Clinical trial NCT00630032
Conditions: Breast Cancer
Keywords: stage II breast cancer stage IIIA breast cancer stage IIIB breast cancer stage IIIC breast cancer
Sponsor: UNICANCER
Start date: 2007-09-01; Completion date: 2020-09-03
Enrollment: 762 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving them after surgery may kill any tumor cells remaining after surgery. It is not yet known whether docetaxel is more effective than ixabepilone when given after surgery and combination chemotherapy in treating breast cancer.

PURPOSE: This randomized phase III trial is studying giving combination chemotherapy followed by docetaxel or ixabepilone to compare how well they work in treating patients who have undergone surgery for nonmetastatic breast cancer.

Detailed description:
OBJECTIVES:

Primary

* To evaluate the benefit from sequential administration of 3 courses of combination chemotherapy (FEC100) followed by 3 courses of ixabepilone versus docetaxel on the 5-year disease-free survival of women with nonmetastatic, poor-prognosis breast cancer.

Secondary

* To compare the 5-year distant metastasis-free survival.
* To compare the 5-year event-free survival.
* To compare the 5-year overall survival.
* To compare the safety profiles for the two chemotherapy regimens.
* To identify and/or validate predictive-gene expression profiles of clinical response/resistance to the two treatment regimens.
* To bank frozen and fixed tumor and frozen serum prospectively for future translational studies in both genomics and proteomics (transcriptome and proteome analyses, tissue array analyses).
* To compare the cost-effectiveness of these 2 regimens.
* To compare the quality-of-life of patients treated with these 2 regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center, menopausal status (pre- vs post-menopausal), and tumor hormone-receptor status (triple-negative vs progesterone-receptor negative, HER negative, and estrogen-receptor \[ER\] positive). Patients are randomized to 1 of 2 treatment arms.

* Docetaxel Arm: Patients receive epirubicin hydrochloride IV, fluorouracil IV, and cyclophosphamide IV every 3 weeks in courses 1-3 and docetaxel IV alone every 3 weeks in courses 4-6.
* Ixabepilone Arm: Patients receive treatment in courses 1-3 as in arm I and ixabepilone IV alone every 3 weeks in courses 4-6.

In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients also complete a quality of life questionnaire periodically.

After completion of study treatment, patients are followed periodically for up to 10 years.

Arms: arm 1: 3 cycles of FEC100 (F and C, each at 500 mg/m², E 100 mg/m², every 3 weeks) followed by 3 cycles of D (100 mg/m² every 3 weeks) arm 2: 3 cycles of FEC100 (F and C, each at 500 mg/m², E 100 mg/m², every 3 weeks) followed by 3 cycles of Ixabepilone (40 mg/m² every 3 weeks);
Interventions: intervention 1: cyclophosphamide intervention 2: Docetaxel intervention 3: epirubicin hydrochloride intervention 4: fluorouracil intervention 5: ixabepilone
Intervention descriptions: intervention 1: 500 mg/m² every 3 weeks intervention 2: 100 mg/m² every 3 weeks intervention 3: 100 mg/m² every 3 weeks intervention 4: 500 mg/m² every 3 weeks intervention 5: 40 mg/m² every 3 weeks

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
This document is the property of UNICANCER. Any part of this document may not be reproduced or disclosed 
without the written consent of UNICANCER 
 
 
UNICANCER BREAST Group 
 
 
 
 
Protocol for Adjuvant Therapy in Breast Cancer 
Treatment : 
 
Protocol PACS 08  
 
EudraCT N° 2006-006494-24 
UC- 0140/0610 
 
Randomized, open label, multicentric phase III trial  
evaluating the benefit of a sequential regimen  
associating FEC100 and Ixabepilone in adjuvant treatment  
of non metastatic, poor prognosis breast cancer defined as 
triple-negative tumor [HER2 negative - ER negative - PR 
negative] or [HER2 negative and PR negative] tumor;  
in node positive or node negative patients. 
Abbreviated title: TavIx 
 
 
Version FR 4.0 – 23 November 2011 
 
PRINCIPAL 
INVESTIGATOR 
 
Dr Mario CAMPONE 
Medical Oncology Department 
Institut de Cancérologie de l’Ouest 
Centre René Gauducheau - Bd Jacques Monod 
44805 NANTES SAINT-HERBLAIN Cedex  
FRANCE 
Phone: + 33 (0)2 40 67 99 77 
Fax: + 33 (0)2 40 67 97 76 
Email: mario.campone@ico.unicancer.fr 
 
SPONSOR 
 
UNICANCER
101, rue de Tolbiac - 75654 PARIS Cedex 13 - FRANCE 
Phone: +33.(0)1.44.23.04.04  - Fax: +33.(0)1.44.23.55.69 
 


 
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APPROVALS AND CONTACT DETAILS 
PROTOCOL PACS 08 
 
Randomized, open label, multicentric phase III trial evaluating the benefit  
of a sequential regimen associating FEC100 and ixabepilone in adjuvant treatment  
of non metastatic, poor prognosis breast cancer defined as triple-negative tumor [HER2 negative-ER 
negative-PR negative] or [HER2 negative and PR negative] tumor; in node positive or node negative 
patients. 
 
FRENCH COMPETENT 
AUTHORITY 
 
Agence Française de Sécurité 
Sanitaire des Produits de Santé 
(AFSSAPS) 
Date of initial authorization:  
02 May 2007 
 
Ref. number: A70108-41 
FRENCH ETHIC 
COMMITTEE 
 
CPP Ouest V
CHU Pontchaillou 
Pavillon Recherche 
2, rue Henri Le GUILLOUX 
35033 RENNES Cedex 09 
Date of initial approval:  
07 June 2007 
 
Ref. number : 07/09-626 
 
WRITING 
COMMITTEE 
 
Bernard ASSELAIN, Mario CAMPONE, Magali LACROIX-TRIKI,  
Anne-Laure MARTIN, Henri ROCHÉ 
 
NAME AND RESPONSIBILITIES 
 
ADDRESS 
 
E-MAIL 
Dr Jocelyne BERILLE 
Scientific Director) 
UNICANCER 
R&D UNICANCER 
101, rue de Tolbiac 
75654 PARIS Cedex 13 - France 
Phone: + 33 1.44.23.04.19 
Fax: + 33 1.44.23.55.69 
j.berille@unicancer.fr 
Dr Mario CAMPONE 
Principal Investigator 
 
Institut de Cancérologie de L’Ouest
Centre René GAUDUCHEAU 
44805 NANTES SAINT-HERBLAIN Cedex - 
France 
Phone: + 33 (2) 40 67 99 77 
Fax: + 33 (2) 40 67 97 76 
Mario.Campone@ico.unicancer.fr 
Dr Bernard ASSELAIN 
Biostatistician 
 
Institut CURIE 
26, rue d’Ulm 
75231 PARIS Cedex 05 – France 
Phone: + 33 1.56.24.56.05 
Fax: + 33 1.53.10.40.20 
bernard.asselain@curie.net 
R&D UNICANCER 
Coordination Team 
R&D UNICANCER 
101, rue de Tolbiac 
75654 PARIS Cedex 13 - France 
Fax + 33 1.44.23.55.69 or + 33 1.44.23.04.69 
 
PACS08@unicancer.fr 
Anne-Laure MARTIN 
Project Director 
 
 
Jérome LEMONNIER 
Project Leader  
Phone: + 33 1.44.23.55.56 
 
 
Phone: + 33 1 71. 93. 67. 02 
al-martin@unicancer.fr 
 
 
j-lemonnier@unicancer.fr 
 Christel MESLEARD 
Trials Manager
Phone: + 33 1.44.23.55.51 
 
c-mesleard@unicancer.fr 
 
 
 
 


 
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SYNOPSIS – PROTOCOL PACS 08 
 
A) CLINICAL TRIAL IDENTIFICATION  
SPONSOR - PROTOCOL CODE NUMBER: UC-0140/0610 
PACS08 
TRIAL TITLE: 
Randomized, open label, multicentric phase III trial evaluating the benefit of a sequential regimen 
associating FEC100 and Ixabepilone in adjuvant treatment of non metastatic, poor prognosis 
breast cancer defined as triple-negative tumor [HER2 negative - ER negative - PR negative] or 
[HER2 negative and PR negative] tumor; in node positive or node negative patients. 
 
ABBREVIATED TITLE: TAVIX 
PRINCIPAL INVESTIGATOR: Dr. Mario CAMPONE 
Medical Oncology Department 
Institut de Cancérologie de l’Ouest 
Centre René Gauducheau - Bd Jacques Monod 
44805 NANTES SAINT-HERBLAIN cedex  
FRANCE 
 
Phone: + 33 (2) 40 67 99 77 
Fax: + 33 (2) 40 67 97 76 
Email: mario.campone@ico.unicancer.fr 
PLANNED NUMBER OF INVESTIGATIONNAL SITES: ca 80 
NUMBER OF SUBJECTS: 2500 
 
 
B) SPONSOR IDENTIFICATION  
NAME OF THE INSTITUTION: UNICANCER 
CONTACT PERSON: Anne-Laure MARTIN 
R&D UNICANCER 101 rue de Tolbiac - 75654 PARIS CEDEX 13 - France 
Tel.:+33.1.44.23.55.56 
Fax: +33.1.44.23.55.69 
e-mail: al-martin@unicancer.fr 
 
C) TRIAL GENERAL INFORMATION  
MEDICAL CONDITION: non-metastatic operable breast cancer 
METHODOLOGY: open label, multicentric randomized phase III trial comparing two treatment arms: 
sequential regimen (3 FEC100 + 3 docetaxel), versus sequential regimen (3 
FEC100 + 3 ixabepilone). 
MAIN OBJECTIVE: To evaluate the benefit from sequential administration of 3 FEC100 followed by 
3 cycles of Ixabepilone versus standard epirubicin+docetaxel based protocol 
on the disease-free survival (5 year DFS). 


 
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C) TRIAL GENERAL INFORMATION (...) 
SECONDARY OBJECTIVE(S)  
1 - efficacy:  
- 
Whole population : assessment of impact of ixabepilone on: 
o 
the distant metastasis free survival (5 year DMFS)  
o 
the event free survival (5 year EFS; see definition of an event in evaluation criteria 
section)  
o 
the overall survival (5 year OS). 
- 
Triple negative subgroup and ER+/PR-HER2- subgroup : assessment of impact of ixabepilone on 
the 5 year DFS, DMFS, EFS and OS. 
2 - toxicity:  
- 
To compare the safety profiles for the two chemotherapy regimens. 
3 - biology:  
1. gene profiling : to identify and/or validate predictive-gene expression profiles of clinical response / 
resistance to the two treatment regimens 
2. Frozen and fixed tumor and frozen serum banking will be prospectively performed for future 
translational studies in both genomics and proteomics (transcriptome and proteome analyses, 
tissue array analyses) 
4 – cost-effectiveness / quality of life sub-studies  
 
INCLUSION CRITERIA:  
1) Women aged from 18 to 70 years, 
2) Histologically proven invasive unilateral breast cancer (regardless of the type), 
3) Initial clinical condition compatible with complete initial resection, 
4) No residual macro or microscopic tumor after surgical excision, 
5) Beginning of chemotherapeutic treatment no later than day 49 after the initial surgery, 
6) Node positive disease (positive sentinel node or positive axillary clearance) (N+)  
or node negative disease (N-) with the following criteria : SBR II / III and pT > 20 mm, 
7) Patient presenting one of the following criteria (reviewed before randomization by referent 
pathologist): 
o for N+ patients: triple negative tumor [HER2 negative and ER negative and PR negative] or 
[HER2 negative and PR negative status], 
o for N- patients: triple negative tumor only [HER2 negative and ER negative and PR 
negative], 
Hormone receptor negativity is defined as ER<10%, PR<10% (IHC),  
HER2 negativity is defined as IHC 0-1+, or [IHC 2+ and  FISH or CISH negative]. 
8) No clinically or radiologically detectable metastases (M0), 
9) No peripheral neuropathy > 1, 
10) WHO Performance status (ECOG) of 0 or 1, 
11) Adequate recovery from recent surgery (at least one week must have elapsed from 
the time of a minor surgery (excluding breast biopsy); at least three weeks for major surgery), 
12) Adequate hematological function (neutrophil count ≥ 2x109/l, platelet count ≥ 100x 109/l, 
Hemoglobin > 9 g/dl), 
13) Adequate hepatic function: ASAT and ALAT ≤ 1.5 ULN, alkaline phosphatases ≤ 2.5 ULN, total 
bilirubin ≤ 1.0 ULN, 
14) Adequate renal function: serum creatinine ≤ 1.5 ULN, 
15) Patients accepting contraception intake during the overall length of treatment if of childbearing 
potential, 
16) Adequate cardiac function, LEVF value ≥ 50% by Muga scan or echocardiography, 
17) Signed written informed consent. 
 


 
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C) TRIAL GENERAL INFORMATION (...) 
NON INCLUSION CRITERIA:  
1) Bilateral breast cancer or patient with controlateral DCIS, 
2) Any metastatic impairment, including homolateral sub-clavicular node involvement, regardless of 
its type, 
3) Any tumor ≥ T4a (UICC1987) (cutaneous invasion, deep adherence, inflammatory breast cancer), 
4) HER 2 overexpression defined as [IHC 3+] or [IHC 2+ and FISH or CISH positive], 
5) Any clinically or radiologically suspect and non-explored damage to the controlateral breast, 
6) Any chemotherapy, hormonal therapy or radiotherapy before surgery, 
7) Concomittant treatment with the following strong inhibitors of CYP3A4 from 72 hours prior to 
the initiation of study therapy until end of treatment with ixabepilone or docetaxel: amiodarone, 
clarithromycin, amprenavir, delavirdine, voriconazole erythromycin, fluconazole, itraconazole, 
ketoconazole, indinavir, nelfinavir, ritonavir, and saquinavir, 
8) Previous cancer (excepted cutaneous baso-cellular epithelioma or uterin peripheral ephitelioma) in 
the preceding 5 years, including invasive controlateral breast cancer, 
9) Patients already included in another therapeutic trial involving an experimental drug, 
10) Patients with other concurrent severe and/or uncontrolled medical disease or infection which could 
compromise participation in the study, 
11) LEVF < 50% (MUGA scan or echocardiography), 
12) Clinically significant cardiovascular disease (e.g. unstable angina, congestive heart failure, 
uncontrolled hypertension (>150/90), myocardial infarction or cerebral vascular accidents) within 
6 months prior to randomization, 
13) Known prior severe hypersensitivity reactions to agents containing Cremophor EL, 
14) Women of childbearing potential who are unwilling or unable to use an acceptable method to avoid 
pregnancy for the entire study period and up to 8 weeks after treatment completion, 
15) Women who are pregnant or breastfeeding. Adequate birth control measures should be taken 
during study treatment phase, 
16) Women with a positive pregnancy test en enrollment or prior to study drug administration, 
17) Patients with any psychological, familial, sociological or geographical condition potentially 
hampering compliance with the study protocol and follow-up schedule; those conditions should be 
discussed with the patient before registration in the trial, 
18) Individual deprived of liberty or placed under the authority of a tutor. 
 
EVALUATION CRITERIA: 
PRIMARY (EFFICACY ENDPOINT):  
- 
Disease Free Survival rate (DFS) at 5 years (disease is defined as a local, regional or metastatic 
relapse, a controlateral breast cancer, or a death of any cause). 
SECONDARY:  
1. Efficacy:  
o triple negative and ER+/PR-HER2- subgroups: DFS at five years; 
o whole population and subgroups: Distant Metastasis Free Survival (DMFS), Event Free 
Survival (EFS; an event is defined as a local, regional or metastatic relapse, 
a controlateral breast cancer, a second cancer or a death of any cause) and Overall 
Survival (OS) rates at five years. 
2. Toxicity: CTC-AE scale version 3.0. 
3. Biotheque: transcriptom and proteom analysis. 
4. Quality of life: QlQ C30 / Br23. 
 


 
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D) DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCTS 
DRUGS:  
Drug Name
(DCI) 
Commercial
Name 
Pharmaceutical
Form 
Administration
Route
Posology 
5 fluorouracil 
 
Infusion solution 
I.V. 
500 mg/m²  
every  3 weeks 
 
 
 
 
 
Drug Name
(DCI) 
Commercial
Name 
Pharmaceutical
Form 
Administration
Route
Posology 
Epirubicin 
Farmorubicine 
Infusion solution 
I.V. 
100 mg/m²  
every  3 weeks 
 
 
 
 
 
Drug Name 
 (DCI) 
Commercial
Name  
Pharmaceutical
Form 
Administration
Route 
Posology
Cyclophosphamid 
Endoxan 
Powder for 
injection solution 
I.V. 
500 mg/m²  
every 3 weeks  
 
 
 
 
 
Drug Name
(DCI) 
Commercial
Name  
Pharmaceutical
Form 
Administration
Route 
Posology
Docetaxel 
Taxotere 
Infusion solution  
I.V. 
100 mg/m²   
every 3 weeks 
 
 
 
 
 
Drug Name
 (DCI) 
Commercial
Name  
Pharmaceutical
Form 
Administration
Route 
Posology
Ixabepilone 
NA 
Powder and 
solvent for infusion 
I.V. 
40 mg/m² 
THERAPEUTIC SCHEME: 
After confirmation of their HER2, hormone receptor and node involvement status the patients will be 
randomized in the study and will receive the following treatments: 
 
Arm A : 
Cycles 1 to 3 : epirubicin 100 mg/m²  
 
5 fluorouracil 500 mg/m²   
 
cyclophosphamide 500 mg/m² 
 
1 cycle = 21 days 
Cycles 4 to 6 : docetaxel 100 mg/m² 
 
1 cycle = 21 days 
 
Arm B : 
Cycles 1 to 3 : epirubicin 100 mg/m²  
 
5 fluorouracil 500 mg/m²  
 
cyclophosphamide 500 mg/m²  
 
1 cycle = 21 days 
Cycles 4 to 6 : ixabepilone 40 mg/m² 
 
1 cycle = 21 days 
For both arms:  
• 
The treatment will be given every 21 days if the neutrophil count is ≥ 1,500 / mm3 and 
the platelet count is ≥ 100,000 / mm3. 
• 
A blood cell and platelet count will be systematically performed in case of fever > 38.5°C and 
controlled 7 days later. 
 


