| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early stage node positive breast cancer |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine whether a regimen of dose -dense doxorubicin and cyclophophamide followed by dose-dense paclitaxel and gemcitabine (DD AC-PG) will be superior to a regimen of docetaxel, doxorubicin and cyclophosphamide (TAC) as well as to a regimen of dose dense doxorubicin and cyclophosphamide followed by dose-dense paclitaxel alone (DD AC-P) in improving disease free survival (DFS).
To compare the relative DFS of TAC and DD AC-P. |
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| E.2.2 | Secondary objectives of the trial |
Determine whether a regimen of DD AC-PG will be superior to a regimen of TAC as well as to a regimen of DD AC-P in improving survival (S), recurrence-free interval (RFI), and distant recurrence-free interval (DRFI).
Compare S,RFI, and DFRI between TAC and DD AC-P;
Determine the relative toxicities of DD AC-PG, TAC, and DD AC-P |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Must sign an approved informed consent form
Life expectancy of at least 10 years and an ECOF PS of 0 or 1
Interval between last surgery for breast cancer staging or treatment randomisation must be no more than 84 days
Histologicall confirmed invasive carcinoma of the breast
Staging as follows;
T1-T3,
By clinical evaluation ipsilateral nodes should be cN0,cN1 or cN2a
By pathological evaluation ipsilateral nodes should be pN1(pN1mi,pN1a,pN1b,pN1c,) pN2a, pN3a,or pN3b(only if due to microscopic involvement of internal mammary node detected by sentinel lymph node dissection and with more than 3 positive axillary lymph nodes).
ER analysis. If patient is ER negative PR status must be performed.
Lumpectomy or total mastectomyOne of the following procedures for evaluation of pathological nodal status
*Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes
*Sentinel lymphadenectomy alone if one of teh following criteria is met:
-Pathological nodal staging based on Sentinel lymphadenectomy is pN1mi or pN1b
-Surgeon elcts not to remove additional non-sentinel nodes
*Axillary lymphadectomy without sentinel node isolation procedure
No clincial or radiologic evidence of metastatic disease
Patients with skeletal pain or ALKP that is >ULN but ≤ 2.5 XULN are eligible for inclusion in the study if bone scans fail to demonstrate metastatic disease. Suspicious findings on bone scan must be confirmed as benign by x-ray, MRI or biopsy.
Patients with AST or ALKP >ULN are eligible for inclusion in the study if liver imaging fails to demonstrate metastatic disease and teh requirements in criteria 5.1.12
At time of randomisation;
-Post operative AGC must be ≥12../mm3
-Post operative platelet count must be ≥100,000 mm3
Adequate hepatic function must be met and is defined as follows;
-total bilirubin must be ≤ ULN for the lab unless the patienst has a grade 1 bilirubin elevation (>ULN to 1.5 X ULN) due to Gilbert's disease or similar syndrome due to slow conjugation of bilirubin; and
-ALKP must be ≤2.5 x ULN for the lab
-the AST muct be ≤ 1.5 X ULN for the lab
-ALKP and AST cannot both be >ULN
-Postoperative serum creatinine must be ≤ULN
At randomisation the patient must have had the following: history and physical exam, ECG nd imaging of the chest within the past 3 months and bilateral mammogram within the past 6 months.
3 months prior to entry the patient must have a baseline LVEF, measured by MUGA scan or echocardiograph,≥ LLN for the facility performing the procedure and no evidence of regional wall abnormailities
Patients with a history of non-breast malignancies are eligible if tehy have been disease free for 5 or more yeasr prior to randomisation and are deemed by their physician to be low risk for recurence. Patients with the following cancers are eligible if diagnosed and treated within the past 5 years;carcinoma in situ of teh cervix, carcinoma in situ of the colon,melanoma in situ and basal cell and squamous cell carcinoma of teh skin
Patients who have had a lumpectomey must meet all conditions above in addition to the following;
-Lumpectomy should generally be reserved for tumours >5 cm. However at the investigators discretion patients treated with lumpectomy for tumours ≥5cm are eligible if eligibility criteria for lumpectomy are met.
