Clinical trial NCT00130533: Maintenance Treatment With Capecitabine Versus Observation in Breast Cancer Patients
Official title: Multicenter, Open-label, Randomized Phase III to Evaluate Efficacy of Maintenance Treatment With Capecitabine Following Standard Adjuvant Chemotherapy in Operable Triple Negative Breast Cancer Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Triple-Negative Early Breast Cancer
Maintenance Adjuvant Chemotherapy
Capecitabine
Basal-like genotype
Triple-Negative
Lead sponsor: Spanish Breast Cancer Research Group
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
name: IBEROAMERICAN COALITION FOR BREAST ONCOLOGY RESEARCH (CIBOMA)
First posted: 2005-08-15
Enrollment: 876
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* Written informed consent.
* Histological diagnoses of operable invasive adenocarcinoma of the breast (T1-T3). Tumours must be HER2 negative. Time window between end of adjuvant chemotherapy and study randomization must be less than 8 weeks. In patients receiving adjuvant radiotherapy, time window allowed between last session and randomisation is 4 weeks.
* Surgery must consist of mastectomy or conservative surgery with axillary lymph node dissection. Margins free of disease and ductal carcinoma in-situ (DCIS) are required. Lobular carcinoma is not considered a positive margin.
* Node negative patients with tumour size \> 2 cm.
* Positive axillary lymph nodes defined as at least 1 out of 6 nodes with presence of disease. If sentinel node technique is used, sentinel node can be the only node affected. Patients belonging to the following classifications are eligible: pN1a (Metastases in 1-3 axillary lymph nodes, at least one metastasis greater than 2.0 mm), pN2a (Metastases in 4-9 axillary lymph nodes (at least one tumor deposit greater than 2 mm)), pN3a (Metastases in 10 or more axillary lymph nodes \[at least one tumor deposit greater than 2 mm\]; or metastases to the infraclavicular \[level III axillary lymph\] nodes).
* Status of hormone receptors in primary tumour. Negative results must be available before the end of adjuvant chemotherapy.
* Patients must not present evidence of metastatic disease.
* Negative status of HER2 in primary tumour, known before randomization.
* Adjuvant chemotherapy consisting of a minimum of 6 courses with anthracyclines and/or taxanes.
* Age \>= 18 and \<= 70 years old.
* Performance status (Karnofsky index) \>= 80.
* Laboratory results (within 14 days prior to randomization):
* Hematology:

  * neutrophils \>= 1.5 x 10e9/l;
  * platelets \>= 100x 10e9/l;
  * hemoglobin \>= 10 mg/dl
* Hepatic function:

  * total bilirubin \<= 1 upper normal limit (UNL);
  * Aspartate aminotransferase (AST or SGOT) and Alanine aminotransferase (ALT or SGPT) \<= 2.5 UNL;
  * alkaline phosphatase \<= 2.5 UNL.
  * If values of SGOT and SGPT \> 1.5 UNL are associated to alkaline phosphatase \> 2.5 UNL, patient is not eligible.
* Renal Function:

  * creatinine \<= 175 µmol/l (2 mg/dl).
  * creatinine clearance \>= 60 ml/min.
* Pharmacogenetics:

  * one blood sample is needed for single nucleotide polymorphism (SNP) assessment.
* Patients able to comply with treatment and study follow-up.
* Negative pregnancy test done in the 14 previous days to randomization.

Exclusion Criteria:

* Prior therapy with anthracyclines or taxanes (paclitaxel or docetaxel) for any malignancy.
* Pregnant or lactating women. Adequate contraceptive methods must be used during chemotherapy and hormone therapy treatments. Negative pregnancy test in the 14 previous days to randomization.
* Bilateral invasive breast cancer.
* Any T4 or M1 tumour.
* Axillary lymph nodes: patients belonging to the following classifications are excluded: pN1b (Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected), pN1c (Metastases in 1-3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected), pN2b (Metastases in clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases), pN3b (Metastases in clinically detected ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected), pN3c (Metastases in ipsilateral supraclavicular lymph nodes).
* Any other serious medical pathology, such as congestive heart failure, unstable angina, history of myocardial infarction during the previous year, uncontrolled hypertension or high risk arrhythmias.
* History of neurological or psychiatric disorders, which could preclude the patients to free informed consent.
* Active uncontrolled infection.
* Active peptic ulcer, unstable diabetes mellitus.
* Previous or current history of neoplasms different to breast cancer, except for skin carcinoma, cervical in situ carcinoma, or any other tumour curatively treated and without recurrence in the last 10 years; ductal in situ carcinoma in the same breast; lobular in situ carcinoma.
* History of hypersensitivity to capecitabine, fluorouracil.
* Patients lacking physical integrity of upper gastrointestinal tract or with history of bad absorption syndrome.
* History of dihydropyrimidine dehydrogenase (DPD) deficiency.
* Anticoagulant treatment with coumadin anticoagulants.
* Current treatment with sorivudine or its chemical family.
* Concomitant treatment with other investigational products. Participation in other clinical trials with a non-marketed drug in the 30 previous days before randomization.
* Concomitant treatment with other therapy for cancer.
* Males.

