Conditions: Breast Cancer
Keywords: Triple-Negative Early Breast Cancer Maintenance Adjuvant Chemotherapy Capecitabine Basal-like genotype Triple-Negative
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 876
Healthy volunteers: no

Brief summary:
This is a prospective, open-label, randomized phase III study assessing adjuvant capecitabine after standard chemotherapy for patients with early triple negative breast cancer.

Detailed description:
Patients will be stratified as per investigational site, previous adjuvant chemotherapy (anthracyclines versus anthracyclines plus taxanes), and number of affected axillary lymph nodes (0, 1-3, \>= 4). Node negative patients must present a tumour size \> 2 cm to be eligible. At least 6 lymph nodes must be analysed to confirm the number of affected nodes. Patients will be randomised to receive: 8 courses of capecitabine 1000 mg/m2 by mouth, twice a day (p.o. bid) for 14 days, followed by a 7 day rest versus observation.

Tissue samples must be analysed by a central laboratory, to confirm estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor-2 (HER2), cytokeratins (CK) 5/6 and epidermal growth factor receptor (EGFR) status.

The following data were obtained from the database of the "El Alamo" project. One thousand six hundred and twenty-seven (1,627) in total were considered during the years 1990 to 1997. The population is formed of patients with operable breast cancer, with surgery, positive nodes, and negative hormone receptors, or negative nodes, negative hormone receptors and T2-3 tumors.

For these patient groups, estimated 5-year disease-free survival is 64.72%. Assuming an exponential distribution, the aim is to detect an increase of 64.72% to 73.7% in 5 years Disease Free survival rate corresponds to a Hazard Ratio of 0.701 and a risk reduction of about 30%, with a power of 80% using a two-tailed log-rank test at 0.05 and whereas 4 years of recruitment period and 3 years of follow-up period. We would need 255 events, 834 patients without considering any dropouts.

Considering a drop-out rate of 5% post-randomization, the final sample size will be 876 patients, 438 per treatment arm.

The sample size calculation was performed by the program package "EAST" version 5.2.

Arms:
arm 1: 1000 mgrs/m2 twice a day, tablets, 8 cycles arm 2: Observation. No intervention.

Interventions: intervention 1: Capecitabine
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 1 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
 
 
 
 
 
 
 
 
 
 
 
 
COALICIÓN IBEROAMERICANA DE INVESTIGACIÓN EN ONCOLOGÍA 
MAMARIA (CIBOMA) (IBEROAMERICAN COALITION FOR BREAST ONCOLOGY 
RESEARCH) 
CIBOMA/2004-01 
 
PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO 
EVALUATE THE EFFICACY OF MAINTENANCE THERAPY WITH 
CAPECITABINE (X) AFTER STANDARD (NEO-) AND/OR ADJUVANT 
CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER 
CIBOMA/2004-01 
Chemotherapy vs. Observation 
 
SPONSOR: CIBOMA (IBEROAMERICAN COALITION FOR BREAST ONCOLOGY 
RESEARCH) 
 
 
AVENIDA DE LOS PIRINEOS 7, OFICINA 1-14 
 
 
28703 SAN SEBASTIÁN DE LOS REYES (MADRID) 
 
 
SPAIN 
 
EudraCT Nº: 2005-002838-36 
 
STUDY MEDICAL COORDINATORS 
Dr. Ana Lluch 
Servicio de Oncología Medica 
Hospital Clínico U. De Valencia 
Av. Blasco Ibáñez 17 
46010 Valencia (Spain) 
Tel:+34963862625 
Fax:+34963622238 
Dr. Laura Torrecillas 
Centro 
Médico 
de 
Especialidades 
20 
de 
Noviembre 
ISSSTE 
Mexico 
Tel: +52-55-5575 3072 
Fax:: +52-55-5575 3072 
Dr. Carlos H. Barrios 
Servicio de Oncología Médica 
Hospital Sao Lucas-PUC 
Avda. Iìranga, 6690   
SL 228-Porto Alegre RS 
CEP 90,610-000 
Brazil 
Tel: + 55 51 33203319 
Fax: + 55 51 33203319 
 
Final version (3): 
June 10, 2005 / Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
CONFIDENTIAL: The information and data included in this protocol is confidential and proprietary to the 
Iberoamerican Coalition for Research in Breast Oncology (CIBOMA). The publication of this material is not 
permitted except with the prior authorization in writing from CIBOMA. These limitations will be applied 
equally to any information considered as privileged or confidential that is provided in the future. This 
material may be revealed and used by your team and co-workers as required for the performance of the 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 2 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
clinical study.
 
1.- STUDY SUMMARY 
 
Type of request 
Clinical trial with a pharmaceutical product in a new indication.  
Sponsor details 
Coalición 
Iberoamericana 
de 
Investigación 
en 
Oncología 
Mamaria 
– 
Iberoamerican Coalition for Investigation in Breast Oncology (CIBOMA) 
Avenida de los Pirineos 7, oficina 1-14 
28703 San Sebastián de los Reyes (Madrid) 
Spain 
Tel.: + 34 916592870 
Fax:  +34 916510406 
E-mail: ciboma@ciboma.org 
Web page: www.ciboma.org 
 
Study title 
“Phase IV.III, multicenter, open, randomized treatment study to evaluate the 
efficacy of maintenance therapy with capecitabine (X) after standard (neo-) and/or 
adjuvant chemotherapy in patients with operated, hormone receptor and HER2neu 
negative breast cancer”. 
Protocol Code 
CIBOMA/2004-01 
Principal 
investigators  
Dr. Ana Lluch, Dr. Ruiz Borrego, Dr. Calvo (Spain), Dr. Laura Torrecillas 
(Mexico), Dr. Carlos H. Barrios (Brazil) (See Appendix 7). 
Centers in which 
trial will be carried 
out  
University Hospital Clinic, Valencia; University Hospital Virgen del Rocío, Juan 
Canalejo Hospital Complex (Spain). 
Specialist Medical Center 20 de Noviembre (Mexico). 
Hospital Sao Lucas-PUC (Brazil) (See appendix 7). 
Clinical Research 
Ethics Committees 
which have 
approved the study
Committees corresponding to the participating centers (see Appendix 7). 
 
Spain: The Clinical Research Ethics Committee (CREC) of the University 
Hospital Clinic, Valencia will act as reference CREC for the single approval of the 
protocol for all centers in Spain. 
Good Clinical 
Practice (GCP) 
Study Monitors  
Yolanda Amigo: yamigo@ciboma.org 
Victoria Ruiz: vruiz@ciboma.org 
Nuria Caparroso: ncaparroso@ciboma.org  
Beatriz Pardo: bpardo@ciboma.org  
Lourdes del Burgo: lburgo@ciboma.org  
Patricia Jou: pjou@ciboma.org  
Anabel García: agarcia@ciboma.org  
Gema Sanz: gsanz@ciboma.org  
Sara Perales: sperales@ciboma.org  
Cristina del Monte: cmonte@ciboma.org
Overall Project 
Coordinator 
Dr. Eva Carrasco 
CIBOMA 
Avenida de los Pirineos 7, oficina 1-14 
28703 San Sebastián de los Reyes (Madrid) 
Spain 
Tel: +34916592870 
Fax:+34916510406 
E-mail: evacarrasco@geicam.org  
Study 
Coordination 
Andrés Hernando 
CIBOMA 
Avenida de los Pirineos 7, oficina 1-14 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 3 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
28703 San Sebastián de los Reyes (Madrid) 
Spain 
Tel.: +34916592870 
Fax:+34916510406 
E-mail: ahernando@ciboma.org 
Administrative 
Coordinators 
Elena Gutiérrez and Mª Ángeles Jimeno 
CIBOMA 
Avenida de los Pirineos 7, oficina 1-14 
28703 San Sebastián de los Reyes (Madrid) 
Spain 
Tel: +34916592870 
Fax:+34916510406 
E-mail: egutierrez@ciboma.org / majimeno@geicam.org  
Statistical Team 
Mª José Escudero and María Isabel Casas 
CIBOMA 
Avenida de los Pirineos 7, oficina 1-14 
28700 San Sebastián de los Reyes (Madrid) 
Spain 
Tel: +34916592870 
Fax:+34916510406 
E-mail: mjescudero@ciboma.org; micasas@ciboma.org 
Biological sample 
management 
coordination 
César García 
CIBOMA 
Avenida de los Pirineos 7, oficina 1-14 
28703 San Sebastián de los Reyes (Madrid) 
Spain 
Tel: +34916592870 
Fax:+34916510406 
E-mail: cgarcia@ciboma.org  
Central laboratory 
for analysis of 
physiological 
samples 
 
CIBOMA main offices 
Avenida de los Pirineos 7, oficina 1-14 
28703 San Sebastián de los Reyes (Madrid) 
Spain 
Tel: +34916592870 
Experimental drug 
and control 
Control arm: Observation 
Experimental arm: Capecitabine 1000 mg/m2 twice a day for 14 days, followed 
by a rest period of 7 days, for 8 cycles. 
 
Clinical trial phase This is a Phase IV.III clinical trial. It is considered Phase IV because the study 
drug to be used has a marketing license in all the participating countries.  
However, the study product will be administered in an indication not approved in 
the marketing license, with the aim of evaluating its efficacy in increasing disease-
free survival (Phase III study design). 
Objectives 
Principal objective: Compare disease-free survival after maintenance therapy 
with 8 cycles of capecitabine (X) compared to observation, in patients with 
operated, hormone receptor and HER2neu negative breast cancer who have 
received standard (neo-) and/or adjuvant chemotherapy. 
 
Secondary objectives: 
• 
Compare the 5-year Disease-Free Survival (DFS).  


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 4 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
• 
Compare Overall Survival (OS) between the two above-mentioned groups 
• 
Compare toxicity between the two above-mentioned groups. 
 
Tertiary objectives: 
Determine the effect of treatment with capecitabine on the development and 
duration of amenorrhea in premenopausal women. 
 
(In selected centers): Study the presence of thymidylate synthase (TS) and 
methylenetetrahydrofolate reductase (MTHFR) polymorphisms and confirm their 
relation with toxicity and efficacy of treatment with capecitabine. 
 
Study design 
 
Phase IV.III prospective, open, randomized treatment study. At the time of 
inclusion, after completing 6 cycles of standard (neo-) and/or adjuvant 
chemotherapy with anthracyclines and/or taxanes (NOTE: Patients without 
axillary node involvement may receive four cycles of adriamycin and 
cyclophosphamide (AC) as single chemotherapy treatment). The stratification will 
be carried out according to participating hospital, prior to chemotherapy 
(anthracyclines vs. anthracyclines and taxanes) and the number of ipsilateral 
axillary nodes involved (0, 1-3, ≥4), and the phenotype (basal vs. triple negative) 
and will be distributed randomly to receive: 
 
X x 8:  capecitabine 1000 mg/m2 p.o. administered twice a day (morning and 
evening) for 14 days, followed by a 7-day rest period, for 8 cycles. 
 
Observation 
 
Dose reduction and treatment delay and interruption have been planned in case of 
severe hematological or non-hematological toxicities. 
 
Indication for radiation therapy - Both groups: Patients will receive radiotherapy 
following the guidelines of each institution. Radiation therapy protocol/guidelines 
will be collected from each site. Not more than 4 weeks should elapse between the 
end of radiation therapy and patient registration of the patients in study 
CIBOMA/2004-01.  
 
Estrogen and progesterone receptor status: 
Estrogen and progesterone receptor status must be analyzed from a sample of the 
patients’ primary tumor in the designated central laboratory. The results should be 
known before randomization. Any tumor which is not considered definitely 
negative, ie. on the limit, will be considered positive. 
HER2 expression status: An immunohistochemical analysis of the HER2 protein 
expression status must be made in the designated central laboratory. For tumors 
with a result of 2+, the number of copies of the c-erbB2 gene from the patients’ 
primary tumor must be determined by FISH. 
Baseline genotype profile: An immunohistochemical analysis of cytokeratins 
CK5/6 and EGF receptor (EGFR) expression status must be performed in the 
designated central laboratory. 
Disease or disorder 
under study 
Patients with operated breast cancer with no metastatic involvement (AJCC, 
2002).  Patients will be able to participate whether they present axillary node 
involvement (node positive) or not (node negative).  Node-negative patients must 
have a tumor greater than or equal to 1 cm diameter. 
At least six axillary nodes must be studied. For patients undergoing biopsy of the 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 5 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
sentinel node, this node will count for the purposes of the number of nodes 
removed and with disease involvement. The patients’ tumors must be estrogen and 
progesterone receptor negative and HER2 negative, according to the determination 
of the designated central laboratory. 
 
Principal endpoint Disease-free survival (DFS). 
 
Inclusion criteria 
1. Informed consent must be obtained and documented in writing before any 
protocol-specific procedures are performed, including the expected cooperation 
of patients in treatment and follow-up, in accordance with the ICH guidelines 
for Good Clinical Practice. The patient must sign informed consent for sending 
her tumor sample to the central laboratory. Subsequently, if the patient is 
eligible, a consent form must be signed for participation in the clinical trial. 
2. Histologically-proven breast cancer (histological examination: invasive 
adenocarcinoma).  
3. Patients with ispilateral axillary node involvement. If the sentinel node 
technique is used, the sentinel node will count as a resected involved node.  
Patients who can be classified in the following groups (AJCC 2002) will be 
admitted: 
- 
pN1a: Metastasis in 1 to 3 axillary nodes. 
- 
pN2a: Metastasis in 4 to 9 axillary nodes (at least one tumor 
deposit >0.2 cm). 
- 
pN3a: Metastasis in 10 or more axillary nodes (at least one tumor 
deposit >0.2 cm). Patients with a diagnosis of pN3a with 
infraclavicular node metastasis will not be eligible. 
Nota: Patients without axillary node involvement (N0), provided the primary 
tumor is greater than or equal to 1 cm in diameter. If the sentinel node technique is 
used, lymphadenectomy will not be necessary. 
4. Out patient women aged≥ 18 years. 
5. Karnofsky performance status >80 (ECOG 0,1). 
Exclusion criteria 
1. Definitive surgical treatment for operable breast cancer (T1-3, M0) must be 
mastectomy or breast-conserving surgery. The margins of the sample extracted 
in definitive surgery must be histologically free of invasive adenocarcinoma 
and ductal carcinoma in situ (DCIS). Lobular carcinoma in situ is not 
considered as a positive margin. 
2. (Neo-) and/or adjuvant chemotherapy treatment with anthracyclines and/or 
taxanes (paclitaxel, docetaxel) of at least 6 cycles has not been received. 
NOTE: For patients without axillary node involvement that have not received 
at least four cycles of adriamycin and cyclophosphamide as single 
chemotherapy treatment. The allowed treatments are available in appendix 1. 
Any other treatment schedule should be approveb by the study medical 
coordinators. 
3. In lymphadenectomy, resection of less than 6 nodes (For patients undergoing 
biopsy of the sentinel node, if it is positive, will count as a resected). 
4.  Previous treatment with anthracyclines or taxanes (paclitaxel, docetaxel) for 
any neoplasm other than the breast cancer being treated. 
5.  For patients that receive radiation therapy, no more than 8 weeks (2 months) 
should elapsed between day 1 of last (neo-) and/or adjuvant chemotherapy 
cycle and the clinical trial entry. For those patients in which the administration 
of adjuvant radiation therapy, more that 4 weeks (1 month) can be elapsed 
between the last session and the clinical trial entry.  


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 6 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
For patients that receive antineoplastic treatment before surgery, the interval 
between definitive surgical treatment and clinical trial entry is longer than 
60 days. 
6. Patients with unknown or positive estrogen, progeterone and HER2 receptor 
tumors. 
7. Pregnant or nursing patients. Patients of child-bearing potential must have a 
negative result in a urine pregnancy test with the 14 days before treatment 
assignation. 
8. Women in a fertile age that do not want to use a reliable and suitable 
contraceptive method. The postmenopausal women should have been with 
amenorrhea during at least 6 months to be considered as infertile (see section 
6.5). 
9. Diagnosis of invasive bilateral breast cancer. 
10. Clinically relevant heart failure, such as congestive heart failure or 
symptomatic coronary artery disease, heart arrhythmia uncontrolled with 
treatment or history of myocardial infarction during the year before study 
inclusion, or uncontrolled hypertension. 
11. History of significant neurological or psychiatric disease, including psychotic 
disorders, dementia or attacks which would impede the patient’s understanding 
and giving informed consent, will interfere in compliance of the study drug 
regimen. 
12. Uncontrolled active infection or other diseases or serious medical pathologies, 
such as active peptic ulcer, unstable diabetes mellitus. 
13. Presence of anomalies in any laboratory parameter, as defined next: (in the 
previous 14 days to the treatment assigment): 
• 
Hemoglobin < 10 mg/dl; absolute neutrophil count < 1,5 x 109/l; platelet 
count < 100 x 109/l. 
• 
 ASAT (SGOT) and ALAT (SGPT) > 2,5 ULN; alkaline phosphatase > 5 
ULN; total bilirrubin > 2.0 ULN. Patients with ASAT and/or ALAT 
values >1.5 x ULN associated with an alkaline phosphatase level >2.5 x 
ULN will not be selected for the study. 
• 
Severe renal impairment , defined as creatinine clearance below 30 
ml/min, according to the Cockroft and Gault formula (see appendix 9) or 
serum creatinine > 1,5 ULN. 
14. Previous or present history of neoplastic disease other than breast cancer, with 
the exception of: 
• Non-melanoma skin cancer, cervical cancer in situ or other form of 
tumor curatively treated and without signs of disease for at least 10 
years. 
• Ipsilateral ductal carcinoma in situ (DCIS) of the breast. 
• Lobular carcinoma in situ (LCIS) of the breast. 
15. Known hypersensitivity to capecitabine, doxifluridine, fluorouracil or any of its 
excipients. 
16. Patients with lack of upper gastrointestinal tract physical integrity or 
malabsorption syndrome, or with impossibility to take medication administered 
orally. 
17. Previous treatment with capecitabine or with continuous infusion (> 24 h) with 
5-FU, or with other oral fluoropyrimidines, such as eniluracil/5-FU, 
uracil/tegafur, S1 or emitefur. 
18. Blood transfusions or administration of growth factors to help the 
hematological recovery in the 2 weeks prior to the beginning of the study 
treatment. 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 7 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
19. Hormone treatment in the 10 days prior to the beginning of the study treatment.
20. Possibility of unexpected severe reaction in combination therapy with  
fluoropyrimidine, with or without proven dihydropyrimidine dehydrogenase 
(DPD) deficiency. 
21. Allograft transplants of organs that require immunosuppressive therapy. 
22. Patients treated with coumarin–derived anticoagulants. 
23. Patients treated with sorivudine or chemically related analogs, such as 
brivudine. 
24. Concomitant treatment with other investigational drugs. Participation in 
another clinical trial with any unmarketed investigational product during the 30 
days prior to study inclusion. 
25. Concomitant treatment with any other anticancer therapy. 
26. Inaccessible patients for the treatment and monitoring. The patients registered 
on this trial should be treated and monitored in the participating center, that 
could be the center of the principal investigator or co-investigator. 
27. Patients that cannot or do not want to comply with the protocol, considering the 
total duration of the study. 
Study population 
and total number 
of patients 
Assuming an exponential distribution, the aim is to detect an increase from 
64.72% to 73.7% in 5-year disease-free survival (DFS), corresponding to a hazard 
ratio of 0.701 and a risk reduction of approximately 30%, with a power of 80% at 
a two-sided level of 0.05, considering 4 years of recruitment and 3 of follow-up. 
We would need to see a total of 255 events for DFS, 834 patients without 
considering drop-outs.. 
Considering a drop-out rate of 5% post-randomization, the final sample size will 
be 876 patients, 438 per treatment arm. 
The sample size calculation has been completed using the EAST statistical 
software, version 5.2. 
The randomization process will be centralized and patients will be stratified 
according to participating center, prior chemotherapy treatment (anthracyclines vs. 
anthracyclines and taxanes), and the number of involved nodes (0 vs 1-3 vs >4) 
and the phenotype (basal vs. triple negative). 
Treatment 
duration 
Planned treatment duration with X in the study treatment arm is 24 weeks. The 
same visit schedule will be followed for patients in the observation arm.  
 
Timing and 
planned 
completion date 
Initiation of inclusion: October 2006. 
Completion of inclusion: October 2010. 
Clinical follow-up: 5 years. 
Final analysis: Fourth quarter 2013. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 8 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
STUDY DESIGN CIBOMA/2004-01:  
This is a prospective, randomized clinical trial designed to evaluate the efficacy and safety of 
maintenance therapy with capecitabine in women with operated, hormone receptor and 
HER2neu negative breast cancer, who have previously received standard (neo-) and/or adjuvant 
chemotherapy. Node-negative patients are eligible if they have a tumor size greater than or 
equal to 1 cm. 
Control treatment is observation. 
Study treatment consists of the administration of 8 cycles of capecitabine at a dose of 1000 
mg/m2, twice a day, administered p.o. for 14 days, followed by a week’s rest. The study will be 
carried out according to the following schedule: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Description of study population 
Patients with operated breast cancer and no metastatic involvement (AJCC, 2002). Patients will 
be eligible whether they present axillary node involvement (node positive) or not (node 
negative), but node-negative patients must have a tumor greater than or qual to 1 cm diameter. 
At least six axillary nodes must be studied. For patients undergoing biopsy of the sentinel node, 
this node will count for the purposes of the number of nodes removed and with disease 
involvement. 
Only patients with estrogen and progesterone receptor negative and HER2 negative tumors will 
be eligible. 
Estrogen and progesterone receptor status: An analysis of estrogen and progesterone 
receptors must be carried out using a sample of the patients’ primary tumor which will be sent 
to the designated central laboratory. The best time for sending the tumor sample is at the 
beginning of standard chemotherapy treatment. Tumors which cannot definitively be considered 
negative, i.e. on the limits, will be considered positive. Only patients whose tumor samples are 
estrogen and progesterone negative will be eligible for the study. 
The quantification system used will be a consensus between the UK NEQAS, SBCPG & 
EORTC from the year 2000: 
Operated breast cancer 
ER/PR negative 
HER2neu negative 
T1-3, N+, M0 / T1c-3, N0, M0 
Randomization: 
• 
Participating site,  
• 
Prior chemotherapy treatment (anthracyclines vs. anthracyclines and 
taxanes), 
• 
Number of affected nodes (0, 1-3, ≥4) and 
• 
Phenotype (basal vs. triple negative) 
Arm A 
Capecitabine x 8 
Arm B 
Observation
Follow-up 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
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Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
 
 
Proportion of staining  
Intensity 
0 
No nuclear staining 
0 
No staining 
1 
≤ 1% 
1 
Slight staining 
2 
1-10% 
2 
Moderate staining 
3 
11-33% 
 
3 
 
Intense staining 
4
34-66%
5 
67-100% 
 
The percentage of stained cells is evaluated and scored; the intensity of staining will be 
evaluated and another score will be applied; the final score will be the sum of both scores. 
Patients with tumors with no cell staining or slight staining (<1%) will be eligible. 
 
HER2 expression status: HER2 protein expression status will be analyzed by 
immunohistochemistry, from the sample of patients’ primary tumor, which will be sent to the 
designated central laboratory. In the tumors with result 2+, the number of copies of the c-erbB2 
gene will be determined by FISH, from the sample of patients’ primary tumor. 
 
Cytokeratin CK5/6 expression status: cytokeratin CK5/6 expression status will be analyzed 
by immunohistochemistry on the sample of patients’ primary tumor sent to the designated 
central laboratory. The result will be correlated with hormone receptor, HER2 and HER1 
(EGFR) receptor expression status, to establish concordance or divergence between the triple 
negative genotype and the baseline genotype. 
 