-Margins of the resected specimen must be histologically free of invasive tumour and DCIS as deterrmined by the local pathologist. In patienst for whom pathologic examination demonstrates tumour present at teh line of resection additional operative procedures may be performed to obatin clear margins. This is permissable even if axillary evaluation has been completed. Patients in whom tumour is still present at the resected margin after re-excision must undergo total mastectomy to be eligible (Patients with margins positive for LCIS are eligible without additional resection)
Irradiation of regional lymph nodes is optional but plans for radiation therapy must be declared by the investigator prior to randomisation for stratification purposes
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| E.4 | Principal exclusion criteria |
Male patients are not eligible.
Her 2 positive patients as determined by IHC 3+ or FISH testing
Contralateral breast cancer (invasive or DCIS) or a mass or mammographic abnormality in the opposite breast suspicious fcr malignancy unless there is biopsy proof that the mass is not malignant
Primary tumour staged as T4 for any reason
Clinical nodal stages including cN2 and cN3 or pathological nodal stages including pN0(1+) ,pN2b, pN3b with clinically apparent internal mammary nodes, or pN3c
Suspicious nodes in the contralateral axilla or suspicious supraclavicular nodes. Patients with these conditions are considered ineligible unless there is biopsy evidence that these are not involved with tumour
Prior history of breast cancer, including DCIS (patients with a history of LCIS are eligible)
Treatment including radiation therapy, chemotherapy, and or hormonal therapy administered for currently diagnosed braest cancer prior to randomisation
One exception is hormonal therapy which may have been given for up to a total of 28 days anytime after diagnosis and before study entry. In such a case hormonal therapy must stop at or before randomisation and be re-started if indicated following chemotherapy
Prior therspy with anthracyclines or taxanes for any malignancy
Any sex hormonal therapy e.g birth control pills, ovarian hormonal replacement therapy
Therapy with any hormonal agents such as raloxifene, tamoxifen or other selective estrogen receptor modulators either for osteoporosis or braest cancer prevention
Cardiac disease taht would preclude the use of anthracyclines;
-history of mycocardial infarction documented by elevated cardiac enzymes or regioan wall abnormalities on assessment of LV function
Angina pectoris that requires the use of anti-anginal meducation;
any history of documented congestive heart failure
serious cardiac arrhythmia requiring medication
severe conduction abnormality
valvular disease with documented cardiac function compromise;and
uncontrolled hypertension defined as blood pressure >160/100 on antihpertensive therapy
conditions that would prohibit administration of corticosteroids
Sensory motor neuropathy ≥ grade 2
Non malignant systemic disease (cardiovascular, renal, hepatic etc) taht woudl preclude a patient from receiving any of the treatment options or woudl prevent prolonged follow-up
History of hepatitis B or C
Pregnancy or lactation at the time of proposed randomisation. Women of reproductive potentail must agree to use an effective non-hormonal method of contraception
Concurrent treatment with other investigational agents for the treatment of breast cancer
Psychiatric or addictive dosorders or other conditions that in the opinion of the investigator would preclude the patient from meeting teh study requirements
For lumpoectomy patients,radiation therapy amd surgey the following patients will be ineligible
-Patients with diffuse tumours treated with lumpectomy
Patients treated with lumpectomy in hom there is another clinically dominant mass or mammography suspicious abnormality within the ipsilateral breast remnant. Such a mass must be biposied and demonstrated to be histologically benign prior to randomisation or if malignanat must be surgically removed with clear margins
Patients in whom the margins of the resected specimen are involved with invasive tumour or DCIS |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Disease Free Survival (DFS) is the primary end point Events for DFS include
-local recurrence following mastectomy
-local recurrence in the ipsilateral breast following lumpectomy
-regional recurrence
-distant recurrence
-contralateral breast cancer second primary cancer (other than squamous or basal -cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, or lobular carcinoma in situ of teh breast) and
-death from any cause prior to recurrence or second primary cancer
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Information not present in EudraCT |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.3.1 | Comparator description |
| Docetaxl, Doxorubicin, Cyclophosphamide (TAC) also Paclitaxel |
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| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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