Clinical trial NCT00129389: FAC Versus FAC Plus Weekly Paclitaxel as Adjuvant Treatment of Node Negative High Risk Breast Cancer Patients
Official title: Multicenter Randomized Phase III Trial to Compare 6 FAC Cycles vs 4 FAC Cycles Followed by 8 Weekly Paclitaxel Administrations, as Adjuvant Treatment for Node Negative Operable Breast Cancer Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Node negative, high risk breast cancer.
Prognostic gene profile.
Saint Gallen high risk criteria.
Weekly paclitaxel.
Lead sponsor: Spanish Breast Cancer Research Group
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2005-08-11
Enrollment: 1925
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 trial. Patients will be stratified after breast surgery, as per investigational site; menopausal status; node negative diagnosis, as per sentinel-node technique versus lymphadenectomy; hormone receptor status (positive versus negative).

Detailed description: Patients will be randomized to:

* Fluorouracil, doxorubicin, and cyclophosphamide (FAC) x 6 (cycles): 5-fluorouracil 500 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2 day 1, every 3 weeks, for 6 cycles.
* FAC x 4 (cycles) → Paclitaxel x 8 (cycles): 5-fluorouracil 500 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2 day 1, every 3 weeks, for 4 cycles, followed by 8 administrations of weekly paclitaxel 100 mg/m2

Premenopausal women with hormone receptor positive tumors must receive tamoxifen 20 mg daily for 5 years, after the end of chemotherapy.

Postmenopausal women with hormone receptor positive tumors are allowed to receive aromatase inhibitors as initial adjuvant hormone therapy or after tamoxifen.

All patients with breast conservative surgery must receive radiotherapy.

Estimated 5-year disease-free survival in the control arm (FAC x 6) is expected to be 80%. It is expected that disease-free survival will increase by 5% in the experimental arm (FAC-paclitaxel). 906 patients per arm must be recruited, to detect this difference with an alpha error of 0.05 and 80% power. Assuming a 6% post-randomization drop-out rate, 960 patients per arm are needed, 1920 in total.

Eligibility criteria: Inclusion Criteria:

* Written informed consent.
* Histological diagnoses of operable invasive adenocarcinoma of the breast (T1-T3). Tumors must be Human Epidermal Growth Factor Receptor 2 (HER2) negative. Patients must be free of disease in the axilla (node negative). If lymphadenectomy is done, at least 10 nodes must be examined. If sentinel node technique is used, sentinel node must be free of disease. Patients must present at least one high risk criterion (St. Gallen, 1998) as follows:

  * Tumor size \> 2 cm; and/or
  * ER and Progesterone Receptor (PgR) negative; and/or
  * Histological grade 2-3; and/or
  * Age \< 35 years old.
* Time window between surgery and study randomization must be less than 60 days.
* Surgery must consist of mastectomy or conservative surgery. Margins free of disease and ductal carcinoma in situ (DCIS) are required. Lobular carcinoma is not considered a positive margin.
* Patients must not present evidence of metastatic disease.
* Status of hormone receptors in primary tumor. Results must be available before the end of adjuvant chemotherapy.
* Status of HER2 in primary tumor, known before randomization. Patients with Immunohistochemistry (IHC) 0 or +1 are eligible. For patients with IHC 2+, fluorescent in situ hybridization (FISH) is mandatory and result must be negative.
* Age \>= 18 and \<= 70 years old.
* Performance status (Karnofsky index) \>= 80.
* Normal electrocardiogram (EKG) in the 12 weeks prior to randomization. If needed, normal cardiac function must be confirmed by left ventricular ejection fraction (LVEF).
* Laboratory results (within 14 days prior to randomization):

  * Hematology: neutrophils \>= 1.5 x 10\^9/l; platelets \>= 100x 10\^9/l; hemoglobin \>= 10 mg/dl;
  * Hepatic function: total bilirubin \<= 1 upper normal limit (UNL); Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) \<= 2.5 UNL; alkaline phosphatase \<= 2.5 UNL. If values of AST and ALT \> 1.5 UNL are associated with alkaline phosphatase \> 2.5 UNL, patient is not eligible.
  * Renal function: creatinine \<= 175 mmol/l (2 mg/dl); creatinine clearance \>= 60 ml/min.
* Complete stage workup during the 12 weeks prior to randomization (mammograms are allowed within a 20 week time window). All patients must have a bilateral mammogram, thorax x-ray, abdominal echography and/or computed tomography (CT)-scan. If bone pain, and/or alkaline phosphatase elevation, a bone scintigraphy is mandatory. This test is recommended for all patients. Other tests, as clinically indicated.
* Patients able to comply with treatment and study follow-up.
* Negative pregnancy test done in the 14 previous days to randomization.

Exclusion Criteria:

* Prior systemic therapy for breast cancer.
* Prior therapy with anthracyclines or taxanes (paclitaxel or docetaxel) for any malignancy.
* Prior radiotherapy for breast cancer.
* Bilateral invasive breast cancer.
* 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.
* Any T4 or N1-3 or M1 tumor.
* HER2 positive breast cancer (IHC 3+ or positive FISH result).
* Pre-existing grade \>=2 motor or sensorial neurotoxicity by the National Cancer Institute Common Toxicity Criteria (NCICTC) v-2.0.
* 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 from breast cancer, except for skin carcinoma, cervical in situ carcinoma, or any other tumor curatively treated and without recurrence in the last 10 years; ductal in situ carcinoma in the same breast; lobular in situ carcinoma.
* Concomitant treatment with other investigational products. Participation in other clinical trials with a non-marketed drug in the 20 previous days before randomization.
* Concomitant treatment with other therapy for cancer.
* Males.