HER1 (EGFR) expression status: HER1 protein expression status will be analyzed by 
immunohistochemistry on the sample of patients’ primary tumor sent to the designated central 
laboratory. The result will be correlated with hormone receptor, HER2, cytokeratin CK 5/6 
expression status, to establish concordance or divergence between the triple negative genotype 
and the baseline genotype. 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 10 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
 
2. 
INDEX 
 
1.- STUDY SUMMARY............................................................................................................... 2 
STUDY DESIGN CIBOMA/2004-01: ......................................................................................... 8 
Capecitabine x 8 ....................................................................................................................... 8 
2. 
INDEX ................................................................................................................................ 10 
PROTOCOL SIGNATURE PAGE ............................................................................................. 14 
DECLARATION OF PRINCIPAL INVESTIGATOR AND TEAM......................................... 15 
1. 
JUSTIFICATION ............................................................................................................... 16 
1.1 
Background ................................................................................................................ 16 
1.2 
Adjuvant chemotherapy in the treatment of breast cancer ........................................ 16 
1.3 
Adjuvant chemotherapy in operable node-positive, or node-negative, high-risk breast 
cancer 18 
1.4 Neoadjuvant chemotherapy in breast cancer75-103 ............................................................ 20 
1.5 
Capecitabine .............................................................................................................. 20 
1.6 
Pharmacology of capecitabine .................................................................................. 21 
1.7 
Preclinical antitumor efficacy of capecitabine .......................................................... 21 
1.8 
Phase I clinical studies with capecitabine: regimens tested, maximum tolerated dose 
and recommended dose ........................................................................................................... 21 
1.9 
Phase I clinical studies with capecitabine: Pharmacokinetics of capecitabine in 
humans 22 
1.10 
Capecitabine in monotherapy. Phase II breast cancer studies. ................................. 23 
1.11 
Capecitabine in the neoadjuvant treatment of breast cancer .................................... 25 
1.12 
Polymorphisms related with efficacy and effectiveness of capecitabine ................... 25 
1.13 
Basal-like breast cancer ............................................................................................ 27 
1.15 
Justification for the present study .............................................................................. 29 
2. 
STUDY OBJECTIVES AND AIMS .................................................................................. 30 
2.1 
Principal objective ..................................................................................................... 30 
2.2 
Secondary objectives .................................................................................................. 30 
2.3 
Tertiary objectives ..................................................................................................... 30 
3. 
PATIENT SELECTION ..................................................................................................... 30 
3.1 
Inclusion criteria........................................................................................................ 30 
3.2 
Exclusion criteria ....................................................................................................... 31 
4. 
STRATIFICATION AND RANDOMIZATION TO TREATMENT ARM ..................... 33 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 11 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
4.1 
Timing of registration and randomization to study ................................................... 33 
4.2 
Treatment randomization procedure ......................................................................... 33 
4.3 
Treatment groups ....................................................................................................... 33 
4.4 
Stratification .............................................................................................................. 34 
5. 
PATIENT TREATMENT .................................................................................................. 34 
5.1 
Provision of drug supplies ......................................................................................... 34 
5.2 
Capecitabine administration ...................................................................................... 34 
5.3 Concomitant medication (only applicable to patients of the capecitabine treatment arm)
 
35 
Halopurinol ............................................................................................................................. 35 
Metronidazol ........................................................................................................................... 35 
Cimetidine ............................................................................................................................... 35 
Hematopoietic growth factors................................................................................................. 35 
Laxatives ................................................................................................................................. 36 
5.4 
Permitted dose adjustments ....................................................................................... 36 
Skin toxicity: grade 2/3 hand-foot syndrome .......................................................................... 37 
5.4.1 Warnings and cautions .............................................................................................. 38 
5.5 Drug accountability .......................................................................................................... 38 
5.6 Standard (neo-) and/or adjuvant chemotherapy ............................................................... 38 
6. 
EVALUATION OF EFFICACY ........................................................................................ 39 
6.1 
Primary endpoint: evaluation of treatment efficacy .................................................. 39 
6.1.1 
Objective Recurrence ............................................................................................ 39 
6.1.2 
Local Recurrence ................................................................................................... 39 
6.1.3 
Regional Recurrence ............................................................................................. 39 
6.1.4 
Distant Recurrence ................................................................................................ 39 
6.1.5 
Second primary tumor ........................................................................................... 40 
6.2 
Secondary endpoint: 5-year Disease-Free Survival .................................................. 40 
6.3 
Secondary endpoint: Overall 5-year survival ............................................................ 40 
6.4.1 
Clinical Safety ....................................................................................................... 40 
6.5 
Tertiary endpoint (in specific patient populations) ................................................... 40 
6.6 
Tertiary endpoint ....................................................................................................... 41 
7. 
STUDY EVALUATIONS .................................................................................................. 43 
7.1 
Time and events schedule .......................................................................................... 43 
7.2 
Withdrawal criteria and planned analysis for withdrawals and dropouts ................ 44 
7.3 
Treatment after discontinuation of study treatment ................................................... 44 
7.4 
Adverse events............................................................................................................ 44 
8. 
DATA COLLECTION AND PROCESSING .................................................................... 47 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 12 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
8.1 
Monitoring, Auditing and Inspection ......................................................................... 47 
8.2 
Data recording ........................................................................................................... 47 
8.3 
Identification of data which can be recorded directly onto the CRF and as such will 
be considered as source documents ........................................................................................ 48 
9. 
STATISTICS ...................................................................................................................... 49 
9.1 
Study populations ....................................................................................................... 49 
9.2 
Statistical methods ..................................................................................................... 49 
9.3 
Safety evaluation ........................................................................................................ 49 
9.4 
Determination of sample size ..................................................................................... 50 
9.5 
Statistical analysis of TS and MTHFR pharmacogenetic data .................................. 50 
9.5.1 
Hypothesis ............................................................................................................. 50 
9.5.2 
Calculation of sample size ..................................................................................... 50 
9.5.3 
Statistical analysis ................................................................................................. 51 
10. PRACTICAL CONSIDERATIONS .................................................................................. 52 
10.1 
Independent Data Monitoring Committee (IDMC) ................................................... 52 
10.1.1 
Composition and Mission of IDMC .................................................................. 52 
10.1.2 
IDMC meetings ................................................................................................. 52 
10.1.3 
IDMC recommendations ................................................................................... 52 
10.2 
Study budget ............................................................................................................... 52 
10.3 
Third-party insurance policy ..................................................................................... 52 
10.4 
Study archives ............................................................................................................ 52 
10.5 
Publication policy ...................................................................................................... 53 
11. ETHICAL CONSIDERATIONS ....................................................................................... 54 
11.1 
Declaration of Helsinki .............................................................................................. 54 
11.2 
Informed Consent (Appendix 4) ................................................................................. 54 
11.3 
Confidentiality ........................................................................................................... 54 
11.4 
Clinical Research Ethics Committee (CREC) ............................................................ 54 
11.5 
Protocol Modifications .............................................................................................. 54 
11.6 
Patient Identification ................................................................................................. 55 
12. REFERENCES ................................................................................................................... 56 
APPENDIX 1: 
Minimum acceptable regimens for chemotherapy for participation in the 
CIBOMA study 2004-01 ............................................................................................................. 62 
APPENDIX 2: KARNOFSKY PERFORMANCE SCALE AND EASTERN COOPERATIVE 
ONCOLOGY GROUP (ECOG) CRITERIA .............................................................................. 63 
APPENDIX 3: TNM CLASSIFICATION – BREAST (American Joint Committee on Cancer 
2002) ........................................................................................................................................... 64 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 13 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
APPENDIX 4: 
PATIENT INFORMED CONSENT MODEL ............................................. 66 
APPENDIX 5.- INFORMATION SHEET AND INFORMED CONSENT TO PARTICIPATE 
IN THE PHARMACOGENETIC SUBSTUDY. ........................................................................ 75 
APPENDIX 6: ADVERSE EVENT REPORT FORM ............................................................... 79 
APPENDIX 7: LIST OF PARTICIPANT COUNTRIES ........................................................... 81 
APPENDIX 8: RECORD OF MENSTRUAL STATUS ............................................................ 84 
APPENDIX 9: COCKROFT AND GAULT CRITERIA ........................................................... 85 
APPENDIX 10: CAPECITABINE DOSE CALCULATION IN RELATION TO THE BODY 
SURFACE AREA (ONLY TABLETS OF 500 MG). ................................................................ 86 
APPENDIX 11: DISCONTINUANCE AND EXTENSION OF THE REST PERIOD IN THE 
CAPECITABINE TREATMENT ............................................................................................... 88 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 14 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
PROTOCOL SIGNATURE PAGE 
 
PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO 
EVALUATE THE EFFICACY OF MAINTENANCE THERAPY WITH 
CAPECITABINE (X) AFTER STANDARD (NEO-) AND/OR ADJUVANT 
CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER 
CIBOMA/2004-01 
Chemotherapy vs. Observation 
 
Approved by: 
President of the Iberoamerican Coalition for Breast Oncology Research (CIBOMA) 
Prof. Dr. Miguel Martín 
 
 
_____________________________________        
 
 
____________ 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
 
Approved by:  
Coordinator of Spanish Investigators 
Dr. Ana Lluch 
 
_____________________________________        
 
 
____________ 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
Approved by:  
Coordinator of American Investigators 
Dr. Laura Torrecillas 
 
_____________________________________        
 
 
____________ 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
 
Approved by:  
Coordinator of American Investigators 
Dr. Carlos H. Barrios 
 
_____________________________________        
 
 
____________ 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 15 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
DECLARATION OF PRINCIPAL INVESTIGATOR AND TEAM 
 
With reference to the protocol: 
 
PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO 
EVALUATE THE EFFICACY OF MAINTENANCE THERAPY WITH 
CAPECITABINE (X) AFTER STANDARD (NEO-) AND/OR ADJUVANT 
CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER 
CIBOMA/2004-01 
Chemotherapy vs. Observation 
 
I agree that this protocol contains all the necessary details for carrying out the study. I will carry 
out the study as explained in this document and in compliance with Good Clinical Practice 
Guidelines and with the Declaration of Helsinki (www.wma.net). I will endeavor to conclude 
recruitment of patients for the study by October 2010. I will provide copies of the protocol and 
all data on the drug regarding prior preclinical and clinical experience provided to me by 
CIBOMA to all doctors working under me who are participating in the clinical trial. I will 
discuss this material with the doctors to ensure that they are duly informed about the drug and 
the performance of the study. I agree to keep a record of all patient data (case report forms and 
patient informed consent), forms for receipt and return of drug, and other information collected 
during the study, in accordance with the legal requirements. 
 
 
 
______________________________________ 
Investigator (NAME IN BLOCK CAPITALS)  
 
 
 
______________________________________ 
Signature of Investigator 
 
 
 
 
Date 
 
 
 
______________________________________ 
Co-investigator (NAME IN BLOCK CAPITALS) 
 
 
 
 
______________________________________ 
Signature of Co-investigator 
 
 
 
 
Date 
 
 
 
______________________________________ 
Co-investigator (NAME IN BLOCK CAPITALS) 
 
 
 
 
______________________________________ 
Signature of Co-investigator 
 
 
 
 
Date 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 16 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
1. 
JUSTIFICATION 
1.1 
Background 
 
Breast cancer is the most common type of cancer in women throughout the world. In 1999, 
more than 796,000 new cases were diagnosed and 314,000 deaths registered due to the disease 
(14.1%). 
In the year 2000, 182.000 new cases (30.4% of all cancers in women in the U.S.) and 40,800 
deaths (15.2% of all deaths due to cancer) were registered in the United States. It is calculated 
that approximately 30% of patients affected in the United States will die of the disease, and that 
1 in 8 women will develop breast cancer at some stage in their lives. 
In the European Community, 220,836 new cases were registered in 1997, which represents 
51.67 cases of breast cancer per 100,000 inhabitants and 74,984 deaths (16.06 breast cancer 
deaths per 100,000 inhabitants). It is estimated that 1 in 10 European women will develop breast 
cancer at some stage in their lives. 
In Spain, in 1997, 15,906 new cases of breast cancer were reported, which constitutes 69.98 
cases of breast cancer per 100,000 inhabitants, with 5,766 deaths (22.67 per 100,000 
inhabitants). The authorities calculate an annual mortality rate due to breast cancer of 29.3 per 
100.000 women. It is estimated that 1 in 20 Spanish women will develop breast cancer before 
the age of 75. 
Breast cancer is the principal cause of cancer death in Spanish women, with an adjusted 
mortality rate of 17.4%. 
In Mexico, it is estimated that by 2010 the mortality rate will be 13 per 100,000 adult women 
and there will be about 4,500 breast cancer deaths a year. 
In Columbia, breast cancer represents the third cause of death due to malignant tumors, after 
gastric cancer and cervical cancer. The weighted incidence in women aged between 30 and 50 is 
80 per 100,000 women and 80% of the cases are diagnosed at a late stage, with a limited life 
expectancy. 
In Cuba, one woman in 9 can expect to suffer this disease, with breast cancer constituting the 
principal cause of death due to cancer in women in this country. 
In Peru, 7,837 deaths due to malignant processes among women were registered in the year 
2000, with 736 breast cancer deaths. 
A progressive increase in the incidence of breast cancer has been observed in Venezuela, which 
is only overtaken by cervical cancer. The estimated incidence rate is 28.08 per 100,000 women; 
the estimated cumulative rate is 3.10%, which indicates that 1 in 33 women in Venezuela will 
develop breast cancer during the course of her life. In 2000, 1,107 deaths due to this disease 
were registered and 2,704 cases were diagnosed. It is situated in the third place for death due to 
cancer, with 9.22 deaths per 100.000 women. 
In Argentina, an increase in breast cancer mortality has been detected, from 20.9 per 100,000 
women, recorded in 1988 to 26.7 per 100,000 women during the period 1997-2000. 
In Costa Rica, the incidence recorded for breast cancer in 1998 was 9 per 100,000 women. 
All these data come from official bodies. It seems clear that breast cancer has become a 
healthcare, social and economic problem of the first order in all countries, or will be soon. 
 
1.2 
Adjuvant chemotherapy in the treatment of breast cancer 
 
Surgery is the primary therapeutic option for patients with breast cancer. Surgery and/or 
radiation therapy can control locoregional disease in the majority of patients. However, more 
than 60% of affected patients will finally die as a result of disease dissemination1. 
 
In recent years, there has been an increase in the administration of adjuvant hormone or 
cytostatic therapies. Studies ongoing at the moment show that adjuvant treatment can prolong 
time to disease recurrence and probably also survival in some patient groups2,3. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 17 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
Adjuvant chemotherapy is chemotherapy administered after primary surgery, with the aim of 
controlling clinically occult micrometastasis. 
 
Although the optimal protocol has not yet been identified, various chemotherapy regimens have 
demonstrated their efficacy in the adjuvant treatment of breast cancer. They are grouped 
principally into regimens without anthracyclines, such as CMF (cyclophosphamide, 
methotrexate, 5-FU) and anthracycline-containing regimens, e.g. AC (doxorubicin, 
cyclophosphamide), CAF (cyclophosphamide, doxorubicin, 5-FU), FAC (5-FU, doxorubicin, 
cyclophosphamide), AVCF (doxorubicin, vincristine, cyclophosphamide, 5-FU) or FEC (5-FU, 
epirubicin, cyclophosphamide)4-10. 
 
Several randomized clinical trials have been performed comparing the CMF regimen or its 
variants, with cyclophosphamide-containing combination chemotherapies. The superiority of 
combination chemotherapy with anthracyclines appears to be real, but modest6-10. The results of 
the metaanalysis carried out by the Early Breast Cancer Trialists’ Collaborative Group have 
confirmed that in general, both in patients with negative axillary lymph nodes and in those with 
positive axillary nodes and high-risk criteria, adjuvant chemotherapy significantly improves 
disease-free survival and overall survival11. 
Among the conclusions which can be drawn from the study results, it has been confirmed that it 
is better to administer 6 treatment cycles than 3. 
Among new chemotherapeutic agents which emerged in the 90s, the taxanes are notable for 
their efficacy. Nevertheless, although the results tend to suggest that these agents could 
represent a significant advance in the management of breast cancer, their impact on the natural 
course of the disease remains to be defined. 
 
Two different strategies have been adopted in the evaluation of the potential role of the taxanes 
in adjuvant treatment, as reflected in several large Phase III clinical trials: 
 
a) The first strategy is associated with the concept of sequential chemotherapy, and is being 
investigated for both paclitaxel and docetaxel. Some cooperative groups which have performed 
clinical trials using this strategy are the CALGB (Cancer Leukemia Group B) with the ATC 
regimen (doxorubicin followed by paclitaxel followed by cyclophosphamide), the MD 
Anderson group with TFAC (paclitaxel followed by FAC), the CALGB and NSABP (National 
Surgical Adjuvant Breast and Bowel Project) with AC followed by paclitaxel or docetaxel, the 
Breast Adjuvant Study Team and the IBCSG (International Breast Cancer Study Group) with 
AT (docetaxel) followed by CMF, the French Cooperative Group with the FEC regimen (5-
fluorouracil, epidoxorubicin, cyclophosphamide) followed by docetaxel, the BCIRG (Breast 
International Research Group) with AC followed by docetaxel + trastuxumab (in HER2neu 
positive patients) and GEICAM with FEC followed by weekly paclitaxel12. 
 
b) The second strategy is based on the classic concept of combination chemotherapy, in which 
almost exclusively docetaxel-based combinations are studied. Comparative protocols with TAC 
(docetaxel, doxorubicin, cyclophosphamide) compared to FAC (BCIRG-001)15, carried out by 
the BCIRG in axillary lymph node positive patients, or the protocol comparing the AT regimen 
(docetaxel) with AC, coordinated by the ECOG (Eastern Cancer Oncology Group) in patients 
with 1 to 3 positive nodes or with negative nodes and high-risk criteria. In addition, trials are 
being carried out to study whether triple combination is better than sequential chemotherapy, for 
example, the work coordinated by the BCIRG (BCIRG-005) in which TAC is compared to AC 
followed by T in node-positive, HER2-negative patients. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 18 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
1.3 
Adjuvant chemotherapy in operable node-positive, or node-negative, high-risk 
breast cancer 
The most recent results from two of the combination regimens with taxanes have shown greater 
efficacy in the population of patients with operable breast cancer. These are the dense-dose 
regimen of bi-weekly AC followed by paclitaxel, based on the results of the CALGB-9741 
study, and the TAC schedule (docetaxel, doxorubicin, cyclophosphamide), based on the results 
of the BCIRG001 study. Indirect comparison of the results of both studies suggests similar 
efficacy and tolerance, and both show an increase in overall survival, compared to standard 
regimens. In both cases, these are multicenter studies with large sample sizes, so the results can 
be considered as type I scientific evidence. 
 
Study CALGB-974114 
Two thousand and five (2,005) node-positive patients were included with the aim of 
determining whether the dose density of the drugs would improve disease-free survival and 
overall survival. Patients were randomized to 4 arms, 2 sequential and 2 concurrent: Ax4  T 
(paclitaxel) x4  Cx4 (one arm had the cycles administered every 2 weeks and the other every 
3 weeks), and ACx4  Tx4 (one arm had the cycles administered every 2 weeks and the other 
every 3 weeks). The results after 36 months of follow-up in the CALGB-9741 study showed an 
increase in disease-free survival and in overall survival for the dose-dense regimen (ACP 
biweekly) of 85% vs 81% (p=0.01) and 92% vs. 90% (p=0.013) respectively, compared to the 
conventional treatment regimen (administration every 21 days). 
 
Study BCIRG 00115 
In the BCIRG 001 study, 6 cycles of TAC (docetaxel) were compared to 6 cycles of FAC in 
1,491 node-positive patients. The results after 55 months of follow-up of study BCIRG 001 
confirm the superiority of the TAC regimen in overall survival, compared to FAC (odds ratio 
0.7 [0.53-0.91], p=0,0080). With regard to disease-free survival, a subgroup analysis (number of 
affected nodes, hormone receptor status) produced the following results: 
 
N= 1,491 
Odds ratio (Hazard Ratio) 
P value 
DFS 
 
 
All patients 
0,72 (0,59-0,88) 
0,0010 
1-3 nodes (n=923) 
0,61 (0,46-0,82) 
0,0009 
≥ 4 nodes (n=568) 
0,82 (0,63-1,08) 
0,1629 
HR positive 
0,73 (0,57-0,94) 
0,0132 
HR negative 
0,66 (0,47-0,93) 
0,0163 
 
As can be observed, the patients who benefited most from TAC treatment are those with the 
least number of affected nodes and hormone receptor negative patients. 
 
The study results described above have served as a basis for a new generation of randomized 
Phase III clinical trials which are currently ongoing, and are summarized below: 
 
US Oncology 01-062 Study 
This study will recruit 1,810 patients with operable, node-positive or node-negative breast 
cancer and high-risk criteria. Eligible patients are randomized to receive 4 cycles of AC 
followed by 4 cycles of docetaxel (ACx4T4), compared to 4 cycles of AC followed by 4 
cycles of docetaxel and capecitabine (ACx4TXx4) 
 
SWOG-50221 Study 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 19 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
This study will recruit 4,500 patients with operable, node-positive or node-negative breast 
cancer and high-risk criteria. Eligible patients are randomized to receive one of the following 
four treatment arms: 
• 
6 cycles of bi-weekly AC followed by 6 cycles of bi-weekly paclitaxel (ACX6Px6) 
• 
15 cycles of weekly AC (with oral cyclophosphamide on days 1-7) followed by 6 cycles 
of bi-weekly paclitaxel (ACx15Px6) 
• 
6 cycles of bi-weekly AC followed by 12 cycles of weekly paclitaxel (ACx6Px12) 
• 
15 cycles of weekly AC with oral cyclophosphamide on days 1-7) followed by 12 
cycles of weekly paclitaxel (ACx15Px12) 
 
NSABP B-38 Study 
This study will recruit 4,500 patients with operable, node-positive breast cancer. Eligible 
patients are randomized to receive one of the following three treatment arms: 
• 
6 cycles of TAC (docetaxel, doxorubicin, cyclophosphamide) every 21 days (TACx6) 
• 
4 cycles of bi-weekly AC followed by 4 cycles of bi-weekly paclitaxel (ACx4Px4) 
• 
4 cycles of bi-weekly AC followed by 4 cycles of bi-weekly paclitaxel/gemcitabin 
(ACx4PGx4). 
 
NCIC-CTG MA.21 Study 
This study will recruit 1,500 patients with operable, node-positive or node-negative and high-
risk breast cancer. Eligible patients are randomized to receive one of the following three 
treatment arms: 
• 
6 cycles of epirubicin and fluorouracil (days 1-8) with oral cyclophosphamide (days 1-
14) every 28 days (FECx6) 
• 
6 cycles of bi-weekly EC followed by 4 cycles of paclitaxel every 3 weeks 
(ECx6Px4) 
• 
4 cycles of AC every 3 weeks followed by 4 cycles of paclitaxel every 3 weeks 
(ACx4Px4) 
 
CALGB 49907 
This is a phase III trial which will include patients >65 years of age with operable, node-positive 
or node-negative, high-risk breast cancer. The aim is to offer a viable alternative to this large 
group of older patients who frequently receive suboptimal treatment for fear of increasing 
toxicity42. Patients will be randomized to one of the following arms: 
• 
Oral CMF x 6 cycles 
• 
AC x 4 cycles 
• 
Capecitabine x 6 cycles 
 
Study GEICAM/2003-10  
This study will recruit 1,302 patients with operable, node-positive breast cancer. Eligible 
patients are randomized to receive one of the following two treatment arms: 
• 
4 cycles of epirubicin and cyclophosphamide every 21 days followed by 4 cycles of 
docetaxel every 21 days (ECx4Tx4) 
• 
4 cycles of epirubicin and docetaxel every 21 days followed by 4 cycles of capecitabine 
on days 1-14 of every 21-day cycle (ETx4Xx4) 
 
All these studies have a series of criteria in common: 
• 
The combination regimens of anthracyclines and cyclophosphamide are administered 
either in a dose-dense or in a metronomic regimen. 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
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Amendment No. 2: September 16, 2009 
 
• 
A minimum of 4 cycles of chemotherapy are administered (doxorubicin + docetaxel) 
and the treatment periods tend to be extended, with an increase in the number of cycles 
administered. 
• 
New products which have shown efficacy in the treatment of advanced or metastatic 
breast cancer (capecitabine, gemcitabin) are added to the drugs already well-known in 
adjuvant treatment (anthracyclines and taxanes). 
 
1.4 Neoadjuvant chemotherapy in breast cancer75-103 
Adjuvant chemotherapy is the only systemic treatment that has been administered to patients 
with triple-negative tumors. The absence of hormone receptors and HER2 expression means 
that the alternative hormone therapy and treatment with trastuzumab is not applicable. 
 
Development of neoadjuvant treatment was based on treatment of women with locally advanced 
tumors, which could not undergo surgery, and they were treated with chemotherapy regimens 
with promising results. Some patients obtained good responses, which allowed a surgical 
procedure. Subsequently, a large number of cases have reported the use of neoadjuvant 
chemotherapy in patients with tumors with possibility of surgery. Initially, the objective was to 
obtain a response which would allow a surgical procedure keeping the breast. The results found 
in many cases allowed the use of this strategy as perfectly acceptable with this objective. 
 
A second aspect of neoadjuvant treatment is that it allows in vivo evaluation of the tumor 
response, which has been related to the patient's prognosis and survival. A variable rate of 10-
30% of complete pathological responses has been reported with a very clear association with 
improved survival compared to the survival of patients who do not respond, or who partially 
respond to treatment. 
 
Thus, neoadjuvant treatment is currently established as an alternative, which should be 
discussed with the patient when her specific objectives apply to the specific situation. If the 
patient wishes to keep the breast and the tumor size does not allow it, chemotherapy treatment 
before surgery has the possibility of helping to reduce the tumor size and allow conservative 
surgery. One of the neoadjuvant approach limitations is that it has to take place before the 
surgical procedure, and we do not have pathological information regarding the number of 
axillary nodes involved. Demonstrating that results are equivalent when we assess survival 
parameters makes this limitation not to have a high impact on clinical management of patients. 
 
One of the questions raised and analyzed in different clinical studies is associated with the 
comparison of results between treatment administration before or after surgery. It is very 
important to highlight that in none of the clinical trials that have been conducted up to now, 
neoadjuvant treatment obtained results inferior to adjuvant treatment. In a meta-analysis 
published by Mauri et al, it was clearly proven that the comparison of both treatments does not 
show differences in relation to disease-free survival and overall survival. In this sense, it is 
critical to consider that there is no biological reason that has been proven up to now, which 
justifies that the results of the same regimen, before or after surgery, are different. 
 
