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Breast CancerPhase 322-00NCT00022516

Low-dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-negative Early Breast Cancer

A Phase 3 study testing Cyclophosphamide and Methotrexate in people with Breast Cancer, run by ETOP IBCSG Partners Foundation at 36 sites in 11 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

This randomized, phase III trial was designed to test the efficacy of a low-dose chemotherapy-maintenance regimen, hypothesized to have anti-angiogenic activity, administered following standard chemotherapy in patients with early breast cancer whose tumors are hormone receptor negative. Read more about this study

Who is it for?
Ages 18 to 120 years
Conditions the study is for
Breast Cancer
What is being tested?
Cyclophosphamide and Methotrexate
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,086 participants
Where
36 sitesin 11 countries
Study dates
Nov 2000to Aug 2016
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

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 18 to 120 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

DISEASE CHARACTERISTICS:

  • Histologically confirmed stage I, II, or III breast cancer
  • T1-3, N0-2, M0
  • Patients with sentinel node biopsy positive disease must have undergone axillary dissection
  • Tumor must be confined to the breast without detected metastases elsewhere
  • T4 disease with minimal dermal invasion allowed
  • No T4 disease with ulceration of skin, infiltration of skin (except pathologically minimal dermal involvement), peau d'orange, or inflammatory breast cancer
  • No bilateral breast cancer (except in situ carcinoma) or suspicious mass in opposite breast that has not been proven benign
  • No distant metastases
  • No skeletal pain of unknown cause, elevated alkaline phosphatase, or bone scan showing hot spots that cannot be ruled out as metastases by x-ray, MRI, and/or CT
  • Must have undergone prior total mastectomy OR breast-conserving procedure (e.g., lumpectomy, quadrantectomy, or partial mastectomy with negative margins) with radiotherapy planned
  • Patients must begin or have begun an approved induction chemotherapy regimen within 8 weeks after definitive surgery
  • Negative surgical margins
  • Axillary clearance with at least 6 lymph nodes examined OR negative sentinel node biopsy
  • Known HER2 status by immunohistochemistry or fluorescence in situ hybridization
  • Hormone receptor status:
  • Estrogen and progesterone receptor negative
  • Less than 10% positive tumor cells by immunohistochemistry

PATIENT CHARACTERISTICS:

Age:

  • Not specified

Sex:

  • Not specified

Menopausal status:

  • Premenopausal, defined as less than 6 months since last menstrual period (LMP) AND no prior bilateral ovariectomy AND not on estrogen replacement (OR under age 50) OR
  • Postmenopausal, defined as prior bilateral ovariectomy OR more than 12 months since LMP without prior hysterectomy (OR age 50 and over)

Performance status:

  • Not specified

Life expectancy:

  • Not specified

Hematopoietic:

  • WBC greater than 3,000/mm3
  • Platelet count greater than 100,000/mm3

Hepatic:

  • See Disease Characteristics
  • Bilirubin less than 2.0 mg/dL
  • ALT less than 1.5 times upper limit of normal OR AST less than 60 IU/L

Renal:

  • Creatinine less than 1.2 mg/dL

Other:

  • Not pregnant or lactating within the past 6 months
  • Fertile patients must use effective barrier contraception
  • No other prior or concurrent malignancy except adequately treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or contralateral or ipsilateral in situ breast carcinoma
  • No psychiatric or addictive disorders that would preclude study
  • No non-malignant systemic disease that would preclude study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

  • Prior trastuzumab (Herceptin) allowed

Chemotherapy:

  • See Disease Characteristics
  • No prior adjuvant or neoadjuvant chemotherapy for breast cancer

Endocrine therapy:

  • No prior endocrine therapy for breast cancer or prevention
  • No prior tamoxifen or raloxifene for breast cancer

Radiotherapy:

  • No prior radiotherapy for breast cancer except primary irradiation

Surgery:

  • See Disease Characteristics

Other:

  • No prior preventative therapy for breast cancer

Trial locations and contacts

36 sites in 11 countries.

