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Breast CancerPhase 3NCT00017095

Biomarker (p53 Gene) Analysis and Combination Chemotherapy Followed by Radiation Therapy and Surgery in Treating Women With Large Operable or Locally Advanced or Inflammatory Breast Cancer

A Phase 3 study testing filgrastim, cyclophosphamide and docetaxel in people with Breast Cancer, run by European Organisation for Research and Treatment of Cancer - EORTC at 39 sites in 9 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Currently patients with breast cancer are treated with one of several very similar combinations of drugs. Read more about this study

Who is it for?
Ages Up to 70 years, women only
Conditions the study is for
Breast Cancer
What is being tested?
filgrastim, cyclophosphamide and docetaxel
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,856 participants
Where
39 sitesin 9 countries
Study dates
Mar 2001to Nov 2006
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 70 years
  • Women only
  • No healthy volunteers
  • Child, Adult, Older adult

DISEASE CHARACTERISTICS:

  • Histologically confirmed breast cancer
  • Locally advanced or inflammatory disease
  • T4a-d, any N, M0 OR
  • Any T, N2 or N3, M0
  • Large operable T2 or T3 tumors
  • No bilateral breast cancer
  • Frozen tumor sample available
  • 1 incisional biopsy OR
  • 2 trucut biopsies from a 14G needle
  • Hormone receptor status:
  • Not specified

PATIENT CHARACTERISTICS:

Age:

  • 70 and under

Sex:

  • Female

Menopausal status:

  • Not specified

Performance status:

  • WHO 0-1

Life expectancy:

  • Not specified

Hematopoietic:

  • Neutrophil count greater than 1,500/mm^3
  • Platelet count greater than 100,000/mm^3

Hepatic:

  • Bilirubin less than 1.2 mg/dL
  • SGOT less than 60 IU/L

Renal:

  • Creatinine less than 1.35 mg/dL

Cardiovascular:

  • LVEF normal by echocardiography or MUGA

Other:

  • No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
  • No serious uncontrolled medical condition
  • No uncontrolled psychiatric or addictive disorders
  • Not pregnant or nursing
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

  • Not specified

Chemotherapy:

  • No prior chemotherapy

Endocrine therapy:

  • Not specified

Radiotherapy:

  • No prior radiotherapy

Surgery:

  • See Disease Characteristics

Trial locations and contacts

39 sites in 9 countries.