1.5 
Capecitabine 
Capecitabine is an oral fluoropyrimidine carbamate which is tumor-activated via a cascade of 3 
enzymes which supply high and prolonged levels of the active fraction, 5-fluorouracil (5-FU), 
within tumor cells. Fluorouracil is one of the most widely used cytotoxic agents, but its efficacy 
is limited by its lack of selectivity. Capecitabine was developed in the laboratory as a tumor-
selective agent which would alter favorably the risk-benefit ratio, particularly in the context of 
advanced, resistant breast cancer31. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 21 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
1.6 
Pharmacology of capecitabine 
After oral administration, capecitabine is absorbed unchanged in the gastrointestinal tract and 
metabolized in the liver by 60kDa carboxylesterase, a 5’-DFCR. It is then converted to 5’-
DFUR by cytidine deaminase which is found in the liver and in tumor tissues. Metabolism of 
5’-DFUR to 5-FU is subsequently produced in the tumor itself, due to the action of thymidine 
phosphorylase (dTHdPasa). Consequently, the exposure of healthy tissue to systemic 5-FU is 
minimized.16 
It was recently determined that the enzyme responsible for the final catalytic conversion of 
capecitabine to 5-FU (dThdPasa) has an identical structure and function to that of the tumor-
associated angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF)17-19. 
PD-ECGF is a 55 kDa polypeptide which exists in vivo as a homodimer. It was originally 
isolated from the platelets as a endothelial mitogen and angiogenic factor20,21. PD-ECGF has 
been shown to be an important angiogenic factor in breast cancer. Its expression is correlated 
with the intensity of angiogenesis, an increase in tumor size and in the invasive capacity of the 
tumor, and with a worse outcome21,22. Tumor areas with poorer perfusion, defined by hypoxia 
and acidosis, have a greatly increased expression of PD-ECGF20. The fact that within the tumor, 
and in particular in more aggressive tumors, there are elevated levels of FD-ECGF/dThdPasa, 
responsible for the final activation of capecitabine, supports the antitumor efficacy of this drug. 
 
1.7 
Preclinical antitumor efficacy of capecitabine 
Capecitabine demonstrated cytotoxicity only after conversion to 5’-DFUR and 5-FU. In 12 
xenograft models of human cancers tested in mice, capecitabine was always more active than 5-
FU. In addition, it showed activity in 5-FU-resistant xenografts. The therapeutic indexes were 
much more favorable than those observed with 5-FU. Antitumor efficacy in mice was correlated 
with tumor levels of 5-FU and blood levels of 5’-DFUR. In addition, also in mice, capecitabine 
showed anticachetic activity, by normalizing body weight, loss of adipose tissue and episodes of 
hypoglycemia. In this same model, capecitabine showed antimetastatic action at doses 40 to 50 
times lower than those required for activity against the primary disease16,23. 
Preclinical studies have revealed that the antitumor activity of capecitabine depends on the total 
dose administered, so that the regimen (uninterrupted daily administration; days 1-5 of each 
week; days 1-14 every 3 weeks) does not influence its antitumor activity24. 
 
1.8 
Phase I clinical studies with capecitabine: regimens tested, maximum tolerated 
dose and recommended dose 
The maximum tolerated dose (MTD) for capecitabine in continuous or intermittent 
monotherapy25-27 or in combination with leucovorin28 was defined in four Phase I studies 
(SO14693, SO14794, JO14865, SO14798). The recommended doses determined by these 
studies were later used with satisfactory results in phase II and III studies. In general the three 
regimens used (continuous, intermittent or combined with leucovorin) showed significant 
antitumor efficacy, including complete responses. The three regimens tested were tolerable with 
very few grade 3/4 events, all manageable with dose modification and/or symptomatic 
intervention. The overall evaluation carried out by the investigators and the sponsor based on 
these phase I studies and on a randomized phase II study in colorectal cancer29 was that the 
intermittent regimen was the most promising, being associated with a reasonable toxicity profile 
and longer time to disease progression, while at the same time allowing the administration of a 
higher intensity of dosing to the patient (approximately 25% more than the continuous 
regimen). The additional advantage of the “off drug” periods meant this regimen was also 
considered by the patients as more satisfactory. 
From the European phase I study with an intermittent regimen (2 weeks treatment and one week 
rest), a MTD was defined to be 1500 mg/m2 twice a day, while the dose recommended for the 
phase II studies was established at 1250 mg/m2 twice a day26. In this same study, which 
included heavily pre-treated patients, seven with breast cancer and 17 with colorectal cancer, 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
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Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
four objective responses were described (1 CR and 3 PR). The tumors which responded were 
breast, esophagus, colon and rectal cancers. 
A Phase I treatment study of the combination of capecitabine with paclitaxel30 defined a 
recommended dose for phase II studies of oral capecitabine 1331 mg/m2/day, divided in 2 daily 
doses administered continuously, and 175 mg/m2 paclitaxel in a 3 hour IV infusion, every three 
weeks. No clinically relevant pharmacokinetic interactions were observed between both drugs.  
No responses were observed (15 of 17 patients were clearly resistant to 5-FU and 13 of 17 
patients had cancers considered intrinsically resistant to taxanes). 
Phase I study SO15304 investigated the combination of capecitabine administered on days 1-14 
together with docetaxel administered on day 1 of each 3-week cycle31. The progressive dose 
increase was applied in two phases. Initially the dose of docetaxel was increased (75, 85 and 
100 mg/m2) in combination with a fixed dose of capecitabine (1650 mg/m2/day). Then the dose 
of capecitabine was increased (2000 and 2500 mg/m2/day) in combination with a fixed dose of 
docetaxel, defined as tolerable in the first phase. Thirty-three (33) patients were included (15 
men, 18 women) distributed over seven dosing levels: docetaxel 75 (4 patients), 85 (6 patients) 
and 100 (6 patients) mg/m2 combined with capecitabine 1650 mg/m2/day; docetaxel 100 (5 
patients) mg/m2 combined with capecitabine 2000 mg/m2/day; and then capecitabine 2000 (6 
patients) and 2500 (6 patients) mg/m2/day combined with docetaxel 75 mg/m2. Uncomplicated 
grade 4 neutropenia (afebrile and duration less than 7 days) was observed at all dosing levels. 
One case of grade 3-4 neutropenia associated with grade 2 fever was observed in the final 
treatment cycles of each of the dosing levels 85/1640, 100/1650 and 100/2000 mg/m2 
docetaxel/capecitabine. One patient with dosing levels of 100/2000 and 85/1650 mg/m2 
docetaxel/capecitabine experienced mucositis NCIC/CTC grade 3. The five patients treated at 
the dose level of 100/2000 mg/m2 docetaxel/capecitabine reported grade 2 chronic asthenia and 
fulfilled the definition of MTD. Other common toxicities (grade 2) were alopecia, diarrhea, 
mucositis, hand-foot syndrome/skin toxicity, nail dystrophy, nausea and vomiting. Dose 
reductions were required in 7 patients, 5 due to hand-foot syndrome or nail dystrophy, one due 
to stomatitis and one due to thrombocytopenia. Partial responses were observed in three out of 
four patients with breast cancer and minor responses in adenocystic submandibular carcinoma, 
non-small cell lung cancer, colorectal carcinoma and an adenocarcinoma of unknown primary 
origin. Minimal toxicity other than the expected neutropenia was observed at a dose level of 
75/2500 mg/m2 docetaxel/capecitabine, with only two patients experiencing short-term grade 2 
asthenia (which occurred during a hold in dexamethasone co-medication). As such, this dose 
level was selected for subsequent studies. 
 
1.9 
Phase I clinical studies with capecitabine: Pharmacokinetics of capecitabine in 
humans 
The pharmacokinetic parameters for the product were obtained from phase I studies. The 
communication from Twelves32 summarizes the majority of the data determined to date. These 
data are based on 32 patients who received doses of 502 to 2510 mg/m2/day separated in two 
doses. Capecitabine absorption was rapid and practically complete. Peak plasma concentrations 
of the drug and of the two principal metabolites (5’-DFCR and 5’-DFUR) were reached rapidly 
(0.5 to 1.5 hours) after administration. Plasma protein binding of capecitabine and its 
metabolites was less than 60%. Concentrations then fell exponentially with a half-life of 0.5 to 1 
hour. More than 70% of the administered dose of capecitabine was recovered in the urine. After 
administration of 829 mg/m2, the greatest AUC was obtained for 5’-DFUR (11.8 µg.mL-1.h, 
CV=44%, n=15). Logistic regression techniques were used to evaluate the relation between 
toxicity and systemic exposure. The two patients with the greatest exposure to 5’-DFUR had 
grade 3 toxicity. Similar pharmacokinetic parameters were obtained on days 1 and 15+1. The 
pharmacokinetic characteristics of capecitabine and its metabolites were dose-proportional at 
doses up to 1657 mg/m2/day. 
A correlation between the presence of food with a modification of some pharmacokinetic 
parameters (reduction in maximum plasma concentration and of AUC and increase in time to 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
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Amendment No. 2: September 16, 2009 
 
maximum plasma concentration) compared to the administration of capecitabine in fasting 
conditions was observed in one study33. Until then, the other clinical studies were carried out in 
the presence of food. For this reason, and in the absence of safety/efficacy data for capecitabine 
administered in fasting conditions, the current recommendation is to continue administering the 
drug 30 minutes after ingestion of food (breakfast or lunch). 
A pharmacokinetic study was carried out in 19 patients with colorectal cancer undergoing 
surgery with the aim of studying the differential concentrations of 5-FU (in tumor, healthy 
tissue and plasma) after administration of capecitabine. After oral administration of capecitabine 
(1255 mg/m2 twice a day for 5 to 7 days before surgery), concentrations of 5-FU were 
significantly greater (mean geometric ratio 2.5; CI: 1.5 to 4.1) in the primary tumor than in 
normal adjacent tissue34. This finding is consistent with other studies. Thus, human tumors, in 
particular breast, gastric, colorectal, cervical and ovarian tumors, have shown much higher 
levels of dThdPasa (responsible for the conversion of 5’-DFUR to 5-FU) than corresponding 
normal tissue16. 
 
1.10 
Capecitabine in monotherapy. Phase II breast cancer studies. 
A Phase II study was carried out in 162 patients with metastatic and/or advanced breast cancer 
who had failed treatment with paclitaxel35. 90% of these patients had been treated previously 
with anthracycline-based regimens. In addition, 81% of the patients had received treatment 
regimens which included 5-FU. The average number of previous treatments was 2.5. One 
hundred and thirty-five (135) patients had bidimensionally measurable disease. Twenty-seven 
(27) had evaluable disease. The treatment schedule was capecitabine 2510 mg/m2/day for 14 
days, followed by a 7-day rest period. An objective response rate of 20% was observed (CI 
95%: 14-28%) which was shown to be robust, according to the consistency of the results 
obtained over the different centers and patient subpopulations. Median duration of response in 
responders was 241 days. At the end of the observation period, disease progression had still not 
been observed in 11 of these patients. Median time to progression was 93 days. Median survival 
observed in all cases was 384 days, greater or equal to that obtained in currently available 
chemotherapies used as second or third line treatment. Treatment was relatively well tolerated, 
with very few drop-outs due to toxicity (8%). The most common adverse effects were, in order 
of frequency, hand-foot syndrome, diarrhea, nausea and vomiting and fatigue (see table below). 
Grade 4 diarrhea was detected in 4 patients. There were no toxic deaths. Rare (<5%) cases of 
grade 3-4 neutropenia were observed. Most significant among the laboratory findings was 
hyperbilirubinemia, which reached grade 3-4 in 17 patients (10.49%) although in 9 of these 
cases, it coincided with progressive liver disease. In the other 8 cases, hyperbilirubinemia was 
more moderate (grade 3, i.e. rise of total bilirubin of 1.5 to 3 x UNL) and transient, and did not 
require treatment withdrawal. In general, toxicity was predictable and manageable. Essentially, 
on the basis of these results, the Food and Drug Administration (FDA) approved capecitabine 
for treatment of metastatic disease after progression on anthracyclines and taxanes in September 
1998. 
 
 
Table: Summary of adverse effects related with capecitabine treatment (Blum, JCO 1999) 
 
Total (%) 
Severe(%) 
Life-threatening (%) 
Hand-foot syndrome 
56.2 
9.9 
_ 
Diarrhea 
54.3 
11.1 
3.1 
Nausea 
51.9 
4.3 
_ 
Vomiting 
37.0 
3.7 
_ 
Fatigue 
36.4 
7.4 
_ 
Constipation 
14.4 
1.2 
_ 
Dermatitis
15.4
1.2
_
Stomach pain 
14.8 
3.1 
_ 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
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Amendment No. 2: September 16, 2009 
 
Loss of appetite
11.1
0.6
_
Fever 
11.1 
0.6 
_ 
Erythematous rash 
10.5 
_ 
_ 
Paresthesia
9.9
_
_
Stomatitis 
9.3 
2.5 
_ 
Inflammation of mucous 
membranes 
9.3 
4.3 
_ 
Dehydration
6.8
3.1
_
Coagulation changes * 
0.6 
_ 
0.6 
*prolonged prothrombin time in one patient treated with warfarin. Labeled by investigator as 
possibly related. 
 
Another phase II study also carried out in heavily pretreated patients36 (100% had received 
paclitaxel and/or docetaxel, 92% had received anthracyclines) using a very similar capecitabine 
regimen (1250 mg/m2 twice a day, days 1-14, every 3 weeks). One hundred and five (105) 
patients were evaluable for toxicity, while 100 were evaluable for response. A response rate of 
18% was observed (16% PR, 2% CR). Toxicity was generally moderate, grade 1-2, and 
consisted of hand-foot syndrome (42% of patients), nausea and vomiting (40%), diarrhea (26%), 
stomatitis (16%) and lethargy (15%). Grade 3 hand-foot syndrome was reported in 13% of 
patients. In addition, grade 3 emesis and diarrhea was observed in 5% and 3% of cases, 
respectively. 
Jakob et al37 treated 13 patients with the same capecitabine regimen. All patients had received 
anthracyclines, taxanes and high dose chemotherapy. A response rate of 54% (CI 95%:26-81%) 
was obtained. The median time to progression was 128 days. The toxicity spectrum was similar 
to that described in the previous studies. Five patients (37.5%) developed grade 3 hand-foot 
syndrome. 
In another study carried out in patients previously treated with anthracyclines, paclitaxel at the 
usual doses (175 mg/m2 every three weeks) versus intermittent capecitabine (2510 mg/m2/day in 
two doses, days 1-14, every three weeks) was evaluated38. The study closed prematurely due to 
lack of recruitment (refusal for randomization). Finally only 22 patients received capecitabine 
and 20 paclitaxel. Eight responses were observed (36%, CI 17-59%), including 3 complete 
responses, in the group treated with capecitabineFour partial responses were observed in the 
paclitaxel group (21%, CI 95% 6-46%). The median time to progression was 92 and 95 days for 
capecitabine and paclitaxel, respectively. The proportion of patients with grade 3-4 toxicity was 
22% in the capecitabine group and 58% in the paclitaxel group. The study, although notably 
limited by its small sample size, supported similar efficacy between both drugs, with a better 
tolerance profile for capecitabine. 
Similarly, in a Japanese phase II study carried out in 50 patients previously treated 
heterogeneously (previous exposure to anthracyclines 36%, to alkylating agents 54%, to 5-FU 
64%, and to hormones 74%), a response rate of 28.3% was described for the total group and 
23.5% for the group pretreated with anthracyclines39. 
A randomized treatment study carried out in 95 treatment-naïve patients40 compared 
capecitabine administered in an intermittent regimen to iv CMF administered on day 1 every 
three weeks. The response rate for capecitabine and CMF was 25% (CI 95%, 14-37%) and 16% 
(CI 95%, 5-33%) respectively. The median time to progression was greater with capecitabine 
(132 vs 94 days). A higher proportion of grade 3 toxicity was observed in the capecitabine 
group (132 vs 94 days). A greater proportion of grade 3 toxicity was observed in the 
capecitabine group (44 vs 20%). These differences were due essentially to a higher frequency of 
hand-foot syndrome (16 vs 0%) and diarrhea (8 vs 3%) in the group which received the oral 
regimen. No statistical analysis was made for any of the efficacy or toxicity parameters. The 
authors concluded that capecitabine showed at least similar efficacy to CMF when administered 
as first-line treatment. 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 25 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
Subsequent studies have confirmed the efficacy and tolerance of capecitabine treatment in 
metastatic breast cancer43. Capecitabine in combination with docetaxel has also been shown to 
be more effective in the treatment of metastatic breast cancer than docetaxel in monotherapy, in 
terms of survival and response rates44. 
Given the role of capecitabine in metastatic breast cancer as a highly effective agent with no 
cross resistances, and the advantage of oral administration, the study of its administration in the 
adjuvant area seems justified. 
 
1.11 
Capecitabine in the neoadjuvant treatment of breast cancer 
Primary treatment of stage II/III breast cancer with a combination of docetaxel and capecitabine 
provides higher pathological and clinical response rates than other regimens, such as 
doxorubicin/cyclophosphamide (AC). In the study carried out by Hong Gi Lee et al45, patients 
were stratified by disease stage (II vs III), estrogen receptor status and age. Patients were 
randomized to receive 4 cycles of AC (doxorubicin/cyclophosphamide 60/600 mg/m2) every 21 
days, or 4 cycles of TX (docetaxel 75 mg/m2, day 1 of each 21-day cycle; oral capecitabine 
1000 mg/m2 twice a day, day 1-14 of each 21-day cycle). After the fourth treatment cycle, 
breast-conserving surgery or mastectomy was performed on the patients and there was a 
treatment cross-over. Patients could subsequently receive radiation therapy and tamoxifen, 
where indicated. An interim analysis was performed which included data from 53 patients in the 
TX arm and 47 in the AC arm. Patients in the TX arm presented a clinical response rate of 91% 
compare to 74% in the AC arm. Nine percent of patients in this arm had disease progression on 
treatment, which did not occur in the patients in the TX arm. 
The following table summarizes the characteristics of patients who achieved complete 
pathological response in the breast and lymph nodes for each treatment group: 
 
Characteristics 
AC (n=47) 
TX (n= 53) 
Tumor 
 
 
Stage II/III 
3/11 
23/23 
ER+/ER-
0/14
17/30
PgR+/PgR- 
0/12 
19/25 
HER2 (3+/0-2+)
7/6
36/18
Total (% patients) 
6% 
23% 
Lymph nodes 
 
 
Stage II/III 
31/22 
36/32 
ER+/ER- 
12/48 
33/35 
PgR+/PgR-
10/42
33/34
HER2 (3+/0-2+) 
29/27 
64/23 
Total (% patients)
28%
34%
ER: estrogen receptor; PgR: progesterone receptor  
 
As can be seen in the table, the complete pathological response rate was higher in the TX 
treatment arm, both in breast (23% vs. 6%) and axillary nodes (34% vs. 28%). In addition, the 
TX combination seems to be equally effective in HER2 positive and negative patients. 
With regard to the safety profile, patients who received AC experienced more episodes of 
nausea and vomiting, while patients treated with TX experienced more myalgia and skin and 
nail events. 
 
1.12 
Polymorphisms related with efficacy and effectiveness of capecitabine 
5-Fluorouracil (5-FU) inhibits thymidilate synthase (TS) which catalyzes the conversion from 
uridilate to thymidilase. TS is the only de novo source of thymidilate, which is a precursor of the 
thymidilate triphosphate necessary for DNA synthesis. Attempts to administer 5-FU orally have 
failed due to its low and unpredictable bioavailability caused by its being metabolized by 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
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Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
dihydropyrimidine dehydrogenase (DPD) in the liver and intestinal walls46-48. This has led to the 
development of active oral analogs of 5-FU, such as capecitabine49. 
Capecitabine is a member of the drug family of the fluoropyrimidines. It is metabolized to 5’-
deoxy-5-fluorocytidine by hepatic carboxylesterase. Histidine deaminase converts the 5’-deoxy-
5-fluorocytidine to 5’-deoxy-5-fluorouridine. The tumor selectivity of capecitabine is due to the 
conversion of 5’-deoxy-5-fluorouridine to 5-FU by thymidine phosphorylase, an enzyme which 
is usually present in high levels in human tumors50. 
Takeishi et al51 showed that the TS gene has a satellite in the 5’ region which is not transcribed, 
which consists of a tandem of 3 repetitions (3R), each one 28 base pairs long. Subsequent 
research has shown that the promotor of this gene is polymorphic, with individuals which have 
only 2 repetitions (2R) and others which have up to 9 repetitions (9R)52-54. The number of 
repetitions in tandem affects the transcription of the TS gene55. Patients who are homozygous 
for three repetitions (3R/3R) have higher levels of TS protein than heterozygous 2R/3R patients.  
Using in vitro expression of genes with 2R and 3R, higher levels of the TS protein were 
obtained due to the better transcriptional efficacy of the 3R messenger DNA, compared to an 
increase in production of messenger DNA. 
Various studies have suggested that 3R/3R TS genotypes are associated with a poorer response 
to 5-FU chemotherapy in colorectal cancer. It is suspected that the reason for this is that 3R/3R 
genotypes are associated with higher levels of TS protein, which confers resistance to 5-FU. In a 
retrospective analysis, in which patients with colorectal cancer were treated with capecitabine, 
response rates were 14% in the subjects with 3R/3R genotype, compared to a response rate of 
80% in subjects with the 2R/2R genotype56. 
Recent studies have shown that TS tandem repeat polymorphisms contain potential binding sites 
called E-box (CACTTG) which bind transcription factors on the binding site for stimulatory 
factor 1 (USF-1) and stimulatory factor 2 (USF-2)57. In genotypes 3R/3R, there are two E-box 
binding sites in the second and third repeats, while in the 2R genotype, there is only one E-box 
binding site. The final repeat in both genotypes 2R and 3R in nucleotide 12 is imperfect, so 
while the first repeat is a G, it has been replaced here by a C. A polymorphism was discovered 
in position 12 GC in the second repeat of the genotype 3R which inhibits the binding of 
transcription factors USF-1 and USF-2. The effects of this polymorphism on the efficacy or 
toxicity of drugs which inhibit TS activity must be determined in retrospective or prospective 
studies. 
The most frequent toxicities associated with the administration of capecitabine are hand-foot 
syndrome, diarrhea, nausea, vomiting and mouth irritation. In general, capecitabine is well 
tolerated; the percentages of patients who present severe toxicities after the first cycle is 22% 
for hand-foot syndrome, 16% for diarrhea and 12% for mouth irritation. For patients with severe 
toxicity, the dose can be reduced in subsequent cycles, without a reduction in efficacy. 
Unfortunately there is no way of predicting which patients will experience greater toxicity. As 
TS genotypes are identical in primary colorectal tumors and in normal tissues, it could be 
expected that individuals with 3R/3R genotype would have increased expression of TS in 
normal tissues, which would protect them from capecitabine toxicity58. A small retrospective 
study of patients with colorectal cancer treated with different 5-FU-based regimens showed that 
overall grade 3 toxicity was 36% lower in individuals with 3R/3R polymorphisms compared to 
patients with 2R/2R59. The effects of polymorphisms on the risk of capecitabine toxicity in 
early-stage breast cancer are still unknown. 
 
Methylenetetrahydrofolate reductase: MTHFR may also play an important role in the toxicity 
and efficacy of capecitabine. A single nucleotide polymorphism (SNP) in position 677 of 
MTHFR, due to a conversion from C to T, produces a thermolabile enzyme which is rapidly 
degraded60. The allele frequency of polymorphisms in MTHFR varies with geographical 
location and race. It is estimated that homozygosity for TT is present in approximately 10% of 
North 
Americans61. 
Individuals 
homozygous 
for 
TT 
have 
increased 
levels 
of 
methylenetetrahydrofolate, a compound with stabilizes the binding of 5-FU to TS62, resulting in 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 27 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
the formation of the ternary complex of 5-FU, TS and methylenetetrahydrofolate. Our 
hypothesis is that the increased stabilization of this ternary complex can cause an increase in 
both capecitabine toxicity and efficacy. 
 
A retrospective study carried out by Cohen et al3 supports the hypothesis that MTHFR 
polymorphisms 
can 
influence 
toxicity 
and 
response 
to 
fluoropyrimidine-based 
chemotherapeutic treatment. In this study, 43 patients were treated with one of the following 
regimens: i) capecitabine twice a day for 2 weeks with one week rest, ii) tegafur plus uracil 
three times a day for 28 days with 7 days rest, iii) the Mayo Clinic 5-FU/LV regimen. Response 
rates and frequency of toxicities were combined for the three studies: wild-type homozygous 
MTHFR genotype (C/C) had a response rate of 47% compared to a response rate of 67% in 
MTHFR heterozygous individuals, and a 100% response rate in MTHFR T/T homozygous 
individuals. These differences were not statistically significant due to the small sample size. 
When the patients are analyzed according to the frequency of mutant alleles, patients with a T 
allele had a response rate of 77% compared to a 55% response rate in patients with a C allele. 
This comparison reached statistical significance. 
 