 
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D) DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCTS (…) 
Treatment delay and dose adaptations in case of acute toxicities: 
Myelosuppression (both arms) 
On day D21 : if neutrophil count < 1,500 / mm3 or platelets < 100,000 / mm3, the treatment is postponed for 
7 days and pursued with the addition of G-CSF at each cycle for all the remaining cycles of 
both sequences. 
On day D28 : if the neutrophil count or platelets count do not allow continuation of the treatment, 
the treatment will be definitively stopped.  
In both arms, if no treatment delay due to neutropenia and/or if no G-CSF administration was required 
during the first 3 cycles, the first administration of docetaxel or ixabepilone (4th cycle of the sequential 
regimen) will be performed without any G-CSF support. Conversely, the G-CSF will be maintained during 
the first cycle of docetaxel or ixabepilone in case of previous delay of treatment due to neutropenia or 
previous G-CSF administration. 
Febril Aplasia (both arms) 
In case of a fever > 38.5°c occurring during a peri od of medullar aplasia (neutrophil count 
< 500 /mm3) and having required antibiotherapy or having lasted more than 24 hours, 
the treatment will be pursued with the same doses, but with addition of G-CSF in all remaining cycles of 
the experimental treatment (both sequences whatever the arm). 
In case another febrile episode (neutrophil count < 500 /mm3) occurs despite G-CSF, the doses of 
the products of the ongoing therapeutic sequence will be decreased by:  
 
FEC 100: 25% 
 
Docetaxel: 25% 
 
Ixabepilone: 20% 
in all remaining cycles of the sequence.  
Neurotoxicity 
Ixabepilone 
In case of a grade 2 neurotoxicity occurring during the ixabepilone sequence, the treatment will be 
decreased by 20% (32 mg/m²) in all remaining cycles. In case the grade 2 neurotoxicity is not resolved by 
decreasing the dose, ixabepilone will be definitively stopped. 
Docetaxel 
In case of a grade 2 neurotoxicity occurring during the docetaxel sequence, the treatment will be decreased 
by 25 % (75 mg/m²) in all remaining cycles.  
In case the grade 2 neurotoxicity is not resolved by decreasing the dose, docetaxel will be definitively 
stopped. 
THERAPEUTIC SCHEME (…) 
 
Beyond chemotherapy:  
(Treatments described bellow are not part of the study but local practices must be homogenized as follow): 
 
Breast irradiation is mandatory in case of conservative breast surgery for all patients and must 
begin within 8 weeks after the last course of chemotherapy.  
After total mastectomy, chest wall irradiation is mandatory for pT3-4 and/or ≥ 4N+. 
It is optional for intermediate risk patients (1-3N+ or pT2, grade III with lymphovascular invasion). 
Irradiation of internal mammary and supraclavicular nodes is mandatory for patients ≥ 4N+. It is 
optional in patients with 1-3N+ and in pT2N- tumors located in the inner or central quadrants of 
the breast. If sentinel node biopsy of internal mammary lymph nodes is done systematically, 
the internal mammary chain RT indication should be done according to the final results of 
the biopsy and investigator decision. 


 
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Axillary 
irradiation 
is 
not 
mandatory 
in 
case 
of 
large 
axillary 
node 
clearance 
(> or = 8). In case of massive axillary nodes involvement (80 to 100%) or Positive Sentinel Node 
(not followed by axillary dissection), the participating center should adopt its own policies regarding 
the benefit/risk ratio for such irradiation. 
Participating centers should adopt the same radiation technique and the same policies for all their 
patients.  
 
Hormonal treatment for patients with positive estrogen receptor  
(ER ≥10% in immunohistochemistry)  
o 
Premenopausal women: tamoxifen for 5 years 
o 
Postmenopausal 
women 
(over 
the 
age 
of 
60, 
or 
bilateral 
oophrectomy, 
or 
age 
≤ 
60 
with 
a 
uterus 
and 
amenorrhea 
for 
at 
least 
12 
months, 
or age ≤ 60 without a uterus and with FSH>30 IU/l) : aromatase inhibitors (AI) for 
5 years or tamoxifen if AI are contra-indicated.  
o 
For perimenopausal women (premenopausal status at time of randomization followed by 
secondary prolonged amenorrhea after chemotherapy over 1 year): tamoxifen 2/3 years + 
aromatase inhibitor 2/3 years or tamoxifen 5 years followed by aromatase inhibitor 
2/3 years. The switch in favour of AI will be allowed only if FSH > 30 IU/l and/or oestradiol 
< 30 ng/l. 
 
E) SAMPLE SIZE DETERMINATION and STATISTICAL CONSIDERATIONS 
To show a benefit of 5 % in the 5-year DFS (70 % in the reference arm vs. 75 % in 
the ixabepilone arm) corresponding to a relative risk of 0.81 (about 20% of relapse risk reduction) 2,500 
patients should be enrolled (1,250 patients in each arm) to ensure a power of 80 % (beta = 20 %) 
assuming a two-sided situation (Log rank test) and accepting a significance level of 5 %. A minimum of 682 
events are to be observed for ensuring a power of more than 80 % for detecting the pre-specified 0.81 
hazard ratio. 
This sample will allow us to show a gain of 6 % in 5-year DFS in the triple negative subgroup 
(corresponding to a relative risk of 0.77 and a relapse risk reduction of 23%) with a power of 80%. 
This triple-negative subgroup is considered as being equal to two thirds of the whole population (i.e. about 
1,700 patients). 
To avoid any increase of the type I error, the second analysis will be performed only if 
the difference observed on the whole population (main objective) is statistically significant. 
Randomizations will be stratified based on: 
- 
center 
- 
menopausal status (premenopausal status versus postmenopausal status at time of randomization) 
- 
triple negative tumors versus the remainder of the population (HER2-, PR -, ER+) 
 
After the enrolment of the first 300 patients, the hypothesis concerning the proportion of the triple negative 
subgroup will be verified. If the proportion of triple negative patients is not equal to two thirds of the whole 
population, the sample size will be re-calculated. 
 
One interim efficacy analysis will be performed 2 years after the recruitment of the last patient. 
The objective of this interim analysis is to assess whether it is possible to disseminate the results of 
the study earlier than the final 5-year analysis. This will be possible only in case of overwhelming results in 
favor of one of the treatment groups. The Peto procedure will be used, considering a p-value less or equal 
0.001 to declare the results as positive, in order to keep a type one error close of 0.05 for the final analysis. 
 
F) TRIAL DURATION 
INCLUSION PERIOD: 6 YEARS 
TREATMENT DURATION: 5 MONTHS 
FOLLOW-UP DURATION: 5 YEARS+5 YEARS OF LONG TERM FOLLOW-UP 
OVERALL TRIAL DURATION: 11 YEARS (MAIN CRITERION) 


 
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TABLE OF CONTENT 
 
1. RATIONAL OF THE TRIAL ......................................................................................................... 11 
1.1 Synthesis of prior results ........................................................................................................... 11 
1.2 Treatment’s data to be evaluated ............................................................................................... 12 
2. TRIAL’S OBJECTIVES ............................................................................................................... 16 
2.1 Main Objective ........................................................................................................................... 16 
2.2 Secondary Objectives ................................................................................................................ 16 
2.2.1 – Efficacy ................................................................................................................................................... 16 
2.2.2 – Toxicity ................................................................................................................................................... 16 
2.2.3 - Biology ..................................................................................................................................................... 16 
2.2.4 – Other objectives...................................................................................................................................... 17 
3. METHODOLOGY ........................................................................................................................ 18 
4. PATIENT SELECTION ................................................................................................................ 19 
4.1 Inclusion Criteria ........................................................................................................................ 19 
4.2 Non-inclusion Criteria ................................................................................................................ 20 
5. RANDOMIZATION ...................................................................................................................... 21 
6. TREATMENTS ............................................................................................................................ 22 
6.1 Description of the treatment to be evaluated .............................................................................. 22 
6.2 Labeling of treatment products .................................................................................................. 24 
6.3 Dispatch, distribution and accounting ........................................................................................ 24 
6.4 Course of the Treatment ............................................................................................................ 25 
6.4.1 Adjuvant chemotherapy ............................................................................................................................. 25 
6.5 Dose adaptation ........................................................................................................................ 27 
6.5.1 Hematological toxicities ............................................................................................................................. 27 
6.5.2 Extra-hematological toxicities .................................................................................................................... 27 
6.6 Retreatment criteria ................................................................................................................... 29 
6.7 Concomitant Treatments............................................................................................................ 29 
6.7.1 Growth factors ........................................................................................................................................... 29 
6.7.2 Hormonal therapy ...................................................................................................................................... 29 
6.7.3 Premedications .......................................................................................................................................... 29 
6.7.4 Prohibited concomitant treatments ............................................................................................................ 30 
6.8 Radiotherapy ............................................................................................................................. 31 
6.9 Hormonotherapy ........................................................................................................................ 31 
7. INCLUSION AND FOLLOW-UP ASSESSMENTS ...................................................................... 32 
7.1 Baseline assessment ................................................................................................................. 32 
7.2 Follow-up assessments during chemotherapy ........................................................................... 33 
7.3 Assessments at the end of radiotherapy .................................................................................... 34 
7.4 Follow-up visits .......................................................................................................................... 34 
8. PREMATURE END OF THE TREATMENT ................................................................................. 35 
9. TRIAL TERMINATION CRITERIA ............................................................................................... 35 
10. EVALUATION CRITERIA .......................................................................................................... 35 
10.1 Main criterion ........................................................................................................................... 35 
10.2 Secondary criteria .................................................................................................................... 36 
10.2.1 Efficacy .................................................................................................................................................... 36 
10.2.2 Toxicity .................................................................................................................................................... 36 
10.2.3 Quality of life ............................................................................................................................................ 36 
10.2.4 Other criteria ............................................................................................................................................ 36 
11. SUB-STUDIES .......................................................................................................................... 37 
12. SAMPLE SIZE DETERMINATION AND STATISTICAL ANALYSIS ......................................... 37 
12.1 Required number of subjects ................................................................................................... 37 
12.2 Statistical analysis ................................................................................................................... 38 
13. SERIOUS ADVERSE EVENTS ................................................................................................. 39 
13.1 General definition..................................................................................................................... 39 
13.2 Definition of an expected serious adverse event (E-SAE) ........................................................ 40 
13.3 Definition of unexpected serious adverse event (U-SAE) ......................................................... 40 


 
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13.4 Intensity criterion ..................................................................................................................... 40 
13.5 Measures to take in the case of a serious adverse event ......................................................... 40 
13.6 SAE follow-up .......................................................................................................................... 41 
14. INDEPENDENT DATA MONITORING COMMITTEE ................................................................ 42 
15. QUALITY INSURANCE AND QUALITY CONTROL ................................................................. 42 
16. DATA PROTECTION AND CONFIDENTIALITY MANAGEMENT ............................................ 42 
17. PUBLICATION OF RESULTS ................................................................................................... 43 
18. ETHICAL AND REGULATORY ISSUES ................................................................................... 43 
18.1 Ethic Committee (CPP) ............................................................................................................ 44 
18.2 Competent authority ................................................................................................................ 44 
18.3 Information and consent of the participants.............................................................................. 44 
18.4 Responsibility of the sponsor ................................................................................................... 46 
18.5 Responsibilities of the investigators ......................................................................................... 46 
18.6 Federation of the Patient Committees for Clinical Research in Cancerology ............................ 47 
19. REFERENCES .......................................................................................................................... 48 
Appendix 1 – Flowchart of investigations and study drugs administration ........................................ 51 
Appendix 2 – ECOG peformance status scale ................................................................................. 52 
Appendix 3 – Histopathological assessment and Central review ..................................................... 53 
Appendix 4 – Sample collection ....................................................................................................... 56 
Appendix 5 – Sub-studies ................................................................................................................ 58 
Appendix 6 – Serious Adverse Event Form ..................................................................................... 60 
Appendix 7 – Toxicity criteria (CTCAE) ............................................................................................ 62 
Appendix 8 – Products summaries .................................................................................................. 63 
 


 
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1. RATIONAL OF THE TRIAL 
 
Bonadonna [1] was the first who demonstrated that the addition of adjuvant 
chemotherapy (CMF) in patients presenting a breast cancer with node involvement 
improved disease-free survival (DFS) as well as overall survival (OS). Almost all of  
the clinical trials published to date confirm these results [2;3]. Recently, the mature 
results of taxane-based clinical trials [4,5,6,7,8,9,10,11,12] have demonstrated  
the benefits of adding taxanes in the adjuvant setting, in terms of DFS and OS  
for patients with a breast cancer with node involvement or node negative (HER2 
positive or negative patients). 
Despite better outcome with taxanes, some subgroups still have intermediate (basal 
like ER/PR/HER2 negative, HER2/PR negative) prognosis. It’s important to identify 
biologically these subgroups and to challenge new therapeutic direction. 
 
 
1.1 Synthesis of prior results 
 
THE PACS 01 TRIAL 
 
 
Clinical trial results [11] 
 
The PACS01 trial has been reported by UNICANCER BREAST Group [11]. This 
multicentric, prospective study included 1999 patients randomized to receive either 6 
cycles of FEC100 (5fluoro-uracil 500 mg/m²; epirubicine 100mg/m²; cyclophosphamide 
500 mg/m²) or 3 cycles of FEC 100 followed by 3 cycles of docetaxel (100 mg/m²). The 
main end-point was DFS and secondary end-points were OS and toxicity. Tamoxifen 
was given after chemotherapy for postmenopausal women with ER+ and /or PR+. 
After a protocol amendment tamoxifen was given to all patients with ER+ and/or PR+. 
The randomization was stratified on investigational center, age (less or more than  
50 years old) and the number of involved nodes. 
With a median follow up of 59,7 months the PACS01 trial demonstrated that  
the sequential use of docetaxel significantly improved DFS (78.3% vs 73.2%, HR : 
0.83) and OS (90.7% vs. 86.7%; HR:0.77) compared to 6 cycles of FEC 100.  
This advantage was more significant for patients with 1-3 involved nodes and age ≥50 
years.  
Both triple negative (ER/PR/HER2 negative) and PR/HER2 negative profiles are 
significantly associated to a worse prognosis. Moreover, although the adjunction  
of docetaxel significantly improves the DFS and OS of the whole population of PACS 
01, this sequential regimen does not improve significantly the outcome of the two 
subgroups [13, 14]. 


 
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Whole population 
Triple negative  
Non Triple negative 
 
DFS, 5 years 
65.5% 
77.3% 
p=0.001 
OS, 5 years 
83.3% 
89.4% 
p=0.004 
FEC arm 
 
 
 
DFS, 5 years 
63.0%* 
74.0% 
NS 
OS, 5 years 
79.8% 
87.1% 
NS 
FEC-D arm 
 
 
 
DFS, 5 years 
68.1%* 
80.5% 
p=0.020 
OS, 5 years 
87.0% 
91.0% 
NS 
* Triple negative subgroup : DFS by arm not statistically significative 
 
Whole population 
ER+/PR-/HER2- 
Non ER+/PR-/HER2-  
DFS, 5 years 
69.0% 
76.8% 
p=0.056 
OS, 5 years 
85.3% 
89.1% 
NS 
FEC arm 
 
 
 
DFS, 5 years 
68.1% 
73,2% 
NS 
OS, 5 years 
81.4% 
86,8% 
NS 
FEC-D arm 
 
 
 
DFS, 5 years 
69.9% 
80.4% 
p=0.047 
OS, 5 years 
88.8% 
91.4% 
NS 
 
These results indicate that despite better outcome with taxanes, some subgroups 
(triple negative, PR negative) still have poor prognosis. These subgroups could easily 
be biologically defined and justify innovative treatments. 
 
 
 
1.2 Treatment’s data to be evaluated  
 
EPOTHILONES 
Taxane, paclitaxel and docetaxel, promotes the polymerization of tubulin heterodimers 
into MTs and stabilizes preformed MTs under various set of depolymerizing conditions 
[15]. In the early 1990s a second class of cytotoxic natural product was discovered. 
These compounds have been termed epothilones. Epothilone possesses a paclitaxel-
like mechanism of action [16]. Epothilones are secondary metabolites that are 
produced by myxobacteria, Sorangium cellulosum. Two major fermentation products 
were reported, epothilone A and epothilone B, that differ only by the absence or 
presence of a methyl group at the trisubstituted epoxide moiety [17].  However, in 
contrast to paclitaxel, epothilones were also shown to inhibit the growth of cells 
overexpression, the P-gp efflux pump [18]. Epothilone have also been quoted as being 
significantly more water soluble than paclitaxel.  
Epothilones have been the subject of an extensive chemistry effort, which has 
culminated in no less than 17 different total syntheses of these natural products.  
Their most promising agent are deoxy-epothilone B, deoxy-epothilone F and the 15-
deoxy-15-aza-epothilone (Ixabepilone) [19,20] . 