36 sites in 11 countries

Italy10 sites

  • Ospedali Riuniti di Bergamo

    Bergamo, 24100

  • Ospedale degli Infermi - ASL 12

    Biella, 13900

  • Ospedale Civile Ramazzini

    Carpi, 41012

  • Ospedale Alessandro Manzoni

    Lecco, 23900

  • Ospedale San Paolo

    Milan, 20142

  • European Institute of Oncology

    Milan, 20141

  • Azienda Ospedaliera di Padova

    Padova, 35128

  • Ospedale Civile Rimini

    Rimini, 47900

  • Ospedale Sant' Eugenio

    Rome, 00144

  • Policlinico Universitario Udine

    Udine, 33100

Other trials in Italy

Switzerland8 sites

  • Kantonsspital Aarau

    Aarau, CH-5001

  • Istituto Oncologico della Svizzera Italiana - Ospedale San Giovanni

    Bellinzona, CH-6500

  • Inselspital Bern

    Bern, CH-3010

  • Kantonsspital Graubuenden

    Chur, CH-7000

  • FMH Onkologie/Haematologie

    Rheinfelden, 4310

  • Kantonsspital - St. Gallen

    Sankt Gallen, CH-9007

  • Regionalspital

    Thun, 3600

  • UniversitaetsSpital Zuerich

    Zurich, CH-8091

Other trials in Switzerland

Australia6 sites

  • Queen Elizabeth Hospital

    Adelaide, South Australia, 5011

  • Box Hill Hospital

    Box Hill, Victoria, 3128

  • Christchurch Hospital

    Christchurch, 1

  • Maroondah Hospital

    East Ringwood, Victoria, 3135

  • Tweed Heads Hospital

    Tweed Heads, New South Wales, 2485

  • Murray Valley Private Hospital and Cancer Treatment Centre

    Wodonga, Victoria, 3690

Other trials in Australia

Chile5 sites

  • Fundacion Arturo Lopez Perez

    Santiago, 29

  • Centro de Estudios Oncologicos Santiago

    Santiago

  • Hospital Clinico San Borja Arriaran

    Santiago

  • Hospital Clinico Universidad de Chile

    Santiago

  • Hospital Carlos Van Buren

    Valparaíso

Other trials in Chile

Belgium1 site

  • CHU Liege - Domaine Universitaire du Sart Tilman

    Liège, B-4000

Other trials in Belgium

Brazil1 site

  • Hospital de Clinicas de Porto Alegre

    Porto Alegre, Rio Grande do Sul, 90035-003

Other trials in Brazil

Hungary1 site

  • National Institute of Oncology - Budapest

    Budapest, 1122

Other trials in Hungary

Nigeria1 site

  • University of Ibadan Health Center

    Ibadan

Other trials in Nigeria

Peru1 site

  • Instituto Nacional de Enfermedades Neoplasicas

    Lima, 34

Other trials in Peru

Romania1 site

  • Institutul Oncologic - Universitatea de Medicina

    Cluj-Napoca, 3400

Other trials in Romania

South Africa1 site

  • Sandton Oncology Centre

    Johannesburg, 2121

Other trials in South Africa

About this study

Official title: Low-dose Cytotoxics as "Anti-angiogenesis Treatment" Following Adjuvant Induction Chemotherapy for Patients With ER-negative and PgR-negative Breast Cancer

This randomized, phase III trial was designed to test the efficacy of a low-dose chemotherapy-maintenance regimen, hypothesized to have anti-angiogenic activity, administered following standard chemotherapy in patients with early breast cancer whose tumors are hormone receptor negative.

Read the detailed description

PURPOSE:

  • Evaluate a low-dose cyclophosphamide and methotrexate chemotherapy-maintenance regimen in early breast cancer.
  • Compare the disease-free survival, overall survival, and systemic disease-free survival of patients treated with these regimens.
  • Compare the toxic effects of these regimens in these patients.

OUTLINE:

This is a randomized, open-label, multicenter study. Patients are stratified according to participating center, menopausal status (pre vs post), and approved induction chemotherapy (anthracycline and cyclophosphamide vs other agents). Treatment duration is 12 months of low-dose chemotherapy-maintenance regimen (CM-maintenance) vs no chemotherapy-maintenance regimen (no-CM) following standard adjuvant chemotherapy. Patients are randomized to one of two treatment arms. Patients are followed every 6 months for 5 years, and yearly follow-up thereafter.

