive to an increased transformation of capecitabine to its active form
5-Fluorouracil. Apart from this synergy, the EC-TX regimen includes now 4 highly active
compounds for the treatment of breast cancer. The total doses of Epirubicin and Paclitaxel
are identical in both arms. The dosage of Cyclophosphamide is lower in the experimental arm,
which is preferred due to the induction of leukaemia at higher doses of Cyclophosphamide.
The duration of both arms with 18 and 20 weeks is nearly similar.
The 2 by 2 factorial design of the trial provides the additional possibility to explore the
efficacy of a bisphosphonate as another strategy to further improve the prognosis of node
positive breast cancer. As the mechanism of action of cytotoxic drugs and bisphosphonates
appear to be independent the factorial design is an adequate statistical model for this
trial. Up to now only limited information is available on the potential role of
bisphosphonates in this setting and they have all been generated by using the 1st generation
bisphosphonate Clodronate. 3rd generation bisphosphonates like ibandronate are much more
active, less toxic and their application is more convenient (which is of high importance
regarding the long duration of treatment).
Primary aims of this trial are to improve disease-free survival by using the EC-TX regimen
and by using ibandronate as adjuvant treatment for 2 years.
Inclusion Criteria:
Written informed consent prior to beginning specific protocol procedures, including
expected cooperation of the patients for the treatment and follow-up, must be obtained and
documented according to the local regulatory requirements, Histologically confirmed
unilateral or bilateral primary carcinoma of the breast Age at diagnosis at least 18 years
and biologically younger than 65 years Adequate surgical treatment with histological
complete resection (R0) of the tumor and at least 10 axillary nodes At least one
histological involved axillary or internal mammarian lymph node No evidence for distant
metastasis after complete diagnostic work up Primary wound healing from breast surgery
without signs of infection Performance Status ECOG < 2 Estimated life expectancy of at
least 10 years irrespective of the diagnosis of breast cancer The patient must be
accessible for treatment and follow-up. Patients registered on this trial must be treated
and followed at the participating center which could be the Principal or an Co-
investigator's site
Exclusion Criteria:
Known hypersensitivity reaction to the compounds or incorporated substances or known
dihydropyrimidine dehydrogenase (DHP) deficiency.
Inadequate organ function including: ANC < 1.5 G/l, Platelets < 100 G/l , Transaminases,
Creatinine or Bilirubin > 1.25 times above upper normal limits (UNL), AP > 3 times above
UNL, Creatinine Clearance < 30ml/min (if Creatinine is above UNL, according to
Cockroft-Gault), severe and relevant co-morbidity that would interact with the application
of cytotoxic agents or the participation in the study Insufficient and uncompensated
cardiac function with LVEF below the normal range of the institution, history of severe
heart disease, myocardial infarction within the last 6 months, cardiac arrhythmias LOWN
II Evidence for infection including wound infections, HIV, Hepatitis Secondary malignancy,
except curatively treated basalioma of the skin and carcinoma in situ of the cervix Time
since axillary dissection > 3 months (optimal < 1 month) Non-operable breast cancer
Previous and already (neoadjuvant or adjuvant) treated invasive breast carcinoma Previous
or concurrent anti-tumor treatment for any reason Simultaneous therapy with Sorivudine or
Brivudine as virostatics, immunosuppressive treatment or concurrent treatment with
aminoglycosides Pregnancy or lactation period. Adequate non hormonal contraception is a
prerequisite in premenopausal patients Concurrent treatment with other experimental drugs.
Participation in another clinical trial with any investigational not marketed drug within
30 days prior to study entry.
Male patients
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
A: To compare the disease-free survival after adjuvant chemotherapy with "ETC" (Arm A1) or "EC-TX" (Arm A2) in patients with primary node-positive breast cancer.
Outcome Time Frame:
US-law not applicable
Safety Issue:
No
Principal Investigator
Volker Möbus, Prof. Dr.
Investigator Role:
Principal Investigator
Investigator Affiliation:
Städtische Kliniken Frankfurt a.M.-Höchst, Gotenstr. 6-8, 65929 Frankfurt, Germany
Authority:
Germany: Federal Institute for Drugs and Medical Devices
Study ID:
GBG 33
NCT ID:
NCT00196872
Start Date:
July 2004
Completion Date:
December 2012
Related Keywords:
- Breast Cancer
- dose dense sequence
- dose dense combination
- node positive disease
- Breast Neoplasms
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