 
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Ixabepilone 
 
o Preclinical data 
 
Ixabepilone is developed by Bristol Meyer Squibb [21]. It is a lactam analogue of 
epothilone B and has a mode of action similar to that of paclitaxel inducing MTs 
stabilization. Ixabepilone induces cell cycle arrest in G2/M transition and subsequent 
apoptotic cell death. Yamagushi et al. demonstrated in MDA-MB 468 cell, that 
ixabepilone induces apoptosis through a Bcl-2 suppressible pathway that controls  
a conformational change of the pro-apoptotic BAX protein [22]. 
Ixabepilone was as active as epothilone B in inducing cytotoxicity in a large panel  
of cancer cell lines and human tumor models.  
Ixabepilone retains its antineoplastic activity in cancer cells and human tumor models 
that have developed resistance to paclitaxel, overexpression of P-gp or mutation  
of β-tubulin.  
 
 
o Clinical data 
 
Ixabepilone demonstrated definite activity in metastatic setting for patients resistant to 
anthracycline (ORR= 42%) or resistant to anthracyclines and taxanes (ORR= 12-22%) 
or resistant to anthrayclines-taxanes and capecitabine (ORR=18%). 
 
 
Phase I trials [23,24,25] 
 
In one phase I monotherapy study, ixabepilone was administered once a day every  
3 weeks. 31 patients were treated at 6 dose levels. One patient at the first level 
(30mg/m²) presented a hypersensitivity reaction. Hypersensitivity reaction was 
prevented by oral antihistaminics (H1/H2). At the level of 65 mg/m², two patients 
experienced grade 4 neutropenia. At the level 50 mg/m² no DLT was observed and  
an antitumor activity was seen: 1 complete response, 3 partial responses and  
11 stable diseases. The PK/PD of Ixabepilone appears to be linear and produce dose-
dependant increase of tubulin polymerization in peripheral blood mononuclear cells. 
Three others phase I were reported in combination with carboplatinum or irinotecan or 
capecitabine.  
 
 
Ixabepilone and breast cancer in metastatic setting 
 
Clinical trial in patients previously treated by anthracyclines [26] 
 
Patients enrolled in this study had metastatic breast cancer and were previously 
treated with an anthracycline in the adjuvant and/or neoadjuvant setting. To avoid 
neuropathies seen with the original 50 mg/m2 over 1 hour regimen the infusion duration 
was extended to 3 hours. After observing increased mucositis and abdominal pain in 
patients treated with this regimen in other studies, the dose was reduced to 40 mg/m2 
over 3 hours every 21 days. Sixty-five women have been enrolled to the 40 mg/m2  
3-hour regimen; preliminary safety data are now available on 38 patients over 145 
cycles. Average age of the patients was 51 years (range 33-70 years) and the baseline 
ECOG performance status was equal to 0, 1, or unknown in respectively 19, 17, and 


 
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2 patients. Grade 3/4 neutropenia incidence was 24%/24%. Grade 3/4 non 
hematological toxicities occurred in 44% of patients and included myalgia (11%), 
arthralgia (5%), and fatigue (5%). Grade 3 neuropathy was equal to 16% compared  
to 37% for the 50 mg/m2 per 1 hour regimen. Overall response rate was 41%(29-54), 
median duration of response 8.2 months and overall survival 22 months. This analysis 
indicates that Ixabepilone, administered at the dose of 40 mg/m2 IV over 3 hours, is  
an active therapy and has acceptable safety in patients with metastatic breast cancer 
who have received prior (neo)adjuvant anthracycline therapy. 
 
Clinical trial in patients previously treated by anthracyclines and taxanes [27] 
 
This study was designed to evaluate the efficacy and safety of Ixabepilone in women 
with metastatic breast cancer previously treated with both an anthracycline and  
a taxane. Patients must have progressed during or within 4 months of their taxane 
therapy for metastatic disease (6 months of adjuvant therapy). To avoid neuropathies 
seen with the initial 50 mg/m2 over 1 hour regimen, the infusion duration was extended 
to 3 hours. After observing increased mucositis and abdominal pain in patients treated 
with this regimen in other studies, the dose was reduced to 40 mg/m2 over 3 hours 
every 21 days.  
Forty-nine women have been enrolled to the 40 mg/m2/3-hour regimen; preliminary 
safety data are now available on 42 patients over 148 cycles. Median age was  
52 years (range 30-81 years); ECOG PS 0/1 in 10/32; and 38 of 49 patients 
progressed within 30 days of last taxane dose. Grade 3 and 4 neutropenia occurred  
in 40% and 20%, respectively. Febrile neutropenia incidence was 5%. Drug-related 
Grade 3/4 non hematologic toxicities occurred in 36% of the patients and included: 
fatigue (21%), myalgia (7%), nausea/vomiting (5% each), constipation (5%), and 
diarrhea (2%). Grade 3 sensory neuropathy was 7% compared to 25% for  
the 50 mg/m2/1-hour regimen. Among the 28 patients, now out of the study, only  
1 (3.6%) discontinued due to peripheral neuropathy (at Cycle 7) compared to 25% for 
the 50 mg/m2/1-hour regimen. Preliminary efficacy data collected on 49 patients have 
been reported: partial responses were reported in 6 patients and stable disease (SD) 
in 22 patients (4 SD patients are still ongoing). Four of the six responders had 
previously progressed within 1 month of their last taxane dose and at least 2 have 
received Ixabepilone for a longer duration than their prior taxane. Eight SD patients 
have received 6 cycles or more. This preliminary analysis indicates that Ixabepilone, 
administered at 40 mg/m2 IV over 3 hours, has a favorable safety profile and is active 
in patients with anthracycline pre-treated and strictly defined taxane-resistant 
metastatic breast cancer. 
 
Clinical trial in patients previously treated by anthracyclines, taxanes and  
capecitabine [28] 
 
This study was designed to evaluate the efficacy and safety of Ixabepilone in women 
with metastatic breast cancer previously treated with both an anthracycline, a taxane 
and capecitabine. One hundred twenty six have been enrolled to the 40 mg/m2/3-hour 
regimen.  
Grade 3/4 neutropenia incidence was 31%/23%. Grade 3/4 non hematological 
toxicities included grade 3/4 sensory neuropathy (14%/1%). Overall response rate was 
18%, median duration of response 5,7 months and overall survival 8,6 months. 


 
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Ixabepilone in neoadjuvant setting [29] 
 
Women with invasive stage IIA-IIIB breast cancer with tumors ≥3 cm diameter received 
40 mg/m2 ixabepilone as a 3-hour infusion on Day 1 for up to four 21-day cycles, 
followed by surgery within 3-4 weeks of completion of chemotherapy. Biopsies  
for analysis of mRNA expression were obtained both pre- and post-therapy. Adjuvant 
chemotherapy with an anthracycline combination regimen followed by radiotherapy 
and tamoxifen were administered as indicated. Pathological response was assessed 
using the Sataloff criteria. A total of 164 patients were enrolled. Preliminary results are 
available for 96 patients.  
Median age was 56 years (range 27-79) and 99% were ECOG 0. TNM status T2/T3/T4 
was 57%/23%/16%, Grade 1/2/3/unknown was 11%/40%/24%/25% and ER status  
of +/-/unknown was 51%/46%/3%. A complete pathological response (pCR) in  
the breast was achieved in 19 patients (19%), of whom 13 (13%) also had pCR in  
the axillary lymph nodes. Grade 3/4 neutropenia occurred in 14%/5%. Grade 2 
toxicities for arthralgia/myalgia neuropathy and mucositis were 23%, 12% and 3%; 
grade 3 toxicities were 2%, 2% and 1% respectively. ER has been identified as 
predictive marker for the treatment response of ixabepilone. 
 
Conclusion: 
 
Ixabepilone demonstrated definite activity in metastatic setting for patients resistant  
to anthracycline (ORR= 42%) or resistant to anthracyclines and taxanes (ORR= 12-
22%) or resistant to anthrayclines-taxanes and capecitabine (ORR=18%). 
Roché et al. demonstrated that Ixabepilone is active in triple negative (HER/ER/PR 
negative) patients in neoadjuvant and metastatic setting [30].  
 
Efficacy in neoadjuvant trial: 
 
 
Triple negative: n=42 
Non triple negative: n=119 
ORR , n, (%) 
27 (64) 
71 (60) 
pCR breast, n (%) 
11 (26) 
18 (15) 
pCR breast+ lymph nodes, n(%) 
8 (16) 
9 (8) 
 
Efficacy in metastatic setting (patients anthracyclines pretreated): 
 
 
Triple negative : n=11 
Non triple negative: n=54 
ORR, n, (%) 
6 (55) 
21 (39) 
Duration of response month 
4,6 
8,3 
PFS, month 
4,6 
5,7 
 
 
Ixabepilone has notable clinical activity in breast cancer patients with triple-negative 
tumors, a population with extremely limited treatment options and poor prognosis  
in arm FEC-D of the PACS 01 trial. Ixabepilone represents a promising therapeutic 
option for these patients in the adjuvant setting.   


 
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Node negative patients with poor prognosis and who did not receive adjuvant 
treatment show the same evolutivity profile as node positive patients. Adjuvant 
chemotherapy improves both recurrence free and overall survival in these patients. 
The intergroup trial [8] shows that with a taxane-based (docetaxel) anthracycline free 
regimen the recurrence risk was decreased by 27%. Thus, it seems legitimate to offer 
a chemotherapy comprising taxane to these patients. 
 
 
 
The objective of this prospective, multicentric, phase III clinical trial is to evaluate  
the benefit of a sequential regimen associating FEC100 and Ixabepilone in adjuvant 
treatment of non metastatic, poor prognosis breast cancer defined as triple-negative 
tumor with node positive disease (HER2 negative-ER negative-PR negative) or HER2 
negative and PR low (less than 10% in immunochemistry) in patients with node 
positive or node negative disease. 
 
2. TRIAL’S OBJECTIVES 
 
2.1 Main Objective 
 
The main objective of this trial is to evaluate the benefit from the sequential 
administration of 3 FEC100 followed by 3 cycles of Ixabepilone versus standard 
epirubicin + docetaxel based protocol on the disease-free survival at 5 years.  
See definition of the DFS section 10.1. 
 
 
2.2 Secondary Objectives 
 
2.2.1 – Efficacy 
 
o For the Whole Population : to compare the impact of ixabepilone and docetaxel 
on the distant metastasis free survival (DMFS), the event free survival (EFS) 
and the overall survival (OS). See definition of an event section 10.2.1. 
 
o For both Triple Negative subgroup and [ER+/ PR-/HER2-] subgroup :  
to compare the impact of ixabepilone and docetaxel on the DFS, DMFS, EFS 
and OS. 
 
2.2.2 – Toxicity 
 
o To compare the safety profiles of the two sequential chemotherapy regimens. 
 
2.2.3 - Biology 
 
o Gene profiling: to identify and/or validate predictive gene expression profiles  
of clinical response / resistance to the two sequential treatment regimens. 
 
o Frozen and fixed tumor and frozen serum banking will be prospectively 
performed for future translational studies in both genomics and proteomics 
(transcriptome and proteome analysis, tissue array analysis). 
 


 
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2.2.4 – Other objectives 
 
o Cost-effectiveness evaluations. 
o Assessment of the quality of life in both groups of patients. 


 
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3. METHODOLOGY 
 
This trial is an open label, multicentric randomized phase III trial, comparing two 
treatment arms: sequential regimen (3 FEC100 + 3 docetaxel), versus sequential 
regimen (3 FEC100 + 3 ixabepilone) in the treatment of non metastatic, operable, poor 
prognosis breast cancer. 
 
 
Surgery 
Patients T1-3 N0-1 M0
Patients N-, SBR II/III, T2-3
HER2- / ER- / PR- 
49 days 
Arm A
 
3FEC – 3D 
RANDOMIZATION 
+ / - hormonal therapy (ER +) 
 
Radiotherapy  
Patients N+ 
 HER2- / ER- / PR- 
or HER2- / PR- 
Arm B
 
3FEC – 3I 
Regional pathological 
analysis :  
validation of pathological 
eligibility criteria  
(ER/PR/HER status) 
7 days 


 
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4. PATIENT SELECTION 
 
4.1 Inclusion Criteria 
 
All the following conditions are to be fulfilled: 
1) 
Women aged from 18 to 70 years, 
2) 
Histologically proven invasive unilateral breast cancer (regardless of the type), 
3) 
Initial clinical condition compatible with complete initial resection, 
4) 
No residual macro or microscopic tumor after surgical excision, 
5) 
Beginning of chemotherapeutic treatment no later than day 49 after the initial 
surgery, 
6) 
Node positive disease (positive sentinel node or positive axillary clearance) (N+)  
or node negative disease (N-) with the following criteria : SBR II / III and 
pT>20mm, 
7) 
Patient presenting one of the following criteria: 
o for N+ patients: triple negative tumor [HER2 negative and ER negative 
and PR negative] or [HER2 negative and PR negative status], 
o for N- patients: triple negative tumor only [HER2 negative and ER 
negative and PR negative]  
HER 2 negativity is defined as IHC 0, or IHC 1+, or [IHC 2+ and FISH or CISH 
negative]. 
Hormonal receptor (progesterone and estrogen receptors) negativity is defined as 
a rate <10% in immunohistochemistry. 
All tumors will be centrally analysed before randomization by a regional web  
of reference pathologists to assess final diagnosis of HER2 expression and 
hormonal receptor status. 
8) 
No clinically or radiologically detectable metastases (M0), 
9) 
No peripheral neuropathy > 1, 
10) WHO Performance status (ECOG) of 0 or 1, 
11) Adequate recovery from recent surgery (at least one week must have elapsed 
from the time of a minor surgery (excluding breast biopsy); at least three weeks 
for major surgery), 
12) Adequate hematological function (neutrophil count ≥ 2x109/l,  
platelet count ≥ 100x 109/l, Hemoglobin > 9g/dl), 
13) Adequate hepatic function: ASAT and ALAT ≤ 1.5 ULN, alkaline phosphatase ≤ 
2.5 ULN, total bilirubin ≤ 1.0 ULN, 
14) Adequate renal function: serum creatinine ≤ 1.5 ULN, 
15) Patients accepting contraception intake during the overall length of treatment if  
of childbearing potential, 
16) Adequate 
cardiac 
function, 
LEVF 
value 
≥ 
50% 
by 
Muga 
scan 
or 
echocardiography, 
17) Signed written informed consent.


 
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Women of childbearing potential (WOCBP) must be using an adequate method  
of contraception to avoid pregnancy throughout the study and for up to 8 weeks after  
the last dose of chemotherapy in such a manner that the risk of pregnancy is 
minimized. WOCBP include any woman who has experienced menarche and who has 
not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or 
bilateral oophrectomy) or is not postmenopausal [defined as amenorrhea ≥ 12 
consecutive months; or women on hormone replacement therapy (HRT) with 
documented serum follicle stimulating hormone (FSH) level > 30 IU/l]. Even women 
who are using oral, implanted or injectable contraceptive hormones or mechanical 
products such as an intrauterine device or barrier methods (diaphragm, condoms, 
spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile 
(e.g., vasectomy), should be considered to be of child bearing potential. WOCBP must 
have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) within 72 hours prior to the start of study medication. 
 
 
4.2 Non-inclusion Criteria 
 
1) 
Bilateral breast cancer or patient with controlateral DCIS, 
2) 
Any 
metastatic 
impairment, 
including 
homolateral 
sub-clavicular 
node 
involvement, regardless of its type, 
3) 
Any 
tumor 
≥ 
T4a 
(UICC1987) (cutaneous 
invasion, 
deep 
adherence, 
inflammatory breast cancer), 
4) 
HER2 overexpression defined as [IHC 3+] or [IHC 2+ and FISH or CISH positive], 
5) 
Any 
clinically 
or 
radiologically 
suspect 
and non-explored 
damage 
to  
the controlateral breast, 
6) 
Any chemotherapy, hormonal therapy or radiotherapy before surgery, 
7) 
Concomittant treatment with the following strong inhibitors of CYP3A4 from  
72 hours prior to the initiation of study therapy until end of treatment with 
ixabepilone or docetaxel: amiodarone, clarithromycin, amprenavir, delavirdine, 
voriconazole erythromycin, fluconazole, itraconazole, ketoconazole, indinavir, 
nelfinavir, ritonavir, and saquinavir. 
8) 
Previous cancer (excepted cutaneous baso-cellular epithelioma or uterin 
peripheral ephitelioma) in the preceding 5 years, including invasive controlateral 
breast cancer, 
9) 
Patients already included in another therapeutic trial involving an experimental 
drug, 
10) Patients with other concurrent severe and/or uncontrolled medical disease or 
infection which could compromise participation in the study, 
11) LEVF < 50% (MUGA scan or echocardiography), 
12) Clinically significant cardiovascular disease (e.g. unstable angina, congestive 
heart failure, uncontrolled hypertension (>150/90), myocardial infarction or 
cerebral vascular accidents) within 6 months prior to randomization, 
13) Known prior severe hypersensitivity reactions to agents containing Cremophor EL,


 
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14) Women of childbearing potential who are unwilling or unable to use  
an acceptable method to avoid pregnancy for the entire study period and up to  
8 weeks after treatment completion, 
15) Women who are pregnant or breastfeeding. Adequate birth control measures 
should be taken during study treatment phase, 
16) Women with a positive pregnancy test en enrollment or prior to study drug 
administration, 
17) Patients with any psychological, familial, sociological or geographical condition 
potentially hampering compliance with the study protocol and follow-up schedule; 
those conditions should be discussed with the patient before registration in  
the trial, 
18) Individual deprived of liberty or placed under the authority of a tutor. 
 
 
5. RANDOMIZATION 
 
Screening : prior to entering into the PACS 08 trial, all patients defined by a local non 
reference pathologist as triple negative or PR-/HER2- patient should be requested  
to sign a screening informed consent to consent to the sending of a tumor sample  
to the local reference pathologist for validation of the pathological diagnosis, and will 
be registered in a screening file. 
 
After the basal assessment and all inclusion / non inclusion criteria are validated and 
the “study” written informed consent is signed, the eligible patients will be randomized 
to receive either the arm A regimen (3 FEC100 + 3 docetaxel) or the arm B regimen  
(3 FEC100 + 3 ixabepilone). 
 
Patient’s 
randomization 
is 
performed 
via 
a 
web 
platform 
(ATLANSTAT).  
To randomize patients, please connect to the website: www.atlanstat.com. 
For further information, please refer to the current randomization’s SOP. 
 