39 sites in 9 countries

France10 sites

  • Centre Paul Papin

    Angers, 49036

  • Institut Bergonie

    Bordeaux, 33076

  • Centre de Lutte Contre le Cancer Georges-Francois Leclerc

    Dijon, 21079

  • Centre Hospitalier Departemental

    La Roche-sur-Yon, F-85025

  • Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle

    Montpellier, 34298

  • Centre Regional Rene Gauducheau

    Nantes-Saint Herblain, 44805

  • Centre Henri Becquerel

    Rouen, 76038

  • Centre Rene Huguenin

    Saint-Cloud, 92211

  • Centre Paul Strauss

    Strasbourg, 67085

  • Centre Alexis Vautrin

    Vandœuvre-lès-Nancy, 54511

Other trials in France

Sweden7 sites

  • Sahlgrenska University Hospital at Gothenburg University

    Gothenburg (Goteborg), S-413 45

  • Lund University Hospital

    Lund, S-22185

  • Malmo University Hospital

    Malmö, S-20502

  • Sahlgrenska University Hospital - Molndal at Gothenburg University

    Mölndal, S-43180

  • Orebro University Hospital

    Örebro, 70185

  • Karolinska University Hospital - Huddinge

    Stockholm, S-171 76

  • Uppsala University Hospital

    Uppsala, S-75185

Other trials in Sweden

Switzerland6 sites

  • Kantonspital Aarau

    Aarau, 5001

  • Swiss Institute for Applied Cancer Research

    Bern, CH-3008

  • Inselspital Bern

    Bern, CH-3010

  • Hopital Cantonal Universitaire de Geneve

    Geneva, CH-1211

  • Centre Hospitalier Universitaire Vaudois

    Lausanne, CH-1011

  • UniversitaetsSpital Zuerich

    Zurich, CH-8091

Other trials in Switzerland

United Kingdom5 sites

  • Ninewells Hospital and Medical School

    Dundee, Scotland, DD1 9SY

  • Edinburgh Cancer Centre at Western General Hospital

    Edinburgh, Scotland, EH4 2XU

  • Scottish Cancer Therapy Network

    Edinburgh, Scotland, EH5 3SQ

  • Northern Centre for Cancer Treatment at Newcastle General Hospital

    Newcastle upon Tyne, England, NE4 6BE

  • Royal South Hants Hospital

    Southampton, England, SO14 0YG

Other trials in United Kingdom

Belgium3 sites

  • Institut Jules Bordet

    Brussels, 1000

  • CHU Liege - Domaine Universitaire du Sart Tilman

    Liège, B-4000

  • Algemeen Ziekenhuis Sint-Augustinus

    Wilrijk, 2610

Other trials in Belgium

Netherlands3 sites

  • Onze Lieve Vrouwe Gasthuis

    Amsterdam, 1091 HA

  • Leiden University Medical Center

    Leiden, 2300 CA

  • Daniel Den Hoed Cancer Center at Erasmus Medical Center

    Rotterdam, 3008 AE

Other trials in Netherlands

Poland2 sites

  • Medical University of Gdansk

    Gdansk, 80-211

  • Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology

    Warsaw, 02-781

Other trials in Poland

Portugal2 sites

  • Hospitais da Universidade de Coimbra (HUC)

    Coimbra, 3049

  • Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, S.A.

    Lisbon, 1099-023 Codex

Other trials in Portugal

Slovenia1 site

  • Institute of Oncology - Ljubljana

    Ljubljana, Sl-1000

Other trials in Slovenia

About this study

Official title: First Prospective Intergroup Translational Research Trial Assessing the Potential Predictive Value of p53 Using a Functional Assay in Yeast in Patients With Locally Advanced/Inflammatory or Large Operable Breast Cancer Prospectively Randomised to a Taxane Versus a Non Taxane Regimen

RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Currently patients with breast cancer are treated with one of several very similar combinations of drugs. Analysis of biomarkers in tumor tissue may help doctors predict how well patients with breast cancer will respond to treatment and help doctors choose the best drug regimen to treat each patient.

PURPOSE: This randomized phase III trial is studying giving different regimens of chemotherapy and comparing how well they work in treating women with large operable or locally advanced or inflammatory breast cancer. This study is also looking at whether analyzing a specific biomarker (p53) in tumor tissue may help doctors predict how well patients will respond to treatment and help doctors choose the best drug to treat each patient.

Read the detailed description

OBJECTIVES:

Primary

  • Compare neoadjuvant fluorouracil, epirubicin, and cyclophosphamide vs docetaxel and epirubicin followed by radiotherapy and surgery in women with locally advanced, inflammatory, or large operable breast cancer.
  • Assess overall differences between the two arms.
  • Assess interaction between p53 status and outcomes in each arm.
  • Compare the progression-free survival of patients treated with these regimens.

Secondary

  • Compare the distant metastasis-free survival and survival of patients treated with these regimens.
  • Compare the clinical and pathological responses to these regimens in these patients.
  • Compare the toxicity of these regimens in these patients.

Translational

  • Determine the p53 status in order to study the treatment effect in each of the p53 subgroups and test the interaction between treatment and p53 status.
  • Assess the level of agreement between p53 assessment by IHC method and functional test in yeast.
  • Evaluate the prognostic and predictive value of "high risk" p53 mutations.
  • Perform a survival analysis according to gene clusters defined with the use of microarrays.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to stage of disease (large T2-3 vs locally advanced or inflammatory), p53 status (negative vs positive vs unknown), and participating center. Patients are randomized to 1 of 2 chemotherapy treatment arms.

  • Arm I (non-taxane arm): Patients receive 1 of 3 chemotherapy regimens comprising fluorouracil, epirubicin, and cyclophosphamide (FEC) (according to participating institution).
  • FEC 100: Patients receive fluorouracil IV over 15 minutes, epirubicin IV over 1 hour, and cyclophosphamide IV over 1 hour on day 1. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
  • Canadian FEC: Patients receive oral cyclophosphamide on days 1-14 and epirubicin IV and fluorouracil IV on days 1 and 8. If oral medications are not tolerated, patients may switch to cyclophosphamide IV on days 1 and 8. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
  • Tailored FEC: Patients receive fluorouracil IV over 15 minutes, epirubicin IV over 1 hour, and cyclophosphamide IV over 1-2 hours on day 1. Patients also receive filgrastim (G-CSF) subcutaneously on days 2-15 or until blood counts recover. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
  • Arm II (taxane arm): Patients receive docetaxel IV over 1 hour on days 1, 22, and 43 followed by epirubicin IV over 15 minutes and docetaxel IV over 1 hour on days 64, 85, and 106 in the absence of disease progression or unacceptable toxicity.

