Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer

• Sponsor: UNICANCER
• Information provided by (Responsible Party): UNICANCER

Study Description

Brief Summary:

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Radiation therapy uses high-energy x-rays to damage tumor cells. It is not yet known which regimen of chemotherapy plus radiation therapy with or without trastuzumab is more effective in treating breast cancer.

PURPOSE: Randomized phase III trial to compare two different chemotherapy regimens plus radiation therapy with or without trastuzumab in treating women who have breast cancer that has spread to lymph nodes in the axilla (under the arm).

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Biological: Trastuzumab; Drug: Cyclophosphamide; Drug: docetaxel; Drug: Epirubicin; Drug: Fluorouracil	Phase 3

Detailed Description:

OBJECTIVES:

• Compare the efficacy of adjuvant cyclophosphamide, epirubicin, and fluorouracil vs adjuvant docetaxel and epirubicin, in terms of 5-year survival without relapse, in women with nonmetastatic adenocarcinoma of the breast with lymph node invasion.
• Determine survival of patients treated with these regimens.
• Compare the tolerability of trastuzumab (Herceptin) in patients treated with these regimens.
• Determine the efficacy and tolerability of trastuzumab in patients with hormone receptor-positive tumors.
• Evaluate the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to participating center. Patients are treated in 2 parts.

• Part I: Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive fluorouracil IV, or epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 3 weeks for 6 courses. Patients then undergo radiotherapy 5 days a week for 5 weeks.
  • Arm II: Patients receive epirubicin IV over 10 minutes and docetaxel IV over 1 hour on day 1. Treatment repeats every 3 weeks for 6 courses. Patients then undergo radiotherapy as in arm I.

Patients with HER2/neu-positive tumors then proceed to part II. Patients with HER2/neu-negative tumors receive no further treatment.

Patients with hormone (estrogen or progesterone) receptor-positive tumors also receive oral tamoxifen daily beginning after chemotherapy is completed and continuing for 5 years.

• Part II: Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive trastuzumab (Herceptin) IV over 30-90 minutes every 3 weeks for 1 year.
  • Arm II: Patients are followed without treatment. Patients not receiving trastuzumab are followed at 4 months, 6 months, every 4 months for 1 year, and then every 6 months for 3 years. Patients receiving trastuzumab are followed at 4 months and then every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 2,600 patients will be accrued for this study within 3 years.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	3010 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Randomized And Multicentric Opened Phase III Study Evaluating The Concomitant Administration Of Docetaxel 75MG/M2 and Epirubicine 75MG/M2 Versus FEC 100 In Non Metastatic With Positive Lymphatic Nodes Breast Cancer Subjects, And The Sequential Addition Of Herceptin In (HER2+++) And (HER2++ And FISH+) Subjects
Study Start Date :	June 2001
Actual Primary Completion Date :	June 2009
Actual Study Completion Date :	December 2009

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 6 FEC; Patients receive fluorouracil IV, or epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 3 weeks for 6 courses. Patients then undergo radiotherapy 5 days a week for 5 weeks.	Biological: Trastuzumab; 8 mg/kg at month M6, followed by a maintenance dose of 6 mg/kg every 3 weeks for a 1 year (i.e. 18 injections in total); Other Name: Herceptin; Drug: Cyclophosphamide; 500 mg/m², D1 and every 3 weeks; Drug: Epirubicin; 100 mg/m², D1 and every 3 weeks; Other Name: epirubicin hydrochloride; Drug: Fluorouracil; 500 mg/m², D1 and every 3 weeks
Experimental: 6 DE; Patients receive epirubicin IV over 10 minutes and docetaxel IV over 1 hour on day 1. Treatment repeats every 3 weeks for 6 courses. Patients then undergo radiotherapy as in arm I	Biological: Trastuzumab; 8 mg/kg at month M6, followed by a maintenance dose of 6 mg/kg every 3 weeks for a 1 year (i.e. 18 injections in total); Other Name: Herceptin; Drug: docetaxel; on day D1 of each cycle : dose: 75 mg/m², route: i.v. injection over 1 hour, every 3 weeks; Drug: Epirubicin; 100 mg/m², D1 and every 3 weeks; Other Name: epirubicin hydrochloride