Randomization will be stratified based on: 
- the center, 
- the menopausal status (premenopausal versus postmenopausal patients), 
- triple negative patients (HER2- / PR- / ER-) versus the remainder  
of the population (HER2- / PR– patients) 
 
The treatment must begin within 49 days following the date of surgery.  
 


 
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6. TREATMENTS 
 
6.1 Description of the treatment to be evaluated 
 
Ixabepilone 
Ixabepilone for injection and its vehicle for constitution (diluent) will be supplied 
by BMS Pharmaceutical Research Institute. 
 
Ixabepilone (BMS-247550) is a semi synthetic derivative of the natural product 
epothilone B, a non-taxane tubulin polymerization agent obtained by fermentation  
of the myxobacteria Sorangium cellulosum. Ixabepilone has a molecular formula  
of C27H42N2O5S and its molecular weight is 506.71 grams/mole. Ixabepilone for 
injection is supplied as a lyophilized, white to off-white, whole or fragmented cake  
in a vial. The drug product is available as a 15 mg/vial. The vial containing vehicle for 
constitution of ixabepilone for injection, 8.0 mL/vial, will be supplied with the freeze 
dried product. The vehicle is a mixture of dehydrated alcohol + BMS-purified 
polyoxyethylated castor oil, which appears as a clear to slightly hazy, colorless to pale 
yellow solution. One vial of 8.0 mL/vial vehicle product is provided whenever a  
15 mg/vial of ixabepilone for injection is supplied. 
 
Packaging: 
Both ixabepilone for injection and vehicle for constitution are packaged in Type I glass 
vials, stoppered with butyl rubber closures and sealed with aluminum seals.  
A sufficient excess of drug and vehicle is provided in the respective vials to allow for 
withdrawal losses.  
 
Storage requirements / Stability: 
Ixabepilone for injection should be stored refrigerated at 2°C to 8°C (36 to 46°F) and 
should be protected from light.  The vehicle for constitution should be stored at 2°C  
to 8°C or 2°C to 25°C.  If the vehicle is refrigerated, it must be allowed to warm to room 
temperature before constitution of the lyophile. After initial constitution with  
the accompanying vehicle, the solution may be stored in the vial for a maximum of one 
hour at room temperature and room light. The constituted solution should not be stored 
in the syringe. After final dilution with LRI to ixabepilone concentration between  
0.2 mg/mL and 0.6 mg/mL, the solution is stable when stored at room temperature and 
room light for a maximum of 6 hours. Administration of the entire infusion volume must 
be completed within the 6-hour time period as noted above.  LRI should be used to 
flush the IV line or extension set at the end of the infusion. 
 
Preparation and Administration: 
Prior to constitution of the lyophile, the vehicle should be kept at room temperature  
for approximately 1 hour. Using a suitable syringe, slowly inject the appropriate volume 
of vehicle into the vial of ixabepilone. Gently swirl the vial until the lyophile is 
completely dissolved. When completely dissolved the solution concentration of 
ixabepilone is 2 mg/ml. This solution must be further diluted to a final ixabepilone 
concentration ranging from 0.1 mg/mL to 0.6 mg/mL before administration  
to the subject.  
For dilution, an infusion fluid that maintains the stability of ixabepilone must be used, 
such as: 
o Lactated Ringer’s Injection (LRI) with pH from 6.0 to 7.5 
o PLASMA-LYTE A Injection pH 7.4® with pH from 6.5 to 8.0 


 
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o 0.9% Sodium Chloride Injection, with pH adjusted to > 6.0 with Sodium 
Bicarbonate Injection. 
Withdraw 
the 
appropriate 
volume 
of 
the 
constituted 
solution 
containing  
2 mg/mL of active drug, and transfer the constituted solution into the IV bag containing 
the appropriate volume of infusion fluid to achieve the final desired concentration of 
ixabepilone.  
Dilution in a 250 mL infusion bag is sufficient in most cases to obtain the final required 
concentration of ixabepilone. 
The infusion must be administered through an appropriate inline filter with  
a microporous membrane of 0.22 to 5.0 microns. Infusion fluid should be used to flush 
the IV line or extension set at the end of the infusion if flushing is required.  
Any remaining solution should be discarded according to the institutional procedures 
for cytotoxics. 
 
Note 15 mg/vial:  The label fill for the drug is 15 mg/vial lyophile, which is to be 
constituted to a concentration of 2 mg/ml with the vehicle. To account for 
via/needle/syringe (VNS) loss the actual amount of drug in the vial is 16 mg (+/- 3%). 
Hence the drug should be constituted using 8.0 mL of the vehicle for constitution  
(to achieve a concentration of ixabepilone of 2 mg/ml). 
 
The following infusion components have been qualified for use with Ixabepilone: 
 
IV sets containing an in-line 0.22 micron filter: 
o Baxter Vented Paclitaxel Set (Catalog # 2C7553) 
o Abbott Primary IV Plumset (Catalog #11947) 
 
IV sets not containing an in-line 0.22 micron filter: 
o McGaw AccuPro Pump Nitroglycerin IV Set (Catalog # V8333) 
o Clintec IV Fat Emulsion Set (Catalog # 2C1105) 
 
Filter Extension Sets (to be used with IV sets not containing an in-line filter): 
o Braun Filtered Extension Set with 5 Micron Filter (Catalog #FE-5010Y) 
 
The infusion must be administered through an appropriate in-line filter with  
a microporous membrane of 0.20 to 5.0 microns. 
Diluted ixabepilone solutions may also be administered using a syringe pump and 
polyethylene-lined extension sets. 
 
 
Incompatibilities: 
In order to minimize subject exposure to the plasticizer di-(2-ethylhexyl)phthalate 
(DEHP) which may be leached from some brands of polyvinyl chloride (PVC) infusion 
bags or administration sets, diluted ixabepilone solutions should be stored in bottles 
(glass, polypropylene) or plastic bags (polyethylene, polypropylene, polyolefin, 
ethylene-vinyl-acetate) and administered through polyethylene-lined administration 
sets plasticized with TOTM (trioctyl trimellitate). IV sets and components, including 
filters 0.20 to 0.22, typically used for the administration of paclitaxel, have been found 
to be compatible with infusions of BMS-247550. Lactated Ringers Injection (LRI) in 
non-DEHP Excel bags is available from B. Braun McGaw, Inc., and can be used for 
preparing the infusion. 


 
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Safety Precautions 
Appropriate mask, protective clothing, eye protection, gloves and Class II 
vertical-laminar-airflow safety cabinets are recommended during preparation and 
handling. 
 
6.2 Labeling of treatment products 
 
Investigational drugs supplied by the sponsor (Ixabepilone and docetaxel for N- 
patients randomized in arm A) will be labeled in accordance with the guidelines  
of the annex 13 of the EEC directive: Good Manufacturing Practices for  
the manufacture of investigational medicinal products (revised and adopted in July 
2003).  
Other medicinal products will be supplied by the pharmacies of the health care centers.  
Packaging will be made by the CRO CREAPHARM. 
 
 
6.3 Dispatch, distribution and accounting  
The distribution of the investigational medicinal products supplied to the health care 
centers’ pharmacies by the sponsor will be performed by CREAPHARM in conformity 
with the Good Distribution Practices.  
The pharmacist of the health care centre will acknowledge reception of all shipments 
by returning to the distributor a duly completed receipt. 
Investigational medicinal products will have to be stored in locked room with limited 
access and in accordance with the recommendations of the manufacturer (see section 
6.1).  
It is the responsibility of the Investigator to ensure that investigational product is only 
dispensed to study subjects. The investigational product must be dispensed only from 
official study sites by authorized personnel according to local regulations.  
The pharmacist of the health care centre will keep accurate records of the drugs 
delivered, used, unused and/or returned by the patient.  
The clinical research assistant mandated by the sponsor will be in charge of verifying 
the accounting records for the supplied medicinal products and ensure that  
an accounting form is validated and signed by the pharmacist of the health care center 
prior to any demand for destruction.  
Drug destruction:  
Unused investigational product will be destroyed on site. It is Investigators 
responsibility to ensure that arrangements have been made for the disposal, written 
authorization has been granted, procedures for proper disposal have been established 
according to applicable regulation and guidelines and institutional procedures, and 
appropriate records of the disposal have been documented.. 
 


 
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6.4 Course of the Treatment  
 
6.4.1 Adjuvant chemotherapy 
 
After randomization, the patients will receive one of the following treatments within 49 
days after surgery: 
 
Arm 1: 
 
Cycles 1 to 3: 
D1: epirubicin 100 mg/m²  
 
D1: 5 fluorouracil 500 mg/m²   
 
D1:cyclophosphamide 500 mg/m² 
 
1 cycle = 21 days 
 
Cycles 4 to 6:  
D1: docetaxel 100 mg/m² , 1-hour IV infusion 
 
1 cycle = 21 days 
 
Premedication: 
A pre-medication will be systematically associated to the treatment on the first cycle 
and all the others as well:  
- prednisolone (Solupred) 50 mg, oral route, at H -12, H -3 et H - 1, that is to say  
the day before, the morning and an hour before the docetaxel injection, then 60 mg 
every 12 hours the next 2 days (H+12,H+24,H+36), i.e. 6 intakes in total. 
- or methylprednisolone (Medrol), 48mg at each intake according the same modalities 
as described above.  
 
Arm 2: 
 
Cycles 1 to 3: 
epirubicin 100 mg/m²  
 
5 fluorouracil 500 mg/m²  
 
cyclophosphamide 500 mg/m²  
 
1 cycle = 21 days 
 
Cycles 4 to 6:  
ixabepilone 40 mg/m² , 3-hour IV infusion.  
 
1 cycle = 21 days 
 
Premedication: 
All patients must be premedicated before each treatment with Ixabepilone to prevent  
a hypersensitivity reaction. The regimen described below (regimen 1) is  
the premedication regimen recommended for routine use: 
Regimen 1 : premedicate approximately one hour prior to the infusion of Ixabepilone 
with: 
a) Oral H1 blocker (may consist of diphenhydramine 50 mg or equivalent H1 
blocker), and 
b) Oral H2 blocker (may consist of ranitidine 150 - 300 mg or cimetidine 300 - 800 
mg or nizatidine 150 - 300 mg or famotidine 20 - 40 mg or other H2 blocker). 
 
Note that, in the event of patient intolerability to the antihistamines specified, 
alternatives may be substituted at the Investigator’s discretion. In addition, if  
the specified antihistamine is not available, alternate antihistamines may be substituted 
(including intravenous formulations at equivalent doses). 


 
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Patients will receive a 3-hour IV infusion of ixabepilone at 40 mg/m2. Study therapy will 
be administered on Day 1 of every 21-day cycle, for a maximum of 3 continuous 
cycles. A cycle may be delayed for a maximum of 2 weeks due to drug-related toxicity. 
See Section 6.5 for re-treatment criteria.  
Patients who experience unacceptable toxicity at any cycle will be discontinued from 
ixabepilone. Subsequent therapy for these patients is at the investigator’s discretion. 
 
The details of preparation of ixabepilone infusion are described in section 6.1. 
 
A nurse must be present in the immediate treatment area throughout the infusion.  
A physician must be in close proximity to the patient treatment area. 
 
Hypersensitivity Reactions 
Ixabepilone is formulated in polyoxyethylated castor oil (CremophorEL), thus, 
hypersensitivity reactions may occur. Therefore, patients should be monitored closely 
for any signs or symptoms of hypersensitivity. Appropriate emergency equipment and 
medications (e.g., epinephrine, corticosteroids, antihistamines) should be made 
available in the event of an HSR. Refer to Section 6.7.3 for additional recommended 
premedication regimens (Regimen 2 and 3) to prevent hypersensitivity reactions in 
patients who developed hypersensitivity reactions despite premedication with Regimen 
1. 
A hypersensitivity reaction will generally occur within seconds or minutes of drug 
administration. Reactions may include urticaria, dyspnea, bronchospasm, angiodema, 
hypotension, tachycardia or occasionally cardio-respiratory arrest. In case of 
hypersensitivity reactions, the Investigator should institute treatment measures 
deemed medically appropriate. 
 
 
For both arms:  
• The treatment will be performed every 21 days if the neutrophil count is  
≥ 1,500 / mm3 and the platelet count is ≥ 100,000 / mm3. 
• A blood cell and platelet count will be systematically performed in case of fever 
> 38.5°C and controlled 7 days later. 
• If the calculated body surface area is greater than 2.2 m², the administered dose 
will be established on the basis of 2.2 m² and will not exceed that value. 
• In calculating surface areas, actual heights and weights should be used. 
Adjustments will not be made to “ideal” weight. 
• The total dose delivered should be rounded to the nearest mg. 
• After confirming that the required volume of experimental drug has been 
administered, the solution remaining in the line and container should be 
disposed of per institution policies for cytotoxics disposal. 
• The use of refrigerated helmets is allowed. 
 


 
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6.5 Dose adaptation 
 
The following adaptation concerning dosage and schedule of administration must be done in 
case of acute toxicities. 
No dose re-escalation will be allowed after dose reduction.  
Only one dose reduction will be allowed. 
If toxicities listed below recur after dose reduction, treatment should be discontinued and  
the patient should switch to FEC or TAXOTERE regimen. 
 
6.5.1 Hematological toxicities 
 
Myelosuppression (both arms) 
On day D21 : if neutrophil < 1,500 / mm3 or platelets < 100,000 / mm3, the treatment is 
postponed for 7 days and pursued with the addition of G-CSF (Neulasta®) at each cycle for all  
the remaining cycles of both sequences. 
On day D28 : if the neutrophil or platelets count does not allow re-treatment (neutrophil 
<1,500/mm3 or PLT<100,000/ mm3), the treatment will be definitively stopped.  
In both arms, if no treatment delay due to neutropenia and/or if no G-CSF administration was 
required during the first 3 cycles, the first administration of docetaxel or ixabepilone (4th cycle 
of the sequential regimen) will be performed without any G-CSF support. Conversely, the G-
CSF will be maintained during the first cycle of docétaxel or ixabepilone in case of previous 
delay of treatment due to neutropenia or previous G-CSF administration.  
 
Febrile aplasia (both arms) 
In case of a fever > 38.5°c occurring during a peri od of medullar aplasia  
(neutrophil < 500/mm3) and having required antibiotherapy or having lasted more than  
24 hours, the treatment will be pursued with the same doses, but with addition  
of G-CSF (Neulasta®) in all remaining cycles of the experimental treatment (both sequences 
whatever the arm). 
 
In case another febrile aplasia episode occurs despite G-CSF, the doses of the products of  
the ongoing therapeutic sequence will be decreased by:  
 
FEC 100: 25% 
 
Docetaxel: 25% 
 
Ixabepilone: 20% 
in all remaining cycles of the sequence. 
 
6.5.2 Extra-hematological toxicities 
 
Perturbations of hepatic function: 
In case of observed Liver biologic abnormalities after FEC Regimen and/or during Ixabepilone 
or Docetaxel regimen, the Treatment administration will be done according to the following 
table: 
  
Toxicity  
Modification  
Transaminases > 1.5 ULN  
and Alkaline phosphatase > 2.5 ULN 
Decrease the dose of Ixabepilone by 20%
Decrease the dose of Docetaxel by 25% 
Total bilirubin > 1 ULN or  
Transaminases (AST/ALT) > 3.5 ULN  
and Alkaline phosphatase > 6 ULN 
Stop 
Treatment
(either 
Docetaxel 
or
Ixabepilone) depends on the arm 
 
 
 
 
 
 


 
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Neurotoxicity 
Ixabepilone 
In case of a grade 2 neurotoxicity occurring during the ixabepilone sequence, the treatment will 
be decreased by 20% (32 mg/m²) in all remaining cycles.  
In case the grade 2 neurotoxicity is not resolved by decreasing the dose, ixabepilone will be 
definitively stopped. 
 
Docetaxel 
In case of a grade 2 neurotoxicity occurring during the docetaxel sequence, the treatment will 
be decreased by 25 % (75 mg/m²) in all remaining cycles.  
In case the grade 2 neurotoxicity is not resolved by decreasing the dose, docetaxel will be 
definitively stopped. 
 
Mucositis 
Grade 1 or 2 : 
No dose modification is planned; 
Grade 3 and 4 : The dose of Docetaxel and FEC will be decreased by 25% and  
the dose of Ixabepilone will be decreased by 20% 
for all the remaining cycles.  
 
Other secondary effects  
- For grade 3 toxicities (alopecia and anemia excepted), the treatment must be postponed for 
at 
most 
2 
weeks 
with 
respect 
to 
the 
theoretical 
date 
until 
reversion  
to a grade ≤ 1 is obtained. 
- If reversion to a grade ≤1 within a 2 week period is not obtained, the patient is withdrawn from 
the treatment. 
- In case of grade 4 toxicity (alopecia excepted), the patient is withdrawn from  
the treatment. 
 
No dose modification is planned for nail and hair disorder. 
 
All dose reductions for ixabepilone according to toxicity type are summarized  
in the following table: 
 
Table A:
Modifications for ixabepilone
Toxicity
Platelets ≤ 25 x 109/L 
decrease dose to 32  mg/m2 
Grade 3 thrombocytopenia with significant bleeding or 
requiring transfusion 
decrease dose to 32  mg/m2 
Any Grade 3 extra hematological toxicity other than 
neuropathy or arthralgia/myalgia or fatigue 
decrease dose to 32  mg/m2 
Grade 2 neuropathy (motor or sensory) resolving to Grade 1 
decrease dose to 32  mg/m2 
Grade 3 neuropathy (motor or sensory), and Grade 2 
neuropathy not resolving to  Grade 1 
discontinue ixabepilone 
 
 


 
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6.6 Retreatment criteria 
 
For both arms, patients may be retreated if ANC ≥ 1,500/mm3, platelets ≥ 
100,000/mm3 and treatment-related non-hematologic toxicity has resolved to baseline 
or ≤ Grade 1 (excluding Grade 2 alopecia and Grade 2 fatigue, for which resolution is 
not required). 
 
