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Trial registered on ANZCTR


Registration number
ACTRN12610000151033
Ethics application status
Approved
Date submitted
5/02/2010
Date registered
15/02/2010
Date last updated
11/07/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
A randomized phase III trial with dose-dense sequential chemotherapy with epirubicin/paclitaxel/Cyclophosphamide-Methotrexate-Fluorouracil (CMF) vs epirubicin/CMF/docetaxel or paclitaxel as adjuvant chemotherapy in high-risk patients with operable breast cancer.
Scientific title
A comparison of disease-free and overall survival following dose-dense sequential chemotherapy with epirubicin/paclitaxel/Cyclophosphamide-Methotrexate-Fluorouracil (CMF) vs epirubicin/CMF/weekly docetaxel or weekly paclitaxel as adjuvant chemotherapy in high-risk patients with operable breast cancer. A 3-arm randomized phase III study conducted by the Hellenic Cooperative Oncology Group
Secondary ID [1] 1384 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
High risk breast cancer patients 256758 0
Condition category
Condition code
Cancer 256908 256908 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group B will be treated with epirubicin [110 mg/m2 intravenous infusion (IV)] every 2 weeks for 3 cycles followed by 3 cycles of CMF (cyclophosphamide; 840 mg/m2 IV , methotrexate; 57 mg/m2 IV and fluorouracil; 840 mg/m2 IV) every 2 weeks followed 3 weeks later by 9 weekly cycles of Docetaxel; 35 mg/m2 IV .
The cumulative dose of docetaxel is 315 mg/m2. The duration of E-CMF-docetaxel chemotherapy would be identical to that of E-T-CMF (22 weeks).
Group C will be treated with epirubicin (110 mg/m2 IV) every 2 weeks for 3 cycles followed by 3 cycles of CMF (cyclophosphamide; 840 mg/m2 IV, methotrexate; 57 mg/m2 IV and fluorouracil; 840 mg/m2 IV) every 2 weeks followed 3 weeks later by 9 weekly cycles of Paclitaxel 80mg/m2 IV. The cumulative dose of Paclitaxel is 720mg/m2.
The duration of E-CMF-paclitaxel chemotherapy would be identical to that of E-T-CMF (22 weeks).
Filgrastim 5 micrograms/kg will be given on days 2-7 of each cycle in group A and during the intensified phase of EPI and CMF treatment (all cycles of EPI/CMF) in groups B and C. Ondansetron + Dexamethazone is recommended as antiemetic treatment in all patients. It is anticipated by the protocol that when trastuzumab will be licensed for the adjuvant treatment of high-risk operable breast cancer with human epidermal growth factor receptor 2 (HER-2) overexpression or HER-2 gene amplification, all such patients entered the study will be eligible to receive trastuzumab 8 mg/kg loading dose followed by 6 mg/m2 q3 weeks for 1 year after the completion of chemotherapy. In these patients hormonal treatment with tamoxifen or anastrazole will be started concurrently with initiation of treatment with trastuzumab. All premenopausal patients with receptor positive status will receive tamoxifen 20 mg by mouth (p.o.) daily for 5 years and goserelin (zoladex) 10.8 mg p.o. every 3 months for 2 years. All postmenopausal patients with receptor positive status will be treated with anastrazole 1mg daily for 5 years. Radiotherapy (RT) is required for all patients (pre- or post -menopausal), providing that they had either a partial mastectomy or tumor size > 5cm and /or more than 4 positive lymph nodes, irrespectively the type of surgery (conservative or radical).
Intervention code [1] 255970 0
Treatment: Drugs
Comparator / control treatment
Group A will be treated with epirubicin [110 mg/m2 intravenous infusion (IV)] every 2 weeks for 3 cycles followed by 3 cycles of paclitaxel (200 mg/m2 IV) every 2 weeks and 3 cycles of CMF (cyclophosphamide; 840 mg/m2 IV, methotrexate; 57 mg/m2 IV and fluorouracil; 840 mg/m2 IV) every 2 weeks.
The overall duration of treatment in group A is 19 weeks.
Control group
Active

Outcomes
Primary outcome [1] 257782 0
To compare the time from initial operation to recurrence (disease free survival-DFS)
Timepoint [1] 257782 0
3 year. All patients will be followed at the clinic every 6 months for 5 years and then annually thereafter for up to 10 years with clinical examination, complete blood count (CBC), complete biochemistry, serological markers, chest X- ray, bone scan (only for the first 3 years of follow-up) and mammography (annually).
Primary outcome [2] 257783 0
To compare the overall survival. This outcome is assessed using clinical data records
Timepoint [2] 257783 0
3 year following commencement of chemotherapy
Secondary outcome [1] 263185 0
The secondary objective is the comparison of the acute and long-term toxicity caused by the 3 regimens.
Timepoint [1] 263185 0
1 month since the last administration of chemotherapy for acute toxicity.1 month since the last infusion of Trastuzumab for those patients who receive the drug. Toxicity is assessed by laboratory evaluation of hematology and biochemistry, physical examination etc.
Secondary outcome [2] 263198 0
Quality of Life.
We use the EUroQol (EQ-5D) valuation questionnaire
Timepoint [2] 263198 0
Baseline-End of Chemotherapy-6 months after the completion of chemotherapy (and/or Trastuzumab)