Following chemotherapy, patients may undergo loco-regional therapy comprising radiotherapy with or without breast conservation surgery or mastectomy. Patients with estrogen- and/or progesterone-receptor-positive disease also receive tamoxifen or an aromatase inhibitor for 5 years.

Two tumor samples (incisional or tricut biopsies) are taken before chemotherapy. Samples are analyzed by IHC, a functional test in yeast, and microarray analysis.

Patients are followed every 3 months for 1 year, every 4 months for 1.5 years, and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 1,850 patients will be accrued for this study within 5.5 years.

Conditions
Breast Cancer
Being tested
filgrastim, cyclophosphamide, docetaxel, epirubicin hydrochloride, fluorouracil
Keywords
stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, inflammatory breast cancer
Medical subject headings
Breast Neoplasms, Inflammatory Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT00017095
Study groupRoleWhat they receive
non taxane based chemotherapyActive comparatoreither FEC 100 or Canadian CEF or Tailored FEC for 6 cycles
Receives: Biological: filgrastim; Drug: cyclophosphamide; Drug: epirubicin hydrochloride; Drug: fluorouracil; Genetic: microarray analysis; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis; Procedure: biopsy; Procedure: conventional surgery; Procedure: neoadjuvant therapy; Radiation: radiation therapy
taxane based chemotherapyExperimentalDocetaxel for 3 cycles followed by Epirubicin/Docetaxel for 3 cycles
Receives: Drug: docetaxel; Drug: epirubicin hydrochloride; Genetic: microarray analysis; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis; Procedure: biopsy; Procedure: conventional surgery; Procedure: neoadjuvant therapy; Radiation: radiation therapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-free survival

    Measured: from randomization till first evidence of progression

Secondary outcomes (7)

  1. Distant metastasis-free survival

    Measured: randomization till first evidence recurrence

  2. Overall survival

    Measured: randomization till death

  3. Clinical and pathological responses

    Measured: after 3rd and 6d cycle of chemotherapy

  4. Clinical response according to RECIST criteria without pathologic response

    Measured: after 3rd and 6d cycle of chemotherapy

  5. Toxicity according to CTC v2.0

    Measured: from randomization

  6. Agreement between p53 assessment by IHC method and functional test in yeast by analyzing the correlation between p52 and tumor status after 3 and 6 cycles of chemotherapy

    Measured: after 3 and 6 cycles of chemotherapy

  7. Tumor assessment using cDNA microarray technology

    Measured: end of treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jan 2003 (estimated)
  2. Study startMar 2001
  3. Primary completionNov 2006

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
1,856 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00017095
Sponsor's protocol ID
EORTC-10994-p53
Other IDs
EORTC-10994, ACCOG-EORTC-10994, SAKK-EORTC-10994, SBGC-EORTC-10994, BIG-1-00
Status last verified
Oct 2013
First submitted
6 Jun 2001
Last updated
24 Oct 2013
Results posted
No

Publications

  • Bonnefoi H, Potti A, Delorenzi M, Mauriac L, Campone M, Tubiana-Hulin M, Petit T, Rouanet P, Jassem J, Blot E, Becette V, Farmer P, Andre S, Acharya CR, Mukherjee S, Cameron D, Bergh J, Nevins JR, Iggo RD. Retraction--Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00-01 clinical trial. Lancet Oncol. 2011 Feb;12(2):116. doi: 10.1016/S1470-2045(11)70011-0. No abstract available.

    PubMed 21277543

  • Desmedt C, Di Leo A, de Azambuja E, Larsimont D, Haibe-Kains B, Selleslags J, Delaloge S, Duhem C, Kains JP, Carly B, Maerevoet M, Vindevoghel A, Rouas G, Lallemand F, Durbecq V, Cardoso F, Salgado R, Rovere R, Bontempi G, Michiels S, Buyse M, Nogaret JM, Qi Y, Symmans F, Pusztai L, D'Hondt V, Piccart-Gebhart M, Sotiriou C. Multifactorial approach to predicting resistance to anthracyclines. J Clin Oncol. 2011 Apr 20;29(12):1578-86. doi: 10.1200/JCO.2010.31.2231. Epub 2011 Mar 21.