MTHFR and folate interaction: MTHFR polymorphisms have been studied as possible risk 
factors in diseases such as neural tube defects in children64, colon cancer65, and ischemic heart 
disease66. The epidemiological studies of MTHFR as a risk factor in diseases measured folate 
levels in study subjects to determine whether they influenced the role of the MTHFR 
polymorphisms as risk factors. The doctors’ health study65 showed that the MTHFR 
polymorphism C677T conferred protection against the development of colon cancer only if 
patients had adequate folate levels. Christiansen et al67 showed that women with MTHFR 
genotype TT had a higher risk of having a child with a neural tube defect, and that the risk 
increased significantly if the mother had a folate deficiency. In contrast, a study on the effects of 
the C677T polymorphism in methotrexate toxicity did not show any difference in patients on 
folate supplements or not. This study did not measure folate levels and used folate supplements 
as a substitute for folate level status. 
 
Dihydropyrimidine dehydrogenase: Dihydropyrimidine dehydrogenase (DPD) deficiency has 
been identified as the cause of life-threatening reactions which appear rarely due to the 
administration of fluoropyrimidines68,69. Individuals with a complete deficiency of this enzyme 
have significantly raised levels of uracil and thymine in blood and urine. Etienne et al70 studied 
the possibility of using DPD activity as a marker for predicting the risk of fluoropyrimidine 
toxicity, in a prospective study of 185 patients treated with 5-FU-containing regimens. They 
found a normal distribution of DPD activity among the patients, and no correlation between 
activity and 5-FU activity. 
 
In conclusion, we are setting out from the hypothesis that TS and MTHFR polymorphisms can 
predict which patients will experiment toxicities and require dose reductions of capecitabine. In 
addition, TS and MTHFR polymorphisms could predict which patients would not benefit from 
the standard capecitabine dose. We speculate that the following genotypes will be found in the 
study: i) TS genotype 2R/2R (severe toxicity, benefit from adjuvant therapy, need for dose 
reduction; ii) TS genotype 2R/3R (intermediate toxicity, intermediate benefit from adjuvant 
therapy); iii) TS genotype 3R/3R (slight or no toxicity, no benefit from adjuvant therapy). 
 
1.13 
Basal-like breast cancer 
 
The work of the various investigator groups has consolidated the development of a tumor 
classification for breast cancer based on three types of genetic profile: luminal tumors (hormone 
receptor positive), HER2 tumors (HER2neu positive) and basal-like tumors (hormone receptor 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
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Amendment No. 2: September 16, 2009 
 
and HER2neu negative). The latter, also known as “triple negative” are the object of the present 
study protocol. 
 
Basal-like tumors receive this name because their genetic expression profile is similar to that of 
a normal basal epithelial cell. These similarities include the absence of expression of the 
estrogen receptor and other genes related with this and the HER2 receptor. They also share with 
the basal epithelial cells overexpression of cytokeratins 5/6 and 17, EGFR and genes associated 
with proliferation. p53 mutations in thyrosine are also basal cell characteristics. 
 
Numerous independent studies indicate that basal-like tumors have a poor outcome. Indeed, 
treatment is complicated, since patients with triple-negative tumors are not candidates for 
endocrine treatment or trastuzumab. However, this type of tumor is very sensitive to 
chemotherapy. Investigators at the MD Anderson Cancer Center examined the chemosensitivity 
of this type of tumor71. The genetic profile was obtained by fine needle biopsy in 83 breast 
tumors, before neoadjuvant treatment with paclitaxel and FAC.  Complete pathological response 
was more frequent in basal-like tumors, compared to luminal-type tumors. This result was 
confirmed by a study from the University of North Carolina, in which the type of cancer was 
classified in 105 patients treated with AC and taxanes.  Twenty-seven percent (27%) of the 
tumors were basal-like, 21% were HER2 positive and 52% were luminal.  The best clinical 
responses to treatment with chemotherapy were obtained in patients with basal-like tumors 
(86%, compared to 68% in the HER2 positive patients, and 60% in the luminal tumors)72. In 
parallel, the complete pathological response rate was greater in patients with basal-like tumors 
(30%, compared to 27% in HER2 positive and 13% in luminal tumors). 
Despite the greater sensitivity to chemotherapy, basal-like tumors have a poor outcome.  With a 
median follow-up of 2.5 years in the University of North Carolina study, patients with basal-like 
tumors presented a clear tendency towards early recurrence.  The reason appears to be the lack 
of a satisfactory therapeutic arsenal for the treatment of hormone receptor negative, HER2 
negative patients, so that, if there is residual disease, outcome is poor. 
 
The North American cooperative group, Cancer and Leukemia Group B (CALGB), following 
this line of reasoning, made a retrospective evaluation of their chemotherapy studies which 
reveals that the benefits of each new generation of more aggressive chemotherapy are centered 
particularly in estrogen receptor negative patients. This would suggest that patients with basal-
like tumors are those which respond best to strategies such as increases in dose or dosing 
intensity for anthracyclines, addition of taxanes to anthracycline regimens, or increased dose-
density for the drugs administered. 
 
1.14 Justification for the administration of 4 cycles of AC to patients without axillary node 
involvement. 
The first AC studies were carried out at the University of Arizona by Jones, S.B. Adriamycin 
used in multiple solid tumors began to be investigated in breast cancer showing tumor activity. 
Based on laboratory 
study results regarding synergy between 
doxorubicin, and 
cyclophosphamide, the first trials were conducted in 1973, in patients with metastatic breast 
cancer, and were published by S. Jones and S. Salmon (Combination Chemotherapy with 
Adriamycin and Cyclophosphamide for advanced breast cancer. Jones S.B., Durie B., Salmon S. 
Cancer 1975, vol. 36. No. 1: 90-97). The use of this combination quickly moved from the 
metastatic field, to the adjuvant field, both in patients with node involvement (NSABP B15 
study) (Fisher B Brown AM, Dimitrov NV, et al. Two months of doxorubicin-
cyclophosphamide with and without interval reinduction therapy compared with 6 months of 
cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with 
tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 29 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
Project B-15. J Clin Oncol 1990; 8:1493-96) without node involvement (Fisher B et al. J Clin 
Oncol 19 (4): 931-942, 2001). 
Cyclophosphamide doses in the AC combination were defined in the NSABP B22 and B25 
studies, using doses of 600, 1,200 and up to 2,400 mg/m2 in 2 to 4 cycles. The ideal dose was 
defined as 600 mg/m2 every 3 weeks in relation to efficacy results (same overall survival and 
disease-free survival).  
• 
Doxorubicin doses were determined via the CALGB 9344 study, in which a standard 
dose of “A” 60 mg/m2 was used versus a higher dose of “A” (90 mg/m2). The efficacy 
results were similar. For this reason, the ideal AC dose was estimated at AC 60/600. 
• 
The North American cooperative group NSABP compared AC vs CMF in the B15 and 
B23 studies.  
• 
The B15 study was completed on 2,194 patients with positive nodes, who were 
recruited between October 1984 and October 1988, and were considered as “non-
responsive to tamoxifen”. They were randomized to receive 4 cycles of AC at the 
aforementioned doses, vs 6 cycles of CMF vs 4 cycles of AC, followed by 3 cycles of 
CMF. The disease-free survival was similar in the three arms (p=0.57) as well as for 
overall survival (p=0.49). In view of the fact that the standard adjuvant treatment at the 
time was CMF, the equivalence of AC x 4 cycles was established with CMF x 6 cycles 
and was the base for the design of multiple subsequent adjuvant studies in patients with 
positive nodes.  
• 
Given the efficacy equivalence proven by the NSABP study of CMFX6=ACX4 in 
positive nodes, the B23 study was carried out on 2,008 patients with negative estrogen 
receptors and negative nodes. They were randomized to receive 4 cycles of AC vs 6 
cycles of CMF. The disease-free survival was similar in the 2 arms (p=0.9) as well as 
for overall survival (p=0.6). These results have been the base for multiple Medical 
Oncology groups to apply 4 cycles of AC in patients with negative nodes within their 
treatment standards106.  
The clinical guidelines in certain countries in Latin America establish that patients with negative 
axillary nodes should receive systemic adjuvant chemotherapy treatment containing 6 cycles of 
CMF or 4 cycles of AC. 
 
1.15 
Justification for the present study 
(Neo-) and/or adjuvant treatment studies are the most favorable framework for the evaluation of 
new proposals for chemotherapy. The subjectivity of evaluation of the response rate observed in 
the metastatic studies will be replaced by the objectivity of the variables used in these studies 
(disease-free survival, and finally, overall survival). 
 
As commented, the majority of the relevant studies which are being performed in (neo-) and/or 
adjuvant treatment at the moment use sequential protocols, with the idea of permitting the 
administration of the highest possible dose of each drug, while diminishing additional toxicity 
which may be produced by the simultaneous administration of various chemotherapeutic agents. 
In this sense, the design of the CIBOMA/2004-01 study is particularly interesting for the 
following reasons: 
• 
It is directed at a type of tumor with poor outcome, ie. basal-like or triple negative. 
It is postulated that this type of tumor will be best treated by chemotherapy treatments. 
In addition, in these patients there is no possibility of receiving complementary 
treatment with hormone therapy or trastuzumab. 
• 
The hypothesis of the possible benefit of a longer chemotherapy treatment (6 cycles of 
standard (neo-) and/or adjuvant chemotherapy + 8 cycles of capecitabine). 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
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Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
• 
The study drug is capecitabine, which has been shown to be one of the most effective 
and safest in the treatment of metastatic breast cancer. 
• 
Capecitabine is a drug which is administered orally, and this will allow a long (neo-) 
and/or adjuvant treatment with chemotherapy for up to 12 months, without affecting the 
quality of life of the patients treated. 
 
 
 
2. 
STUDY OBJECTIVES AND AIMS 
 
2.1 
Principal objective 
Compare disease-free survival after maintenance therapy with 8 cycles of capecitabine (X) 
compared to observation, in patients with operated, hormone receptor and HER2 negative breast 
cancer who have received standard (neo-) and/or adjuvant chemotherapy. 
 
2.2 
Secondary objectives 
• 
Compare 5-year Disease-Free Survival (DFS). 
• 
Compare Overall Survival (OS) between the two above-mentioned groups 
• 
Compare toxicity between the two above-mentioned groups. 
 
2.3 
Tertiary objectives 
• 
Determine the treatment effect of capecitabine on the development and duration of 
amenorrhea in premenopausal women. 
 
• 
(In selected centers): Study the existence of thymidylate synthase (TS) and 
methylenetetrahydrofolate reductase (MTHFR) polymorphisms and confirm their 
relation with toxicity and efficacy of treatment with capecitabine. 
 
3. 
PATIENT SELECTION 
 
3.1 
Inclusion criteria 
 
1. Informed consent must be obtained and documented in writing before any protocol-specific 
procedures are performed. Information must be included on the expected cooperation of 
patients in treatment and follow-up, in accordance with the ICH guidelines for Good 
Clinical Practice. The patient must sign informed consent for sending her tumor sample to 
the central laboratory. Subsequently, if the patient is eligible, a consent form must be signed 
for participation in the clinical trial. 
 
2. Histologically-proven breast cancer (histological examination: invasive adenocarcinoma). 
 
3. Patients with ispilateral axillary node involvement. If the sentinel node technique is used, 
the sentinel node will count as a resected involved node. Patients who can be classified in 
the following groups (AJCC 2002) will be admitted: 
- 
pN1a: Metastasis in 1 to 3 axillary nodes. 
- 
pN2a: Metastasis in 4 to 9 axillary nodes (at least one tumor deposit >0.2 cm). 
- 
pN3a: Metastasis in 10 or more axillary nodes (at least one tumor deposit >0.2 
cm). Patients with a diagnosis of pN3a with infraclavicular node metastasis will 
not be eligible. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 31 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
Nota: Patients without axillary node involvement (N0), provided the primary tumor is greater 
than or equal to 1 cm in diameter. If the sentinel node technique is used, lymphadenectomy will 
not be necessary. 
 
4. Out patient women aged≥ 18 years. 
5. Karnofsky performance status >80 (ECOG 0,1). 
 
 
3.2 
Exclusion criteria 
 
1. Definitive surgical treatment for operable breast cancer (T1-3, M0) must be mastectomy or 
breast-conserving surgery. The margins of the sample extracted in definitive surgery must 
be histologically free of invasive adenocarcinoma and ductal carcinoma in situ (DCIS).  
Lobular carcinoma in situ is not considered as a positive margin. 
2. (Neo-) and/or adjuvant chemotherapy treatment with anthracyclines and/or taxanes 
(paclitaxel, docetaxel) of at least 6 clycles has not been received. NOTE: For patients 
without axillary node involvement that have not received at least four cycles of adriamycin 
and cyclophosphamide as single chemotherapy treatment. The allowed treatments are 
available in appendix 1. Any other treatment schedule should be approveb by the study 
medical coordinators. 
3. In lymphadenectomy, resection of less than 6 nodes (For patients undergoing biopsy of the 
sentinel node, if it is positive, will count as a resected). 
4.  Previous treatment with anthracyclines or taxanes (paclitaxel, docetaxel) for any neoplasm 
other than the breast cancer being treated. 
5.  For patients that receive radiation therapy, no more than 8 weeks (2 months) should elapsed 
between day 1 of last (neo-) and/or adjuvant chemotherapy cycle and the clinical trial entry. 
For those patients in which the administration of adjuvant radiation therapy, more that 4 
weeks (1 month) can be elapsed between the last session and the clinical trial entry. For 
patients that receive antineoplastic treatment before surgery, the interval between definitive 
surgical treatment and clinical trial entry is longer than 60 days. 
6. Patients with unknown or positive estrogen, progeterone and HER2 receptor tumors. 
7. Pregnant or nursing patients. Patients of child-bearing potential must have a negative result 
in a urine pregnancy test with the 14 days before treatment assignation. 
8. Women in a fertile age that do not want to use a reliable and suitable contraceptive method. 
The postmenopausal women should have been with amenorrhea during at least 6 months to 
be considered as infertile (see section 6.5). 
9.  Diagnosis of invasive bilateral breast cancer. 
10. Clinically relevant heart failure, such as congestive heart failure or symptomatic coronary 
artery disease, heart arrhythmia uncontrolled with treatment or history of myocardial 
infarction during the year before study inclusion, or uncontrolled hypertension. 
11. History of significant neurological or psychiatric disease, including psychotic disorders, 
dementia or attacks which would impede the patient’s understanding and giving informed 
consent, will interfere in compliance of the study drug regimen. 
12. Uncontrolled active infection, or other diseases or serious medical pathologies, such as 
active peptic ulcer, unstable diabetes mellitus. 
13. Presence of anomalies in any laboratory parameter, as defined next: (in the previous 14 days 
to the treatment assigment): 
• 
Hemoglobin < 10 mg/dl; absolute neutrophil count < 1,5 x 109/l; platelet count 
< 100x 109/l. 
• 
ASAT (SGOT) and ALAT (SGPT) > 2,5 ULN; alkaline phosphatase > 5 ULN; 
total bilirrubin > 2.0 ULN. Patients with ASAT and/or ALAT values >1.5 x 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 32 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
ULN associated with an alkaline phosphatase level >2.5 x ULN will not be 
selected for the study. 
• 
Severe renal impairment , defined as creatinine clearance below 30 ml/min, 
according to the Cockroft and Gault formula (see appendix 9) or serum 
creatinine > 1,5 ULN. 
14. Previous or present history of neoplastic disease other than breast cancer, with the exception 
of: 
• 
Non-melanoma skin cancer, cervical cancer in situ or other form of tumor 
curatively treated and without signs of disease for at least 10 years. 
• 
Ipsilateral ductal carcinoma in situ (DCIS) of the breast. 
• 
Lobular carcinoma in situ (LCIS) of the breast. 
15. Known hypersensitivity to capecitabine, doxifluridine, fluorouracil or any of its excipients. 
16. Patients with lack of upper gastrointestinal tract physical integrity or malabsorption 
syndrome, or with impossibility to take medication administered orally. 
17. Previous treatment with capecitabine or with continuous infusion (> 24 h) with 5-FU, or 
with other oral fluoropyrimidines, such as eniluracil/5-FU, uracil/tegafur, S1 or emitefur. 
18. Blood transfusions or administration of growth factors to help the hematological recovery in 
the 2 weeks prior to the beginning of the study treatment. 
19. Hormone treatment in the 10 days prior to the beginning of the study treatment. 
20. Possibility of unexpected severe reaction in combination therapy with fluoropyrimidine, 
with or without proven dihydropyrimidine dehydrogenase (DPD) deficiency. 
21. Allograft transplants of organs that require immunosuppressive therapy. 
22. Patients treated with coumarin–derived anticoagulants. 
23. Patients treated with sorivudine or chemically related analogs, such as brivudine. 
24. Concomitant treatment with other investigational drugs. Participation in another clinical 
trial with any unmarketed investigational product during the 30 days prior to study 
inclusion. 
25. Concomitant treatment with any other anticancer therapy. 
26. Inaccessible patients for the treatment and monitoring. The patients registered on this trial 
should be treated and monitored in the participating center, that could be the center of the 
principal investigator or co-investigator. 
27. Patients that cannot or do not want to comply with the protocol, considering the total 
duration of the study. 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 33 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
 
4. 
STRATIFICATION AND RANDOMIZATION TO TREATMENT ARM 
 
Participating investigators will be responsible for ensuring that each new patient fulfills the 
study inclusion criteria, is informed appropriately about the study, reads and understands the 
patient information sheet and dates and signs the informed consent form for participation in the 
study. 
 
4.1 
Timing of registration and randomization to study 
Potentially eligible patients should sign the informed consent form for sending their tumor 
sample to the central laboratory at the beginning of the standard chemotherapy. Receipt of the 
sample will coincide with registration of the patient in the study. The tests to be made on the 
sample are : progesterone, estrogen and HER2 receptor status. 
 
Before the end of treatment with standard chemotherapy, the investigator will receive the 
response from the central laboratory stating whether the patient can participate in the study. 
If the patient is eligible, she must sign a new informed consent form agreeing to participation in 
the study. 
 
The interval between day 1 of the last cycle of (neo-) and/or adjuvant chemotherapy and 
randomization to the study must be no more than 8 weeks (2 months). For patients in whom the 
administration of adjuvant radiation therapy is indicated, the interval between the last session 
and study entry must be no more than 4 weeks (1 month). For patients that receive 
antineoplastic treatment before surgery, the interval between definitive surgical treatment and 
clinical trial entry should be no longer than 60 days. CLARIFICATION NOTE: The 
maximum interval in order to be able to randomize the patient will be taken into account from 
the last curative treatment that the patient received (surgery, chemotherapy or radiotherapy). 
 
The administrative coordinator of the study must register all selected patients before the 
beginning of study treatments. Patients who were not registered before administration of the 
first treatment will not be permitted subsequently to participate in the study. 
No more than 8 days must elapse between the date of treatment randomization and the date of 
the beginning of the first capecitabine maintenance cycle. 
The study monitor will notify the investigator by fax and/or electronic mail, within a period of 
one working day, of the patient study number and treatment arm to which she has been 
randomized. 
 
4.2 
Treatment randomization procedure 
The registration forms should be sent by fax or electronic mail to the study administrative 
coordinator (CIBOMA Central Operations Department) 
 
 
CIBOMA 
 
 
Telephone: +34916592870 
 
 
Fax: +34916510406 
 
 
ciboma@ciboma.org 
Treatment randomization will be carried out when it has been confirmed that the patient was 
previously registered and is eligible. 
 
4.3 
Treatment groups 
Patients will be assigned by the randomization system to one of the following groups: 
 
• 
Arm A: maintenance treatment with capecitabine 
• 
Arm B: observation 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 34 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
 
4.4 
Stratification 
Each selected patient will be randomized to a treatment arm, according to a specific block 
(center, previous chemotherapy treatment with anthracyclines vs. anthracyclines and taxanes, 
number of involved nodes (0 vs. 1-3 vs. >4); and the phenotype (basal vs. triple negative)), to 
receive X x 8 or observation. 
 
5. 
PATIENT TREATMENT 
 
Experimental arm: capecitabine 1,000 mg/m2 twice a day for 14 days, followed by a 7-day rest 
period, for 8 cycles. 
 
The study treatment is capecitabine (Xeloda®). For study purposes, medication will be defined 
as the administration of capecitabine in the treatment arm during active treatment. Xeloda® 
(capecitabine) is a non-cytotoxic fluoropyrimidine carbamate, which, when administered orally, 
acts as a precursor for the cytotoxic 5-fluorouracil (5-FU). Capecitabine is activated by several 
enzymatic steps. The enzyme responsible for the final conversion to 5-FU, thymidine 
phophorylase, is found in tumor tissues, and also in normal tissues, but generally at lower levels. 
 
Control arm: Observation. 
 
5.1 
Provision of drug supplies 
The pharmaceutical company Roche will provide Xeloda® free of charge, in the form of 
commercial drug, in sufficient quantities for the treatment of the study patients. The study 
medication will be delivered by the Pharmacy Departments to the study investigators, who 
should dispense them to the patients and ensure compliance. 
 
Xeloda® is presented in boxes of film-coated tablets: 
• 
Xeloda® 500 mg: 120 film-coated tablets (12 blister packs containing 10 tablets). 
 
The tablets are not fissured, and should not broken. 
 
Xeloda® must not be stored at temperatures above 30ºC. The principal investigators at each 
center will be provided with a temperature chart which must be completed for the area where 
the drug is stored at least once a week. Patients will be properly informed about storage 
conditions for Xeloda®. 
 
5.2 
Capecitabine administration  
Xeloda® chemotherapy doses will be administered according to body surface area, rounding up 
or down to the nearest multiple of 500. Please see the table on appendix 10 to determine the 
proper rounding of the doses according to the body surface area. If variation of the body surface 
area take place during the study, it will be assumed that the body surface area keep 
approximately constant, i.e adjustments due to changes in the corporal weight will not be made 
during the study. 
 
Capecitabine  
It will be administered a dose of 1,000 mg/m2, twice a day (morning and night); equivalent to a 
dayly dose of 2,000 mg/m2. A cycle consist on the administration during 14 days, followed by a 
7 day rest period. At the discretion of the investigator and patient, the cycles can be calculated 
in two ways: the first regimen, permit the first dose of each cycle to be administered in the 
morning of day 1, and the last dose, in the evening of day 14, followed by a 7 day rest period. In 
this way, the cycle consist on the administration of 28 doses in a period of 14 days. The second 
regimen permit the first dose of each cycle to be administered in the evening of day 1, and the 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 35 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
last dose in the morning of day 15, followed by a 6.5 day rest period. This results in a total of 28 
doses per cycle, in 15 days. Any of these regimens can be used, providing the patient receive 28 
doses administered in consecutive days. The patient does not need to follow the same regimen 
in all the cycles, and can choose to change the regimen from a determined cycle. For example, 
in the cycle 1, the patient goes to the hospital consulting room and starts the cycle in the 
evening. Take the last dose in the moning of day 15. In the second cycle, the patient take the 
first dose in the morning of day 1, and the last one in the evening of day 14. The regimen 
followed in each cycle should be registered in the CRF. The morning and evening doses must be 
at least 12 hours distant. The dose must be taken with 200 ml of water during the 30 minutes 
after the meal. For example, a patient with a body surface area of 1,6 m2, should receive 1,600 
mg. This will be rounded up to administer 4 x 500 mg tablets. The patient will be given enough 
drug to complete the 28 doses in each cycle of 21 days. 8 cycles of treatment will be 
administered. 
 
Starting dose in patients with moderate renal impairment 
Patients with moderate renal impairment at baseline, defined as creatinine clearance between 30-
50 ml/min (calccalculated according to the Cockroft and Gault formula, appendix 9), will start 
with a dose reduction to 75%, i.e. instead of 1000 mg/m2 twice a day, they will receive 750 
mg/m2 twice a day. 
 
5.3 Concomitant medication (only applicable to patients of the capecitabine treatment 
arm) 
 
Phenytoin 
A rise in the plasma concentration of phenytoin has been reported, during the concomitant 
administration with capecitabine. Formal studies of interaction between the two drugs have not 
been realized. The patients that receive phenytoin concomitantly with capecitabine, Should be 
regularly monitored to control the phenytoin plasma levels and the associated symthoms. 
 
Halopurinol 
Interactions between halopurinol and 5-FU have been observed, with a possible decrease of the 
5-FU efficacy. The concomitant administration of halopurinol and capecitabine should be 
avoided. 
 
Metronidazol 
In this study is not permitted the concomitant administration of metronidazol and capecitabine.  
 
Cimetidine 
It has been reported that the prior treatment during 4 weeks with cimetidine rise the plasma 
concentration of fluorouracil, after intravenous and oral administration in 6 patients. The effect 
was probably due to a combination in the hepatic enzymes inhibition and a reduction in the liver 
blood flow. This effect has not been observed after the administration of lonely doses of 
cimetidina to 5 patients or during the 1 week pretreatmentin 6. Caution is advised if an study 
patient should be concomitantly administered cimetidine and capecitabine. 
 
