COALICIÓN IBEROAMERICANA DE INVESTIGACIÓN EN ONCOLOGÍA

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)

COALICI?N IBEROAMERICANA DE INVESTIGACI?N EN ONCOLOG?A 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 SEBASTI?N DE LOS REYES (MADRID) SPAIN

EudraCT N?: 2005-002838-36

STUDY MEDICAL COORDINATORS

Dr. Ana Lluch

Dr. Laura Torrecillas Dr. Carlos H. Barrios

Servicio de Oncolog?a Medica Centro M?dico de Servicio de Oncolog?a M?dica

Hospital Cl?nico U. De Valencia Especialidades

Hospital Sao Lucas-PUC

Av. Blasco Ib??ez 17

20 de Noviembre Avda. I?ranga, 6690

46010 Valencia (Spain)

ISSSTE

SL 228-Porto Alegre RS

Tel:+34963862625

Mexico

CEP 90,610-000

Fax:+34963622238

Tel: +52-55-5575 3072 Brazil

Fax:: +52-55-5575 3072 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

Final version (3): June 10, 2005 Amendment No. 1: June 29, 2007 Amendment No. 2: September 16, 2009

CONFIDENTIAL

Page 1 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 (CIBOMA/2004-01)

clinical study.

1.- STUDY SUMMARY

Type of request Sponsor details

Clinical trial with a pharmaceutical product in a new indication.

Coalici?n Iberoamericana de Investigaci?n en Oncolog?a Mamaria ? Iberoamerican Coalition for Investigation in Breast Oncology (CIBOMA) Avenida de los Pirineos 7, oficina 1-14 28703 San Sebasti?n de los Reyes (Madrid) Spain Tel.: + 34 916592870 Fax: +34 916510406 E-mail: ciboma@ Web page:

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

Dr. Ana Lluch, Dr. Ruiz Borrego, Dr. Calvo (Spain), Dr. Laura Torrecillas

investigators

(Mexico), Dr. Carlos H. Barrios (Brazil) (See Appendix 7).

Centers in which University Hospital Clinic, Valencia; University Hospital Virgen del Roc?o, Juan

trial will be carried Canalejo Hospital Complex (Spain).

out

Specialist Medical Center 20 de Noviembre (Mexico).

Hospital Sao Lucas-PUC (Brazil) (See appendix 7).

Clinical Research Committees corresponding to the participating centers (see Appendix 7).

Ethics Committees

which have

Spain: The Clinical Research Ethics Committee (CREC) of the University

approved the study Hospital Clinic, Valencia will act as reference CREC for the single approval of the

protocol for all centers in Spain.

Good Clinical

Yolanda Amigo: yamigo@

Practice (GCP)

Victoria Ruiz: vruiz@

Study Monitors Nuria Caparroso: ncaparroso@

Beatriz Pardo: bpardo@

Lourdes del Burgo: lburgo@

Patricia Jou: pjou@

Anabel Garc?a: agarcia@

Gema Sanz: gsanz@

Sara Perales: sperales@

Cristina del Monte: cmonte@

Overall Project Dr. Eva Carrasco

Coordinator

CIBOMA

Avenida de los Pirineos 7, oficina 1-14

28703 San Sebasti?n de los Reyes (Madrid)

Spain

Tel: +34916592870

Fax:+34916510406

E-mail: evacarrasco@

Study

Andr?s Hernando

Coordination

CIBOMA

Avenida de los Pirineos 7, oficina 1-14

Final version (3): June 10, 2005 Amendment No. 1: June 29, 2007 Amendment No. 2: September 16, 2009

CONFIDENTIAL

Page 2 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 (CIBOMA/2004-01)

Administrative Coordinators

28703 San Sebasti?n de los Reyes (Madrid) Spain Tel.: +34916592870 Fax:+34916510406 E-mail: ahernando@

Elena Guti?rrez and M? ?ngeles Jimeno CIBOMA Avenida de los Pirineos 7, oficina 1-14 28703 San Sebasti?n de los Reyes (Madrid) Spain Tel: +34916592870 Fax:+34916510406 E-mail: egutierrez@ / majimeno@

Statistical Team

Biological sample management coordination

M? Jos? Escudero and Mar?a Isabel Casas CIBOMA Avenida de los Pirineos 7, oficina 1-14 28700 San Sebasti?n de los Reyes (Madrid) Spain Tel: +34916592870 Fax:+34916510406 E-mail: mjescudero@; micasas@

C?sar Garc?a CIBOMA Avenida de los Pirineos 7, oficina 1-14 28703 San Sebasti?n de los Reyes (Madrid) Spain Tel: +34916592870 Fax:+34916510406 E-mail: cgarcia@

Central laboratory for analysis of physiological samples

Experimental drug and control

CIBOMA main offices Avenida de los Pirineos 7, oficina 1-14 28703 San Sebasti?n de los Reyes (Madrid) Spain Tel: +34916592870

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 Objectives

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 diseasefree survival (Phase III study design).

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).

Final version (3): June 10, 2005 Amendment No. 1: June 29, 2007 Amendment No. 2: September 16, 2009

CONFIDENTIAL

Page 3 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 (CIBOMA/2004-01)

? 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 Patients with operated breast cancer with no metastatic involvement (AJCC,

under study

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

Final version (3): June 10, 2005 Amendment No. 1: June 29, 2007 Amendment No. 2: September 16, 2009

CONFIDENTIAL

Page 4 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 (CIBOMA/2004-01)

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.

Final version (3): June 10, 2005 Amendment No. 1: June 29, 2007 Amendment No. 2: September 16, 2009

CONFIDENTIAL

Page 5 of 88

 ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download