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

NCT ID: NCT00022516

Last Updated: 2016-09-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1086 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2000-11-30
• Study Completion Date: 2016-08-31

Brief 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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

No-CM

No further chemotherapy following standard adjuvant chemotherapy.

Group Type: NO_INTERVENTION

No interventions assigned to this group

CM-Maintenance

12-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)

Group Type: EXPERIMENTAL

Cyclophosphamide

Intervention Type: DRUG

50 mg/day orally continuously for 1 year

Methotrexate

Intervention Type: DRUG

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

Interventions

Cyclophosphamide

50 mg/day orally continuously for 1 year

Intervention Type: DRUG

Methotrexate

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

Intervention Type: DRUG

Other Intervention Names

Endoxan; Cytoxan; Trexall

Eligibility Criteria

Inclusion Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ETOP IBCSG Partners Foundation

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marco Colleoni, MD

Role: STUDY_CHAIR

European Institute of Oncology

Locations

Tweed Heads Hospital

Tweed Heads, New South Wales, Australia

Queen Elizabeth Hospital

Adelaide, South Australia, Australia

Box Hill Hospital

Box Hill, Victoria, Australia

Maroondah Hospital

East Ringwood, Victoria, Australia

Murray Valley Private Hospital and Cancer Treatment Centre

Wodonga, Victoria, Australia

Christchurch Hospital

Christchurch, , Australia

CHU Liege - Domaine Universitaire du Sart Tilman

Liège, , Belgium

Hospital de Clinicas de Porto Alegre

Porto Alegre, Rio Grande do Sul, Brazil

Fundacion Arturo Lopez Perez

Santiago, , Chile

Centro de Estudios Oncologicos Santiago

Santiago, , Chile

Hospital Clinico San Borja Arriaran

Santiago, , Chile

Hospital Clinico Universidad de Chile

Santiago, , Chile

Hospital Carlos Van Buren

Valparaíso, , Chile

National Institute of Oncology - Budapest

Budapest, , Hungary

Ospedali Riuniti di Bergamo

Bergamo, , Italy

Ospedale degli Infermi - ASL 12

Biella, , Italy

Ospedale Civile Ramazzini

Carpi, , Italy

Ospedale Alessandro Manzoni

Lecco, , Italy

Ospedale San Paolo

Milan, , Italy

European Institute of Oncology

Milan, , Italy

Azienda Ospedaliera di Padova

Padua, , Italy

Ospedale Civile Rimini

Rimini, , Italy

Ospedale Sant' Eugenio

Rome, , Italy

Policlinico Universitario Udine

Udine, , Italy

University of Ibadan Health Center

Ibadan, , Nigeria

Instituto Nacional de Enfermedades Neoplasicas

Lima, , Peru

Institutul Oncologic - Universitatea de Medicina

Cluj-Napoca, , Romania

Sandton Oncology Centre

Johannesburg, , South Africa

Kantonsspital Aarau

Aarau, , Switzerland

Istituto Oncologico della Svizzera Italiana - Ospedale San Giovanni

Bellinzona, , Switzerland

Inselspital Bern

Bern, , Switzerland

Kantonsspital Graubuenden

Chur, , Switzerland

FMH Onkologie/Haematologie

Rheinfelden, , Switzerland

Kantonsspital - St. Gallen

Sankt Gallen, , Switzerland

Regionalspital

Thun, , Switzerland

UniversitaetsSpital Zuerich

Zurich, , Switzerland

Countries

Australia; Belgium; Brazil; Chile; Hungary; Italy; Nigeria; Peru; Romania; South Africa; Switzerland

References

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.

Reference Type: RESULT

PMID: 27325862 (View on PubMed)

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.

Reference Type: RESULT

PMID: 27372069 (View on PubMed)

Other Identifiers

IBCSG-22-00

Identifier Type: OTHER

Identifier Source: secondary_id

2005-005666-36

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EU-20119

Identifier Type: REGISTRY

Identifier Source: secondary_id

CDR0000068827

Identifier Type: -

Identifier Source: org_study_id