If the patient fails to meet criteria for retreatment on Day 22, then retreatment should 
be delayed and the patient should be re-evaluated at least weekly. See section 6.5 
(Dose modifications) if the retreatment delay is due to toxicity. Initiation of subsequent 
cycles may be delayed for a maximum of two weeks. Any patient who fails to recover 
from a treatment-related toxicity to baseline or Grade 1 (except Grade 2 alopecia and 
Grade 2 fatigue) within two weeks of scheduled retreatment will be discontinued from 
treatment. 
 
6.7 Concomitant Treatments 
 
The prescriptions that are not related to cancer treatment will be noted in the case 
report form.  
 
6.7.1 Growth factors  
 
G-CSF (filgrastim) must be used in case of febrile neutropenia preventing the 
therapeutic compliance for all remaining cycles of the therapeutic sequence (see 
chapter 6.5.1).  
The use of prophylactic G-CSF before the second sequence of treatment (C4 to C6) is 
recommended. 
The use of prophylactic G-CSF (primary prophylaxis) is allowed at investigators’ 
discretion and following the institution standard of care. 
 
Growth factor use must be consistent with product label. Growth factor may not be 
given for 24 hours before or after cytotoxic chemotherapy including ixabepilone. 
 
6.7.2 Hormonal therapy  
 
Hormonal therapy will be prescribed at the end of chemotherapy courses as described 
in section 6.9 with the following policies: 
 
- 
each center shall treat all patients homogeneously and following the protocol (refer 
to section above in which hormonal therapy is described), 
  
- 
the treatment shall start immediately after chemotherapy or during the year 
following the end of the treatment by chemotherapy and radiotherapy.  
 
6.7.3 Premedications  
 
Recommended premedications for both arms are described in section 6.4.1. 
 
Corticoids will be allowed for use as antiemetics and as premedications before and 
after the Docetaxel injections.  
It will be possible to deliver a treatment with antiemetics of the setron family to 
prevent nausea and vomiting. 


 
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Additional Recommended Pre-medication to Prevent Hypersensitivity Reactions 
if Oral Medication Fails during Ixabepilone courses:  
 
If a patient experiences a hypersensitivity reaction with oral H1 and H2 blockers 
(Regimen 1) then the patient, if re-treated, should be premedicated according to  
the recommended regimen below: 
Regimen 2: Premedicate approximately 30 - 45 minutes prior to each infusion of 
ixabepilone with: 
a) Dexamethasone 20 mg IV (or equivalent),  
b) Diphenhydramine 50 mg IV (or equivalent), and 
c) Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent). 
If a patient continues to experience a hypersensitivity reaction with Regimen 2 then  
the patient, if retreated, should be premedicated according to the recommended 
regimen below: 
Regimen 3: Premedicate with: 
a) Dexamethasone 20 mg po administered, approximately 12 and  
6 hours prior to the infusion of ixabepilone, 
b) Diphenhydramine 50 mg IV, approximately 30 - 45 minutes prior 
to each infusion of ixabepilone, 
c) Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent), 
approximately 30 - 45 minutes prior to each infusion of ixabepilone. 
A suggested approach for retreatment with ixabepilone after a Grade 2 or greater 
hypersensitivity reaction despite premedication with Regimens 1, 2 or 3 is as follows:i 
• Dexamethasone 20 mg IV or po (or equivalent) every 6 hours for 4 doses with  
the last dose administered 30 minutes before rechallenge with ixabepilone. 
• With the last dexamethasone dose begin: 
- 
Diphenhydramine 
50 mg 
IV 
(or 
equivalent) 
30 minutes 
before 
ixabepilone, 
- 
Cimetidine 300 mg or ranitidine 50 mg IV (or equivalent) 30 minutes 
before ixabepilone. 
• Begin ixabepilone at 25 % of the previous rate for 1 hour. 
• Increase rate gradually to complete the total infusion within 6 hours from the time 
the drug was initially diluted in Lactated Ringer’s Injection (LRI) (see Section 6.1). 
 
During each visit, the investigator will record all the information concerning  
the diseases and concomitant medications.  
 
 
6.7.4 Prohibited concomitant treatments  
 
Subjects must not continue or institute treatment with the following strong inhibitors  
of CYP3A4 from 72 hours prior to the initiation of study therapy until end of treatment 
with ixabepilone or docetaxel: amiodarone, clarithromycin, amprenavir, delavirdine, 
voriconazole, 
erythromycin, 
fluconazole, 
itraconazole, 
ketoconazole, 
indinavir, 
nelfinavir, ritonavir, and saquinavir. 


 
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6.8 Radiotherapy 
 
According to the S.O.R. Breast and the recommendations of the Expert Committee  
of the SFRO: 
o Breast irradiation is mandatory in case of conservative breast surgery for  
all patients.  
o After total mastectomy, chest wall irradiation is mandatory for pT3-4 and/or ≥ 
4N+. It is optional for intermediate risk patients (1-3N+ or pT2, grade III with 
lymphovascular invasion).   
o Irradiation (RT) of internal mammary and supraclavicular nodes is 
mandatory for patients ≥ 4N+. It is optional in patients with 1-3N+ and  
in pT2N- tumors located in the inner or central quadrants of the breast.  
If sentinel node biopsy of internal mammary lymph nodes is done 
systematically, the internal mammary chain RT indication should be done 
according to the final results of the biopsy and investigator decision. 
o Axillary irradiation is not mandatory in case of large axillary node clearance (> or 
= 8). In case of massive axillary nodes involvement (80 to 100%) or Positive 
Sentinel Node (not followed by axillary dissection), the participating center 
should adopt its own policies regarding the benefit/risk ratio for such irradiation. 
 
The same policy and same radiation technique should be adopted by each 
investigational site for all included patients. 
 
Radiotherapy must begin within 8 weeks after the last cycle of chemotherapy. 
 
The recommended dose is 45 to 50 Gy (1.8 to 2 Gy per fraction – 5 times per week)  
at the level of the breast, the chest wall and the lymph nodes areas. Equivalent 
fractions but not less than 4 times per week will be possible. Additional irradiation of 
the tumoral bed can vary from 10 to 16 Gy (1.8 to 2 Gy per fraction).  
 
 
6.9 Hormonotherapy 
 
Patients with positive estrogen receptor (ER ≥ 10% in immunohistochemistry) will 
receive hormonal treatment as indicated bellow: 
 
o Premenopausal women: tamoxifen for 5 years. 
 
o Postmenopausal women: aromatase inhibitors for 5 years, or tamoxifen  
if aromatase inhibitors are contra-indicated.  
 
o For perimenopausal women (premenopausal status at time of randomization 
followed by subsequent prolonged amenorrhea after chemotherapy over  
1 year): tamoxifen 2/3 years + aromatase inhibitor 2/3 years, or tamoxifen  
5 years + aromatase inhibitor 2/3 years. Before the introduction of  
the aromatase inhibitor (AI), a dosage of FSH and oestradiol levels will be done. 
The AI will be allowed only if FSH > 30 IU/l and/or oestradiol < 30 ng/l.  
 


 
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The postmenopausal status will be defined as: 
o Patient over the age of 60,  
o or bilateral oophrectomy,  
o or age ≤ 60 with a uterus and amenorrhea for at least 12 months before 
randomization,  
o or age ≤ 60 without a uterus and with FSH>30 IU/l). 
 
7. INCLUSION AND FOLLOW-UP ASSESSMENTS  
Patient monitoring from the date of randomization till 5 years after surgery and  
5 additional years (long term follow-up) and the patient’s assessments’ schedule are 
described in appendix 1.  
 
7.1 Baseline assessment  
 
The patients eligible for the trial and who have signed an informed consent form will 
undergo initial assessment within 30 days prior to randomization.  
 
However, to include a patient it will be possible to use some examination results 
performed before enrollment in the trial. 
 
 Clinical examination  
Complete clinical examination with weight, height and body surface area 
determination,  
ECOG performance status (see appendix 2), 
Medical history, 
Concomitant therapies.  
 
 QlQ C30 / Br23 completion  
 
 
Radiological examination  
Within the past year: 
Bilateral mammography, 
 
Within 3 months prior to the randomization:  
Chest radiography, 
Liver imaging (echography or tomodensitometry), 
Bone scintigraphy (with centered printing plate in case of hyperfixation). 
 
 
Cardiac examination  
ECG,  
Left VEF assessments by isotopic or echocardiographic method (LVEF 
assessments must always be done and evaluated with the same method). 
 
 
Hematology and biochemistry examination  
Hematology: WBC count, platelets count, 
Blood ionogram, 
Hepatic assessment (bilirubin, ALAT, ASAT, alkaline phosphatases), 
Glycemia, 
Calcemia, 
Renal assessment (blood creatinine level, creatinine clearance), 
Pregnancy test, 
FSH assessment for women < 60 years without an uterus and women with HRT. 


 
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 
Mandatory histopathological assessment   
Pathological tumor size, type and EE grade (Scarff-Bloom & Richardson's (SBR) 
classification as modified by Elston and Ellis), 
Excision quality, margin status, 
Presence of in situ component, 
Presence of lymphatic or vascular emboli, 
Number of excised and invaded lymph nodes, 
Capsular rupture, 
Measurement of estrogen and progesterone receptors (immunohistochemistry 
only), 
Immunohistochemical determination of cerbB2 expression (FISH or CiSH). 
 
A central review of HR receptors and HER2 status will be performed by reference local 
pathologists to confirm the eligibility of the patients before randomization. Detailed 
guidance for central review is given in appendix 3. 
 
 
Sample collection 
One serum aliquot and one tumor sample will be collected and preserved in liquid 
nitrogen. See section 11. 
 
 
7.2 Follow-up assessments during chemotherapy 
 
 Clinical examination (Day 21 of each cycle) 
Complete clinical examination with weight, height and body surface area 
determination, 
ECOG performance status (see appendix 2), 
Concomitant therapies, 
Toxicities reporting. 
 
 
Hematology and biochemistry examination  
- C1 to C3, Day 21 
Hematology: WBC count, platelets count  
Blood ionogram, 
Glycemia, 
Calcemia, 
Renal assessment (blood creatinine level, creatinine clearance). 
 
- C3, Day 21 (before the first administration of the second sequence of treatment) 
Hepatic assessment (bilirubin, ALAT, ASAT, alkaline phosphatases) 
 
- C4 to C6 
Day 7: 
Hematology: WBC count, platelets count 
Hepatic assessment (bilirubin, ALAT, ASAT, alkaline phosphatases) 
If abnormal liver tests and a concomitant grade 4 neutropenia are observed, the 
investigator has to contact the patient and to reassess WBC count every two days 
until recovery. 
 
Day 21 
Hematology: WBC count, platelets count 
Blood ionogram, 


 
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Hepatic assessment (bilirubin, ALAT, ASAT, alkaline phosphatases)  
Glycemia, 
Calcemia, 
Renal assessment (blood creatinine level, creatinine clearance). 
 
All examinations revealing a treatment-related toxicity must be periodically repeated 
until toxicity is reverted or until it is assumed irreversible.   
 
 QlQ C30 / Br23 completion (Day 21 of cycle 3 and 6). 
 
 
7.3 Assessments at the end of radiotherapy 
 
During the week following the last course of radiotherapy, all patients will undergo  
the following examinations: 
 
Clinical examination 
Complete clinical examination with weight, height and body surface area 
determination,  
ECOG performance status (see appendix 2), 
Concomitant therapies, 
Toxicities reporting. 
 
7.4 Follow-up visits 
 
After radiotherapy, the patients will be followed: 
o every 4 months for the first two years post surgery (Months 12, 16, 20, 24), 
o every 6 months for the next three years (Months 30, 36, 42, 48, 54, 60), 
o then annually during the 5 years long-term follow-up. 
 
Years 1-2, 
o every 4 months: clinical examination and toxicities reporting. 
o month 12 (M12) only: LVEF assessment by isotopic or echocardiographic 
method (LVEF assessments must always be done and evaluated with the same method). 
o every year: Mammography. Other radiological assessments will be done if 
clinically relevant (Chest X-ray, Hepatic echography, Bone scintigraphy). 
 
Years 3-5, 
o every 6 months: clinical examination and toxicities reporting. 
o month 60 (M60) only: LVEF assessment by isotopic or echocardiographic 
method (LVEF assessments must always be done and evaluated with the same method). 
o every year: Mammography. Other radiological assessments will be done if 
clinically relevant (Chest X-ray, Hepatic echography, Bone scintigraphy). 
 
Years 6-10, 
o every year: clinical examination, vital status reporting. 
 


 
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8. PREMATURE END OF THE TREATMENT 
 
Study therapy MUST be immediately discontinued for the following reasons: 
 
The treatment can be prematurely stopped for the following reasons:  
- toxicity (any clinical adverse event, laboratory abnormality or intercurrent illness 
which in the opinion of the investigator indicates that continued treatment with study 
therapy is not in the best interest of the patient, 
- pregnancy 
- imprisonment or the compulsory detention for treatment of either a psychiatric or  
  physical (e.g., infectious disease) illness 
- disease progression, 
- patient’s refusal, 
- consent withdrawal, 
- patient lost to follow-up, 
- major protocol violation 
- termination of the study by the sponsor. 
 
The same follow up modalities will be applied to patients for whom the treatment is 
prematurely ended within the limits of what can be reasonably achieved. 
 
 
9. TRIAL TERMINATION CRITERIA 
 
The trial can be suspended or stopped by the sponsor in consultation with the principal 
investigator at the request of the competent authority and/or the Committee for  
the Protection of Persons (CPP) for the following reasons: 
- unexpected occurrence or severity of toxicity,  
- insufficient patient recruitment, 
- poor quality of data collection. 
 
 
10. EVALUATION CRITERIA 
 
10.1 Main criterion 
 
Disease free survival rate (DFS) at 5 years. 
 
The relapse will be defined as: 
o a local or regional relapse, 
o a metastatic relapse,  
o a contraloteral breast cancer,  
o or a death of any cause. 
 
The DFS is defined as the interval between the date of randomization and the date of 
breast cancer relapse (local, regional or distant) or the date of invasive contralateral 
breast cancer or death from any cause, whichever occurs first. 


 
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10.2 Secondary criteria  
 
10.2.1 Efficacy 
 
- Distant Metastasis Free Survival (DMFS) rate and Overall Survival rate (OS) for  
the whole population at 5 years.  
 
- DMFS, DFS and OS at 5 years for triple negative subgroup 
 
- DMFS, DFS and OS at 5 years for the remainder HER2-, PR - , ER+ population  
 
The DMFS is defined as the interval between the date of randomization and the date of 
the metastatic relapse. 
 
The OS is defined as the interval between the date of randomization and the date of 
death from any cause. 
 
- Second Neoplasia : Event Free Survival  (EFS) will be evaluated both for whole 
population and subgroups. An Event is defined as a Local Relapse, a Regional 
Relapse, a Distant Metastasis, an invasive  Controlateral Breast cancer, a Neoplasia 
or a Death from any cause. 
 
The EFS is defined as the interval between the date of randomization and the date of 
breast cancer relapse (local, regional or distant) or the date of invasive contralateral 
breast cancer or the date of second neoplasia, or the date of death from any cause, 
whichever occurs first. 
 
 
10.2.2 Toxicity 
 
In order to be considered as eligible for toxicity evaluation the patients must have 
received at least one course of treatment.  
 
The toxicity will be evaluated according to the scale: CTC-AE version 3.0 (see 
appendix 7).  
 
 
10.2.3 Quality of life  
 
QlQ C30 / Br23 forms will be completed by the patients before randomization,  
at the end of third cycle of chemotherapy, and at the end of the last cycle of 
chemotherapy for both arms. In case of premature end of treatment, a final 
Questionnary will be completed. 
 
 
10.2.4 Other criteria  
 
- biology,  
- genomics,  
- proteomics. 


 
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11. Sub-studies 
 
Biology, genomics, proteomics. 
 
This study will collect frozen breast cancer tissue samples and frozen serum samples 
to analyze them at the RNA and protein levels. The objective is to identify  
the molecular signatures associated with clinical outcome (metastasis-free survival) in 
each chemotherapy arm.  
 
 
- Tumor and serum sample collection 
 
A portion of the resected tumor obtained during initial surgery before treatment will be 
collected, aliquoted (after cutting off with a scalpel two pieces of the sample, 
respectively one for the genomic- and one for proteomic study), immediately frozen 
and stored in liquid nitrogen in the tumor bank of the institution. A pathological control 
verifying the number of malignant cells in the sample will be done before RNA and 
protein extraction. 
Whenever possible, one serum sample (2.5 ml) will be collected before initiation of  
the first cycle of chemotherapy. Serum will be immediately processed after collection 
(within 2 hours) including centrifugation (3000 rpm over 10 minutes), then aliquoted in 
tubes of 100 to 500 µl rapidly frozen and stored in liquid nitrogen. It is planned to 
collect a total of 300 patients in each arm. 
All samples will be labeled with the institution and patient numbers allocated by  
UNICANCER. 
(see appendix 4).  
 
 
12. SAMPLE SIZE DETERMINATION AND STATISTICAL ANALYSIS 
 
12.1 Required number of subjects 
 
To show a benefit of 5% in the 5-year DFS (70% in the reference arm versus 75 %  
in the ixabepilone arm) corresponding to a relative risk of 0.81 (about 20% of relapse 
risk reduction), 2,500 patients should be enrolled (1,250 patients in each arm)  
to ensure a power of 80% (beta = 20%) assuming a two-sided situation (Log rank test) 
and accepting a significance level of 5%. 
A minimum of 682 events are to be observed for ensuring a power of more than 80% 
for detecting the pre-specified 0.81 hazard ratio. 
 