Primary outcomes:
measure: Disease-free Survival (DFS) Event
timeFrame: Up to 5 years
Secondary outcomes:
measure: Overall Survival (OS) Event
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Elche
country: Spain
facility: Hospital General Univ. De Elche
state: Alicante
city: Elda
country: Spain
facility: Hospital General de Elda
state: Alicante
city: Manresa
country: Spain
facility: Complejo Hospitalario de Manresa
state: Barcelona
city: Sabadell
country: Spain
facility: Consorci Sanitari Parc Tauli
state: Barcelona
city: Santa Coloma De Gramenet
country: Spain
facility: Hospital del Espíritu Santo
state: Barcelona
city: Terrassa
country: Spain
facility: Consorci Sanitari Terrassa
state: Barcelona
city: Terrassa
country: Spain
facility: Hospital Mutua Terrassa
state: Barcelona
city: Jerez De La Frontera
country: Spain
facility: Hospital General Jerez de la Frontera
state: Cadiz
city: Castellón De La Plana
country: Spain
facility: Hospital Provincial de Castellón
state: Castellón
city: Barbastro
country: Spain
facility: Hospital Comarcal de Barbastro
state: Huesca
city: Las Palmas De Gran Canaria
country: Spain
facility: Hospital Insular de Gran Canaria
state: Las Palmas
city: Alcorcón
country: Spain
facility: Fundación Hospital de Alcorcón
state: MAdrid
city: Boadilla Del Monte
country: Spain
facility: Hospital Madrid- Montepríncipe
state: Madrid
city: Móstoles
country: Spain
facility: Hospital de Móstoles
state: MAdrid
city: El Palmar
country: Spain
facility: Hospital Virgen de la Arrixaca
state: Murcia
city: Vigo
country: Spain
facility: Hospital Policlínico Vigo POVISA
state: Pontevedra
city: La Laguna
country: Spain
facility: Hospital Universitario de Canarias
state: Santa Cruz De Tenerife
city: Reus
country: Spain
facility: Hospital Sant Joan de Reus
state: Tarragona
city: Alzira
country: Spain
facility: Hospital de la Ribera
state: Valencia
city: A Coruña
country: Spain
facility: Complejo Hospitalario Juan Canalejo
city: A Coruña
country: Spain
facility: Centro Oncológico de Galicia
city: Albacete
country: Spain
facility: Complejo Hospitalario de Albacete
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Alicante
country: Spain
facility: Hospital Virgen de los Lirios
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Clínica Corochan S.A.
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital General de Vic
city: Bilbao
country: Spain
facility: Hospital de Basurto
city: Burgos
country: Spain
facility: Hospital General Yagüe
city: Cadiz
country: Spain
facility: Hospital Puerta del Mar
city: Ciudad Real
country: Spain
facility: Hospital General de Ciudad Real
city: Cuenca
country: Spain
facility: Hospital Virgen de la Luz
city: Córdoba
country: Spain
facility: Hospital Reina Sofía
city: Gerona
country: Spain
facility: ICO Hospital Universitari Josep Trueta
city: Guadalajara
country: Spain
facility: Hospital General de Guadalajara
city: Jaén
country: Spain
facility: Complejo Hospitalario de Jaén
city: Lugo
country: Spain
facility: Hospital Xeral Calde
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Madrid
country: Spain
facility: Hospital Doce de Octubre
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Ruber Internacional
city: MAdrid
country: Spain
facility: Hospital Puerta de Hierro
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital La Paz
city: Madrid
country: Spain
facility: CIOCC Hospital Norte-Sanchinarro
city: Murcia
country: Spain
facility: Hospital Morales Messeguer
city: Málaga
country: Spain
facility: Complejo Hospitalario Virgen de la Victoria
city: Málaga
country: Spain
facility: Hospital Carlos Haya
city: Orense
country: Spain
facility: Hospital Sta María Nai
city: Palencia
country: Spain
facility: Hospital General Río Carrión
city: Salamanca
country: Spain
facility: Hospital Clínico Universitario de Salamanca
city: San Sebastián
country: Spain
facility: Instituto Oncológico de Guipuzcoa
city: San Sebastián
country: Spain
facility: Hospital de Donostia
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Univ. 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: Hospital Universitario La Fe
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 Arnau de Vilanova
city: Vitoria
country: Spain
facility: Hospital Txagorritxu
city: Zamora
country: Spain
facility: Hospital Provincial de Zamora
city: Zaragoza
country: Spain
facility: Hospital Lozano Blesa
city: Zaragoza
country: Spain
facility: Hospital Miguel Servet
Study officials:
affiliation: Hospital Universitario San Carlos
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Martin M, Ruiz A, Ruiz Borrego M, Barnadas A, Gonzalez S, Calvo L, Margeli Vila M, Anton A, Rodriguez-Lescure A, Segui-Palmer MA, Munoz-Mateu M, Dorca Ribugent J, Lopez-Vega JM, Jara C, Espinosa E, Mendiola Fernandez C, Andres R, Ribelles N, Plazaola A, Sanchez-Rovira P, Salvador Bofill J, Crespo C, Carabantes FJ, Servitja S, Chacon JI, Rodriguez CA, Hernando B, Alvarez I, Carrasco E, Lluch A. Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. J Clin Oncol. 2013 Jul 10;31(20):2593-9. doi: 10.1200/JCO.2012.46.9841. Epub 2013 Jun 3.