Outcome Measures

Primary Outcome Measures :

1. Progression Free Survival [ Time Frame: 5 years from randomization ]

Secondary Outcome Measures :

1. Herceptin safety [ Time Frame: 5 years from randomization ]
2. Overall survival [ Time Frame: 5 years from randomization ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 64 Years (Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed nonmetastatic, unilateral adenocarcinoma of the breast

  • Axillary lymph node invasion (N1, N2, or N3)
  • No cutaneous invasion
  • No T4a or greater disease
• No clinically or radiologically suspected metastases
• No clinically or radiologically suspected contralateral lesion
• No deeply adherent or inflammatory disease
• Complete surgical resection performed, including removal of at least 5 lymph nodes, and with no residual tumor, within the past 42 days
• No prior breast cancer

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age

• 18 to 64

Sex

• Female

Menopausal status

• Not specified

Performance status

• WHO 0-1

Life expectancy

• Not specified

Hematopoietic

• WBC at least 2,000/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• ALT and AST no greater than 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase no greater than 2.5 times ULN
• Bilirubin no greater than ULN
• Hepatitis B and hepatitis C negative
• No hepatic dysfunction

Renal

• Creatinine less than 1.3 mg/dL OR
• Creatinine clearance greater than 60 mL/min

Cardiovascular

• ECHO normal
• LVEF at least 50%

Pulmonary

• FEV normal
• No dyspnea at rest
• No supplemental oxygen dependence

Other

• Not pregnant
• Fertile patients must use effective contraception
• HIV negative
• No active infection
• No other prior malignancy except basal cell skin cancer or carcinoma in situ of the cervix
• No contraindication to anthracycline therapy
• No chronic medical or psychological condition
• No geographic or social reason that would preclude study therapy

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• At least 4 weeks since prior chemotherapy
• No other concurrent chemotherapy
• No contraindication to anthracycline therapy

Endocrine therapy

• No prior hormonal therapy

Radiotherapy

• No prior radiotherapy

Surgery

• See Disease Characteristics

Other

• At least 4 weeks since prior experimental therapy

Contacts and Locations

Locations

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France
Centre Paul Papin
Angers, France, 49036
Centre Hospitalier d'Annecy
Annecy, France, 74011 Cedex
Institut Bergonie
Bordeaux, France, 33076
C.H. Bourg En Bresse
Bourg En Bresse, France, 01012
Centre Regional Francois Baclesse
Caen, France, 14076
Centre Jean Perrin
Clermont-Ferrand, France, 63011
Hopital Intercommunal De Creteil
Creteil, France, 94010
Centre de Lutte Contre le Cancer Georges-Francois Leclerc
Dijon, France, 21079
Institut Prive de Cancerologie
Grenoble, France, 38100
Clinique du Petit Colmouilins
Harfleur, France, 76700
Centre Hospitalier de Lagny
Lagny Sur Marne, France, 77405
Hopital Andre Mignot
Le Chesnay, France, 78157
CMC Les Ormeaux
Le Havre, France, 76600
Institut J. Paoli and I. Calmettes
Marseille, France, 13273
Centre Hospitalier Regional Metz Thionville
Metz, France, 57038
Centre Hospitalier General Andre Boulloche
Montbeliard, France, 25209
Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
Montpellier, France, 34298
Centre Hospitalier de Mulhouse
Mulhouse, France, 68051
Centre Regional Rene Gauducheau
Nantes-Saint Herblain, France, 44805
Hopital Avicenne
Paris, France, 75674
Clinique Saint - Pierre
Perpignan, France
CHU Poitiers
Poitiers, France, 86021
Institut Jean Godinot
Reims, France, 51056
Centre Eugene Marquis
Rennes, France, 35042
Clinique Sainte Clotilde
Sainte Clotilde, France, 97492
Centre Paul Strauss
Strasbourg, France, 67065
Hopitaux Universitaire de Strasbourg
Strasbourg, France, 67091
Institut Claudius Regaud
Toulouse, France, 31052
Institut Gustave Roussy
Villejuif, France, F-94805