This sample will allow us to show a gain of 6% in 5-year DFS in the triple negative 
subgroup (corresponding to a relative risk of 0.77 and a relapse risk reduction of 23%) 
with a power of 80%. This triple-negative subgroup is considered as being equal to two 
thirds of the whole population (i.e. about 1700 patients). 
 
To avoid any increase of the type one error, the second analysis will be performed only 
if the difference observed on the whole population (main objective is statistically 
significant). 
 


 
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Randomization will be stratified based on the following parameters: 
 
- center 
- premenopausal status versus postmenopausal status (see definition of menopausal 
status in section 6.9), 
- triple negative tumors versus the remainder of the population. 
 
After the enrollment of the first 300 patients, the hypothesis concerning the proportion 
of the triple negative subgroup will be verified. If the proportion of triple negative 
patients is not equal to two thirds of the whole population, the sample size will be re-
calculated. 
 
 
12.2 Statistical analysis  
 
Analysis of the main evaluation criterion will make use of the methodology developed 
for censored data. The curves of the relapse-free interval and survival curves will be 
established with the Kaplan-Meïer method.  
The efficacy analysis will use the Cox model to estimate the therapeutic effect taking 
into account a possible unbalanced repartition of the prognosis factors. The relative 
risks associated to the therapeutic effect will be presented along with their 95% 
confidence interval. The prognosis factors taken into account in the multivariate 
analysis will be the following: menopausal status, triple negative tumors, pathological 
tumor size, lymph node involvement, SBR grading as modified by EE. A sensitivity 
analysis will also be performed using a stratified logrank test, adjusted on  
the stratification criteria (except the center). 
 
Statistical analyses will be mainly performed based on the intent-to-treat population for 
efficacy parameters. Whenever appropriate and necessary, they will be also performed 
on the eligible patient population or the per-protocol population. 
 
One interim efficacy analysis will be performed 2 years after the recruitment of the last 
patient. The objective of this interim analysis is to assess whether it is possible  
to disseminate the results of the study earlier than the final 5-year analysis. This will be 
possible only in case of overwhelming results in favor of one of the treatment groups. 
The Peto procedure will be used, considering a p-value less or equal 0.001 to declare 
the results as positive, in order to keep a type one error close of 0.05 for the final 
analysis. 
 
Definition of populations: 
 
Intent-to-treat population 
All randomized patients will be included in the intent-to-treat population (ITT), whether 
or not any study medication was administered, and regardless of the eligibility status. 
As far as statistical inferences are concerned, patients are analyzed in the treatment 
group and in the stratum to which they were assigned by the randomization.  
 
Eligible population 
Eligible patients are patients with no major violations of the inclusion and exclusion 
criteria. The final decision on patients’ eligibility rests with the IDMC that will eventually 
give a decision on the eligibility of all patients. 


 
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Per protocol population 
Per-protocol patients are patients with no violation of the major inclusion and exclusion 
criteria and who received all the 6 cycles of the treatment allocated to by  
the randomization arm. 
 
Safety population  
The safety population will consist of all treated patients, that is, all patients who started 
at least one infusion of at least one study drug, regardless of their eligibility for  
the study. Moreover, patients will be analyzed according to the treatment regimen  
they actually received. 
 
Patients lost to follow-up will be censored at the date of last contact. A patient lost  
to follow-up is a patient who never came back to the hospital and for whom repeated 
attempts to contact have failed. 
Patients free of disease and not lost to follow-up at the cut-off date for the analysis will 
be censored at that cut-off date if data exists that documents patient status beyond  
the cut-off date, or censored at the date of the last visit otherwise.   
 
 
13. SERIOUS ADVERSE EVENTS 
 
13.1 General definition 
 
It is considered that a serious adverse event (SAE) is any event that:  
 
 leads to the patient’s death, 
 put the vital prognosis at stake, 
 results in an hospitalization or a prolonged hospitalization of the patient, 
 induces a permanent invalidity or a severe transient incapacity, 
 induces a congenital anomaly, a fetal malformation or an abortion, 
 is medically relevant. 
 
The terms invalidity and incapacity correspond to any clinically relevant physical or 
psychic 
handicap, 
transient or 
permanent, 
with 
impacts on 
the 
physical 
condition/activity and/or the quality of life of the patient.  
Any clinical event or laboratory result that is considered as serious by the investigator 
and that does not correspond to any of the serious adverse event criteria listed above 
is considered as medically relevant. That which can put the patient at risk and/or 
require a medical intervention to prevent the development of any serious adverse 
event previously cited (e.g.: overdosing, a second cancer, pregnancy and new events 
can be considered medically relevant). 
 
The following events are not considered to be serious adverse events: 
 
 a hospitalization < 24 hours, 
 a hospitalization that was programmed prior to the trial’s beginning and/or 
scheduled by the protocol (biopsy, chemotherapy..). 


 
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13.2 Definition of an expected serious adverse event (E-SAE) 
 
An E-SAE is a serious event already mentioned in the latest version of the investigator 
brochure or in the summary of product characteristics (SPC) for the drugs that have 
been already approved by the CA.  
 
13.3 Definition of unexpected serious adverse event (U-SAE) 
 
A U-SAE is an event that is not mentioned in the investigator brochure or that is 
differing from the brochure’s description due to its nature, intensity or evolution; or that 
is differing from the summary of product characteristics (SPC) for the drugs with CA 
approval.  
 
13.4 Intensity criterion 
 
The intensity criterion must not be confused with the seriousness criterion that is 
utilized to define the obligations of declaration. 
 
The events intensity will be estimated according to the extract from the CTC-AE 
version 3.0 classification (see appendix 7). The intensity of the adverse events not 
listed in this classification will be appreciated according to the following scale:  
 
Light (grade 1): does not affect the usual daily activity of the patient;  
Moderate (grade 2): perturbs the usual daily activity of the patient; 
Serious (grade 3): hampers the usual daily activity of the patient; 
Very serious (grade 4): requires reanimation measures / threatens the vital prognosis; 
Lethal (grade 5): prematurely ends patient’s life. 
 
13.5 Measures to take in the case of a serious adverse event 
 
The investigator informs the pharmacovigilance department of R&D UNICANCER of all 
serious adverse events, expected (E-SAE) and unexpected ( U-SAE), imputable or not 
to the research process, that might occur during the study or within 30 days following 
the last treatment administration.  
 
All delayed serious adverse events (that occur more than 30 days after the end  
of the study) that are reasonably considered to be linked to the protocol’s treatment(s) 
or the ongoing research must be declared without delay.  
 
The SAE declaration must be sent to the pharmacovigilance unit of R&D UNICANCER 
by FACS within 48 working hours of their observations:  
 
R&D UNICANCER 
Pharmacovigilance, France 
Tel.: +33.(0)1 44 23 04 16 – Fax: +33.(0)1 44 23 55 70 
Email: pv-rd@unicancer.fr 
 
using an SAE notification form (cf appendix 6) according to the nature of the event 
(see Ixabepilone Investigator Brochure and appendix 8 SPC). 
 


 
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For each event, the investigator will note:  
 The event’s description, as clearly as possible and in accordance with  
the medical terminology,  
 The intensity, 
 The date of the event’s beginning and end,  
 The measures undertaken and whether or not the use of a correcting treatment 
was necessary,  
 If the trial’s treatment was interrupted,  
 Its evolution will be followed until remission or recovery of the prior state or 
stabilization of possible sequels,   
 The causality between the observed event and the tested treatment or  
a constraint linked to the research protocol (e.g. a period without treatment, 
complementary examinations requested within the framework of the research 
protocol, etc…),    
 The causality relating to the drug(s) used in the trial, the treated pathology, 
another type of pathology, or another treatment.  The investigator must also 
attach a serious adverse event report every time it is applicable:  
 A copy of the hospitalization report or of the prolongation of hospitalization,  
 A copy of the autopsy report,  
 A copy of the results of all complementary examinations, including the relevant 
negative results and providing the normal laboratory values, 
 Any other document that is relevant in the investigator’s opinion.  
 
All these documents must be made anonymous. 
 
More information might be requested by the study monitor (by facs or telephone or on 
a visit to the investigational site).  
 
However, all expected event but that is differing in its intensity, its evolution or 
its frequency will be considered as unexpected by the pharmacovigilance 
department.  
 
13.6 SAE follow-up 
 
The investigator is responsible for the appropriate medical follow-up of the patients 
until the recovery, the stabilization or the death of the patient. This can indicate that 
the SAE follow-up is prolonged after the patient has exited the trial.   
 
The investigator transmits complementary information to the pharmacovigilance cell  
of R&D UNICANCER using a SAE declaration form and ticks the box: Follow-up # X, 
to specify that it is about a follow-up and not an initial report. She/he sends the form 
within 48 hours after having obtained the information.  She/he also transmits the last 
follow-up report after reversion to normal or stabilization of the SAE.  
 
The investigator keeps the documents regarding the presumed adverse event  
to further complement the transmitted information in case of necessity.  
 
She/he answers to the request for complementary information of the PC of R&D 
UNICANCER to document the initial observation. 
 


 
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14. INDEPENDENT DATA MONITORING COMMITTEE  
 
A trial monitoring committee (IDMC = Independent Data Monitoring Committee) will be 
set up to ensure: (1) protection of the patients; (2) that the trial is conducted according 
to the ethics; (3) that the scientific results are reviewed independently during  
the course and at the end of the trial; and (4) to evaluate the benefit/risk ratio for  
the trial. This committee has a consultative role with respect to the sponsor.  
The sponsor takes the final decision regarding the recommendation proposed by  
the committee.  
 
 
15. QUALITY INSURANCE AND QUALITY CONTROL 
 
In order to guaranty the authenticity and credibility of the data in accordance with  
the Good Clinical Practices, the sponsor will set up an insurance quality program that 
includes: 
 
- management of the trial according to procedures specific to UNICANCER.  
- control of the quality of the data provided by the investigation site  is performed by 
the study monitor  the role of which is to match and check the consistency of  
the data reported in the observation handbook with respect to the source-
documents, 
-  possible audit of investigational sites,  
- conducting a centralized review covering certain aspects of the protocol (to be 
specified). 
 
 
16. DATA PROTECTION AND CONFIDENTIALITY MANAGEMENT  
 
Until the trial results are published, the investigator is responsible for insuring  
the confidentiality of the totality of the information, handled by herself/himself and all 
other individuals involved in the course of the trial, that are supplied by UNICANCER. 
This obligation holds neither for the information that the investigator may communicate 
to the patients within the context of the trial nor for the already published information.  
The investigator commits not to publish, not to spread or use in any manner, directly or 
indirectly, the scientific and technical information related to the trial.  
 
Nevertheless, in conformity with the article R 5121-13 of the Public Health Code, both 
the center and the investigator may communicate information relative to the trial: 
 
- 
to the Health Minister, 
- 
to the public health inspectors who are doctors, 
- 
to the public health  inspectors who are pharmacists, 
- 
to the Afssaps General Director and inspectors.    


 
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The trial will not be the subject of any written note and/or oral comment without  
the prior agreement of the sponsor; the totality of the information that is communicated 
or obtained during the course of the trial belongs in full right to the French Federation 
of Comprehensive Cancer Centers who can freely use it.    
 
 
17. PUBLICATION OF RESULTS 
 
All information resulting from this trial is considered to be confidential, at least until 
appropriate analysis and checking has been completed by the sponsor, the principal 
investigator and the statistician of the trial.  
 
Any publication, abstract or presentation comprising results from the trial must be 
submitted for examination and approval to the Sponsor (UNICANCER).  
 
Furthermore, any written communication or presentation must imperatively include  
a section that mentions UNICANCER, La Ligue Nationale Contre le Cancer (The 
French League for Treating Cancer) and any institution, investigator, cooperating or 
collaborating group and scientific society that has contributed to the trial as well as any 
organism that has financially supported this research.  
 
The first author and writer of the publication will be the principal investigator.  
She/he may however designate another person to (co-) write the publication.  
 
The other investigators will appear in the list of co-authors in decreasing order, 
according to the number of recruited patients regardless of the importance of  
the cooperating group they belong to, followed by a person representing each 
cooperating group among the investigation centers that have the highest rates of 
recruitment. The statistician and a sponsor representative will be cited as well. 
 
In an equal manner, publication of the sub-studies (biological studies) will make 
mention of the name of the person who has carried out the sub-studies as well as  
the names of all the individuals who have taken part in carrying out these sub-studies.   
 
 
18. ETHICAL AND REGULATORY ISSUES  
 
The clinical trial must be conducted in accordance with:  
-  the principles of ethics as stated in the last version in use of the Declaration of 
Helsinki,  
- the Good Clinical Practices defined by the International Conference on 
Harmonization  (ICH–E6, 17/07/96),  
- the European directive 2001/20/CE on the conduct of clinical trials, 


 
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- Huriet’s law (n° 88-1138) of December 20 th , 1988, relative to the protection of 
persons participating in biomedical research and modified by the Public Health Law 
n°2004-806 of August 9 th , 2004, 
- the law on ‘informatics and freedom’ (Informatique et Libertés n° 78-17) of January 
6th,1978 modified by the law n° 2004-801 of August 6 th, 2004 relative to the protection 
of persons with regard to the computerized processing of personal data, 
 - bioethic law n° 2004-800 of August 6, 2004. 
 
 
18.1 Ethic Committee (CPP)  
 
Before starting a biomedical research on human subjects, the sponsor is obliged to 
submit its project to the opinion of one of the competent committees for the protection 
of persons where the principal investigator is practicing. 
 
Request of substantial modifications in the initial projects are submitted for  
the committee’s opinion by the sponsor as well.  
 
 
 18.2 Competent authority  
 
Before carrying out or letting a biomedical research to be carried out on its behalf,  
the sponsor must file a request with the competent authority. 
The time necessary to process a demand for authorization shall not exceed 60 days 
from the date of receipt of the complete file, excepted for products used in cellular 
therapy and gene therapy for which processing may last 90 days and 120 days 
respectively. Within 30 days of the receipt of the complete file, the competent authority 
notifies the sponsor if there exists well-founded objections that prevent the research 
from being undertaken and informs the committee for the protection of the concerned 
persons.  
 
 
18.3 Information and consent of the participants 
 
Prior to carrying out biomedical research on human subjects, a free and written 
informed consent form must be signed by each individual participating in the trial after 
she/he has been informed by the investigator during a physician-patient consult and 
after sufficient time for reflection has been allowed.  
 
Information given to the trial participants must cover all of the elements defined  
by the public health law of August 9th, 2004 and must be written in a simple and 
comprehensible patient-appropriate manner. 
The French version of the “patient information sheets and informed consents” (PIS/IC) 
are templates which have to be translated and adapted to local regulatory 
requirements. In countries where a national coordinating center (NCC) group is 
identified, the translation and adaptation will be done by this NCC or Group. 


 
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However the NCC/G must tell to UNICANCER what the NCC/G has changed and why. 
This adaptation cannot be validated without the agreement of UNICANCER on the new 
text. 
 
The final translated and approved local PIS & IC must have a version number and date 
which must be quoted in all correspondence with local and national ethics committees. 
 
Once the participant is acquainted with the information, she/he must sign all the pages 
of the information booklet. The original booklet will be kept in the investigator’s folder 
and the duplicate copy will be returned to the participant. The consent form must be 
dated and signed by both the participant in research and the investigator. The original 
document is archived by the investigator; a copy will be returned to the research 
participant).  
 
The patient information sheet (PIS) and informed consent form must be 
associated within the same document to insure that the whole information is given to 
the research participant.  
 
In the case that the objective of the trial is to carry out genomic or proteomic 
analysis, the PIS must specify the type of research that will be undertaken and the 
patient must be given the right to accept or refuse that the biological samples taken 
from her/him be kept for the purpose of conducting scientific research. 
 
In the case that the trial is conducted on minors, an information booklet appropriate 
to their comprehension level will have to be written. The authorization to participate in 
the trial must be issued, in principle, by the two holders of the parental authority. 
However, the authorization can be given by one holder of the parental authority solely 
if the other holder cannot give its authorization within a time delay compatible with  
the methodological requirements inherent to the research process.  
 


 
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18.4 Responsibility of the sponsor 
 
The sponsor of the trial is the natural or moral person that: takes the initiative  
of conducting biomedical research on human subjects, and is therefore accountable  
for the research management and for verifying the financing schedule.  
 
The sponsor must be established within the European Community or have one legal 
representative in an EU member state. 
 
The main sponsor responsibilities are: 
- to subscribe a civil-responsibility insurance, 
- to register the trial in the European data base and to obtain an EudraCT (European 
Drug Regulatory Authorities Clinical Trials) identification number, 
- to request the opinion of the Committee for the Protection of Persons (CPP) on the 
initial project and the substantial amendments, 
- to file the demand of authorization for the initial project and all substantial 
amendments with the competent authority,   
- to provide information on the trial to the heads of the health care centers,  
the  appropriate investigators and the pharmacists,   
- to declare to the competent authorities, i.e. the Afssaps and the EMEA (the European 
pharmacovigilance data bank, Eudravigilance) any suspicion of unexpected serious 
adverse events (U-SAE) related to any of the treatments used in the trial and 
communicate the information to the CPP and the investigators of the trial,   
- the annual declaration of the security report  to the competent authority and the CPP,  
- the declaration  of the beginning and the end of the trial to the competent authority,  
- editing the final report on the trial,  
- communicating the information on the trial’s results to the competent authority,  
the CPP and the research participants,   
- archiving the trial’s essential documents in the sponsor folder for a minimal duration 
of 15 years after the research is ended.  
 
 
18.5 Responsibilities of the investigators  
 
The main investigator of each concerned health care center commits to conducting  
the clinical trial in compliance with the protocol that has been approved by the CPP 
and the competent authority. 
 
The investigator must not bring any modification to the protocol without having 
obtained written authorization of the sponsor and the proposed modifications have 
been authorized by the CPP and the competent authority.   
 