Eligibility
Key inclusion criteria
Histology-confirmed epithelial cancer of the mammary gland.Pre and post menopausal patients with operable breast cancer and involved axillary lymph nodes (T 1-3 N1-2 Mo) or patients without involved axillary nodes (T1-3 N0 Mo) (i.e. those with T>= 2cm or T>1cm with at least one of the following: grade 3, age < 34 years, negative hormonal status, infiltration of blood vessels or lymphatic vessels or nerves, HER-2 (receptor tyrosine kinase) overexpression, high S fraction). White Blood Cells > 4 x 109 / l, platelets > 100 x 109 / l.Serum creatinine, Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma-glutamyltransferase (gamma-GT), serum bilirubin 1.3 mg/ml inside the normal range of the participating hospital.Performance status ((World Health Organisation) ) 0 or 1. Age >= 18 years.Previous surgical treatment: Either radical surgery or, for a partial mastectomy, a histologically confirmed safe margin and the results of the axillary node dissection available.No evidence of significant cardiac disease. No previous antitumor chemotherapy or radiation.Time from surgery 2 to 8 weeks.Informed consent of the patient according to the dispositions of the Helsinki convention and its Tokyo and Venice amendments and to individual institutional policy.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
History of myocardial infarction within the previous 12 months or heart failure (including cardiac insufficiency controlled by digitalis and diuretics) or arrhythmias requiring medication or uncontrolled arterial hypertension (Blood Pressure> 200/110 mm Hg). A normal baseline Left Ventricular Ejection Fraction (LVEF) should be demonstrated by multiple gate acquisition (MUGA) scan or echocardiogram (ECHO).Documented residual or metastatic disease.Prior chemotherapy, hormonal or radiation treatmentPregnant or in puerperium period women, or patients unwilling to follow adequate contraceptive methods during treatment period. History of prior cancer except for curatively treated basal-cell carcinoma of the skin or in situ carcinoma of the cervix uteri. Patients who can not fully understand and complete the inform consent form, or patients who can not follow treatment or follow up schedule.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
20/07/2005
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
1000
Accrual to date
Final
Recruitment outside Australia
Country [1] 2466 0
Greece
State/province [1] 2466 0

Funding & Sponsors
Funding source category [1] 256468 0
Other Collaborative groups
Name [1] 256468 0
Hellenic Cooperative Oncology Group
Country [1] 256468 0
Greece
Primary sponsor type
Other Collaborative groups
Name
Hellenic Cooperative Oncology Group
Address
18, Hatzikostandi str, 11524, Athens
Country
Greece
Secondary sponsor category [1] 255778 0
None
Name [1] 255778 0
Address [1] 255778 0
Country [1] 255778 0

Ethics approval
Ethics application status
Approved

Summary
Brief summary
This is a 3-arm randomized phase III trial in high-risk breast cancer patients. Node-positive patients are randomized to sequential dose-dense epirubicin/paclitaxel/Cyclophosphamide-Methotrexate-Fluorouracil (CMF) or epirubicin/CMF/weekly docetaxel or weekly paclitaxel Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments. Ondansetron + Dexamethazone is recommended as antiemetic treatment in all patients.It is anticipated by the protocol that when trastuzumab will be licensed for the adjuvant treatment of high-risk operable breast cancer with HER-2 overexpression or HER-2 gene amplification, all such patients entered the study will be eligible to receive trastuzumab every 3 weeks for 1 year after the completion of chemotherapy. In these patients hormonal treatment with tamoxifen or anastrazole will be started concurrently with initiation of treatment with trastuzumab. All premenopausal patients with receptor positive status will receive tamoxifen p.o. daily for 5 years and goserelin (zoladex) p.o. every 3 months for 2 years. All postmenopausal patients with receptor positive status will be treated with anastrazole for 5 years.RT is required for all patients (pre- or post -menopausal), providing that they had either a partial mastectomy or tumor size > 5cm and /or more than 4 positive lymph nodes, irrespectively the type of surgery (conservative or radical).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 30805 0
Address 30805 0
Country 30805 0
Phone 30805 0
Fax 30805 0
Email 30805 0
Contact person for public queries
Name 14052 0
Eleni Papakostaki
Address 14052 0
Hellenic Cooperative Oncology Group, 18, Hatzikostandi str, 11524, Athens
Country 14052 0
Greece
Phone 14052 0
+302106912520
Fax 14052 0
Email 14052 0
hecogoff@otenet.gr
Contact person for scientific queries
Name 4980 0
George Fountzilas
Address 4980 0
Hellenic Cooperative Oncology Group, 18, Hatzikostandi str, 11524, Athens
Country 4980 0
Greece
Phone 4980 0
+302106912520
Fax 4980 0
Email 4980 0
fountzil@auth.gr

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseOpposite Prognostic Impact of Single PTEN-loss and PIK3CA Mutations in Early High-risk Breast Cancer.2019https://dx.doi.org/10.21873/cgp.20125
EmbaseDose-dense sequential adjuvant chemotherapy in the trastuzumab era: final long-term results of the Hellenic Cooperative Oncology Group Phase III HE10/05 Trial.2022https://dx.doi.org/10.1038/s41416-022-01846-y
N.B. These documents automatically identified may not have been verified by the study sponsor.