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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Epirubicine
* Drug: Cyclophosphamide
* Drug: Taxol
* Drug: Xeloda
* Drug: Ibandronat


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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. |  | 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 |  | US-law not applicable | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare overall survival between arms A1 vs. A2 and B1 vs. B2 |  | US-law not applicable | 
| To evaluate the compliance in arms A1 vs. A2 and in B1 |  | US-law not applicable | 
| To compare the safety between arms A1 vs. A2 and B1 vs. B2 |  | US-law not applicable | 
| To assess the rate of responders to erythropoesis stimulating factors in arm A1 and A2 |  | US-law not applicable | 
| To compare the incidence of secondary primaries between arms A1 vs. A2 |  | 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 |  | US-law not applicable | 
| Tertiary objectives: |  | 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 |  | US-law not applicable | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dose dense sequence, dose dense combination, node positive disease