It is the responsibility of the main investigator:  
- to provide the sponsor with its own curriculum vitae and co-investigators’ curriculum 
vitas,


 
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- to identify the members of its team that participate in the trial and to define  
their responsibilities,   
- to insure patients recruitment after the sponsor has issued its authorization.  
 
It is the responsibility of each investigator:  
- to collect the informed consent form, dated and signed personally by each individual 
research participant before any selection procedure specific to the trial may start,  
- to regularly fill in the case report form (CRF) for each patient included in the trial and 
to allow the clinical research assistant mandated by the sponsor to have  direct access 
to the source-documents in order to validate the data collected in the observation 
handbook, 
- to date, correct and sign the corrections brought to the CRF for each patient included 
in the trial,   
- to accept regular visits of the study monitor and possibly the auditors mandated by 
the sponsor or the inspectors of the legal competent authorities.  
 
All documentation relative to the trial (protocol, consent forms, CRF, investigators’ 
folders, etc…) as well as all other original documents (laboratory results, radiographic 
pictures, reports of physician-patient consultations and clinical examinations, etc…) 
are confidential material and must be kept in a secured location. The main investigator 
will be obliged to preserve the data and a list of patient identifications during a minimal 
period of 15 years after the study has ended.  
 
 
18.6 Federation of the Patient Committees for Clinical Research in Cancerology 
 
The dedicated task of the Federation of the Patient Committees for Clinical Research 
in Cancerology (FCPRCC) is to make a second read of the clinical trial protocols in 
cancerology. The patient committees’ federation is coordinated by R&D UNICANCER, 
a body of UNICANCER. It gathers both the patient committees of the LNCC and other 
health care centers. It commits to rereading the protocol and proposing improvements 
dealing principally with the quality of the letter of information to the patients, the setting 
up of a treatment and monitoring plan, suggesting measures aimed at ameliorating the 
comfort of the patients. 
 
 


 
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19. REFERENCES  
 
1. Bonadonna G, Valagussa P. Dose-response effect of adjuvant chemotherapy in breast 
cancer. N. Engl. J. Med. 1981;304 (1):10-5. 
 
2. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 
randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. 
Early Breast Cancer Trialists' Collaborative Group. Lancet. 1992;339 (8784):1-15. 
 
3. Polychemotherapy for early breast cancer: an overview of the randomised trials. Early 
Breast Cancer Trialists' Collaborative Group:Lancet. 1998;352(9132):930-42. 
 
4. Henderson C., Berry D.A., Demetri G.D., and al. Improved Outcomes From Adding 
Sequential Paclitaxel but Not From Escalating Doxorubicin Dose in an Adjuvant 
Chemotherapy Regimen for Patients With Node-Positive Primary Breast Cancer. 
J.Clin.Onco. 2003;21:976-983. 
 
5. Mamounas E.P., Bryant J., Lembersky B.C., and al. Paclitaxel (T) following 
doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast 
cancer: Results from NSABP B-28.  Proc. Am. Soc. Clin. Oncol.:2003;22:A 12. 
 
6. Buzdar AU, Singletary SE, Valero V, and al. Evaluation of paclitaxel in adjuvant 
chemotherapy for patients with operable breast cancer: preliminary data of a prospective 
randomized trial. Clin. Cancer Res. 2002;8:1073-9. 
 
7. Citron ML., Berry DA., Cirrincione C.,  and al. Randomized Trial of Dose-Dense Versus 
Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy 
as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First 
Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J. Clin.Oncol. 
2003;21:1431-1439. 
 
8. L. Gianni, J. Baselga, W. Eiermann, V. and al.  ECTO Study Group.European Cooperative 
Trial in Operable Breast Cancer (ECTO): Improved freedom from progression (FFP) from 
adding paclitaxel (T) to doxorubicin (A) followed by cyclophosphamide methotrexate and 
fluorouracil (CMF) Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. 
Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005:513. 
 
9. Martín M, Rodríguez-Lescure A, Ruiz A, and al. On Behalf of the Spanish Breast Cancer 
Research Group (GEICAM):Multicenter, randomized phase III study of adjuvant 
chemotherapy for node positive breast cancer comparing 6 cycles of FE90C versus  
4 cycles of FE90C followed by 8 weekly paclitaxel administrations: interim efficacy analysis 
of GEICAM 9906 Trial. Breast Cancer Research and treatment. 2005;94,supplement1:39. 
 
10.  Martin M., Pienkowski T., Mackey J., and al.TAC improves DFS and OS over FAC in 
node positive early breast cancer patients, BCRIG 001. Breast Cancer Research and 
treatment. 2003;82,supplement 1:A 43. 
 
11. Roché H., Fumoleau P., Spielman M., and al. Sequential Adjuvant Epirubicin-Based and 
Docetaxel Chemotherapy for Node-Positive Breast Cancer Patients: the FNCLCC PACS 
01 Trial. J. Clin.Oncol.2006;24:5664-71. 


 
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12. Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, and al. Final analysis: TC 
(docetaxel/cyclophosphamide, 4 cycles) has a superior disease-free survival compared to 
standard AC (doxorubicin/cyclophosphamide) in 1016 women with early stage breast 
cancer. J. Clin.Oncol.2006;24:5381-87. 
 
13. Roche H., Penault-Llorca F. M., Sagan C., and al.  Prognostic and predictive value of 
HER2, PR, ER, and KI67 in the PACS01 trial comparing epirubicin-based chemotherapy 
to sequential epirubicin followed by docetaxel. Journal of Clinical Oncology, 2005 ASCO 
Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005:605. 
 
14. J. Jacquemier, F. Penault-Llorca, H. Mnif, E. and al. Identification of a basal-like subtype 
and comparative effect of epirubicin-based chemotherapy and sequential epirubicin 
followed by docetaxel chemotherapy in the PACS 01 breast cancer trial: 33 markers 
studied on tissue-microarrays (TMA). Journal of Clinical Oncology, 2006 ASCO Annual 
Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006:509. 
 
15. K. GERTH, N. BEDORF, G. HOFLE, and al. Epothilons A and B-Antifungal and cytotoxic 
compounds from Sorangium cellulosum (Myxobacteria) production, physico-chemical and 
biological properties. J.Antiobiot. (1996) 49:560-564. 
 
16. D.M. BOLLAG, P.A. McQUENEY, J. ZHU and all. Woods, Epothilones, a new class of 
microtubules-stabilizing agents with Taxol like mechanism of action. Cancer Res. (1995) 
55:2325-2333. 
 
17. G. HOFLE, N. BEDORF, H. STEINMETZ and all. Epothilone A and B novel 16 membered 
macrolides with cytotoxic activity: isolation, crystal structure and conformation in solution. 
Angew.Chem.Int.Ed Engl. (1996) 35:1567-1569. 
 
18.  R.J. KOWALSKI, P. GIANNAKAKOU, E. HAMEL. Activities of the microtubule-stabilizing 
agents epothilones A and B with purified tubulin and cells resistant to paclitaxel (taxol). 
J.Biol.Chem.(1997) 272:2534-2541.  
 
19. K.H. ALTMANN, M. WARTMANN and T. O’REIL. Epothilones and related structures-a 
new class of microtubules inhibitors with potent in vivo antitumor activity. Bioch. 
Bioph.Acta. (2000) 147:79-91. 
 
20. T.C CHOU, X.G. ZHANG, C.R. HARRIS, et al. Desoxyepothilone B is curative against 
human tumor that are refractory to paclitaxel. Proc. Natl. Acad. Sci. USA (1998) 95:15798. 
 
21. F.Y.F. LEE, R. BORZILLERI, C.R. FAIRCHILD and all. BMS-247550: a novel epothilone 
analog with a mode of action similar to paclitaxel but possesing superior antitumor 
efficacy. Clin.Can.Res.(2001) 7:1429-1437. 
 
22. H. YAMAGUCHI, S.R. PARANAWITHANA, M.W. LEE, and all. Epothilone B analogue 
(BMS-247550)-mediated cytotoxicity through induction of Bax conformational change in 
human breast cancer cells. Cancer Res (2002) 62:466-71. 
 
23. D. SPRIGGS, S. SOIGNET, B. BIENVENU and all. Phase I first-in –Man study of  
the 
epothilone 
B 
analog 
BMS-247550 
in 
patients 
with 
advanced 
cancer. 
Proc.Am.Soc.Clin.Onc. (2001) abstract n°428. 


 
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24. B.D. DAMLE, S. LETRENT, G. DUNCAN and all. Pharmacokinetics(PK) and 
pharmacodynamics(PD) of BMS-247550 an epothilone B analog in patients with advanced 
solid tumors. Proc.Am.Soc.Clin.Onc. 2001;21:268. 
 
25. S. MANI, H. MACDAID, H.J. SHEN and al. Phase I evaluation of an epothilone B analog 
(BMS-247550): clinical findings and molecular correlates Procc.Am.Soc.Clin.Onc.(2001) 
abstract n°269. 
 
26. Roche H., Cure H., Bunnell C., et al. A phase II study of epothilone analog BMS-247550 in 
patients (pts) with metastatic breast cancer (MBC) previously treated with antracycline. 
Procc.Am.Soc.Clin.Onc.(2003), vol 22:abstract 69. 
 
27. Thomas E., Tabernero J., Fornier M., et al. A phase II study of epothilone analog BMS-
247550 in patients (pts) with taxanes resistant metastatic breast cancer (MBC). 
Procc.Am.Soc.Clin.Onc.(2003), vol 22:abstract 30. 
 
28. Thomas E, Perez E, Mulhopdhyay P. et al. Phase II trial of ixabepilone in patients with 
metastatic breast cancer (MBC) who are resistant to an anthracycline, a taxane and 
capecitabine, Procc.Am.Soc.Clin.Onc.(2006), vol 24:abstract 660. 
 
29. Llombart Cussac, J. Baselga, G. Manikhas, E. Kubista, G. Steger, S. M. Galbraith, M. A. 
Sullivan, K. Zerba, H. Lee, L. Gianni. Phase II genomics study in patients receiving 
Ixabepilone as neoadjuvant treatment for breastcancer (BC): Preliminary efficacy and 
safety data. Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 
23, No. 16S, Part I of II (June 1 Supplement), 2005:586. 
 
30. Roché H, Perez E, Llombard-Cussac A, et al. Ixabepilone, an epothilone analog, is 
effective in ER-, PR-, HER2-negative (triple negative) patients: data from neoadjuvant and 
metastatic breast cancer trials. ESMO 2006. 
 
 


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Appendix 1 – Flowchart of investigations and study drugs administration 
 
 
Baseline 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
End of 
radioth
erapy 
Every 4 months 
for the first 2 
years post 
surgery (M12, 
16, 20, 24) 
Every 6 months 
for the next 3 
years (M30, 36, 
42, 48, 54, 60) 
then annually 
Every year 
during 5 years 
post surgery 
 
D1 
D1 
D1 
D1 
D1 
D1 
 
 
 
 
Arm 1 
FEC 
FEC 
FEC 
Docetaxel 
Docetaxel 
Docetaxel 
 
 
 
Arm 2 
FEC 
FEC 
FEC 
Ixabepilone 
Ixabepilone 
Ixabepilone 
Written Informed 
Consent 
x 
 
 
 
 
 
 
 
 
 
 
Regional Pathological 
re assessment 
x 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
Concomitant therapies 
x 
D21 
D21 
D21 
D21 
D21 
D21 
x 
 
 
 
Clinical examination  
x 
D21 
D21 
D21 
D21 
D21 
D21 
x 
xa 
xa 
x 
ECOG PS 
x 
D21 
D21 
D21 
D21 
D21 
D21 
x 
 
 
 
Toxicities reporting 
x 
D21 
D21 
D21 
D21 
D21 
D21 
x 
xa 
xa 
 
Bilateral mammography 
x 
 
 
 
 
 
 
 
 
 
x 
Chest radiography 
x 
 
 
 
 
 
 
 
 
 
(xa) 
Liver imaging 
x 
 
 
 
 
 
 
 
 
 
(xa) 
Bone scintigraphy 
x 
 
 
 
 
 
 
 
 
 
(xa) 
ECG
x 
 
 
 
 
 
 
 
 
 
 
LVEF assessment 
x 
 
 
 
 
 
 
 
 
 
M12 and M60 
WBC / PLT 
x 
D21 
D21 
D21* D7* + D21* 
D7* + D21* 
D7* + D21*  
 
 
 
Blood ionogram 
x 
D21 
D21 
D21 
D21 
D21 
D21  
 
 
 
Bilirubin, ALAT/ASAT, 
ALP 
x 
 
 
D21 
D7 + D21 
D7 + D21 
D7 + D21  
 
 
 
Glycemia/ calcemia 
x 
D21 
D21 
D21 
D21 
D21 
D21  
 
 
 
Creatinine, creatinine 
clearance 
x 
D21 
D21 
D21 
D21 
D21 
D21  
 
 
 
Pregnancy test – FSH 
dosage c 
x 
 
 
 
 
 
 
 
 
 
 
histology 
x 
 
 
 
 
 
 
 
 
 
 
Serum collection 
x 
 
 
 
 
 
 
 
 
 
 
Frozen and fixed Tumor 
collectionb 
x 
 
 
 
 
 
 
 
 
 
 
QlQ C30 / Br23 
x 
 
 
x  
 
x  
 
 
 
a  in case of suspected recurrence, all necessary imaging will be realized to confirm the diagnosis 
b  frozen sample for participating sites only 
c  for WOCBP treated by HRT and women < 60 years without an uterus 
* If abnormal liver tests and a concomitant neutropenia grade 4 are observed, the WBC count has to be monitored every two days until recover


 
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Appendix 2 – ECOG peformance status scale  
 
 
 
ECOG PERFORMANCE STATUS
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light house work, 
office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 
50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined 
to bed or chair 
 


 
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Appendix 3 – Histopathological assessment and Central review  
 
Mandatory histopathological assessment 
 
To 
ensure 
as 
much 
as 
possible 
uniformity 
in 
pathological 
reports, 
detailed 
recommendations 
for 
management 
of 
surgical 
specimens 
are 
listed 
below.  
It is recommended to follow these guidelines as much as possible. 
− Pathological tumor size, as determined by microscopic measurement according to  
the TNM classification (pT). The largest invasive tumoral focus is measured. 
− Histological type (ductal, lobular or other type as defined by the 2003 WHO 
classification of tumours should be specified). 
− Histological grade according to the Elston & Ellis method (modified Scarff Bloom & 
Richardson’s method).  
− This method is based on an assessment of tubule/gland formation, nuclear 
pleomorphism and mitotic counts (dependent on microscope field area).  
 
Feature
Score
Tubule and gland formation
 
Majority of tumour (>75%)  
1 
Moderate (10-75%) 
 
2 
Few (<10%) 
 
3 
Nuclear pleomorphism
 
Small, regular and uniform  
1 
Moderate increase in size and variability 
2 
Marked variation 
 
3 
Mitotic count 
 
Dependent on microscope field area
1-3 
 
Grade I: well differentiated (3-5 points); 
Grade II: moderately differentiated (6-7 points); 
Grade III: poorly differentiated (8-9 points). 
All histological types are to be graded. The histological grade will be re-assessed  
by the regional referent pathologist (see below). 


 
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− Excision quality, margin status with measurement of the distance between tumor and 
the closest margin. If present, margin tumoral involvement should be quantified 
(focal/extensive). 
− Presence of in situ component, reported in % of the tumor. The presence  
of an extensive ductal in situ component should be specified.  
− Presence of lymphatic or vascular emboli in the peri-tumoral breast tissue.  
− Number of excised and invaded lymph nodes, capsular rupture if present. In case  
of sentinel node procedure, the preferred technique is as follows. The sentinel node is cut  
in half paracentrally, paraffin embedded and then cut in several (at least 3) sections spaced 
200µm apart. Sections are stained by hematoxylin and eosin (H&E). Immunohistochemical 
staining in case of H&E negativity is optional. Frozen section analysis is authorized  
if necessary 
− Measurement 
of 
estrogen 
(ER) 
and 
progesterone 
receptors 
(PgR) 
(immunohistochemistry only)  
− Immunohistochemical (IHC) determination of HER2 expression and FISH or CISH  
if necessary (IHC score 2+) 
 
Central review 
 
A central review of hormone receptors (HR) and HER2 status will be performed by referent 
regional pathologists to confirm the eligibility of the patients before randomization.  
A representative paraffin block of the tumor will be sent to the closest referent regional 
pathologist. The immunohistochemical determination of HR (both ER and PgR) and HER2 
will be re-performed and reported using the guidelines given below. All regional pathologists 
participating in this study are members of the GEFPICS (Group for the Evaluation of 
Immunohistochemical Prognostic Factors in Breast Cancer) and involved in quality 
assurance programs.  


 
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Guidelines for reporting HR and HER2 status 
 
HR (ER and PgR) negative: < 10% immunoreactive tumoral cells 
HR (ER and PgR) positive : ≥ 10% immunoreactive tumoral cells 
HER2 status reported using the Herceptest® (Dako) scoring system i.e.: 
 
Score 0, absence of membranous staining or <10% stained cells 
Score 1+, >10% stained cells with a weak and incomplete staining 
Score 2+, >10% stained cells with a weak or moderate complete staining 
Score 3+, >30% stained cells with a strong and complete staining.  
Score 0 and 1+ are reported “negative”.  
Score 2+ has to be further assessed by FISH or CISH technique. FISH/CISH-HER2 
amplification is defined by a number of HER2 gene copy ≥ 6 or a ratio HER2/centromere  
17 > 2,2.  
Score 2+ showing HER2 amplification and score 3+ are considered “positive” and are 
excluded of this study. Score 2+ showing no amplification are considered “negative”. 
For all HR and HER2 immunostains, presence of adequate internal (normal glands positive 
for HR and negative for HER2) and external controls (weak positive cases) will be 
mandatory. 


