A Study to Compare ETC vs. EC-TX and Ibandronate vs. Observation in Patients With Node-positive Primary Breast Cancer (GAIN)

July 16, 2014 updated by: German Breast Group

A Phase III Trial to Compare ETC vs, EC-TX and Ibandronate vs. Observation in Patients With Node-positive Primary Breast Cancer (GAIN)

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 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

3000

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
    • Hessia
      • Frankfurt, Hessia, Germany, 65929
        • Städtische Kliniken Frankfurt a.M.-Höchst

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: ETC-with Ibandronat
ETC follwoed by Ibandronat
Drug: Epirubicine
Epirbubicne is given
Drug: Cyclophosphamide
Cyclophosphamide is given
Drug: Taxol
Taxol is given
Drug: Ibandronat
Ibandronat is given
Experimental: ETC without Ibandronat
ETC not followed by Ibandronat
Drug: Epirubicine
Epirbubicne is given
Drug: Cyclophosphamide
Cyclophosphamide is given
Drug: Taxol
Taxol is given
Experimental: EC-TX with Ibandronat
EC-TX followed by Ibandronat
Drug: Epirubicine
Epirbubicne is given
Drug: Cyclophosphamide
Cyclophosphamide is given
Drug: Taxol
Taxol is given
Drug: Ibandronat
Ibandronat is given
Drug: Xeloda
Xeloda is given
Experimental: EC-TX without Ibandronat
EC-TX not followed by Ibandronat
Drug: Epirubicine
Epirbubicne is given
Drug: Cyclophosphamide
Cyclophosphamide is given
Drug: Taxol
Taxol is given
Drug: Xeloda
Xeloda is given

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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.
Time Frame: US-law not applicable
US-law not applicable
B: To compare the disease-free survival with (Arm B1) or without ibandronate (Arm B2) treatment for 2 years in patients with primary node-positive breast cancer
Time Frame: US-law not applicable
US-law not applicable

Secondary Outcome Measures

Outcome Measure
Time Frame
To compare overall survival between arms A1 vs. A2 and B1 vs. B2
Time Frame: US-law not applicable
US-law not applicable
To evaluate the compliance in arms A1 vs. A2 and in B1
Time Frame: US-law not applicable
US-law not applicable
To compare the safety between arms A1 vs. A2 and B1 vs. B2
Time Frame: US-law not applicable
US-law not applicable
To assess the rate of responders to erythropoesis stimulating factors in arm A1 and A2
Time Frame: US-law not applicable
US-law not applicable
To compare the incidence of secondary primaries between arms A1 vs. A2
Time Frame: US-law not applicable
US-law not applicable
To compare the event-free survival in subgroups of hormone sensitive and insensitive disease and in groups with 1-3, 4-9 or 10+ involved nodes between arms A1 vs. A2 and B1 vs. B2
Time Frame: US-law not applicable
US-law not applicable
Tertiary objectives:
Time Frame: US-law not applicable
US-law not applicable
To determine prognostic factors like TS or TP and others on tumor tissue collected from primary surgery and to correlate them with study treatment effect
Time Frame: US-law not applicable
US-law not applicable

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

German Breast Group

Investigators

  • Principal Investigator: Volker Möbus, Prof. Dr., Städtische Kliniken Frankfurt a.M.-Höchst, Gotenstr. 6-8, 65929 Frankfurt, Germany

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2004

Primary Completion (Actual)

June 1, 2014

Study Completion (Actual)

June 1, 2014

Study Registration Dates

First Submitted

September 12, 2005

First Submitted That Met QC Criteria

September 12, 2005

First Posted (Estimate)

September 20, 2005

Study Record Updates

Last Update Posted (Estimate)

July 17, 2014

Last Update Submitted That Met QC Criteria

July 16, 2014

Last Verified

August 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GBG 33
  • GAIN

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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