Hematopoietic growth factors 
They can be administered according to the habitual rules in each center, for the treatment of 
febrile neutropenia. It cannot be administered as primary or secondary profilactic treatment. The 
administration of hematopoietic groth factors will be stated in the medical record and in the 
CRF. The administration of groth factors should be interrupted at least 48 hours before the 
initiation of the next capecitabine cycle. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 36 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
Laxatives 
The administration of drugs with laxative properties should be avoided, due to the risk of 
diarrhea increase. 
 
Antiacids 
The effect of an antiacid that contains alunimium hydroxide and magnesium hydroxide over 
capecinabine's pharmacokinetics was studied. There were a slight increase in the plasma 
concentrations of capecitabine and of one metabolite (5´DFCR); there was no effect over the 3 
principal metabolites (5´-DFUR, 5-FU y FBAL). 
 
Leucovorin 
The concomitant administration with capecitabine can interact with this and increase the 5-FU 
concentration. As a consequence the toxicity could be increased, that makes necessary the 
monitoring of these patients. 
 
5.4 Permitted dose adjustments 
 
Toxicities will be classified using the Common Toxicity Criteria of the NCI, version 3.0 
(http://ctep.cancer.gov/reporting/ctc.html). 
 
Two possible dose reductions are permitted in the case of hematological toxicity and/or severe 
non-hematological toxicity as indicated below: 
 
Drug 
From (initial dose) 
To (reduced dose 
-75%)
To (reduced dose 
-50%)
Capecitabine 
2000 mg/m2 (1000 
mg/m2 twice a day)2 
1500 mg/m2 (750 mg/m2 
twice a day) 
1000 mg/m2 (500 mg/m2 
twice a day) 
 
If the dose is reduced, it must not be increased again at any time in the future. The interruptions 
in the capecitabine treatment will be considered as lost treatment days, and the initial treatment 
plan will be maintained. Doses not administered due to toxicity will not be substituted or re-
established (see appendix 9). 
 
If a patient experiments several toxicities of different grade and intesity at the same time, the 
greater possible dose reduction will be applied. 
 
If the value of the creatinine clearance decreases during the study to a value < 50 ml/min, due to 
an increase in the serum creatinine or a decrease in the body weight, this change is not a reason, 
in itselft, for a dose reduction. Dose reductions during treatment may be based in adverse 
events. 
 
Regarding the adverse events that are apparent at baseline, the dose modifications will be 
applied according to the corresponding change in the toxicity gradation, If the investigator 
considers it suitable. For example if a patient presents grade 1 asteny in the baseline, that rises 
to grade 2 during treatment, the different to be considered is the rise to grade 1 in toxicity, to 
make the dose modifications. 
 
In the case of toxicities that the investigator considers improbable to become serious or life 
threatening (for example, alopecia, taste alterations), the drug dose must not be reduced neither 
discontinued. Dose reductions or interruptions are neither required in case of anemia (not 
hemolitic), if it is satisfactory treated by transfusions. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 37 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
In case of grade 1 toxicity, or alopecia, the treatment will continue at the initial dose without 
interruptions. 
 
The following criteria will be applied for the reduction or delay of capecitabine dosing due to 
toxicity: 
 
 
Dose reduction schedule for capecitabine monotherapy- not hematological toxicity 
 
Grades 2 and 3 
Grade 4 
-1stappearance 
Discontinue until the remission to grade 
0-1; 
continue 
the 
capecitabine 
administration to 75% of the initiation 
dose, adding prophylaxis if possible. 
Discontinue indefinitely or hold until 
return to grade 0-1 if the doctor 
considers that it is the patient’s best 
interest to continue, reduce dose to 
50% of that planned. 
-2nd appearance 
Discontinue until the remission to grade 
0-1; 
continue 
the 
capecitabine 
administration to 50% of the initiation 
dose. 
 
-3rd appearance 
Discontinue treatment indefinitely, unless 
the doctor considers that it is the patient’s 
best interest to continue. 
 
 
Capecitabine can cuse diarrhea, serious in occasions. In patients that receive capecitabine 
monotherapy, the median of time until the appearance of grade 2-4 diarrhea is 31 days, and the 
median duration of the grade 3 or 4 diarrheas was of 4.5 days. Patients with serious diarrhea 
should be carefully monitored, and in case of dehydratation the administration of fluids and 
electrolytes will be assured. In case of grade 2, 3 or 4 diarrhea the administration of capecitabine 
may inmediatly discontinue, until its solving or decrease to grade 1. The next episodes of grade 
2 or superior diarrhea, require a capecitabine dose reduction, as stated in the table above. 
Treatment with standard antidiarrheal drugs, such as loperamide, sould be initiated as soon as 
possible. The capecitabine treatment should not be reinitiated until diarrhea has been reduced to 
grade 0-1, having administered the last loperamide dose at least 24 hours before. 
 
Nausea /Vomiting grade ≥ 2 
Patients should be provided with antiemetic drugs for auto-administration in case of nausea and 
vomiting if these happen at home. Metoclopramide +/- antagonist 5-HT3 is recommended for 
the nausea inducted by pecitabine. The proper prophylactic and secondary therapies will be 
initiated if nausea and vomiting have occured. If nausea and vomiting are recurrent, despite the 
prophylaxis, a dose modification will be made according to that stated in the corresponding 
chart. 
 
Skin toxicity: grade 2/3 hand-foot syndrome  
The hand-foot syndrome (Palmar-plantar erythrodysesthesia or chemotherapy inducted 
erythema) are considered as skin toxicity. 
If a grade 2 or 3 hand-foot syndrome occurs, the capecitabine administration must be 
discontinued until the solving of reduction to grade ≤ 1. the later dose reductions are 
summarized in this section. 
The hand-foot syndrome must be symptomatically treated (for example, it is recommended the 
use of emollients). A possible profit of the use of B6 vitamin p pyridoxine73,74, and is permitted 
as symptomatic treatment or secundary profilaxis of the hand-foot syndrome. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 38 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
5.4.1 Warnings and cautions 
The capacitabine is administered with occasional assistance, and in certain cases, adverse effects 
as diarrhea can rapidly become into serious events. In case a patient experiences any toxicity 
between two arranged visits, the patient must be instructed in calling the doctor as soon as 
possible, so that he or she can explain the patient about the possible treatments. It is important to 
instruct the patients in discontinuing capecitabine treatment as soon as the grade 2 toxicities of 
the most frequent events, such as diarrhea, hand-foot syndrome or stomatitis appear. 
 
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance 
below 30 ml/min (appendix 8)). Patients with severe renal impairment are not eligible for this 
project. If the severe renal impairment occurs during the study treatment, it will be immediately 
discontinued. It has been informed that in patients treated with capecitabine, and that presented 
moderate renal impairment (creatinine clearance 30-59 ml/mim), the incidence of grade 3 or 4 
adverse event increases. If a patient with moderate renal impairment is included in the study, the 
treatment will initiate with the corresponding dose to 75%. Patients with mild renal impairment 
(creatinine clearance of 51-80 ml/mim), no adjustment of the baseline dose will be made, but 
the appearance of grade 2, 3 or 4 toxicities will be monitored to make the dose adjustment 
established by protocol. 
 
Events have been reported of cardiotoxicity associated with fluorinated pyrimidines (including 
capecitabine), that include the myocardial infarction, angina, dysrhythmias, cardiogenic shock, 
sudden death and electrocardiograph changes. These adverse events may be more common in 
patients with a prior history of coronary artery disease. 
 
In patients with elevation in bilirubin of > 3 ULN, or with elevations in hepatic transaminase 
enzymes of > 2.5 ULN, treatment related, the administration of capecitabine will be 
discontinued. It will be continued when the bilirubin levels reach <3.0 ULN, or hepatic 
transaminase enzymes reach < 2.5 ULN. 
Patients older than 80 years have more risk to experiment grade 3 or 4 toxicity, particularly 
diarrhea, nausea, hand-foot syndrome and vomiting. 
 
5.5 Drug accountability 
The person responsible for dispensing the medication must maintain an appropriate record of 
the drug administered during the study. This record includes the date in which the study 
medication was received, and the dates on which it was dispensed to the patient, the number of 
tablets administered in each visit and the number of tablets returned in the next patient visit. 
 
5.6 Standard (neo-) and/or adjuvant chemotherapy 
Standard (neo-) and/or adjuvant chemotherapy before randomization will consist of 6 cycles of 
combinations of anthracyclines with other antineoplastic agents, or anthracyclines and taxanes, 
or a minimum of four cycles of adriamycin and cyclophosphamide as single chemotherapy 
treatment for patients without axillary node involvement. Appendix 1 sets out the table of prior 
(neo-) and/or adjuvant chemotherapy regimens permitted in this study which the patients must 
have completed to be eligible for the CIBOMA/2004-01 study. 
 
 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 39 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
6. 
EVALUATION OF EFFICACY 
 
6.1 
Primary endpoint: evaluation of treatment efficacy 
All randomized patients will be included in an intent-to-treat analysis.   
Primary efficacy evaluation will consist of the comparison of disease-free survival (DFS) 
between the treatment groups. Disease-free survival is defined as the interval between the date 
of randomization to the date of local, regional or metastatic recurrence or the date of appearance 
of a second primary cancer (except squamous cell or basal cell skin cancer, cervical carcinoma 
in situ or lobular carcinoma in situ of the breast) or death from all causes, whichever occurs 
first. 
If study treatment is discontinued (for whatever reason), disease-free survival and overall 
survival of the patient will analyzed in the intent-to-treat analysis. 
Variables which will be used to measure treatment efficacy are: 
 
6.1.1 
Objective Recurrence 
Any clinical or radiological sign of tumor recurrence, including in the central nervous system.  
Histological or cytological proof of failure must be obtained, if possible. The appearance of any 
sign of malignant disease must be detailed in the diagrams. The patient will be followed up for 
survival. 
 
6.1.2 
Local Recurrence 
Defined as recurrence of the tumor in the surgical scar in the breast, ipsilateral breast (in the 
case of breast-conserving surgery) or signs of tumor in the ipsilateral anterior chest wall (in the 
case of mastectomy) or in the skin or soft tissues within the local area. Confirmatory histology 
or cytology will preferably be performed. 
 
6.1.3 
Regional Recurrence 
Defined as recurrence of tumor in the axillary scar, ipsilateral nodal areas (axillary, 
supraclavicular, internal mammary and infraclavicular nodes), or in the skin or soft tissues 
within the regional area. Confirmatory histology or cytology will preferably be performed. 
 
6.1.4 
Distant Recurrence 
Defined as signs of tumor outside the locoregional area, as defined above. 
This includes the following: 
1) lymph nodes not included in the above-mentioned areas (i.e. contralateral axillary, 
paratracheal, etc.) 
2) skin, not including the areas defined above. 
3) liver 
4) lung 
5) bones 
6) central nervous system 
7) contralateral breast 
8) other localizations not previously defined. 
 
Confirmatory histology or cytology will preferably be performed, especially for solitary lesions. 
Positive bone scans must correlate with the bone X-ray. 
Multiple pulmonary lesions in the chest X-ray, multiple hepatic lesions in the hepatic ultrasound 
or CT, multiple lytic or blastic bone lesions or multiple foci of increased uptake on bone scan 
will be acceptable without pathological correlation.  
 
 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 40 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
6.1.5 
Second primary tumor 
This is defined as any other histopathologically documented tumor, including second primary 
invasive breast cancer in the ipsilateral or contralateral breast, except for non-melanoma skin 
cancer, cervical carcinoma in situ and breast carcinoma in situ (LCIS/DCIS). 
 
6.2 
Secondary endpoint: 5-year Disease-Free Survival 
 
6.3 
Secondary endpoint: Overall 5-year survival 
Survival will be determined from the date of randomization to the date of death for whatever 
reason. 
 
6.4 Secondary endpoint: Evaluation of treatment safety 
 
6.4.1 
Clinical Safety 
The following tests will be performed before therapy and on specific days during therapy: 
 
• 
Complete history of neoplastic and non-neoplastic diseases, including cardiac history. 
 
• 
Complete clinical examination, vital signs (blood pressure, pulse, temperature), height, 
weight, evaluation of any residual toxicity due to any previous treatment, evaluation of 
Karnofsky performance status. 
 
• 
Chest X-ray 
 
• 
Adverse events: a regular evaluation of each patient will be carried out to determine 
possible adverse events according to the NCI-CTC scale (version 3.0). 
 
• 
Laboratory tests: the following tests will be carried out before and on specific days 
during therapy: 
 
o Hematology: White cell count, neutrophils and platelets, hemoglobin 
o Biochemistry: Usual hepatic and renal function tests (creatinine or clearance) 
 
• 
In case of bone pain, raised alkaline phosphatase or elevated tumor markers, a bone 
scan must be performed. In any case, a baseline bone scan is recommended for use in 
possible subsequent follow-ups. 
 
Toxicities which cannot be classified using the NCI-Common Toxicity Criteria will be defined 
as follows: 
a) mild (asymptomatic) 
b) moderate (symptomatic, but does not interfere significantly with activity) 
c) severe (significantly interferes with activity) 
d) life-threatening 
 
6.5 
Tertiary endpoint (in specific patient populations) 
A blood sample will be obtained from each patient before beginning treatment, for the 
prospective testing of the effect of TS and MTHFR polymorphisms associated with the efficacy 
and toxicity of capecitabine administration. The sample will be processed to obtain white cell 
series and plasma. 
 
In the laboratory, white blood cells will be extracted from the sample and DNA will be isolated 
from these cells using the QIAamp mini-kit for DNA purification from Qiagen. The region of 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 41 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
the TS promoter will be amplified by PCR using primers already described in the literature. The 
products of the reaction will be resolved in 1% agarose gel. The PCR products of different 
lengths will be sequenced and the fragments representative of 2R (220 pb) and 3R (248 pb) will 
be identified. These products will be used as size markers and will be included as controls in 
subsequent studies. 
The 3R products will be sequenced for polymorphisms described in the literature. The samples 
identified as 3R alleles will be cloned by T-vector cloning (Invitrogen) and the insert will be 
sequenced with vector primers, using sequencing kits and a capillary electrophoresis-based 
genetic analyzer from Applied Biosystems. The GeneTools program from Biotool will be used 
to analyze sequencing data. 
The genotype of the patients will be found in the 6 pb region of the 3’UTR end for 
polymorphisms, according to the method of Ulrich. The following primers will be used. 
5´CAAATCTGAGGAGCTGAGT3´and 
5´CAGATAAGTGGCAGTACAGA3´. 
PCR 
conditions will be the following: 1 cycle at 94ºC for 5 minutes; 30 cycles at 94ºC for 30 
seconds; 57ºC for 50 seconds; 74ºC for 45 seconds, and 1 cycle of 5 minutes a 72ºC. The 
fragments will be digested with DraI and will be separated using 3% agarose gel. The 6 pb 
deletion produces 152 pb fragment and wild-types produce fragments of 70 and 88 pb. 
 
To determine MTHFR genotypes, single nucleotide polymorphisms in the nucleotide positions 
677 T/C and 1298 A/C will be analyzed with the databases for the identification of single 
nucleotide polymorphisms rs1801133 and rs1801131 (Genbank ref. mRNA NM 005957), 
respectively, using the PSQ HSA96 pyrosequencer. The following primers will be used: 
- 
C677T forward primer: 5´CTAGGAAGGTGCAAGATCAGAG; 
- 
C677T reverse primer: 5´Biotin-GTGTCAGCCTCAAAGAAAAG 
- 
C677T sequencing primer: GGTGTCTGCGGGA. 
- 
A1298C forward primer: 5´AACTCACTTTGTGACCATTCC 
- 
A1298C reverse primer: 5´Biotin-GGGGAGCTGAAGGACTACTA 
- 
A1298C sequencing primer: 5´AAGACTTCAAAGACACT 
The simple biotinilated DNA chain of MTHFR polymorphisms and nearby regions will be 
generated using standard PCR techniques and by sequencing the genotypes using the 
pyrosequencer according to the instructions of the manufacturer. The PCR primers will be 
designed using the Primer3 program (Whitehead) and the sequencing primers will be designed 
using the Pyrosequencing Inc. program. The synthesis of all primers will be commissioned from 
Qiagen Genomics.  
 
Blood levels of thymine and uracil will be evaluated for the determination of DPD deficiencies. 
Proteins will be eliminated from the plasma using trichloroacetic acid, and it will be neutralized 
with tri-n-octylamine in 1,1,2-trichlorofluoroethane. Nucleosides and bases will be separated by 
reverse phase liquid chromatography using a Symmetry C-18 column, according to methods 
already described. 
 
6.6 
Tertiary endpoint 
The effect of capecitabine treatment on the development and duration of amenorrhea in women 
who are premenopausal pre-treatment will be studied using the questionnaire of Dr Cobleigh of 
the Rush Presbyterian St Luke Hospital, Chicago (Appendix 8). The menopausal status of each 
patient will be defined pre-inclusion, according to the following definitions: 
a) Premenopausal 
• 
No prior hysterectomy; menstruation during the 6 months prior to randomization 
• 
Prior hysterectomy; and/or <40 years of age, or >40 years of age with premenopausal 
LH and FSH values 
b) Postmenopausal/Perimenopausal 
• 
No prior hysterectomy; NO menstruation during the 6 months prior to randomization 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 42 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
• 
Prior hysterectomy; and/or >55 years of age or <55 years of age with postmenopausal 
LH and FSH values. 
Menstrual status questionnaires will be distributed to patients classed as premenopausal in the 
randomization form. 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 43 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
7. 
STUDY EVALUATIONS 
Complete diagnostic disease-staging procedures will be carried out in the months prior to study 
inclusion. If staging carried out before the start of standard chemotherapy is available, it will not 
be necessary to repeat the tests. All patients must have a bilateral mammography, chest X-ray 
(PA and lateral), abdominal ultrasound and/or thoracic-abdominal CT. In case of bone pain 
and/or elevated alkaline phosphatase figures, a bone scan must be performed: in any case, a 
baseline bone scan is recommended in all patients included in the study. Other tests may be 
performed as clinically indicated. 
 
7.1 
Time and events schedule 
(x: obligatory; ♦: if clinically indicated; rd: randomization; CT: chemotherapy;  
Arm A: capecitabine; Arm B: observation) 
 
0= Rd day
Pre-rd
Arm A
Arm B
Cycle day 
 
During CT 
During 
QT 
Years 
1-2 
Years 3-5 
Years 1-2 
Years 3-5 
Frequency
Day 1 or
day -1 of 
each cycle 
Day 1 
or day 
-1 of 
cycle 4 
Every 
3 
months
Every 6 
months 
Every 3 
months 
Every 6 
months 
Informed consent
X
History
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
Blood tests 
 
 
Hematology
X
X
X
♦
♦
Biochemistry 
X 
 
♦
♦
♦
Pharmacogenetics** 
X 
 
 
 
 
 
 
Blood or urine test 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
Tumor evaluation 
Mammography*** 
X 
 
 
♦
♦
Chest X-ray***
X
♦
♦
Abdominal ultrasound 
or CT*** 
X 
 
 
♦ 
♦ 
Bone scan***
♦
Tumor tissue evaluations
Hormone receptor 
status* 
X 
 
 
 
 
 
 
HER2 status* 
X 
 
 
 
 
 
 
 
Other 
Adverse events 
 
X 
X 
X 
X 
X 
X 
Evaluation of 
amenorrhea 
(premenopausal 
women only) 
X 
X 
X 
X 
X 
X 
X 
Menopausal status 
 
X 
X 
X 
X 
X 
X 
 
*To be carried out in the designated central laboratory 
**In selected patients only. 
*** If the extension study is available before starting standard chemotherapy, repetition of the 
tests will not be necessary. 
 
Laboratory tests will be carried out, as far as possible, in the same laboratory throughout the 
study. 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 44 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
Every attempt will be made to use the same radiological examinations from the baseline 
evaluation to follow-up. 
 
7.2 
Withdrawal criteria and planned analysis for withdrawals and dropouts 
Patients may be withdrawn from the study for the following reasons: 
a) Disease recurrence, appearance of a second primary cancer (except for non melanoma 
skin cancer treated with curative intention or cervical carcinoma in situ), death or 
administration of other systemic antineoplastic treatment other than the study drug. 
b) Unacceptable toxicity according to the criteria of the investigator 
c) Capecitabine dose interruption for more than 3 weeks. 
d) Intercurrent disease or other reasons which, in the opinion of the investigator, 
significantly affect the evaluation of the clinical status and which require 
discontinuation of the treatment. 
e) Patient’s request to withdraw 
f) Decision of the sponsor (for example, protocol violation) 
 
The reason and date of treatment discontinuation will be documented for all patients in the case 
report form (e.g., end of study, adverse event, lost to follow-up). 
A regular follow-up will be carried out on patients who leave the study for any reason other than 
to receive treatment for disease recurrence or a second primary cancer. 
 
 
7.3 
Treatment after discontinuation of study treatment 
If the patients withdraw from the study due to disease progression, the administration of 
additional treatment will depend on the investigator’s criteria. 
The administration of any other antitumor therapy (surgery, chemotherapy, immunotherapy) 
before the documentation of tumor progression is not permitted. If this is not possible, it will be 
considered that the patient had progressed on the date on which the new antitumor therapy was 
initiated and the case will be analyzed in the category of failure for the purposes of the 
calculation of disease-free survival. 
 
7.4 
Adverse events 
 
Definition of an Adverse Event 
 
The investigator will instruct the patients to report the occurrence of any adverse event. An 
adverse event is any untoward effect associated with the use of a medication, whether 
considered related to the medication or not, including any side effect, injury, toxicity or 
sensitivity reactions. This also includes any untoward clinical or laboratory changes not 
normally present in the patient. 
 
• 
Serious Adverse Event (SAE) 
 
A serious adverse event is one that has a significant risk, a contraindication, a secondary effect 
or a precaution. A serious advert event is considered one that at any dose, comply with at least 
one of the following criteria: 
 
• 
Results in death (if this is not integrated in the of efficacy effect). 
• 
Is life-threatening (means that the patient had an immediate risk of dying because of the 
event in the moment in which it happened. It does not include the event that, if it had been 
stronger, it would have caused death). 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
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• 
Requires patient hospitalization prolongation (by hospitalation it means an unexpected 
hospital entering ) 
• 
Results in persistent or significant disability/incapacity 
• 
Results in a congenital abnormality or birth defect 
• 
Is considered a clinically important event or require an intervention to prevent any of the 
above mentioned endings. 
Clinically important events are those which may not be immediately life-threatening but are 
clearly clinically significant and relevant. The patient may be jeopardized or may require 
intervention to prevent a serious outcome. Cancer or overdose or drug abuse will normally 
be considered serious. 
Medical and scientific judgement should be made in order to decide the notification to the 
sponsor in other situations, such as medical events that may not be immediately life-
threatening, or cause death or hospitalization, but that jeopardize the patient or may require 
an intervention to prevent the previous list endings. Generally, these situations are also 
considered serious adverse events. Examples of these events are the urgent service 
attendance or the home attendance, due to bronquiospasm, blood dyscrasias or convulsions 
that do not cause hospitalization, or development of drug addiction or drug abuse. 
 
An unexpected adverse event is the one that due to its nature or seriousness is not indicated 
in the product specifications. 
 
The investigator may initially evaluate the causal relation. There are two possibilities: 
• 
No (it is not related with the study drug). 
• 
Yes (remote, possible, probable or definitive relation with the study drug). 
The term “severe” is used as an intensifier, although a severe adverse event has not necessary to 
be serious. For example, nausea of several hours duration can be classified as severe, but are not 
clinically serious. 
 
 
All serious adverse events which occur during the study treatment period or in the 30 days after 
administration of a study drug must be reported in the manner described below. For any late 
onset SAE (occurring after this 30-day period) which is possibly or probably related to study 
treatment, the same reporting procedure must be followed. 
 
The progression of any underlying disease in the patient which results in one of the above 
events must be reported as a serious (but expected) adverse event which (a) is not related to the 
study medication or (b) is caused by the failure of the anticipated therapeutic effect of the study 
medication. 
 
 
If the adverse event is serious, it should be reported to the study administrative coordinator, in 
the Central Operations Department of CIBOMA within one working day from the time in which 
the investigator is aware of the event, using the adverse events report form provided in the 
investigator file: 
 
CIBOMA 
Telephone: +34 9 6512870 
Fax: +34 916510406 
 
The Scientific Office of CIBOMA will report all serious and unexpected adverse events 
possibly related to the study treatments which occur in our country to the person responsible for 
drug safety in the pharmaceutical companies/manufacturers of the study drugs, to the health 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
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authorities in the participating countries, to the Clinical Trials Committees (IRBs) involved in 
the trial and the investigators, within the time limits established by the applicable Spanish 
regulations. 
 
The premature termination of the study and therapeutic measures which should be adopted will 
depend on the investigator’s criteria. A full explanation will be provided in the premature study 
termination section of the case report form page. The investigator will carry out a follow-up of 
all adverse events, whether serious or not, until they have satisfactorily resolved. 
 