 
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Appendix 4– Sample collection  
 
For each patient, the following material will be collected: 
 
- In order to standardize the histopathological inclusion criteria, a representative paraffin 
block from the tumor will be sent to the regional referent pathologist to i) re-assess  
the histological grade on H&E stain ii) repeat the HR and HER2 immunohistochemistry.  
This paraffin block will be then sent to the central pathology laboratory (Institut Claudius 
Regaud, Toulouse) for central pathology review and production of tissue microarrays 
(TMA). The individual paraffin blocks will be returned to the initial laboratory as soon as  
the tissue microarray has been made. Rapid (within 7 days after reception of the paraffin 
block) feedback information of the main standard pathology data will be provided by fax  
to the local pathologist, oncologist and R&D UNICANCER.  
 
- one or two frozen tumor sample(s) will be collected for genomics and proteomics 
analysis. Immediately after surgery (within 30 minutes), the excised breast specimen must 
be transported to the pathology department in a dry container without any fixative.  
The pathologist will take a tissue sample in RNAse-free conditions (i.e. always wearing 
gloves and using RNAse-free/sterile equipments when processing tissue), from  
the periphery of the tumor to optimize the chance of a high proportion of malignant cells 
(>50%) and a good yield of tumor RNA. Tumor tissue samples has to be frozen immediately 
(within maximum 1 hour of surgery, to avoid RNA degradation) in liquid nitrogen and strored 
in the tumor bank of the institution. A pathological control verifying the number of malignant 
cells in the sample will be done before RNA and protein extraction. The availability  
of the frozen tumor sample will be prospectively registered, and collected by a courier. 
 
- one blood sample (2.5 ml) for serum storage will be collected between enrollment and 
the start of treatment, in order to perform proteomics analysis. Serum will be immediately 
processed after collection (within 2 hours) including centrifugation (3000 rpm over  
10 minutes), then aliquoted in tubes of 100 to 500 µl rapidly frozen and stored in liquid 
nitrogen.  


 
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These samples will be firstly stocked in the biological materials bank of each participating 
centre, and then shipped on dry ice at the end of the study from each participating center  
to the proteomics facility (Centre René Gauducheau, Nantes). It is planned to collect  
a total of 300 patients in each arm. 
 
All samples will be labeled with the institution and patient numbers allocated  
by UNICANCER. Each patient has to sign the patient information sheet and informed 
consent form for proteomics and genomics study. 
 
 
Sample schedule and logistics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participating center
(pathologist and 
oncologist) 
Regional referent 
pathology department 
Assessment of HR 
and HER2 status 
Tumor bank 
 
Paraffine Blocks 
Claudius Regaud Institut – Toulouse 
Pathology department 
Central review -TMA 
 
Frozen serum samples 
Centre René Gauducheau - Nantes 
Paraffin block 
HR and HER2 status 
Data  
Return of the 
paraffin block
R&D UNICANCER 
Frozen 
Serum 
sample 
Data  
Paraffin block 
Frozen 
tumor sample


 
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Appendix 5 – Sub-studies  
 
Tissue microarrays 
The central pathology review will allow generation of a database of histopathology criteria 
for all the samples. The tissue microarray will be performed according to the standard 
technique i.e.: determination of representative tumor regions on a H&E stain, punching  
of three tumor cores and one normal breast core from the paraffin (donor) block  
to the empty recipient block, cutting of numerous sections and transfer to glass slides, 
storage at –20°C.  
In addition to routine immunostains such as ER, PgR, HER2 and Ki-67, basal phenotype 
immunostains will be performed using a large panel of markers (Cytokeratins 5/6 and 14, 
HER1/EGFR, P cadherin, moesin, CD10, etc) described in our previous PACS01 study 
(Jocelyne 
Jacquemier). 
Other 
markers 
exploring 
proliferation/apoptosis 
and 
oncogene/antioncogene pathways as previously described will also be analyzed (jocelyne 
Jacquemier). Specific chemotherapy resistance pathway will be studied according  
to the most up-dated litterature and in relevance of genomics data provided in this study. 
CISH (Chromogenic In Situ Hybridization) studies will also be performed on TMA to confirm 
HER2 status but also to determine HER1/EGFR, c-myc, TOP2A gene copy status. 
 
Proteomics  
In order to study post-transciptional gene functions, proteomics analysis of serum and tumor 
tissue will be performed at the proteomics facility of St Herblain (Nantes). These studies, 
encompassing different techniques such as SELDI-TOF, MALDI-TOF mass spectrometry 
and 2D gel electrophoresis, will allow identification of new predictive biomarkers or clinically 
relevant protein profiles, from serum and tumor tissue. The expression protein profiles will 
be correlated with tissue histopathology, TMA analysis and clinical outcome.  
 
Genomics 
A portion of the excised tumor obtained during initial surgery before treatment will be 
collected, aliquoted (after cutting off with a scalpel two pieces of the sample, respectively 
one for the genomics and one for proteomics study), immediately frozen and firstly stored  
in liquid nitrogen in the tumor bank of the institution. Once every six months, the frozen 
tumor tissue samples should be shipped on dry ice to the tumor bank of the Claudius 
Regaud Institute, to collect samples for genomics study. A pathological control verifying  
the number of malignant cells in the frozen sample will be done before RNA and protein 
extraction.


 
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If the malignant cell percentage is sufficient (>50%), RNA will be isolated from the samples, 
and 
tested 
for 
quality 
using 
RNA 
LabChip® 
(Agilent 
technologies).  
RNA expression levels will be measured using microarray technology, in order to determine 
the overall gene expression pattern. Main objectives are to identify new predictive and 
prognostic gene expression profiles, but also to validate previously discovered gene 
profiles. Molecular classification will be performed as previously described in literature,  
to precisely identify basal-type tumors. Further sub-studies of identified genes involved  
in basal-like tumors, such as EGFR or p53, will be performed. These studies will 
encompass several analytical tools. DNA sequencing and new technologies such as array-
based Comparative Genomic Hybridization (CGH array), which allows high-throughput, 
rapid identification and mapping of genomic DNA copy number changes, will be planned  
to further characterize some previously reported genomic alterations involving the EGFR 
gene in particular.  
 
References 
FA Tavassoli, Peter Devilee. Pathology and genetics of tumours of the breast and female genital 
organs. World Health Organization classification of tumours. IARC press: Lyon, 2003. 
 
UICC (2002). TNM classification of malignant tumors. Sixth ed. John Wiley & Sons: New York. 
 
National Co-ordinating Group for Breast Screening Pathology (1995). Pathology reporting. In: breast 
screening pathology, 2nd ed. NHSBSP publications. 
 
Robbins P, Pinder S, de Klerk N, Dawkins H, Harvey J, Sterrett G, Ellis I, Elston C (1995). 
Histological grading of breast carcinomas: a study of interobserver agreement. Hum Pathol 26:873-
879. 
 
Standards Options et Recommandations vol 12. Cancers du sein infiltrants non métastatiques. 2ème 
édition. John Libbey Eurotext:Montrouge, France. 
 
Mac Grogan G, De Mascarel I, Monnereau A, Mathoulin Pelissier S, Rabreau M, Bergouignan MA, 
Julien M, Mollimard J, Pedram M, Pellegrin de Villeneuve M, Cirillo I. Le “compte rendu – fiche 
standardisée” des prélèvements mammaires. Ann Pathol 2003:23;1S50-1S51. 
 
Reis-Filho JS, Pinheiro C, Lambros MBK, et al. EGFR maplification and lack of activating mutations 
in metaplastic breast carcinomas. J Pathol 2006;209:445-453. 
 
Penault-Llorca F et al. evaluation immunohistochimique du statut HER2 dans les carcinomes 
mammaires infiltrants: mise au point du protocole technique et de la lecture des résultats – 
recommandations. Ann Pathol 2002;22:150-7. 
 
Ellis IO et al. Best practice No 176: updated recommendations for HER2 testing in the UK. J Clin 
Pathol 2004;57:233-7. 
 
Vincent-Salomon A et al. Calibration of immunohistochemistry for assessment of HER2 in breast 
cancer: results of the french GEFPICS study. Histopathol 2003;42:337-47. 
 
Wolff AC, Hammond EH, Schwartz JN and al. American society of clinical oncology / College of 
american pathologists guideline recommendations for human epidermal growth factor receptor 2 
testing in breast cancer. J. Clin.Oncol.2007;vol 25. 
 


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Appendix 6 – SAE Form 
PAGE 2 OF 2 
PACS08 Version FR 4.0 du 23 November  2011 
 
60 / 63 
 
 
PROTOCOL N°: 
 
 
 
EUDRACT N°:  
 
 
COUNTRY : 
(DO NOT FULFIL)
SPONSOR IDENTIFICATION N°  
INVESTIGATOR SITE:  
N°: 
1. PATIENT IDENTIFICATION
INCLUSION N°: |___________| 
SURNAME (3 LETTERS):   |__|__|__| 
1ST NAME (2 LETTERS):    |__|__| 
DATE OF BIRTH: |__|__| / |__|__| / |__|__|__|__| 
SEX: 
F   
M  
WEIGHT (KG) :    |_______| 
HEIGHT (CM) :          |_______| 
TREATMENT ARM : |____| 
INITIAL REPORT 
 
FOLLOW-UP REPORT N° 
|__|__| 
FINAL REPORT  
 
2. INFORMATION ON EVENT
DATE OF ONSET : |__|__| / |__|__| / |__|__|                TOXICITY (GRADE NCI – CTC V3) :  
1   
2   
3   
4   
5  
DIAGNOSIS OR MAIN SYMPTOMS :………………………..…………………………………………………..…………...………….…..... 
……………………………………………………………………………………………………………………….………….…….. 
DESCRIBE REACTION AND TREATMENT GIVEN (INCLUDING RELEVANT TEST/LAB DATA)  : 
..........................................................................................................................................................................................................................................................
......................................................................................................................................................................................................................................................... 
3. SERIOUSNESS CRITERIA
 DEATH ………………………..…………………  DATE 
|__|__| / |__|__| / |__|__|  
 PERSISTENT/SIGNIFICANT DISABILITY/INCAPACITY 
 LIFE-THREATENING 
 OTHER CANCER: ........................................................................... 
 REQUIRING/PROLONGING HOSPITALIZATION (> 24H) : DATE OF ADMISSION |__|__| / |__|__| / |__|__|                CONGENITAL DISORDER/BIRTH DEFECT 
 MEDICALLY SIGNIFICANT, SPECIFY : ……………………………………………..…………………………    
  
4. OUTCOME
 ONGOING EVENT 
 RECOVERED WITHOUT SEQUELA, DATE  |__|__| / |__|__| / |__|__|  
 RECOVERED WITH SEQUELA, DATE  
|__|__| / |__|__| / |__|__|  
SPECIFY SEQUELA: ………………………………………………………………. 
DATE OF END OF HOSPITALIZATION:  
|__|__| / |__|__| / |__|__| 
 DEATH RELATED TO THIS EVENT, DATE : 
|__|__| / |__|__| / |__|__| 
 DEATH UNRELATED TO THIS EVENT, DATE : 
|__|__| / |__|__| / |__|__| 
 UNKNOWN  
 AUTOPSY 
YES  
NO  
 
5. INVESTIGATIONAL TREATMENT(S) 
 
TREATMENT(S) 
 
DATES 
DOSE & UNIT 
RELATIONSHIP TO STUDY 
TREATMENT 
INVESTIGATIONAL TREATMENT 
 
(INDICATE THE BRAND NAME OF THE 
TREATMENT) 
ROUTE 
DATE OF FIRST 
ADMINISTRATION  
 
(1ST DAY OF 1ST CYCLE) 
DATE OF  LAST 
ADMINISTRATION  
BEFORE SAE 
LAST DOSE 
ADMINISTRATED 
BEFORE SAE 
 
CUMULATIVE DOSE 
SINCE THE 1ST 
ADMINISTRATION 
0: EXCLUDED
1: DUBIOUS 
2: POSSIBLE 
3: LIKELY 
4: VERY LIKEY 
5: INSUFFICIENT DATA 
DOSE 
UNIT 
DOSE 
UNIT 
INVESTIGATOR 
SPONSOR 
1. 
 
 |__|__||__|__||__|__|
 |__|__||__|__||__|__|
|__| 
|__|
2.
 
 
 |__|__||__|__||__|__|
 |__|__||__|__||__|__|
|__|
|__|
3.
 
 
 |__|__||__|__||__|__|
 |__|__||__|__||__|__|
|__|
|__|
4.
 
 
 |__|__||__|__||__|__|
 |__|__||__|__||__|__|
|__|
|__|
5.
 |__|__||__|__||__|__|
 |__|__||__|__||__|__|
|__|
|__|
6.
 
 
 |__|__||__|__||__|__|
 |__|__||__|__||__|__|
|__|
|__|
7.
 |__|__||__|__||__|__|
 |__|__||__|__||__|__|
|__|
|__|
 HAS ONE (OR SEVERAL) TREATMENT(S) BEEN STOPPED?  
 
 YES  
N° |__| N° |__| N° |__| N° |__| N°|__|    NO    NA 
 
DID THE EVENT DISAPPEAR AFTER TREATMENT(S) STOPPED? 
 
 YES  
 NO 
 NA 
HAS ONE (OR SEVERAL) TREATMENT(S) BEEN REINTRODUCED? 
 
 YES  
N° |__| N° |__| N° |__| N° |__| N°|__|    NO    NA 
 
DID THE EVENT REAPPEAR AFTER TREATMENT REINTRODUCTION? 
 
 YES  
 NO 
 NA 
Notification of A Serious Adverse Event Form 
TO BE FAXED TO PHARMACOVIGILANCE - PARIS OFFICE N° + 33 (0)1 44 23 55 70


 Protocol n°UC-0140/0610  – EudraCTNr2006-006494-24 
Appendix 6 – SAE Form 
PAGE 2 OF 2 
PACS08 Version FR 4.0 du 23 November  2011 
 
61 / 63 
 
 
 
PROTOCOL N°: 
 
 
 
EUDRACT N°:  
 
 
COUNTRY : 
(DO NOT FULFIL)
SPONSOR IDENTIFICATION N°  
INVESTIGATOR SITE:  
N°: 
1. PATIENT IDENTIFICATION
INCLUSION N°: |___________| 
SURNAME (3 LETTERS):   |__|__|__| 
1ST NAME (2 LETTERS):    |__|__| 
DATE OF BIRTH: |__|__| / |__|__| / |__|__|__|__| 
SEX: 
F   
M  
WEIGHT (KG) :    |_______| 
HEIGHT (CM) :          |_______| 
TREATMENT ARM : |____| 
6. CONCOMITANT DRUG(S) – (EXCLUDE THOSE USED TO TREAT REACTION)
CONCOMITANT DRUG 
ROUTE 
DATE STARTED 
DATE STOPPED 
ONGOING 
INDICATION 
CAUSALITY
YES
NO
1. 
 
FROM |__|__||__|__||__|__| 
TO |__|__||__|__||__|__| 
 
|__|  
|__| 
2. 
 
FROM |__|__||__|__||__|__| 
TO |__|__||__|__||__|__| 
 
|__|  
|__| 
3. 
 
FROM |__|__||__|__||__|__| 
TO |__|__||__|__||__|__| 
 
|__|  
|__| 
4.
 
 
FROM |__|__||__|__||__|__| 
TO |__|__||__|__||__|__| 
 
|__| 
|__| 
5.
 
 
FROM |__|__||__|__||__|__| 
TO |__|__||__|__||__|__| 
 
|__| 
|__| 
7. OTHER RELEVANT HISTORY (E.G. DIAGNOSTICS, ALLERGIES, PREGNANCY WITH LAST MONTH OF PERIOD, ETC…)
 
 
 
 
 
8. ASSESSMENT  IN YOUR OPINION, THIS EVENT IS RELATED TO : 
 
 
 INVESTIGATIONAL TREATMENT(S), SPECIFY…......…………..……………………..…. 
 DISEASE PROGRESSION 
 TRIAL SCHEDULE 
 CONCOMITANT DISEASE(S), SPECIFY ……………………………………….. 
 CONCOMITANT TREATMENT(S) 
 OTHER, SPECIFY ……………………………………..……………………… 
9.  EXPECTED SERIOUS ADVERSE EVENT
INVESTIGATOR  YES   NO  SPONSOR  YES           NO 
 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION 
(SUSAR) 
INVESTIGATOR  YES   NO 
SPONSOR  YES           NO 
10. INVESTIGATOR
REPORTER’S NAME AND FUNCTION: 
 
ADDRESS:  
 
 
 
PHONE:  
 
 
FAX: 
E-MAIL:  
DATE |__|__| / |__|__| / |__|__|
 
INVESTIGATOR’S NAME: 
INVESTIGATOR’S SIGNATURE: 
 
 
Notification of A Serious Adverse Event Form 
TO BE FAXED TO PHARMACOVIGILANCE - PARIS OFFICE N° + 33 (0)1 44 23 55 70


            
       
Protocol n°UC-0140/0610 – EudraCTNr2006-006494-24 
 
PACS08 Version FR 4.0 du 23 November 2011 
 
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Appendix 7 – Toxicity criteria (CTCAE) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
http://ctep.cancer.gov/ 
 
 
 
 
 
Common Terminology Criteria for Adverse Events v3.0 (CTCAE)  
(Publish Date December 12, 2003)  
 
CTCAE v3.0, a new version of the CTEP, NCI CTC v2.0, includes Adverse Events applicable 
to all oncology clinical trials regardless of chronicity or modality.  
 
 
 


            
       
Protocol n°UC-0140/0610 – EudraCTNr2006-006494-24 
 
PACS08 Version FR 4.0 du 23 November 2011 
 
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Appendix 8 – Products summaries 
 
 
 
 
 
 
 
http://agmed.sante.gouv.fr/ 
http://www.emea.eu.int/ 
http://www.vidalpro.net/