    PubMed 21422418

  • Bonnefoi H, Piccart M, Bogaerts J, Mauriac L, Fumoleau P, Brain E, Petit T, Rouanet P, Jassem J, Blot E, Zaman K, Cufer T, Lortholary A, Lidbrink E, Andre S, Litiere S, Lago LD, Becette V, Cameron DA, Bergh J, Iggo R; EORTC 10994/BIG 1-00 Study Investigators. TP53 status for prediction of sensitivity to taxane versus non-taxane neoadjuvant chemotherapy in breast cancer (EORTC 10994/BIG 1-00): a randomised phase 3 trial. Lancet Oncol. 2011 Jun;12(6):527-39. doi: 10.1016/S1470-2045(11)70094-8. Epub 2011 May 11.

    PubMed 21570352

  • Bonnefoi HR, Bogaerts J, Piccart M, et al.: Phase III trial (EORTC 10994/BIG 00-01) assessing the value of p53 using a functional assay to predict sensitivity to a taxane versus nontaxane primary chemotherapy in breast cancer: final analysis. [Abstract] J Clin Oncol 28 (Suppl 18): A-LBA503, 2010.

  • Collingridge D. Expression of concern--validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00-01 clinical trial. Lancet Oncol. 2010 Sep;11(9):813-4. doi: 10.1016/S1470-2045(10)70185-6. Epub 2010 Jul 26. No abstract available.

    PubMed 20667781

  • Bonnefoi H, Zimmer AS, Piccart M, et al.: P53 functional assay in yeast: evaluation in 1856 patients in a large prospective clinical trial: EORTC 10994/BIG 00-01. [Abstract] 31st Annual San Antonio Breast Cancer Symposium, December 10-14, 2008, San Antonio, Texas. A-1067, 2008.

  • Bonnefoi H, Potti A, Delorenzi M, Mauriac L, Campone M, Tubiana-Hulin M, Petit T, Rouanet P, Jassem J, Blot E, Becette V, Farmer P, Andre S, Acharya CR, Mukherjee S, Cameron D, Bergh J, Nevins JR, Iggo RD. Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00-01 clinical trial. Lancet Oncol. 2007 Dec;8(12):1071-1078. doi: 10.1016/S1470-2045(07)70345-5. Epub 2007 Nov 19.

    PubMed 18024211

  • Karina M, Bogaerts J, Piccart M, et al.: Preliminary safety data of the EORTC 10994/BIG 00-01 neoadjuvant trial comparing 3 cycles of docetaxel followed by 3 cycles of epirubicin-docetaxel versus 6 cycles of FEC 100 in patients with locally advanced/inflammatory or large operable breast cancer. [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-3067, S146-7, 2006.

  • Bonnefoi H, Farmer P, Delorenzi M, et al.: Is there a regimen-specific gene signature predicting for pathological complete response after neoadjuvant chemotherapy in hormone-negative breast cancer patients? A microarray substudy of 101 patients included in EORTC 10994/BIG 00-01 trial. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-1040, 2005.

  • Farmer P, Iggo R, Becette V, et al.: High quality gene expression microarray data from a multicentre prospective trial: results of the first microarray analysis in the EORTC 10994/ BIG 00-01 study. [Abstract] Eur J Cancer 2 (Suppl 3): A-155, 99, 2004.

  • Chatzipli A, Bonnefoi H, MacGrogan G, Sentis J, Cameron D, Poncet C; EORTC 10994/BIG 1-00 Consortium; Iggo R. Patterns of genomic change in residual disease after neoadjuvant chemotherapy for estrogen receptor-positive and HER2-negative breast cancer. Br J Cancer. 2021 Nov;125(10):1356-1364. doi: 10.1038/s41416-021-01526-3. Epub 2021 Sep 3.

    PubMed 34480095

  • Bonnefoi H, Litiere S, Piccart M, MacGrogan G, Fumoleau P, Brain E, Petit T, Rouanet P, Jassem J, Moldovan C, Bodmer A, Zaman K, Cufer T, Campone M, Luporsi E, Malmstrom P, Werutsky G, Bogaerts J, Bergh J, Cameron DA; EORTC 10994/BIG 1-00 Study investigators. Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial. Ann Oncol. 2014 Jun;25(6):1128-36. doi: 10.1093/annonc/mdu118. Epub 2014 Mar 11.

    PubMed 24618153

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing filgrastim, cyclophosphamide and docetaxel in people with Breast Cancer, run by European Organisation for Research and Treatment of Cancer - EORTC at 39 sites in 9 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Oct 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 39 sites in France, Sweden, Switzerland, United Kingdom, Belgium and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free survival (time frame: from randomization till first evidence of progression). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00017095, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Oct 2013.

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