The investigator and persons responsible for patient care must instigate any complementary 
studies of serious adverse events, on the basis of what, in their clinical opinion, are the possible 
causative factors. This procedure may include the need to obtain the additional opinion of an 
expert in the field of the adverse event. If a patient dies, all post-mortem findings must be 
provided to CIBOMA, including histopathology. 
 
All other adverse events will be collected in the case report form during the course of the study. 
 
The investigator must accept these responsibilities as set out in the terms of the protocol. 
 
Deaths during the Study 
 
Any death which occurs during the active treatment phase of the study or during the 30 days 
following the last administration of study drug, whether related to the study drug(s) or not, must 
be reported within 24 hours to the Scientific Office of CIBOMA. After the 30 days following 
the last administration of study drug, it will only be necessary to report as serious adverse events 
any deaths which are considered as being possibly related to the study drug. All deaths must be 
recorded in the death report section of the CRF, no matter what their cause. 
 
The cause of death (cancer-related, treatment-related, not cancer-related nor treatment-related) 
must be documented. 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 47 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
8. 
DATA COLLECTION AND PROCESSING 
 
8.1 
Monitoring, Auditing and Inspection 
 
This study will be monitored in accordance with Good Clinical Practice Guidelines (GCP), by 
regular visits to the study center and telephone conversations between the study monitor and the 
investigator. During the center visits, the monitor should review the patient source data, the drug 
accountability forms and the study documentation files. In addition, the study monitor must 
observe the study procedures and discuss any problems with the investigator. During the study, 
the health authorities may carry out an inspection of the center. The investigator will provide 
direct access to the source data/documents for study monitoring, audits and review by the 
Clinical Research Ethics Committee and the health authorities. 
 
8.2 
Data recording 
 
CIBOMA will provide Case Report Forms (CRFs) in electronic format, in which the 
investigators can record patient study data. CIBOMA has a Secure Server (SSL certificate) 
exclusively dedicated to the recording of electronic case report form data, set up with the 
bandwidth necessary for obtaining a good connection. CIBOMA guarantees that this server and 
the programming of the case report forms will be maintained throughout the study. 
The electronic case report form will include an electronic signature for authorized access, a 
programming module for traceability of data recorded, changes made, and automatic blockage 
following the time established after recording. 
Data recording on the CRF may be direct (access in real time from the point of origin) or 
deferred, for which a system for replication and transmission on connection will be 
programmed. 
The CRF will be designed with a filter specification developed by the Data Management 
department of CIBOMA. The aim of the filters is to check data omissions, corrections, 
discrepancies and clarifications. The filters are applied to increase precision both in data entry 
and in the Case Report Forms. 
 
After data entry and verification, the validation program will be run, after which the queries will 
be printed for dispatch to the investigator. 
 
The monitor must verify the CRFs, comparing them with the source data (clinical records, 
specialist medical reports, etc). Printed copies of all CRFs from patients included in the study in 
each participating center will be provided on completion of the study. The principal investigator 
should provide a certificate of conformity, indicating agreement with the contents of each CRF, 
which will be kept in the central study file. 
 
The design of the Case Report Form for this study will be electronic and will comply with the 
international ISO guidelines for data protection in “computer networks” and other information-
flow systems, and the IEEE for the standardization of verification, validation and 
documentation plans for the programming used to create the Electronic Case Report Form. The 
FDA guidelines for records and electronic signatures, GMP and GLP, and quality systems 
guidelines will also be complied with. 
 
 
 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
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8.3 
Identification of data which can be recorded directly onto the CRF and as such 
will be considered as source documents 
The following data may be transcribed directly onto the CRF: 
• 
Patient weight before each cycle (except for first visit, in which the body surface area 
must be calculated) 
• 
Performance status in each visit (except in the visit prior to randomization-inclusion 
criteria) 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
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Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
9. 
STATISTICS 
 
9.1 
Study populations 
 
The primary efficacy analysis will be carried out on the intent-to-treat population (ITT), 
which is defined as the population of all randomized patients, analyzed within the treatment 
group to which they were assigned. Randomized patients who did not receive chemotherapy 
will be analyzed with their randomization group. The ITT analysis will be carried out for DFS 
and OS. In addition, the survival analyses will be carried out on the population of selected 
patients, made up of those patients in whom no major protocol violation occurred.  
 
Toxicity and quality of life analyses will be carried out on all study patients who have received 
at least one treatment cycle, or who have completed the observation period equivalent to one 
cycle. 
 
9.2 
Statistical methods 
 
Continuous random variables will be expressed as measures of central tendency: mean and/or 
median and measures of dispersion: standard deviation and range. Quantitative variables will be 
expressed as percentages. The 95% confidence interval of each of the estimates carried out will 
be calculated, where possible. 
 
The Kaplan-Meier limit-product method will be used to estimate DFS and OS. The comparison 
of these 2 parameters between the two treatment groups will be carried out using the Log Rank 
test. All tests of the hypotheses will be two-tailed. 95% confidence intervals will be calculated 
for the medians of survival using the Simon method. 
 
In addition, a Cox’s multiple regression analysis will be performed for DFS and OS, with the 
aim of adjusting the treatment comparison for the principal prognostic factors. These factors 
include age, menopausal status, type of surgery, histopathological findings, and tumor size. The 
Wald test will be used to establish the prognostic importance of each covariant. The covariants 
which appear unbalanced in the baseline values will possibly be added to the Cox model. The 
subgroup analysis will be carried out only if the level of statistical significance in the 
preliminary test is very high (p<0.01). 
 
For the statistical analysis, a center will correspond to a participating hospital. It is expected that 
by the end of the study there will be a large number of centers with few patients included in 
each. Consequently, it is not planned to include center effect in the statistical analysis. 
 
Nevertheless, in case a considerable difference in recruitment is produced some centers, a 
comparison is planned of the consistency of results between these centers and the overall study 
results, in terms of principal baseline characteristics and primary objective. 
 
 
9.3 
Safety evaluation 
 
The Common Toxicity Criteria of the National Cancer Institute (NCI-CTC) and the 
corresponding classification system will be used to classify adverse events recorded in the CRF.   
For adverse events not classified in the NCI-CTC, the COSTART (FDA 1989) classification 
will be used (severity: 1=mild; 2=moderate; 3=serious; 4=life-threatening). 
 
Adverse events will be compared using the Cochran-Mantel-Haenszel test, the Pearson χ2 test or 
the Fisher exact test, all two-tailed. In view of the large number of statistical tests planned, p-


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
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values will not be interpreted in the usual way; instead they will be used as “signaling tool” to 
highlight differences which justify additional attention. 
 
9.4 
Determination of sample size 
 
The following data were obtained from the database of the “El Alamo” project. One thousand 
six hundred and twenty-seven (1,627) in total were considered during the years 1990 to 1997. 
The population is formed of patients with operable breast cancer, with surgery, positive nodes, 
and negative hormone receptors, or negative nodes, negative hormone receptors and T2-3 
tumors. 
Assuming an exponential distribution, the aim is to detect an increase from 64.72% to 73.7% in 
5-year disease-free survival (DFS), corresponding to a hazard ratio of 0.701 and a risk reduction 
of approximately 30%, with a power of 80% at a two-sided level of 0.05, considering 4 years of 
recruitment and 3 of follow-up. We would need to see a total of 255 events for DFS, 834 
patients without considering drop-outs. 
 
Considering a drop-out rate of 5% post-randomization, the final sample size will be 876 
patients, 438 per treatment arm. 
 
The sample size calculation has been completed using the EAST statistical software, 
version 5.2. 
 
9.5 
Statistical analysis of TS and MTHFR pharmacogenetic data  
 
9.5.1 
Hypothesis 
It is estimated that a 40% difference in overall grade 3/4 toxicity will be detected between 
2R/2R patients and 3R/3R patients, the latter being those who present less toxicity. It is 
expected that TT homozygous individuals will have higher toxicity with capecitabine and that 
that clinical significance will be found when patients are stratified for polymorphisms in the TS 
promoter region.  
 
9.5.2 
Calculation of sample size 
Sample size requirements are based on the principal study endpoint, not on pharmacogenetic 
variables. However, the study will have statistical power to determine if polymorphisms in the 
TS promoter are associated with differences in the rate of aggregated toxicity. In a retrospective 
study in patients with metastatic colon cancer, toxicity rates of 63% and 27% were associated 
with 2R/2R and 3R/3R polymorphisms, respectively53. The most common alleles in Caucasians 
and Asians are 2R and 3R. In contrast, the alleles 4R, 5R and 9R are more frequent in those of 
African descent52. The expected frequency of allele tandem repeats 3R and 2R are 0.6 and 0.4, 
respectively, and the assumed genotype frequencies for 2R/2R, 2R/3R and 3R/3R are 0.16, 0.48 
and 0.36, respectively. A minimum of 17 2R/2R and 37 3R/3R patients will be required to 
detect a difference in aggregated toxicity between 2R/2R (60%) and 3R/3R (20%), using the 
two-tailed χ2 test with alfa=0.05 and beta=0.20. 
 
The frequency of MTHFR homozygous individuals in the Caucasian population is at least 
10%64. The study of Cohen et al63 allows the sample size necessary for studying the effects of 
MTHFR on the efficacy of capecitabine to be estimated. Response rates of 58% were observed 
in individuals with CC and CT genotypes compared to a 100% response rate in individuals with 
TT genotype. These estimations of response and allele frequency suggest that a sample size of at 
least 80 patients is required for alfa=0.05 and beta=0.08. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
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CONFIDENTIAL 
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9.5.3 
Statistical analysis 
Patients with DPD deficiencies will be excluded from the analysis, to avoid interferences in the 
interpretation of data for TS genotype and toxicity. Patients who present toxicity during 
capecitabine treatment will be classed as i) grade 1/2, or ii) grade 3/4. The principal analysis 
will compare overall grade 3/4 toxicity rates among the three TS genotypes, using the χ2 test, 
followed by a descriptive analysis of specific toxicities (diarrhea, mucositis, neutropenia and 
palmar-plantar ethryrodysesthesia). Models of association of toxicity and TS and MTHFR 
genotypes will be made using logistic regression tests. 
With regard to survival analysis, Kaplan-Meier curves will be calculated for each TS genotype 
and compared with curves generated for the log-rank test, with levels of significance established 
at p<0.05 for the two-tailed analysis. No adjustments are planned for multiple analyses. The 
following comparisons will be made: 
 
i) 
Only in patients receiving capecitabine: disease-free survival will be compared between 
individuals with 2R/2R genotype and those with different genotypes. 
ii) 
In patients not receiving capecitabine: disease-free survival will be compared between 
individuals with 2R/2R genotype and those with different genotypes, to rule out genotype acting 
as a prognostic factor. 
iii) 
Disease-free survival will be compared between individuals with 2R/2R genotype 
treated with capecitabine, and those with the same genotype not treated with capecitabine. 
iv) 
Disease-free survival will be compared between individuals with 2R/3R genotype 
treated with capecitabine, and those with the same genotype not treated with capecitabine. 
v) 
Disease-free survival will be compared between individuals with 3R/3R genotype 
treated with capecitabine, and those with the same genotype not treated with capecitabine. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 52 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
10. 
PRACTICAL CONSIDERATIONS 
 
10.1 
Independent Data Monitoring Committee (IDMC) 
 
10.1.1 Composition and Mission of IDMC 
 
The Independent Data Monitoring Committee (IDMC) will be composed of three oncologists 
and an expert in statistics. These members will be independent from the clinical study and will 
familiar with the methodology of oncology studies. They must be aware of the danger of 
drawing conclusions from immature data, and will agree with the study design and objectives of 
the protocol. 
 
The mission of the IDMC will be the ethical performance of this clinical study and protection of 
the safety interests of the patients participating in this study. The committee will ensure the 
feasibility and progress of the clinical study. The IDMC will be responsible for the review of 
both study efficacy and study safety. 
 
10.1.2 IDMC meetings 
 
The IDMC will meet annually, unless any important circumstance should occur which requires 
a meeting of its members. The committee will meet annually to review the incidence and 
severity of each of the serious and non-serious events. If a serious unexpected event or incident 
is reported before a programmed meeting, a meeting will be called immediately to evaluate and 
ensure the safety of the study patients. This may also include data from other studies with the 
same product that is being administered in this study, or new efficacy data from other relevant 
studies, the results of which may affect the study CIBOMA/2004-01 in some way. The 
procedures and operations of the IDMC will be recorded in writing, and minutes will be 
produced for all meetings. 
 
10.1.3 IDMC recommendations 
 
At the end of each IDMC meeting, the recommendation will be stated in writing whether to 
modify the study (including reasons), publish the results of the interim analysis (including 
reasons) or continue with the study without modifications. 
 
10.2 
Study budget 
Part of the budget assigned to this study is available for the payment of investigator’s fees. The 
participating hospitals will be paid for the indirect costs generated due to the realization of the 
study. Extraordinary direct costs are not expected, since the diagnostic tests are standard for this 
type of patient. The detailed budget will be provided in a separate document. 
 
10.3 
Third-party insurance policy 
CIBOMA has taken out such an insurance policy with the company HDI HANNOVER 
INTERNACIONAL (ESPAÑA) SEGUROS Y REASEGUROS, S.A. to cover all subjects 
participating in the study for any possible damage they may suffer as a result of their 
participation in the trial. A certificate of the study insurance policy specific to each center will 
be sent to the Clinical Research Ethics Committees involved. 
 
10.4 
Study archives 
The investigator must keep copies of all relevant information for a period of at least 15 years 
from study termination. CIBOMA will provide the investigator with files for all the necessary 
study documents. CIBOMA will also provide a list of all documentation which must be kept. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 53 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
10.5 
Publication policy 
CIBOMA commits to publishing the study results and will respect the rights of the investigators 
and centers participating in the study. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 54 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
 
 
11. 
ETHICAL CONSIDERATIONS 
 
11.1 
Declaration of Helsinki 
This study will be carried out in accordance with the Declaration of Helsinki (amended in 
Edinburgh, 2000), as described in Appendix 1, following the Good Clinical Practice Guidelines 
of the International Conference on Harmonization (GCP/ICH) and in compliance with the 
legislations applicable in each country. 
 
11.2 
Informed Consent (Appendix 4) 
The patient will first sign an informed consent authorizing the dispatch of her tumor sample to 
the designated central laboratory. 
Before screening, the patient will be informed about the nature of the study medication and she 
will be provided with relevant information about the proposed aims, the possible benefits and 
possible adverse experiences. The procedures and the possible risks to which the patient may be 
exposed will be explained. 
 
The patient and the investigator will then read and sign the informed consent. A signed and 
dated copy of the informed consent will be provided to the patient. The patient may withdraw 
from the study at any time, without affecting her future medical care. A note verifying signed 
informed consent will be entered in the study patient’s CRD. 
 
11.3 
Confidentiality 
The investigator will be responsible for maintaining the information required on each patient 
(e.g. initials of name, address, telephone number, social security number and study identity), in 
a way in which the health authorities or  CIBOMA can access this information, if required, while 
maintaining confidential the name of the patient. This information must be kept confidential for 
the legally stipulated period, as required by Spanish legislation. 
 
11.4 
Clinical Research Ethics Committee (CREC) 
A duly constituted Ethics Committee will review the final approved protocol and informed 
consent. The decision of the Ethics Committee regarding the realization of the study will be 
submitted in writing to CIBOMA and to the investigator. 
 
CIBOMA and/or the investigator agree to present to the CREC the necessary reports on study 
progress, and to report any serious adverse events, life-threatening events or deaths. The 
investigator will also inform the CREC of any cases of serious adverse events (provided by 
CIBOMA) reported in other clinical studies carried out with the study drug. The investigator 
must inform the CREC of the termination of the study. 
 
11.5 
Protocol Modifications 
 
A significant protocol amendment is any modification which may affect the realization of the 
study, the potential benefits to the patient or which may affect patient safety, including changes 
in the study objectives, study design, patient population, sample size, study procedures or 
significant administrative changes. The amendment will be authorized by CIBOMA and the 
investigator and approved by the Ethics Committee and the health authorities before 
implementation, in accordance with local legislation. 
 
A non-significant protocol modification consists of minor corrections and/or clarifications 
which do not affect the manner in which the study is performed. These non-significant 
amendments will be authorized by CIBOMA and the investigator and will be documented in a 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 55 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
memorandum. Non-significant modifications will be reported to the CREC and to the health 
authorities, in accordance with local legislation. 
11.6 
Patient Identification 
 
In the initial visit, the initials and date of birth of patients screened for the study will be recorded 
chronologically in the investigator’s file. If any patient is excluded from participation in the 
study, the reason for this must be documented in the space provided. 
 
A study number will be assigned to each patient at the time of registration. The Patient 
Assignation Number and her initials must be recorded on the Case Report Form. 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 56 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
12. 
REFERENCES 
 
1. Henderson IC: Chemotherapy for metastatic disease, in: Harris JR, Hellman S, 
Henderson IC, Kinne DW eds: Breast diseases. Philadelphia: J.B. Lippincott compagny, 
2nd edition, 1991: pp. 604-665. 
2. National Institutes of Health Consensus Development Conference Statement: Adjuvant 
Therapy for Breast Cancer, November 1-3, 2000. J Natl Cancer Inst 2001; 93 (13): 979-
989. 
3. Aapro MS. Adjuvant therapy of primary breast cancer: a review of key findings from 
the 7th International Conference, St. Gallen, February 2001. The Oncologist 2001; 6: 
376-385. 
4. Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an 
adjuvant treatment in operable breast cancer. N Engl J Med 1976; 294: 405. 
5. Fisher B, Brown AM, Dimitrov et al. Two months of doxorubicin-cyclophosphamide 
with and without interval reinduction therapy compared with 6 months of 
cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer 
patients with tamoxifen-non-responsive tumors: results from NSABP B-15. J Clin 
Oncol 1990; 8: 1483. 
6. Carpenter JT, Velez-Garcia E, Aron BS et al. Five-year results of a randomized 
comparison of cyclophosphamide, doxorubicin (Adriamycin) and fluorouracil (CAF) 
vs. cyclophosphamide, methotrexate and flurouracil (CMF) for node positive breast 
cancer: a Southeastern Cancer Study Group Study. Proc ASCO 1994; 13: 66. 
7. Buzzoni R, Bonadonna G, Valagussa P et al. Adjuvant chemotherapy with doxorubicin 
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PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 57 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
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PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
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CONFIDENTIAL 
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Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
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PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
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Amendment No. 2: September 16, 2009 
 
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PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
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Amendment No. 2: September 16, 2009 
 
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PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
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Amendment No. 2: September 16, 2009 
 
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PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 62 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
APPENDIX 1: Minimum acceptable regimens for chemotherapy for participation in the 
CIBOMA study/2004-01 
 
Type of Regimen 
Regimens 
ALL 
REGIMENS 
To be eligible, the patient must have received at least 6 cycles of an approved (neo-) and/or 
adjuvant chemotherapy regimen. In all cases the maximum accumulative dose of 
doxorubicin (A) is 360mg/m2 and of epirubicin (E) 720mg/m2 
NOTE: Patients without axillary node involvement are required to have received at least 
four cycles of adriamycin and cyclophosphamide as single chemotherapy treatment. 
Anthracylines 
without taxanes 
Among the permitted regimens in this category are included the combination of A or E with 
cyclophosphamide (C) with or without 5-fluorouracil (F), and A or E as single agents or 
combined with C followed by several cycles of CMF (where M is methotrexate). 
Initial minimum permitted dose of A or E associated with C and with or without F: 
CAF/FAC: 
50mg/m2 (every 21 days or every 28 days) 
EC: 
 
90mg/m2 
75mg/m2 (administered day 1 every 21 days) if administered for a minimum of 6 cycles 
FEC/CEF: 
50mg/m2 (administered days 1 and 8 every 28 days) 
FE90C: 600/90/600 administered every 21 days or every 15 days. 
FE100C: 500/100/500 administered every 21 days. 
75mg/m2 (administered day 1 every 21 days) 
Permitted initial dose of A or E as single agents or combined with C followed by CMF 
(described below): 
A: 
 
75mg/m2 
E: 
 
90mg/m2 
Anthracyclines 
and taxanes 
21-day regimens 
Among the permitted regimens in this category are included the sequential or combined 
anthracyclines (A or E) and taxanes (paclitaxel [P] and docetaxel [D]). In sequential 
regimens, A or E can be combined with C and with or without F 
When anthracyclines (with or without C and/or F) and taxanes are administered 
sequentially, the initial minimum dose for injection of A is 60mg/m2 (50mg/m2 is also 
accepted for A in regimens of FAC); for E, 90mg/m2 (75mg/m2 is also accepted for E in 
regimens such as FEC); for P, 175mg/m2/3-hours (75mg/m2 every 7 days or 100 mg/m2 
every 7 days for 8 doses or 80 mg/m2 every 7 days for 12 doses); and D, 100 mg/m2 or 
75 mg/m2. 
When anthracyclines are administered (with or without C and/or F) together with taxanes, 
the initial minimum dose for injection of A is 50mg/m2; for E, 75mg/m2; for P, 
135mg/m2/3-hours; and for D, 60mg/m2/1-hour or 75mg/m2. 
Study scheme PACS 01: 3 cycles of FE100C followed by 3 cycles of docetaxel 100 mg/m2 
every 21 days. 
Anthracyclines 
and taxanes  
14-day regimens 
The bi-weekly sequential regimen of anthracyclines and taxanes is accepted as follows: 
4 cycles of doxorubicin 60mg/m2 followed by 4 cycles of paclitaxel 175mg/m2/3-hours, 
followed by 4 cycles of cyclophosphamide 600 mg/m2/3. 
GEICAM 9906 
4 cycles of FE90C: 600/90/600 administered every 21 days, followed by 8 weekly cycles of 
paclitaxel 100 mg/m2. 
 
Other regimens 
Any regimen which forms part of a chemotherapy trial which has been previously approved 
by the Scientific Committee of CIBOMA. 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 63 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
APPENDIX 
2: 
KARNOFSKY 
PERFORMANCE 
SCALE 
AND 
EASTERN 
COOPERATIVE ONCOLOGY GROUP (ECOG) CRITERIA 
 
ECOG 
KARNOFSKY 
DEFINITIONS (Zubrod) 
 
0 
 
100 
 
Absence of symptoms. 
 
1 
80-90 
 
Symptomatic, completely occasional  
 
 
 
assistance. 
 
2 
60-70 
 
Symptomatic, in bed less than 50% of the 
day.  
 
3 
40-50 
Symptomatic, in bed more that 50% of the 
day, but not hospitalized.  
 
4 
20-30 
Hospitalized. 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 64 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
APPENDIX 3: TNM CLASSIFICATION – BREAST (American Joint Committee on 
Cancer 2002) 
PRIMARY TUMOR (T): 
TX 
 Primary tumor cannot be assessed  
T0 
 No evidence of primary tumor  
Tis 
 Carcinoma in situ 
Tis 
 (DCIS) ductal carcinoma in situ 
Tis 
 (LCIS) lobular carcinoma in situ 
Tis 
 Paget's disease of the nipple with no associated tumor. (Paget's disease 
associated with a tumor is classified according to the size of the tumor)  
T1
Tumor 2.0 cm or less in greatest dimension 
T1mic 
 Microinvasion 0.1 cm or less in greatest dimension  
T1a 
 Not more than 0.5 cm in greatest dimension  
T1b 
 Tumor more than 0.5 cm but less than 1.0 cm in diameter  
T1c 
 Tumor more than 1.0 cm but less than 2.0 cm 
T2 
 Tumor more than 2.0 cm but less than 5.0 cm in greatest dimension  
T3 
 Tumor more than 5.0 cm in any dimension  
T4
Tumor of any size with direct extension to chest wall or skin
T4a 
 Extension to chest wall (includes ribs, intercostal muscles, and serratus 
anterior muscle but not pectoral muscle) 
T4b 
 Edema (including peau d'orange) or ulceration of the skin of the breast or 
satellite skin nodules confined to the same breast  
T4c 
 Both of the above (T4a and T4b)  
T4d 
 Inflammatory carcinoma 
 
LYMPH NODES (pN): 
pNX 
 Regional lymph nodes cannot be assessed (previously removed or not 
removed)  
pN0 
 No histological evidence of regional lymph node metastasis, no additional 
study for isolated tumor cells performed. 
pN0(i-) 
 No histological evidence of regional lymph node metastasis, 
immunohistochemistry negative 
pN0(I+) 
 No histological evidence of regional lymph node metastasis, 
immunohistochemistry positive with no cell aggregates >0.2 mm. 
pN0(mol-) 
 No histological evidence of regional lymph node metastasis, no molecular 
findings on reverse transcriptase-polymerase chain reaction (RT-PCR) 
pN0(mol+) 
 No histological evidence of regional lymph node metastasis, molecular 
findings on reverse transcriptase-polymerase chain reaction (RT-PCR) 
positive 
pN1 
 Metastasis in 1-3 axillary lymph nodes and/or internal mammary chain with 
microscopic disease detected by sentinel node resection, but not clinically 
apparent* 
pN1mi 
 Micrometastasis (greater than 0.2 mm and less than 2 mm) 
pN1a 
 Metastasis in 1-3 axillary lymph nodes  
pN1b 
 Metastasis in internal mammary chain with microscopic disease detected by 
sentinel node resection, but not clinically apparent* 
pN1c 
 Metastasis in 1-3 axillary lymph nodes and in internal mammary chain with 
microscopic disease detected by sentinel node resection, but not clinically 
apparent* 
pN2 
 Clinically apparent* metastasis in 4-9 axillary lymph nodes, or in internal 
mammary chain with no axillary node involvement. 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR 
AND HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Final version (3): June 10, 2005 
CONFIDENTIAL 
Page 65 of 88 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
pN2a
Metastasis in 4-9 axillary lymph nodes (at least one tumor deposit >2 mm)
pN2b 
 Clinically detectable* metastasis internal mammary nodes with no axillary 
node involvement.
pN3 
 Metastasis in 10 or more axillary nodes or in infraclavicular nodes; or in 
ipsilateral mammary chain, clinically apparent*, with involvement of 1 o 
more axillary nodes, or in more than 3 axillary nodes with microscopic 
metastatic involvement and not clinically apparent in the internal mammary 
chain; or in ipsilateral supraclavicular nodes. 
pN3a 
 Metastasis in 10 or more axillary nodes or in infraclavicular nodes 
 
 
 
pN3b 
 Clinically detectable metastasis in ipsilateral internal mammary nodes, with 
involvement of 1 or more axillary nodes, or in more than 3 axillary nodes 
and in internal mammary chain with microscopic disease detected on 
sentinel node resection but not clinically apparent.
pN3c 
 Metastasis in ipsilateral supraclavicular nodes. 
 
