6xFU/Epirubicin/Cyclophosphamide (FEC) Compared to 3xFEC-3xDocetaxel in High-risk Node-negative Breast Cancer Patients (NNBC3-Europe)

Randomized Multicenter Study Comparing 6xFEC With 3xFEC-3xDoc in High-risk Node-negative Patients With Operable Breast Cancer: Comparison of Efficacy and Evaluation of Clinico-pathological and Biochemical Markers as Risk Selection Criteria

In low-risk node-negative breast cancer patients adjuvant chemotherapy should be spared. The identification of this subgroup can be based either on clinical and pathological or on tumour-biological criteria. Due to their high prognostic impact, the tumour-biological invasion markers uPA/PAI-1 (urokinase-type plasminogen activator and its inhibitor PAI-1) are potential candidates to effectively assess the risk of relapse in node-negative breast cancer. This study is aimed to compare the risk assessment by the traditional clinico-pathological factors and by tumour-biological factors. The second study question refers to the comparison between an adjuvant combination treatment with FE100C*6 and a sequential treatment with FE100C*3 and Docetaxel*3.

Study Overview

• Status: Unknown
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: 5-Fluorouracil, Epirubicin, Cyclophosphamide, Docetaxel

Detailed Description

1. To compare FEC*6 with FEC*3 followed by DOC*3 with regard to:

   • the primary endpoint of the study: Disease-Free Survival (DFS)
   • the secondary endpoints: Overall Survival (OS), compliance, and toxicity of chemotherapy in each patient group

2. To compare patients with low risk according to clinico-pathological versus those according to biological risk criteria with regard to:

   • the proportion of low risk versus high risk patients
   • DFS
   • OS (secondary endpoint)

• Study Type: Interventional
• Enrollment (Actual): 4150
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Neu-Isenburg, Germany, 63263
    • GBG Forschungs GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Histological proven primary breast cancer
• Tumour size >0.5 cm and <5 cm (pT1b-pT2, pN0, M0)
• Axillary lymph nodes tumour free (node-negative disease)
• Adequate surgical procedure: R0-resection and axillary dissection with more than 10 lymph nodes examined or adequate sentinel procedure in a qualified centre
• Frozen tumour tissue available (for analysis of biological markers and microarrays, centres with biological risk assessment only). The material has to be stored in liquid nitrogen immediately after excision.
• Paraffin blocks or (at least) pathology slides of primary tumour (stained and unstained) and axillary nodes (stained) available for central review.
• HER-2/neu determination by immunohistochemistry. Patients will be stratified to be HER-2/neu-negative or HER-2/neu-positive (HER-2/neu Score 3+, or HER-2/neu Score 2+ and FISH positive).
• No distant metastasis
• Age >18 years, <70 years
• Performance status ECOG <2 (WHO Performance Status 0-1)
• Adequate cardiac function (echocardiographically measured left ventricular ejection fraction (LVEF) or shortening fraction (SF) within the normal limits, i.e. ≥55%)
• Adequate bone function (neutrophil count >1.5 x109 /l and platelet count >100 x109 /l)
• Adequate renal function (serum creatinine <120 µmol/l or 1.35 mg/dl) and hepatic function (serum bilirubin <1 x UNL, ASAT or ALAT (SGOT or SGPT) <2,5 x UNL)
• Before patient registration/randomization, written informed consent must be obtained according to ICH/EU GCP, and national/local regulations

Exclusion Criteria:

• Chemotherapy contraindicated
• Inflammatory breast cancer, tumour infiltrated axillary lymph nodes including the sentinel node.
• Other concomitant pathology compromising survival (at entry), or preventing the administration of chemotherapy with either FEC or Docetaxel
• Other serious illness or medical condition that may interfere with the understanding and giving of informed consent and the conduct of the study
• Estimated life-expectancy <10 years (irrespective of breast cancer diagnosis)
• Patient not accessible for treatment and follow up
• Endocrine treatment not according to the latest standard recommendations of the AGO Kommission "Mamma"
• Pregnancy, lactation (sufficient non-hormonal contraception in fertile women required)
• Surgery more than six weeks ago at the start of chemotherapy
• Pre-existing polyneuropathy
• Previous or concomitant other malignancy (including contralateral breast cancer) except adequately treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix
• Prior chemotherapy or radiotherapy or endocrine therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Observation
Experimental: Arm A Taxane-containing; 3 courses FEC q3weeks followed by 3 courses Docetaxel q3weeks	Drug: 5-Fluorouracil, Epirubicin, Cyclophosphamide, Docetaxel; Arm A 5-FU 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2 q3weeks followed by Docetaxel 100 mg/m² q3weeks Arm B 5-FU 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2 q6weeks
Active Comparator: Arm B standard anthracyclin; 6 courses of FEC q3weeks	Drug: 5-Fluorouracil, Epirubicin, Cyclophosphamide, Docetaxel; Arm A 5-FU 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2 q3weeks followed by Docetaxel 100 mg/m² q3weeks Arm B 5-FU 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2 q6weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Disease-Free Survival	after 10 years follow up

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall Survival	after 10 years follow up

Collaborators and Investigators

• Sponsor: Martin-Luther-Universität Halle-Wittenberg
• Collaborators: German Breast Group
• Investigators: Principal Investigator: Christoph Thomssen, MD, Dpt. Gynecology University Halle Germany; Principal Investigator: Nadia Harbeck, MD, Breast Center University Cologne

Publications and helpful links

General Publications

• Kantelhardt EJ, Vetter M, Schmidt M, Veyret C, Augustin D, Hanf V, Meisner C, Paepke D, Schmitt M, Sweep F, von Minckwitz G, Martin PM, Jaenicke F, Thomssen C, Harbeck N. Prospective evaluation of prognostic factors uPA/PAI-1 in node-negative breast cancer: phase III NNBC3-Europe trial (AGO, GBG, EORTC-PBG) comparing 6xFEC versus 3xFEC/3xDocetaxel. BMC Cancer. 2011 Apr 16;11:140. doi: 10.1186/1471-2407-11-140.

Study record dates

Study Major Dates

• Study Start: January 1, 2002
• Primary Completion (Actual): February 1, 2009
• Study Completion (Anticipated): February 1, 2019

Study Registration Dates

• First Submitted: October 15, 2010
• First Submitted That Met QC Criteria: October 15, 2010
• First Posted (Estimate): October 18, 2010

Study Record Updates

• Last Update Posted (Actual): June 26, 2017
• Last Update Submitted That Met QC Criteria: June 23, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: high risk breast cancer; low risk breast cancer; uPA; urokinase-type plasminogen activator; PAI; plasminogen activator inhibitor-type
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Docetaxel; Cyclophosphamide; Fluorouracil; Epirubicin
• Other Study ID Numbers: GBG 42