Primary outcomes:
measure: Disease Free Survival (DFS) Events
timeFrame: 5 years
Secondary outcomes:
measure: Disease Free Survival (DFS) Events by Phenotype
timeFrame: 5 years
measure: Overall Survival (OS) Event
timeFrame: 5 years
measure: The Number of Participants Who Experienced Adverse Events (AE)
timeFrame: 5 years
Other outcomes:
Locations:
city: Elche
country: Spain
facility: Hospital General Universitario de Elche
state: Alicante
city: L'Hospitalet De Llobregat
country: Spain
facility: Instituto Catalán de Oncología de L'Hospitalet
state: Barcelona
city: Sabadell
country: Spain
facility: Corporació Sanitaria Parc Taulí
state: Barcelona
city: Santa Coloma De Gramenet
country: Spain
facility: Hospital del Espíritu Santo
state: Barcelona
city: Terrassa
country: Spain
facility: Consorci Sanitari de Terrassa
state: Barcelona
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
state: Cantabria
city: Castellón De La Plana
country: Spain
facility: Hospital Provincial de Castellón
state: Castellón
city: Jerez De La Frontera
country: Spain
facility: Hospital General de Jerez
state: Cádiz
city: Donostia-San Sebastián
country: Spain
facility: Onkologikoa
state: Guipúzcoa
city: Donostia-San Sebastián
country: Spain
facility: Hospital de Donostia
state: Guipúzcoa
city: Barbastro
country: Spain
facility: Hospital de Barbastro
state: Huesca
city: Las Palmas De Gran Canaria
country: Spain
facility: Hospital Insular de Las Palmas de Gran Canaria
state: Las Palmas
city: Alcorcón
country: Spain
facility: Hospital Universitario Fundación Alcorcón
state: Madrid
city: San Sebastián de los Reyes
country: Spain
facility: Coalición Iberoamericana de Investigación en Oncología Mamaria (CIBOMA)
state: Madrid
city: Vigo
country: Spain
facility: Complejo Hospitalario Universitario de Vigo
state: Pontevedra
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
city: A Coruña
country: Spain
facility: Centro Oncológico de Galicia
city: Alicante
country: Spain
facility: Hospital Universitario General de Alicante
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial
city: Barcelona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
city: Burgos
country: Spain
facility: Hospital Universitario General Yagüe
city: Cádiz
country: Spain
facility: Hospital Universitario Puerta del Mar
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofía
city: Guadalajara
country: Spain
facility: Hospital General Universitario de Guadalajara
city: Jaén
country: Spain
facility: Complejo Hospitalario de Jaén
city: Lleida
country: Spain
facility: Hospital Universitario Arnau de Vilanova de Lleida
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Ruber Internacional
city: Madrid
country: Spain
facility: Hospital Clínico Universitario San Carlos
city: Madrid
country: Spain
facility: Hospital de Madrid Norte Sanchinarro (CIOCC)
city: Madrid
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
city: Murcia
country: Spain
facility: Hospital General Universitario Morales Meseguer
city: Málaga
country: Spain
facility: Hospital Regional Universitario Carlos Haya
city: Ourense
country: Spain
facility: Complejo Hospitalario de Ourense
city: Salamanca
country: Spain
facility: Hospital Clínico Universitario de Salamanca
city: Santa Cruz De Tenerife
country: Spain
facility: Hospital Universitario Nuestra Señora de Candelaria
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Sevilla
country: Spain
facility: Hospital Universitario de Valme
city: Toledo
country: Spain
facility: Hospital Virgen de la Salud
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncología
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
city: Zamora
country: Spain
facility: Hospital Provincial de Zamora "Rodríguez Chamorro"
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario de Zaragoza "Lozano Blesa"
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Hospital Clínico Universitario de Valencia
name: Study Principal Investigator
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lluch A, Barrios CH, Torrecillas L, Ruiz-Borrego M, Bines J, Segalla J, Guerrero-Zotano A, Garcia-Saenz JA, Torres R, de la Haba J, Garcia-Martinez E, Gomez HL, Llombart A, Bofill JS, Baena-Canada JM, Barnadas A, Calvo L, Perez-Michel L, Ramos M, Fernandez I, Rodriguez-Lescure A, Cardenas J, Vinholes J, Martinez de Duenas E, Godes MJ, Segui MA, Anton A, Lopez-Alvarez P, Moncayo J, Amorim G, Villar E, Reyes S, Sampaio C, Cardemil B, Escudero MJ, Bezares S, Carrasco E, Martin M; GEICAM Spanish Breast Cancer Group; CIBOMA (Iberoamerican Coalition for Research in Breast Oncology); LACOG (Latin American Cooperative Oncology Group). Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01). J Clin Oncol. 2020 Jan 20;38(3):203-213. doi: 10.1200/JCO.19.00904. Epub 2019 Dec 5.
citation: Schettini F, Chic N, Braso-Maristany F, Pare L, Pascual T, Conte B, Martinez-Saez O, Adamo B, Vidal M, Barnadas E, Fernandez-Martinez A, Gonzalez-Farre B, Sanfeliu E, Cejalvo JM, Perrone G, Sabarese G, Zalfa F, Peg V, Fasani R, Villagrasa P, Gavila J, Barrios CH, Lluch A, Martin M, Locci M, De Placido S, Prat A. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer. 2021 Jan 4;7(1):1. doi: 10.1038/s41523-020-00208-2.
citation: Asleh K, Lluch A, Goytain A, Barrios C, Wang XQ, Torrecillas L, Gao D, Ruiz-Borrego M, Leung S, Bines J, Guerrero-Zotano A, Garcia-Saenz JA, Cejalvo JM, Herranz J, Torres R, Haba-Rodriguez J, Ayala F, Gomez H, Rojo F, Nielsen TO, Martin M. Triple-Negative PAM50 Non-Basal Breast Cancer Subtype Predicts Benefit from Extended Adjuvant Capecitabine. Clin Cancer Res. 2023 Jan 17;29(2):389-400. doi: 10.1158/1078-0432.CCR-22-2191.
citation: Ye F, Bian L, Wen J, Yu P, Li N, Xie X, Wang X. Additional capecitabine use in early-stage triple negative breast cancer patients receiving standard chemotherapy: a new era? A meta-analysis of randomized controlled trials. BMC Cancer. 2022 Mar 12;22(1):261. doi: 10.1186/s12885-022-09326-5.