*Clinically apparent, detectable: detected on imaging studies (except 
lymphoscintigraphy) or by clinical examination. 
 
DISTANT METASTASIS:  
 
MX: Presence of distant metastasis cannot be assessed  
M0: No evidence of distant metastasis  
M1: Distant metastasis present  
 
 
Breast cancer staging: 
Stage 0 
Stage I 
Stage IIA 
Stage IIB 
Stage IIIA 
Stage IIIB 
Stage IIIC 
Stage IV 
TisN0M0 
T1N0M0 
T0N1M0 
T2N1M0 
T0N2M0 
T4N0M0 
Any TN3M0 
Any T  
Any N M1 
T1N1M0
T3N0M0
T1N2M0
T4N1M0
 
 
T2N0M0 
 
T2N2M0 
T4N2M0 
 
 
 
 
 
 
T3N1M0 
 
 
 
 
 
 
 
T3N2M0 
 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
PATIENT AND INVESTIGATOR: 
- SIGN AND DATE TWO COPIES OF INFORMED CONSENT 
- KEEP ONE COPY IN CLINICAL RECORDS 
- GIVE THE OTHER COPY TO THE PATIENT 
 
Draft 3 
 
CONFIDENTIAL 
Page 66 of 88 
APPENDIX 4: PATIENT INFORMED CONSENT MODEL 
 
PRE-SCREENING INFORMED CONSENT: TRIPLE NEGATIVE TEST FOR 
CIBOMA STUDY/2004-01 
 
INTRODUCTION AND OBJECTIVES 
 
 
Your doctor is considering you for participation in a clinical study (also known as 
clinical trial) You will be able to take part in this trial once all the other treatments which you 
have been administered for your breast cancer have been completed. Before we continue talking 
about your possible participation in the study, other tests will first have to be carried out on your 
tumor sample, known as hormone receptor and HER2 expression tests. These tests can be 
carried out with a sample we already have, so it will not be necessary to carry out more biopsies, 
operations or blood draws. 
 
The hormone receptor and HER2 expression tests will be carried out routinely in your 
hospital laboratory. If the result is negative, the tests will be repeated in a central laboratory in 
Madrid, Spain, to confirm the negative result. 
In this study is promoted by the Iberoamerican Coalition for Research in Breast Oncology 
(CIBOMA - Coalición Iberoamericano de Investigacíón en Oncología Mamaria), non-profit 
organization which aim is to increase the quality and number of breast cancer clinical trials. 
 
The aim of this document is to provide you with sufficient information for you to 
understand the possible risks and benefits which may be involved in these additional tests and 
confirmations. If you decide later to participate in the clinical trial, your doctor will ask you to 
read and sign a document which contains more details on the trial. 
HORMONE RECEPTOR TEST 
 
Breast tissue contains some hormone receptors, called estrogens and progesterones, 
which regulate many of the processes related with the feminine sex. Approximately 70% of 
breast cancers contain these receptors. These hormone receptors are absent from about 20% of 
tumors, and these tumors are called receptor negative. 
 
In the case of your tumor, your doctor has determined using a technique called 
immunohistochemistry that it has negative hormone receptors, which is one of the two 
conditions necessary for your participation in the clinical trial. 
HER2 TEST 
 
HER2 is a protein which is produced in high levels in about 20% of breast cancer 
tumors.  In approximately the other 80%, high levels of this protein are not detected. If you 
belong to this group (HER2 negative), you can participate in the clinical trial. 
 
The negative result for hormone receptors and HER2 must be confirmed in the central 
laboratory. The laboratories will process the samples, using one of the following methods: 
- Immunohistochemical staining (IHC) 
- Fluorescence in situ hybridation (FISH). 
 
ADDITIONAL TESTS 
 
If you do participate in study CIBOMA 2004-01 in the future, another two tests will be 
carried out on the material sent to the laboratory, to determine if your tumor produces high 
levels of a protein called cytokeratin 5 and of another protein called HER1, which is also known 
as EGF receptor. The process which will be used for these tests is immunohistochemical 
staining. 
POTENTIAL BENEFITS 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
PATIENT AND INVESTIGATOR: 
- SIGN AND DATE TWO COPIES OF INFORMED CONSENT 
- KEEP ONE COPY IN CLINICAL RECORDS 
- GIVE THE OTHER COPY TO THE PATIENT 
 
Draft 3 
 
CONFIDENTIAL 
Page 67 of 88 
 
It is possible that you do not obtain any personal benefit from the additional tests carried 
out on your tumor sample, although the information on the factors analyzed may be useful for 
directing your future treatment. Your doctor will provide you with the results of these tests. 
 
ADDITIONAL COSTS OR PAYMENTS 
 
You will not have to pay for the hormone receptor and HER2 tests, or for any additional 
test. Nor will you be paid for agreeing to the analyses. 
 
SAMPLE HANDLING 
 
Your sample will be identified by a numeric code during the study. When the study has 
finished, any reference to your identity will be eliminated (this numeric code will be eliminated) 
keeping the samples absolutely anonymous. From this moment and providing you do not 
require in writing the returning of the tumor sample from the pathological anatomy service of 
your hospital, it will be added to the CIBOMA breast tumor bank where it will be kept 
indefinitely. The aim of keeping these samples is to test future scientific findings. Some North 
American cooperative oncological groups have been operating this way between 10 and 20 
years, and the tumor availability has let them test scientific hypothesis that have given relevant 
information for the breast cancer knowledge. 
 
DATA CONFIDENTIALITY 
 
You have a right to privacy and all the information which is collected for this study will 
be kept confidential within legal limits. In Spain, the handling of data of a personal nature is 
regulated by the Constitutional Law 15/1999, dated 13 December 1999. Your consent for 
handling your personal data and for allowing the use of the same can be revoked. You can 
exercise your right to access, rectification and cancellation, by asking your doctor, who will put 
you in contact with the sponsor. The personnel authorized by the sponsor for the study 
information managing, by your requirement, will be under the obligation to rectify or cancel 
those data of personal nature that you require. 
 
If the hormone receptor and HER2 levels are positive, and you cannot participate in the 
clinical trial, your doctor will file your signed and dated pre-screening informed consent in your 
clinical records, along with the results of the tests and the medical observations from the pre-
screening period. 
 
If the hormone receptor and HER2 levels are negative, you will be able to participate in 
the CIBOMA 2004-01 clinical trial. In this case, your results will be collected by your doctor 
and sent to CIBOMA, Madrid, Spain, where the research database for the study is located. 
 
Your original clinical records may be analyzed during or after the study by CIBOMA or 
its designated representatives, the health authorities and the local Ethics Committee 
representatives. 
 
If you can, and you decide to, participate in the CIBOMA study, your data may be 
analyzed in any of the member countries of the Coalition, to determine how many patients have 
tumors with the same characteristics as yours (called triple-negative). CIBOMA may send the 
results to the health authorities of the CIBOMA countries which are participating in this study, 
present them in medical meetings, or publish them in specialized journals, so that other doctors 
may know about them. If you withdraw from the study, the information gathered about you up 
to the moment of withdrawal will continue to be used. 
 
The representatives of CIBOMA, of the health authorities and of the local ethics 
committee may be permitted to inspect your clinical record to ensure that the information 
gathered is correct. In these cases, you may be identified personally. 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
PATIENT AND INVESTIGATOR: 
- SIGN AND DATE TWO COPIES OF INFORMED CONSENT 
- KEEP ONE COPY IN CLINICAL RECORDS 
- GIVE THE OTHER COPY TO THE PATIENT 
 
Draft 3 
 
CONFIDENTIAL 
Page 68 of 88 
 
Your participation in the study CIBOMA 2004-01 is described in another consent sheet. 
 
OBTAINING ADDITIONAL INFORMATION 
We encourage you to ask all the questions you want at any time during the study. If problems 
emerge or if you have more questions on prescreening, or on the study or your rights as a 
patient, call Dr…………………….. on …………..(tel.). 
 
BASIS OF PARTICIPATION 
 
The participation in prescreening procedures for the CIBOMA 2004-01 study is 
voluntary. If you do not want to participate, you will not lose any of the benefits to which you 
otherwise have a right nor will you suffer any penalty. 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
PATIENT AND INVESTIGATOR: 
- SIGN AND DATE TWO COPIES OF INFORMED CONSENT 
- KEEP ONE COPY IN CLINICAL RECORDS 
- GIVE THE OTHER COPY TO THE PATIENT 
 
Draft 3 
 
CONFIDENTIAL 
Page 69 of 88 
PATIENT DECLARATION AND SIGNATURE 
 
 
PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO 
EVALUATE THE EFFICACY OF MAINTENANCE THERAPY WITH 
CAPECITABINE (X) AFTER STANDARD (NEO-) AND/OR ADJUVANT 
CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER 
Study Number: CIBOMA/2004-01 
 
I, ________________________  
 
have read the information sheet which has been provided to me and I understand the aim of screening 
for the analysis of hormone receptor and HER2 expression. 
I have been able to ask questions about the study. 
I have received satisfactory answers to my questions. 
I have received sufficient information about the study. 
 
I have spoken with _______________________ 
 
I understand that my participation is voluntary. 
 
I understand that I can withdraw from the study: 
 
 
1. 
whenever I want, 
 
2. 
without have to give explanations, 
 
3. 
without affecting my medical care. 
 
I authorize to the professional personnel of the sponsor of the clinical trial CIBOMA/2004-01, 
the Health Authorities or the pertinent International Bodies, to review my clinical and personal 
data related with the participation in this clinical trial. 
 
I have been informed that I can revoke in any moment the authorization to review my clinical 
and personal data. 
I freely give my agreement to participate in this screening for the analysis of hormone receptors and 
HER2 in a sample of my primary breast cancer. 
 
 
__________________________________________________________________ 
Date 
  
 
 
 
 Signature of participant 
 
I have fully explained the relevant details of this study to the above-named patient  
 
 
 
__________________________________________________________________ 
Date 
  
 
 
 
 Signature of investigator 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
PATIENT AND INVESTIGATOR: 
- SIGN AND DATE TWO COPIES OF INFORMED CONSENT 
- KEEP ONE COPY IN CLINICAL RECORDS 
- GIVE THE OTHER COPY TO THE PATIENT 
 
Draft 3 
 
CONFIDENTIAL 
Page 70 of 88 
PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO 
EVALUATE THE EFFICACY OF MAINTENANCE THERAPY WITH 
CAPECITABINE (X) AFTER STANDARD (NEO-) AND/OR ADJUVANT 
CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER 
Study Number: CIBOMA/2004-01 
 
Your doctor has explained to you that you have breast cancer with a risk of recurrence. There 
are various treatments available which may help you. We are inviting you to participate in a 
research study with the medication Xeloda® (capecitabine, abbreviated to X), an oral 
medication which has been shown to be very effective in the treatment of advanced breast 
cancer. The trial is being carried out in various hospitals in Central/South America and in Spain. 
The participation of 876 patients is expected in this investigational study which has been 
approved by the authorities of your Hospital and the health authorities of your country. This 
study is sponsored by the Iberoamerican Coalition for Research in Breast Oncology (CIBOMA - 
Coalición Iberoamericano de Investigacíón en Oncología Mamaria), which is a non-profit-
making association with the aim of increasing the quality and number of clinical trials in breast 
cancer. 
 
OBJECTIVE 
The objective of this study is to test if prolonging standard intravenous chemotherapy, which 
you have already received, with an oral chemotherapy treatment (capecitabine) is effective in 
preventing recurrence of your disease. You will have the same possibility of receiving treatment 
with 8 cycles of Xeloda® as not receiving any treatment and being assigned to an observation 
group. This will be decided by chance, like tossing a coin. 
 
STUDY PROCEDURES 
Before receiving treatment, you will have a series of tests to determine whether you can 
participate in the study. These tests will include blood tests and a physical examination. You 
may have to have a test of your heart function and radiological procedures to check that your 
disease has not spread to other parts of your body. We will also carry out routine tests on your 
tumor, for example, to check the status of hormone receptors and a protein called HER2. For 
these determinations to be consistent, you have previously allowed a sample of your tumor to be 
sent to a central laboratory, other than that of your own hospital. Your doctor may also request 
another blood sample from you in the case that you are assigned the capecitabine treatment arm 
to analyze the relation between your individual characteristics and a greater sensitivity to the 
study treatments. It is a pharmacokinetics study to determine the existence of polymorphisms in 
the thymidylate synthase enzyme (TS) and in the methylenetetrahydrofolate reductase enzyme 
(MTHFR), and to check their association with the toxicity and efficacy of the capecitabine 
treatment. To participate in this pharmacokinetic study, you may sign other informed consent form 
that your doctor will provide to you if you wish. 
While you are on the study, and if you are in the capecitabine treatment group, you will have a 
blood test before the start of each new cycle (every 21 days). These regular blood tests and other 
tests will be carried out to check that the medications are not adversely affecting your bone 
marrow, kidneys and liver. 
If you are assigned to treatment group A (capecitabine) you will have to receive treatment for 24 
weeks (i.e. 8 cycles every 21 days). Every treatment cycle consists of 2 weeks of treatment 
followed by one week of rest. If you are assigned to group B (observation), you will not receive 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
PATIENT AND INVESTIGATOR: 
- SIGN AND DATE TWO COPIES OF INFORMED CONSENT 
- KEEP ONE COPY IN CLINICAL RECORDS 
- GIVE THE OTHER COPY TO THE PATIENT 
 
Draft 3 
 
CONFIDENTIAL 
Page 71 of 88 
treatment, but your doctor will ask you to come to see him/her routinely. Then, at the end of the 
study, your doctor will perform a follow-up examination. 
After that, your doctor will follow you up in the same way as for other patients with breast 
cancer, to confirm that the tumor has not recurred. 
For the first 2 years, you will have a physical examination every 3 months, and you will have a 
mammography and chest X-ray every 12 months. 
During years 3 to 5, the three monthly visits will be dropped, but you will still have visits every 
6 and 12 months, with the same evaluations. 
The medication Xeloda® will be administered orally, twice a day (morning and evening) with 
water, 30 minutes after a meal. You should follow the treatment for 14 days in a row, after 
which it will be stopped for a week. Then you will start again, and so on, until the treatment is 
completed. 
 
 
POSSIBLE ADVERSE EVENTS 
The following side effects are the most common with the medication used in this study. These 
are side effects which we know about at the moment. However, since this is a study with new 
treatments, there may be other side effects that we still do not know about. For this reason, it is 
very important that you tell your doctor immediately about any unusual symptoms. 
With Xeloda® you may experience diarrhea, abdominal pain, nausea, mouth irritation which 
might distress you when you are eating, and the so-called “hand-foot syndrome”, which consists 
of numbness in your hands and feet, which may be accompanied by pain, flaky skin and 
discomfort which may affect your daily activities. Calcium levels in your blood may also be 
altered, but your doctor will check regularly for this. This drug is marketed, and we attach the 
product specifications, a document that states all the Xeloda side effects. 
These side effects may be small inconveniences or may be severe, but your doctor will monitor 
you closely and if anything happens, he/she will decide to adjust your chemotherapy dose or 
stop treatment. If treatment is discontinued, you will be offered an alternative treatment. 
If you have fever or bruising after receiving any medication, you should contact the department 
doctors. 
 
EXPECTED BENEFITS 
You have already received treatment with standard intravenous chemotherapy before this study. 
You may also have received treatment with radiation therapy. With any of the standard 
treatments, a high percentage of women are completely cured of their breast cancer. This study 
will help us find out if prolonging treatment with chemotherapy increases this percentage of 
patients who are completely cured, or if in contrast, this does not happen, which is to say, that 
the breast cancer reappears, in the form of metastasis, in the same percentage of women who 
received standard treatment. If this happens, your doctor will ensure that you get the best 
treatment available for you at the time. 
Your participation in this study may, then, not provide you with any benefit, but it will help us 
to understand the disease better, and we hope that we can use this information to help women 
who develop this disease in the future. 
 
 
 
ALTERNATIVE TREATMENTS AVAILABLE 
 
At the moment no alternative treatment is available in your situation and for your type of tumor. 
The usual procedure is that you do not receive more treatments, and that you are called for 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
PATIENT AND INVESTIGATOR: 
- SIGN AND DATE TWO COPIES OF INFORMED CONSENT 
- KEEP ONE COPY IN CLINICAL RECORDS 
- GIVE THE OTHER COPY TO THE PATIENT 
 
Draft 3 
 
CONFIDENTIAL 
Page 72 of 88 
routine check-ups, which is what will happen if you are assigned to the observation group of 
this study. 
 
 
STUDY INSURANCE 
In case you are injured during the study, CIBOMA has taken out an insurance policy with the 
HDI HANNOVER INTERNACIONAL (ESPAÑA) SEGUROS Y REASEGUROS S.A. 
Company with the number 130/101/000252 to cover third party responsibility of the study 
sponsor, the principal investigators and their co-workers, as well as the Hospital or Center 
Director, under the terms established in the Royal Decree 223/2004 which regulates the 
performance of clinical trials with medications in Spain. You will be informed of all significant 
new findings about Xeloda® which come to light during the study and which may make you 
change your mind about participating. 
You must not take part in this study if you are pregnant or if there is a possibility that you may 
become pregnant during the study. Consequently, your doctor will check that you are using an 
effective contraceptive method before you start the study. 
Your doctor may decide to withdraw you from the study if participation is not in your best 
interests, if you do not follow the instructions regarding the treatment, if it is discovered that 
you do not fulfill the trial requirements or if the study is terminated. 
 
 
FINANCIAL ASPECTS 
You should know that there is an economic compromise between the center and the principal 
investigator. However, it is not planned to pay you for your participation. It is considered the 
possibility to pay you the expenses of the extra visits to the hospital (those that will not be made 
under the habitual clinical practice), with a previous presentation of the supporting document. 
 
 
VOLUNTARY PARTICIPATION 
Your participation in this study is voluntary. You decide to participate but later change your mind, 
you are free to do so and you do not have to give a reason. However, you should tell your doctor 
about your decision, so that he/she can tell you what procedures should be followed to evaluate 
your clinical disease correctly and proceed with your medical care. The medical attention which 
you receive from your doctor will not be affected by your decision. 
 
 
PEOPLE WITH ACCESS TO YOUR DATA AND CONFIDENTIALITY 
If you participate in this study, your clinical records may be reviewed by professional staff from 
CIBOMA, from the Health Authorities or relevant international bodies. The data derived from 
your participation in the study may be published for scientific purposes, but your identity will 
be kept confidential, i.e. no-one will know your identity from the published data. The 
confidential nature of your personal data will be respected and guaranteed at all times, in 
accordance with the current regulations (Constitutional Law 15/1999, dated 13 December 1999 
for the protection of data of a personal nature ). You can exercise your right to access, 
rectification, cancellation and opposition by asking your doctor, who will put you in contact with 
the sponsor. The personnel authorized by the sponsor for the study information managing, by your 
requirement, will be under the obligation to rectify or cancel those data of personal nature that you 
require. 
If you have any problem or question about the study, your rights as a clinical research 
participant or any research-related injury, you should contact: 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
PATIENT AND INVESTIGATOR: 
- SIGN AND DATE TWO COPIES OF INFORMED CONSENT 
- KEEP ONE COPY IN CLINICAL RECORDS 
- GIVE THE OTHER COPY TO THE PATIENT 
 
Draft 3 
 
CONFIDENTIAL 
Page 73 of 88 
 
Dr:....................................................................tel:.............................................................  
 
 
 
 
 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
PATIENT AND INVESTIGATOR: 
- SIGN AND DATE TWO COPIES OF INFORMED CONSENT 
- KEEP ONE COPY IN CLINICAL RECORDS 
- GIVE THE OTHER COPY TO THE PATIENT 
 
Draft 3 
 
CONFIDENTIAL 
Page 74 of 88 
WRITTEN PATIENT INFORMED CONSENT 
 
PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO 
EVALUATE THE EFFICACY OF MAINTENANCE THERAPY WITH 
CAPECITABINE (X) AFTER STANDARD (NEO-) AND/OR ADJUVANT 
CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER 
Study Number: CIBOMA/2004-01 
 
I……………………………………………………  
 
have read the information sheet provided to me 
have been able to ask questions about the study 
have received satisfactory answers to my questions 
have received sufficient information about the study. 
 
 
I have spoken with………………………………….. 
 
I understand that my participation is voluntary. 
 
I understand that I may withdraw from the study: 
 
 
 
1. 
Whenever I want 
 
2. 
Without having to give explanations 
 
3. 
Without it affecting my medical care 
 
I authorize to the professional personnel of the sponsor of the clinical trial CIBOMA/2004-01, 
the Health Authorities or the pertinent International Bodies, to review my clinical and personal 
data related with the participation in this clinical trial. 
 
I have been informed that I can revoke in any moment the authorization to review my clinical 
and personal data. 
 
I freely give my agreement to participate in this study. 
 
 
 
 
Date 
 
 
 
 
 
Signature of Participant 
 
 
 
 
 
Date 
 
 
 
 
 
Signature of Investigator 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 75 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
APPENDIX 
5.- 
INFORMATION 
SHEET 
AND 
INFORMED 
CONSENT 
TO 
PARTICIPATE IN THE PHARMACOGENETIC SUBSTUDY.  
 
If you have decided to collaborate in the clinical trial CIBOMA/2004-01 “PHASE IV.III, 
MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD 
(NEO-) AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, 
HORMONE RECEPTOR AND HER2neu NEGATIVE BREAST CANCER”, after having 
received the proper explanations about it, and having signed and dated the Informed Consent, 
your doctor will also give you the possibility to participate in a Pharmacogenetic Study of 
polymorphisms related with the efficacy and effectiveness of capecitabine. However, you may 
know that your decision to participate in this project does not affect to your participation in the 
referred clinical trial. 
 
GENERAL INFORMATION ABOUT THE PHARMACOGENETICS UTILITY 
 
Due to the fact that each person is different, cancer treatments do not have the same effect in the 
different patients. In some people, the therapy is shown to be more effective than in other, and 
the same happens with the side effects, some patients are more sensitive than others to them. 
The ideal situation would be that one that could identify the people that are candidate to receive 
treatment, because it would involve a profit that will exceed the risks of it, as well as to select 
the more effective drugs for each patient BEFORE the administration, by means of a tumor or 
blood analysis. To reach this situation, even many studies should be made with the aim to 
identify the genes and proteins involved in these drug response processes. For this reason, we 
request your collaboration in the pharmacogenetic study that we want to perform in parallel with 
the clinical trial that we are going to describe to you next. 
 
DESCRIPTION OF THE SPECIFIC STUDY OBJECTIVES 
 
If you decide to participate in this study, a blood sample will be extracted from you before the 
initiation of the treatment that will be analyzed for the study of an efficacy and side effects 
predictive factors to the treatment that you will receive during the clinical trial participation. 
 
Particularly, what it is intended is to isolate DNA from white blood cells and blood plasma. 
These DNA samples will be studied to determine the existence of a series of polymorphisms 
(genes that vary their sequence in different individuals) related to the capecitabine efficacy and 
toxicity. 
 
Results of previous studies let to propose the hypothesis that the existence of particular 
polymorphisms of the gene that codify for the thymidylate synthase enzyme (TS) and the gene 
that codify for the methylenetetrahydrofolate reductase enzyme (MTHFR), can predict which 
patients are going to experience toxicities and will require capecitabine dose reductions and which 
patients will not take profit from the standard capecitabine dose. 
The aim of this substudy is to prove this association. 
 