Sponsors and Collaborators

UNICANCER

Investigators

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Study Chair:	Marc Spielmann, MD	Gustave Roussy, Cancer Campus, Grand Paris

More Information

Publications of Results:

Roché H, Allouache D, Romieu G, et al.: Five-year analysis of the FNCLCC-PACS04 trial: FEC100 vs ED75 for the adjuvant treatment of node positive breast cancer. [Abstract] 32nd Annual San Antonio Breast Cancer Symposium, December 9-13, 2009, San Antonio, Texas. A-602, 2009.

Spielmann M, Roché H, Delozier T, Canon JL, Romieu G, Bourgeois H, Extra JM, Serin D, Kerbrat P, Machiels JP, Lortholary A, Orfeuvre H, Campone M, Hardy-Bessard AC, Coudert B, Maerevoet M, Piot G, Kramar A, Martin AL, Penault-Llorca F. Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol. 2009 Dec 20;27(36):6129-34. doi: 10.1200/JCO.2009.23.0946. Epub 2009 Nov 16.

Spielmann M, Roché H, Humblet Y, et al.: 3-year follow-up of trastuzumab following adjuvant chemotherapy in node positive HER2-positive breast cancer patients: results of the PACS-04 trial. [Abstract] Breast Cancer Res Treat 106 (1): A-72, S19, 2007.

Spielmann M, Roché H, Delozier T, et al.: Safety analysis from PACS 04--a phase III trial comparing 6 cycles of FEC100 with 6 cycles of ET75 for node-positive early breast cancer patients, followed by sequential trastuzumab in HER2+patients: preliminary results. [Abstract] J Clin Oncol 24 (Suppl 18): A-632, 2006.

Other Publications:

Mancini J, Genre D, Dalenc F, Maylevin F, Martin AL, Viens P, Julian-Reynier C. Transparency in the presentation of trial results may not increase patients' trust in medical researchers. Clin Trials. 2012 Feb;9(1):90-3. doi: 10.1177/1740774511427063. Epub 2011 Nov 2.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

O'Sullivan CC, Bradbury I, Campbell C, Spielmann M, Perez EA, Joensuu H, Costantino JP, Delaloge S, Rastogi P, Zardavas D, Ballman KV, Holmes E, de Azambuja E, Piccart-Gebhart M, Zujewski JA, Gelber RD. Efficacy of Adjuvant Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer and Tumors ≤ 2 cm: A Meta-Analysis of the Randomized Trastuzumab Trials. J Clin Oncol. 2015 Aug 20;33(24):2600-8. doi: 10.1200/JCO.2015.60.8620. Epub 2015 Jun 22.

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Responsible Party:	UNICANCER
ClinicalTrials.gov Identifier:	NCT00054587 History of Changes
Other Study ID Numbers:	UC-0140/0005 - PACS 04; FRE-FNCLCC-PACS-04/0005; EU-20236; PACS04 ( Other Identifier: UNICANCER )
First Posted:	February 6, 2003
Last Update Posted:	July 19, 2013
Last Verified:	July 2013

Keywords provided by UNICANCER:

stage II breast cancer; stage IIIA breast cancer

Additional relevant MeSH terms:

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Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Cyclophosphamide; Fluorouracil; Docetaxel; Trastuzumab; Epirubicin; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating	Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Antimetabolites; Antimetabolites, Antineoplastic; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors