Fluorouracil Plus Doxorubicin and Cyclophosphamide (FAC) Versus FAC Plus Weekly Paclitaxel as Adjuvant Treatment of Node Negative High Risk Breast Cancer Patients

Condition(s) targeted: Breast Cancer

Intervention: paclitaxel (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Spanish Breast Cancer Research Group

Official(s) and/or principal investigator(s):
Miguel Martín, MD., PhD., Study Chair, Affiliation: Spanish Breast Cancer Research Group (GEICAM)

Overall contact:
Miguel Martín, MD., PhD., Email: mmartin@geicam.org

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). Patients will be randomized to:

- 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) → Taxol® 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.

Official title: Multicenter Randomized Phase III Clinical Trial to Compare 6 FAC Cycles(Fluorouracil, Doxorubicin, Cyclophosphamide) vs. 4 FAC Cycles Followed by 8 Weekly Paclitaxel Administrations, as Adjuvant Treatment for Node Negative Operable Breast Cancer Patients

Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study

Primary outcome: Disease-free survival

Secondary outcome:

Overall survival

Toxicity

Quality of life

Prognostic gene profile

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Female.

Criteria:

Inclusion Criteria:

- Written informed consent.

- Histological diagnoses of operable invasive adenocarcinoma of the breast (T1-T3).

Tumors must be 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 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 immune

histochemistry (IHC) 0 or +1 are eligible. For patients with ICH 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); SGOT and SGPT <=

2. 5 UNL; alkaline phosphatase <= 2. 5 UNL. If values of SGOT and SGPT > 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 (National Cancer Institute

Common Toxicity Criteria [NCI CTC] v-2. 0).

- Any other serious medical pathology, such as congestive heart failure, unstable

angina, history of myocardial infarction during the previous year, uncontrolled HA 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.

Miguel Martín, MD., PhD., Email: mmartin@geicam.org

Spanish Breast Cancer Research Group (GEICAM), San Sebastián de los Reyes, Madrid 28700, Spain; Recruiting
Esther Mahillo, PhD, Phone: ´+34916592870, Email: emahillo@geicam.org
Ana Lluch, Principal Investigator
Miguel Martín, Principal Investigator
Lourdes Calvo, Principal Investigator
Amparo Ruiz, Principal Investigator
Sonia González, Principal Investigator
Agustí Barnadas, Principal Investigator
Mireia Margelí, Principal Investigator
Álvaro Rodríguez-Lescure, Principal Investigator
Miguel A Seguí, Principal Investigator
Monserrat Muñoz, Principal Investigator
Antonio Antón, Principal Investigator
Manuel Ruiz-Borrego, Principal Investigator
Ramón Colomer, Principal Investigator
Enrique Espinosa, Principal Investigator
José Manuel López.Vega, Principal Investigator
Pedro Sánchez-Rovira, Principal Investigator
César A Rodríguez, Principal Investigator
Nuria Ribelles, Principal Investigator
Encarna Adrover, Principal Investigator
Blanca Munárriz, Principal Investigator
Carmen Crespo, Principal Investigator
Raquel Andrés, Principal Investigator
Manuel Ramos, Principal Investigator
Javier Salvador, Principal Investigator
Adolfo Frau, Principal Investigator
César Mendiola, Principal Investigator
José R Mel-Lorenzo, Principal Investigator
José I Chacón, Principal Investigator
Arrate Plazaola, Principal Investigator
Carlos Jara, Principal Investigator
Rosa Mª Franquesa, Principal Investigator
Juan de la Haba, Principal Investigator
José M Baena, Principal Investigator
Amparo Oltra, Principal Investigator
Alberto Arcediano del Amo, Principal Investigator
Angela Arcusa, Principal Investigator
Miguel Méndez, Principal Investigator
Amalia Velasco, Principal Investigator
José Alés, Principal Investigator
Francisco J Carabantes, Principal Investigator
Severina Domínguez, Principal Investigator
Vicente Carañana, Principal Investigator
Alfonso Modolell, Principal Investigator
Ricardo Cubedo, Principal Investigator
Mª José García, Principal Investigator
Jesús García-Girón, Principal Investigator
Jesús Florián, Principal Investigator
Antonio Fernández-Aramburo, Principal Investigator
Norberto Batista, Principal Investigator
Alberto Arizcum, Principal Investigator
Adolfo Murias, Principal Investigator
Jesús García-Mata, Principal Investigator
Isabel Álvarez, Principal Investigator
Ana Mª Miguel, Principal Investigator
Cristina Martín, Principal Investigator
Amadeu Pelegrí, Principal Investigator
José V Álvarez, Principal Investigator

Click here for more information about this study: GEICAM 2003-02

Starting date: September 2003
Ending date: December 2011
Last updated: September 4, 2007