 
 
 
 
 
 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 76 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
 
POTENTIAL, INDIVIDUAL AND/OR COLLECTIVE BENEFITS 
 
As in the majority of cases, can be no potential benefits for you in your participation in this 
substudy. However, greater knowledge about the factors involved in the development of breast 
cancer or in its resistance to known drugs, could help the administration in the future of an 
individual treatment for each patient, that minimize the impact of the side effects by increasing 
its success probabilities. 
 
This research does not intend to give you or your doctor new information about your genetic 
status. The results of these tests will not be used to evaluate your disease. This is a research 
study and will not give reliable clinical information that would help your doctor to make 
informed decisions about your health or to determine a suitable treatment for you. 
 
 
POSSIBLE PERSONAL AND/OR FAMILIAR RISKS DERIVED FROM THE 
PARTICIPATION 
 
The possible medical risks derived from the participation in this substudy are the ones 
associated to the extraction of one blood sample and that consist on the possible local 
complications (bruises, small scabs), that could raise after the procedure.  
 
 
VOLUNTARY 
PARTICIPATION 
IN 
THE 
STUDY 
AND 
POSSIBILITY 
TO 
WITHDRAW 
 
Your participation in this study is voluntary. If you decide to participate but later change your 
mind, you are free to do so, and you do not have to give a reason. However, you should tell your 
doctor about your decision, and he/she will take care of the destruction or the total anonymization 
of your sample (not vinculated with the assigned number). 
 
STUDY PROCEDURES 
 
If you decide to participate in this substudy, you will only have to give your consent. You do 
not need to do anymore. 
 
SAMPLE HANDLING 
 
From the extraction moment, your sample will be identified only with a number during all the 
study development.  
 
PATIENT RIGHT TO THE ACCESS AND RECTIFICATION OF THE GENETIC 
INFORMATION 
You can exercise your right to access, rectification, cancellation and opposition by asking your 
doctor, who will put you in contact with the sponsor. The personnel authorized by the sponsor for 
the study information managing, by your requirement, will be under the obligation to rectify or 
cancel those data of personal nature that you require. 
The obtained information will be kept confidential and codified until the study close-out, after 
this it will become anonymous (the assigned number will be eliminated).  
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 77 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
EXPENSE PAYMENTS TO THE PATIENTS 
Due to that it is not considered that the substudy participation may produce additional travels to 
the hospital, the costs for these expenses will not be paid. 
 
COMMERCIAL AND PATENT INTERESTS DERIVED FROM THE STUDY 
This study does not involve any commercial interests, all the interests are completely scientific. 
However, we may remind you that if this study would give place to an industrial or commercial 
patent you will not take any profit from it. 
 
CONFIDENTIALITY 
The information collected as part of this study will be shared with other investigators and 
doctors. However, a strict confidentiality will be kept, and you will not be identified by your 
name in any of the collected data and materials during the study. The Spanish health authority 
agents, the member of the of your hospital’s Clinical Research Ethics Committee, or the 
monitors or agents of the sponsor (CIBOMA) could need to consult your clinical record in 
relation to your study participation. This is part of the quality control process. Every person that 
consult your record will follow the relevant rules in each center and the proper procedures. 
In case that you have any problem or any question about the study, your rights as a participant in 
a clinical trial or about any injure related to the research, you may contact:  
Dr........................................ Tel:......................... 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 78 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
PATIENT CONSENT IN WRITING 
 
PHARMACOGENETIC SUBSTUDY OF THE CLINICAL TRIAL: 
PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO 
EVALUATE THE EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE 
(X) AFTER STANDARD (NEO-) AND/OR ADJUVANT CHEMOTHERAPY IN 
PATIENTS WITH OPERATED, HORMONE RECEPTOR AND HER2neu NEGATIVE 
BREAST CANCER 
Study number: CIBOMA/2004-01 
 
 
I, ................................................................. 
 
Have read the information sheet provided to me 
Have been able to ask questions about the study 
Have received satisfactory answers to my questions 
Have received sufficient information about the study. 
 
I have spoken with ...................................................... 
 
I understand that my participation is voluntary. 
 
I understand that I may withdraw from the study: 
 
 
1. Whenever I want 
 
2. Without having to give explanations 
 
3. Without affecting my medical care 
 
 
I authorize to the professional personnel of the sponsor of the clinical trial CIBOMA/2004-01, 
the Health Authorities or the pertinent International Bodies, to review my clinical and personal 
data related with the participation in this substudy. 
 
I have been informed that I can revoke in any moment the authorization to review my clinical 
and personal data. 
 
I freely give my agreement to participate in this study. 
 
 
 
 
Date 
  
 
 
 
Signature of participant:  
 
 
 
 
Date: 
  
 
 
 
Signature of investigator: 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 79 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
APPENDIX 6: ADVERSE EVENT REPORT FORM 
 
REPORT OF SUSPECTED ADVERSE 
REACTION FOR 
INVESTIGATIONAL MEDICATIONS 
PROTOCOL 
CODE 
(SPONSOR) 
NOTIFICATION 
NUMBER (SPONSOR) 
 
 
PATIENT NUMBER 
NOTIFICATION NO. 
 
I. ADVERSE REACTION INFORMATION 
1a.  
COUNTRY 
2. DATE OF BIRTH 
2a. 
AGE 
3.  SEX 
3a.  
WEIGHT 
3b.  
HEIGHT 
4-6.  DATE OF 
ONSET 
OF 
REACTION
DAY 
 
 
MONTH 
 
YEAR 
 
 
   
MALE 
 
    
FEMALE 
 
 
DA
Y 
 
MO
NTH
 
YE
AR 
 
7.  DESCRIPTION OF ADVERSE REACTION  (Including 
relevant results of physical or laboratory tests, date of 
resolution, if applicable). 
8-13b. 
CRITERIA 
FOR 
SERIOUSNESS/OUTCOME 
   DEATH 
   LIFE-THREATENING 
   HOSPITALIZATION 
 PROLONGATION OF  
HOSPITALIZATION 
   PERMANENT OR SIGNIFICANT 
DISABILITY 
 CLINICALLY SIGNIFICANT AR 
PERSISTENCE 
OF 
ADVERSE 
REACTION 
   RESOLUTION 
 
II. STUDY MEDICATION DATA 
 
14.SUSPECTED 
MEDICATION 
15. 
DAILY 
DOSE 
        
16.  
ROUTE  
17. DISEASE UNDER 
STUDY 
18. DATES OF 
  ONSET             
END 
19.  
DURATION 
OF 
TREATMEN
T 
 
 
 
 
 
 
 
 
 
20. 
DID 
THE 
REACTION 
SUBSIDE WHEN MEDICATION 
WAS SUSPENDED? 
 
              YES         NO       
NOT APPLICABLE
20a.  DID THE REACTION 
SUBSIDE WHEN DOSE WAS 
REDUCED 
 
          YES           NO  
   NOT APPLICABLE
21.  DID THE REACTION 
REAPPEAR 
ON 
RECHALLENGE? 
 
           YES        NO     
NOT APPLICABLE
III. CONCOMITANT MEDICATIONS AND CLINICAL HISTORY 
22.CONCOMITANT MEDICATIONS 
(Indicate suspected medication(s) with 
an asterisk) 
22a.  
DAILY 
DOSE 
22b.  
ROU
TE 
22c.  DATES OF 
  ONSET                    
END 
22d.  REASON FOR 
PRESCRIPTION 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 80 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
 
 
 
 
 
 
23.  CLINICALLY SIGNIFICANT DATA FROM CLINICAL HISTORY (e.g. diagnoses, allergies, 
pregnancies, etc) 
 
 
 
IV. SPONSOR AND INVESTIGATOR DATA 
24a. NAME AND ADDRESS OF SPONSOR 
 
24b. 
NAME 
AND 
ADDRESS 
OF 
INVESTIGATOR 
24c. 
LABORATORY 
CODE 
 (Spanish Drug Agency 
No.) 
25a. TYPE OF REPORT 
ΥINITIAL 
ΥFOLLOW-UP 
24c. SPONSOR CONTACT MAKING REPORT 
NAME: 
TELEPHONE: 
SIGNATURE: 
24e. DATE OF REPORT 
 
24f. 
DATE 
OF 
RECEIPT IN SPANISH 
DRUG AGENCY 
25b. 
COMPLEMENTARY 
REPORT 
ATTACHED 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 81 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
APPENDIX 7: LIST OF PARTICIPANT COUNTRIES 
 
In Spain: The following investigators have shown their interest in participating in this study. 
Their incorporation to the study will be made at intervals. 
Centers from Argentina, Brazil, Chile, , Guatemala, Mexico, Peru, Uruguay,   Venezuela, 
Ecuador and Colombia are also expected to participate in the study. 
 
INVESTIGATOR
HOSPITAL 
Jesús García Mata 
H. Sta. María Nai 
José Ramón Mel Lorenzo 
H. Xeral Calde 
Laura de Paz 
H. Arquitecto Marcide 
Javier Castellanos 
H. Xeral Cíes 
Manuel Constela 
H. Montecelo 
Manuel Ramos 
Centro Oncológico Galicia 
Lourdes Calvo Martínez 
Complejo Hospitalario Universitario A Coruña 
Concepción Almanza Madera 
Policlínico de Vigo POVISA  
Dolores Menendez Prieto 
C.Hospit.Univ. Santiago 
Santiago Albiol Rodríguez 
H. Del Espiritu Santo 
Agustín Barnadas i Molins 
H. de la Santa Creu i Sant Pau 
Sonia González 
H. Mutua Terrassa 
Rosa Mª Franquesa Grané 
H. General de VIC 
Miguel Angel Segui 
Hospital Parc Taulí 
Montserrat Muñoz Mateu 
H. Clínico y Provincial 
Alfonso Modolell 
Ins. Oncológico Corachán 
Amadeu Pelegrí 
Hospital Sant Joan de Reus 
Miguel Gil 
Instituto Catalán de Oncología 
Angels Arcusa Lanza 
Consorci Sanitari de Terrassa 
Ignacio Tusquets Trias de Bes 
Hospital del Mar 
Mireia Margelí 
H. Germans Trias i Puyol 
Ramón Colomer Bosch 
H. Josep Trueta 
Isabel Moreno Solórzano 
H. Municipal de Badalona 
Ana de Miguel 
H. San Juan de Dios de Manresa 
Antonio Llombart 
H. Arnau de Vilanova 
Montserrat LLobera 
H. Tortosa Verge de la Cinta 
Montserrat Boleda 
H. Sant Camil  
Antonio Fernández Aranburo 
Hospital General de Albacete 
Javier Cassinello 
H. Gral. de Guadalajara 
Miguel Ángel de la Cruz Mora 
H. Virgen de la Salud 
Pedro Puñal 
H. Provincial de Toledo 
Mª del Mar Muñoz 
H. Virgen de la Luz 
Encarna Adrover 
H.Gral. Univ. de Alicante 
Mª José Godes Sanz Bremond 
H. General de Valencia 
Vicente Carañana 
H. Arnau de Vilanova 
Amparo Ruiz Simón 
I.V.O. 
Alvaro Rodriguez Lescure 
H. General de Elche 
José Miguel Cuevas 
Hospital de la Ribera 
Ana Lluch 
H. Clínico de Valencia 
Antonio Galán Brotons 
H. Puerto de Sagunto 
Miguel Pastor Borgoñón 
H. Universitario la Fe 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 82 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
Santiago Olmos 
H. Universitario Dr. Peset 
Cristina Llorcas 
H. General de Elda 
Adolfo Frau Llopis 
H. Provincial Castellón 
José Lizón Giner 
H. Clínico San Juan 
Mª Dolores Torregrosa 
H. Lluis Alcanys 
Amparo Oltra  
H. Virgen de los Lirios 
Norberto Batista 
H. Universitario de Canarias 
Adolfo Murias Rosales 
Hospital Insular 
José Aguiar Morales 
H. Gran Canaria Dr. Negrin 
Maria del Pilar López Álvarez 
C. Hosp. Ntra. Sra. De la Candelaria 
José Ignacio Mayordomo 
H. Clinico Univ. de Zaragoza 
Jesús Florián Jericó 
H. Comarcal Barbastro 
Antonio Antón Torres 
H. Miguel Servet 
Alfonso Yubero 
H. Gral de Teruel O. Polanco 
José Ángel García Sáenz 
H. Clínico San Carlos 
Ricardo Cubedo 
Clínica Puerta de Hierro 
Miguel Ángel Lara Álvarez 
H. Severo Ochoa 
Miguel Méndez Ureña 
H. General de Móstoles 
José Enrique Alés Martínez 
H. Ruber Internacional 
Carlos Jara Sánchez 
Fundación Hosp. Alcorcón 
Eduardo García Rico 
Hospital de Madrid 
Eduardo García Rico 
Hospital de Montepríncipe 
Gumersindo Pérez Manga 
H. Gregorio Marañón 
César Mendiola Fernández 
H. Doce de Octubre 
Carmen Crespo 
H. Ramón y Cajal 
Francisco Lobo Samper 
Fundación Jimenez Díaz 
Santos Enrech Francés 
Hospital Gomez Ulla 
Amalia Velasco Ortiz de Taranco 
Hospital la Princesa 
Ramón  Pérez Carrión 
Laura G. Estévez 
Clínica MD. Anderson 
Hospital Madrid Norte Sanchinarro (CIOCC) 
Javier Salvador Bofill 
H. U. De Valme 
Manuel Ruiz Borrego  
H. Univ. Virgen de Rocio 
José Mª Baena Cañada 
H. Puerta del Mar 
Juan Rafael de la Haba 
H. Reina Sofía 
María Lomas Garrido 
Complejo Hospitalario de Jaén 
Liliana Canosa 
Hospital Torrecardenas 
Antonio Lorenzo Peñuelas 
H. Univ. Puerto Real 
Encarnación González Flores 
H. Virgen de la Nieves 
Alberto Luis Moreno Vega 
H.Gral de Jerez Frontera 
Juan Lucas Bayo Calero 
H. Juan Ramón Jimenez 
Pedro Valero Jimenez 
Clínica Sagrado Corazón 
Rafael Trujillo 
Hospital Punta de Europa 
José Luis García Puche 
H. Clínico San Cecilio 
Emilio Alba Conejo 
H. U. Virgen de la Victoria 
Ester Villar Chamorro 
C.H. Carlos Haya 
Arrate Plazaola Alcibar 
Onkologikoa 
Isabel Alvarez López 
Hospital Donostia 
J. Ramón Barceló 
Hospital de Cruces 
Purificación Martinez Prado 
Hospital de Basurto 
Severina Dominguez 
Hospital Txagorritxu 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 83 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
José Luis Alonso Romero 
H. Virgen de la Arrixaca 
Francisco Ayala de la Peña 
H. Morales Meseguer 
José Manuel López Vega 
Hops. U. Marques Valdecilla 
López Lara 
H. Clínico Univ. Valladolid 
Alberto Arizcum 
Hospital Rio Carrión 
César Rodriguez Sánchez 
H. Universitario Salamanca 
García Palomo 
H. General de León 
Blanca Hernando 
H. General Yague 
José Valero Alvarez Gallego 
H. Rodriguez Chamorro 
Juan Carlos Torrego 
H. Univ. del Rio Hortega 
Florestán Juarez 
H. Ntra. Senora del Prado 
Mª Lomas Garrido 
Hospital Infanta Cristina 
Pablo Borrega 
H. San Pedro Alcantara 
Yolanda López del Puerto 
H. Virgen del Puerto 
Mª Ángeles Panadero 
H. Ciudad de Coria 
Antón Avellá 
H.Son Dureta 
José Juan Irramendi Mañas 
Hospital de Navarra 
Edelmira Velez de Mendizabal 
María Valero Arbizu 
Hospital Infanta Luisa de Sevilla 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER 
STANDARD (NEO-) AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND HER2neu NEGATIVE BREAST CANCER 
(CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 84 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
APPENDIX 8: RECORD OF MENSTRUAL STATUS  
RECORD TABLE OF MENSTRUAL STATUS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INSTRUCTIONS:  
Use B if there is bleeding but without need for sanitary protection. 
Use T if you need sanitary protection (towels, tampons, panty-liners, etc). 
Leave blank if there is no bleeding. 
 
 
                                                Date of starting record (M, D, Y) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
Jan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Feb  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mar  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Apr
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
May  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Jun
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Jul  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aug  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sept  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oct  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nov
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dec
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS:_______________________________________________________________________________________________________________________________
____________________________________________________________________________________________________________________________________________
_________________________________________________________________________________________________________________________________________ 
 
_____________________________________________ 
Please write your name in block capitals 
 
 
INVESTIGATOR: Keep a copy for your record 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 85 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
APPENDIX 9: COCKROFT AND GAULT CRITERIA 
 
Cockroft-Gault formula for women: 
 
Creatinine clearance (ml/min) = 
[(140 – age) x current body weight (in Kg) x 0.85] / [72 x serum creatinine (in mg/dL)] 
o 
[(140 – age) x current body weight (in Kg) x 0.85] / [0.81 x serum creatinine (in µmol/L)] 
 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 86 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
APPENDIX 10: CAPECITABINE DOSE CALCULATION IN RELATION TO THE 
BODY SURFACE AREA (ONLY TABLETS OF 500 MG). 
 
The initial dose of 100% corresponds to the administration of 1,000 mg/m2  twice a day 
(total daily dose of 2,000 mg/m2). 
 
Dose level of 100% 
=  1000 mg/m2 twice a day 
Number of tablets of 500 mg
Morning 
Evening 
Body surface area (m2) 
Average dose per 
administration (mg) 
< 1.12
1,000
2
2
1.13 – 1.37 
1,250 
2 
3 
1.38 – 1.62 
1,500 
3 
3 
1.63 – 1.87 
1,750 
3 
4 
> 1.88 
2,000 
4 
4 
 
Dose level of 75% 
Number of tablets of 500 mg 
 
Morning 
Evening 
Body surface area (m2) 
Average dose per 
administration (mg) 
< 1.12 
750 
1 
2 
1.13 – 1.37 
1,000 
2 
2 
1.38 – 1.87 
1,250 
2 
3 
> 1.88 
1,500 
3 
3 
 
Dose level of 50% 
 
Number of tablets of 500 mg 
 
Morning 
Evening 
Body surface area (m2) 
Average dose per 
administration (mg) 
< 1.12 
500 
1 
1 
1.13 – 1.87 
750 
1 
2 
> 1.88 
1,000 
2 
2 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Versión final (3): 10 de junio de 2005 
CONFIDENTIAL 
Page 87 of 96 
Amendment No. 1: June 29, 2007 
Amendment No. 2: September 16, 2009 
 
 
 
 


PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD (NEO-) 
AND/OR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH OPERATED, HORMONE RECEPTOR AND 
HER2neu NEGATIVE BREAST CANCER (CIBOMA/2004-01) 
 
Draft 3 
 
CONFIDENTIAL 
Page 88 of 88 
APPENDIX 11: DISCONTINUANCE AND EXTENSION OF THE REST PERIOD IN 
THE CAPECITABINE TREATMENT 
 
 
Norm al treatm ent: 
Day 
1 
Discontinuances during treatm ent: 
The discontinuances are considered as lost doses. The initial treatm ent plan will be kept.  
 
Rest period extension: 
If a rest period is extended due to toxicity, the com plete cycle will be adm inistered later. 
7 days
14 days
14 days
Day 
8 
Day 
15 
Day 
22 
Day 
29 
Day 
36 
Day 
43 
D ay 
50 

SAP_001.pdf: 
 
 
 
PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD ADJUVANT 
CHEMOTHERAPY IN PATIENTS WITH OPERABLE, HORMONE RECEPTOR AND HER2neu NEGATIVE 
BREAST CANCER. (CIBOMA/2004-01)  
 
 
Statistical Analysis Plan CIBOMA 2004-01 
Final version: Mayo de 2010 
CONFIDENTIAL  
Página 1 
 
 
 
 
 
 
 
 
COALICIÓN IBEROAMERICANA DE INVESTIGACIÓN EN ONCOLOGÍA 
MAMARIA (CIBOMA) 
CIBOMA/2004-01 
 
STATISTICAL ANALYSIS PLAN 
 
PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO 
EVALUATE THE EFFICACY OF MAINTENANCE THERAPY WITH 
CAPECITABINE (X) AFTER STANDARD ADJUVANT CHEMOTHERAPY IN 
PATIENTS WITH OPERABLE, HORMONE RECEPTOR AND HER2neu 
NEGATIVE BREAST CANCER. 
 
CIBOMA/2004-01 
Quimioterapia vs. Observación 
 
 
NCT: 00130533 
 
Date: May 2010 
 
 
 
 


 
 
 
PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD ADJUVANT 
CHEMOTHERAPY IN PATIENTS WITH OPERABLE, HORMONE RECEPTOR AND HER2neu NEGATIVE 
BREAST CANCER. (CIBOMA/2004-01)  
 
 
Statistical Analysis Plan CIBOMA 2004-01 
Final version: Mayo de 2010 
CONFIDENTIAL  
Página 2 
 
 
 
 
STATISTICAL ANALYSIS PLAN  CIBOMA 2004-01_v.1 
 
1. STUDY DATA ANALYSIS 
 
1.1.Description of sample characteristics 
 
               All the demographic, baseline, histologic and treatment data clinically relevant for the 
study will be included and analyzed, including frequency and percentages for qualitative 
variables, and median and range for quantitative variables. When applicable, the associated p-
value for data comparison between the treatment arms will be included to verify that both 
arms are equally balanced for important characteristics that describe the test sample. 
 
1.2.End of Treatment 
 
               All the causes for the end of treatment, including the percentage, will be indicated and 
the situation in both arms will be described. 
 
1.3.Capecitabine: Doses and cycles administered 
 
               The number of cycles administered for the capecitabine arm will be described, 
correlating it with the previous item in order to describe those patients who have not received 
all cycles and why. 
               The cumulative dose received (CDR) (mg/m2) for capecitabine will be calculated. This is 
defined as the sum of all the doses of each cycle of capecitabine divided into the body 
surface(baseline). The median and the range will be described primarily. 
               The dose intensity received (DIR) (mg/m2/week) will be calculated. This is defined as 
the ratio between the total dose received divided into the number of weeks that the 
treatment lasted. The median and the range will be described primarily. 
               The relative dose intensity (RDI) (%) will be calculated. This is defined as the ratio 
between the dose intensity received and the expected dose intensity multiplied by 100. The 
median and the range will be described primarily. 
               Dose reductions, delays and omission doses in the Xeloda arm will be analyzed at each 
treatment cycle. 
 
1.4.Adverse Events and/or Toxicity 
 
               A description of all adverse events, including the percentage, will be included for both 
arms by patient. The applicable and clinically relevant events may be compared by treatment 
arm, using the Chi-Square test or Fisher's test. It will be optional to include the analysis of 
adverse events by treatment cycle. Toxicity corresponding to those adverse events that are 


 
 
 
PHASE IV.III, MULTICENTER, OPEN, RANDOMIZED TREATMENT STUDY TO EVALUATE THE 
EFFICACY OF MAINTENANCE THERAPY WITH CAPECITABINE (X) AFTER STANDARD ADJUVANT 
CHEMOTHERAPY IN PATIENTS WITH OPERABLE, HORMONE RECEPTOR AND HER2neu NEGATIVE 
BREAST CANCER. (CIBOMA/2004-01)  
 
 
Statistical Analysis Plan CIBOMA 2004-01 
Final version: Mayo de 2010 
CONFIDENTIAL  
Página 3 
 
 
 
strictly related to capecitabine should be assessed in the Xeloda arm. The study SAEs should 
also be analyzed and/or described. 
 
Note: The adverse events by patient are calculated as the maximum degree that the patient has had 
throughout the treatment (taking all cycles into account) for a certain adverse event. 
 
1.5.Disease-Free Survival 
 
               All the events for disease-free survival should be described indicating the frequency 
and percentage and comparing them by arm, when applicable, using the Chi-Square test or 
Fisher's test. The description should also include the types of relapse, second primary cancers 
and causes of death for disease-free survival. 
               The disease-free survival curves, the associated p-value comparing the curves 
between both arms, the hazard ratio (taking the control, observation arm as reference) will be 
included, as well as the 95% confidence interval and the survival median (and its 95% interval), 
if it is achieved.  
               The datum of disease-free survival after 5 years will also be included in percentage 
(probability of continuing without relapse). 
 
1.6.Overall Survival 
 
               All the events for overall survival should be described indicating the frequency and 
percentage and comparing them by arm, when applicable, using the Chi-Square test or Fisher's 
test. This description should also include the causes of death for overall survival. 
               The overall survival curves, the associated p-value comparing the curves between both 
arms, the hazard ratio (taking the control(observation) arm as reference) will be included, as 
well as the 95% confidence interval and the survival median (and its 95% interval), if it is 
achieved.  
               The datum of overall survival after 5 years will also be included in percentage 
(probability of continuing alive). 
 
1.7.Multivariate Analyses 
 
               A Cox’s multiple regression analysis will be included for disease-free and overall 
survival, in order to adjust the comparison of treatment for the primary prognostic factors. 
 
1.8.Study Interim Analyses 
 
               The potential interim analyses of the study are at the coordinator’s discretion and will 
include the applicable items of the sections above. These analyses will take into account that 
the use of the p-value for comparison is very restricted and the set value is stricter.