Conditions
Breast Cancer
Keywords
stage IA breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IB breast cancer, estrogen receptor-negative breast cancer, progesterone receptor-negative breast cancer, triple-negative breast cancer, low-dose maintenance chemotherapy, stroma, angiogenesis
Medical subject headings
Breast Neoplasms, Triple Negative Breast Neoplasms

What participants receive

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

  • CyclophosphamideDrug

    Also called Endoxan, Cytoxan

    50 mg/day orally continuously for 1 year

  • MethotrexateDrug

    Also called Trexall

    2.5 mg twice/day orally days 1 and 2 of every week for 1 year

Study groups in NCT00022516
Study groupRoleWhat they receive
No-CMNo interventionNo further chemotherapy following standard adjuvant chemotherapy.
CM-MaintenanceExperimental12-month CM-maintenance regimen (C, cyclophosphamide 50 mg/day orally continuously and M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week for 1 year)
Receives: Drug: Cyclophosphamide; Drug: Methotrexate

What is being measured

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

  1. Disease-free Survival

    Estimated percentage of patients alive and disease-free at 5 years from randomization, where disease-free survival is defined as the time from randomization to the first appearance of one of the following: invasive breast cancer recurrence at local, regional, or distant site, invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without cancer event; or censored at date of last follow-up.

    Measured: 5-year estimates, reported at a median follow-up of 6.9 years

Secondary outcomes (3)

  1. Overall Survival

    Estimated percentage of patients alive and disease-free at 5 years from randomization, where overall survival is defined as the time from randomization to death from any cause; or censored at date last known alive.

    Measured: 5-year estimates, reported at a median follow-up of 6.9 years

  2. Distant Recurrence-free Interval

    Estimated percentage of patients alive and disease-free at 5 years from randomization, where distant recurrence-free Interval is defined as the time from randomization to invasive breast cancer recurrence at distant site, or invasive contralateral breast cancer; or censored at date of last follow up.

    Measured: 5-year estimates, reported at a median follow-up of 6.9 years

  3. Breast Cancer-free Interval

    Estimated percentage of patients alive and disease-free at 5 years from randomization, where breast cancer-free interval is defined as the time from randomization to invasive breast cancer recurrence at local, regional, or distant site, or invasive contralateral breast cancer; or censored at date of last follow up.

    Measured: 5-year estimates, reported at a median follow-up of 6.9 years

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 startNov 2000
  3. Primary completionJan 2015
  4. Study completionAug 2016

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
1,086 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00022516
Sponsor's protocol ID
CDR0000068827
Other IDs
IBCSG-22-00, 2005-005666-36, EU-20119, 2005
Acronym
22-00
Status last verified
Aug 2016
First submitted
10 Aug 2001
Last updated
16 Sep 2016
Data monitoring committee
Yes

Publications

  • Colleoni M, Gray KP, Gelber S, Lang I, Thurlimann B, Gianni L, Abdi EA, Gomez HL, Linderholm BK, Puglisi F, Tondini C, Kralidis E, Eniu A, Cagossi K, Rauch D, Chirgwin J, Gelber RD, Regan MM, Coates AS, Price KN, Viale G, Goldhirsch A. Low-Dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-Negative Early Breast Cancer: International Breast Cancer Study Group Trial 22-00. J Clin Oncol. 2016 Oct 1;34(28):3400-8. doi: 10.1200/JCO.2015.65.6595. Epub 2016 Jun 20.

    PubMed 27325862

  • Pruneri G, Gray KP, Vingiani A, Viale G, Curigliano G, Criscitiello C, Lang I, Ruhstaller T, Gianni L, Goldhirsch A, Kammler R, Price KN, Cancello G, Munzone E, Gelber RD, Regan MM, Colleoni M. Tumor-infiltrating lymphocytes (TILs) are a powerful prognostic marker in patients with triple-negative breast cancer enrolled in the IBCSG phase III randomized clinical trial 22-00. Breast Cancer Res Treat. 2016 Jul;158(2):323-31. doi: 10.1007/s10549-016-3863-3. Epub 2016 Jul 2.

    PubMed 27372069

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Cyclophosphamide and Methotrexate in people with Breast Cancer, run by ETOP IBCSG Partners Foundation at 36 sites in 11 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 16 Sep 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 36 sites in Italy, Switzerland, Australia, Chile, Belgium and 6 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?

Yes. Results are posted in the registry (first posted 11 Dec 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Disease-free Survival (time frame: 5-year estimates, reported at a median follow-up of 6.9 years). 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 NCT00022516, which also lists 2 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 16 Sep 2016.

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