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

NCT00022516 | Completed Phase 3 Results DMC

• 4 other identifiers: CDR0000068827IBCSG-22-002005-005666-36EU-20119
• Study Type: interventional
• Target: 1,086
• Locations: 11 countries
• Sites: 36

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.

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

Outcome Measures

Primary Outcomes (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.

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

Secondary Outcomes (3)

• Overall Survival

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

• Distant Recurrence-free Interval

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

• Breast Cancer-free Interval

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

Study Arms (2)

No-CM

NO INTERVENTION

No further chemotherapy following standard adjuvant chemotherapy.

CM-Maintenance

EXPERIMENTAL

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)

Drug: Cyclophosphamide; Drug: Methotrexate

Interventions

Cyclophosphamide DRUG

50 mg/day orally continuously for 1 year

Also known as: Endoxan, Cytoxan

CM-Maintenance

Methotrexate DRUG

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

Also known as: Trexall

CM-Maintenance

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• ETOP IBCSG Partners Foundation: lead

Study Sites (36)

Tweed Heads Hospital

Tweed Heads, New South Wales, 2485, Australia

Location

Queen Elizabeth Hospital

Adelaide, South Australia, 5011, Australia

Location

Box Hill Hospital

Box Hill, Victoria, 3128, Australia

Location

Maroondah Hospital

East Ringwood, Victoria, 3135, Australia

Location

Murray Valley Private Hospital and Cancer Treatment Centre

Wodonga, Victoria, 3690, Australia

Location

Christchurch Hospital

Christchurch, 1, Australia

Location

CHU Liege - Domaine Universitaire du Sart Tilman

Liège, B-4000, Belgium

Location

Hospital de Clinicas de Porto Alegre

Porto Alegre, Rio Grande do Sul, 90035-003, Brazil

Location

Fundacion Arturo Lopez Perez

Santiago, 29, Chile

Location

Centro de Estudios Oncologicos Santiago

Santiago, Chile

Location

Hospital Clinico San Borja Arriaran

Santiago, Chile

Location

Hospital Clinico Universidad de Chile

Santiago, Chile

Location

Hospital Carlos Van Buren

Valparaíso, Chile

Location

National Institute of Oncology - Budapest

Budapest, 1122, Hungary

Location

Ospedali Riuniti di Bergamo

Bergamo, 24100, Italy

Location

Ospedale degli Infermi - ASL 12

Biella, 13900, Italy

Location

Ospedale Civile Ramazzini

Carpi, 41012, Italy

Location

Ospedale Alessandro Manzoni

Lecco, 23900, Italy

Location

Ospedale San Paolo

Milan, 20142, Italy

Location

European Institute of Oncology

Milan, 20141, Italy

Location

Azienda Ospedaliera di Padova

Padua, 35128, Italy

Location

Ospedale Civile Rimini

Rimini, 47900, Italy

Location

Ospedale Sant' Eugenio

Rome, 00144, Italy

Location

Policlinico Universitario Udine

Udine, 33100, Italy

Location

University of Ibadan Health Center

Ibadan, Nigeria

Location

Instituto Nacional de Enfermedades Neoplasicas

Lima, 34, Peru

Location

Institutul Oncologic - Universitatea de Medicina

Cluj-Napoca, 3400, Romania

Location

Sandton Oncology Centre

Johannesburg, 2121, South Africa

Location

Kantonsspital Aarau

Aarau, CH-5001, Switzerland

Location

Istituto Oncologico della Svizzera Italiana - Ospedale San Giovanni

Bellinzona, CH-6500, Switzerland

Location

Inselspital Bern

Bern, CH-3010, Switzerland

Location

Kantonsspital Graubuenden

Chur, CH-7000, Switzerland

Location

FMH Onkologie/Haematologie

Rheinfelden, 4310, Switzerland

Location

Kantonsspital - St. Gallen

Sankt Gallen, CH-9007, Switzerland

Location

Regionalspital

Thun, 3600, Switzerland

Location

UniversitaetsSpital Zuerich

Zurich, CH-8091, Switzerland

Location

Related Publications (2)

• 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.

  PMID: 27325862 RESULT

• 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.

  PMID: 27372069 RESULT

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

Cyclophosphamide; Methotrexate

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

This trial collected only Grade 3 or higher Adverse Events.

Results Point of Contact

• Title: Rudolf Maibach, Executive Officer for International Trial Activities
• Organization: IBCSG

rudolf.maibach@ibcsg.org

+41 31 389 91 96

Study Officials

• Marco Colleoni, MD

  European Institute of Oncology

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 10, 2001
• First Posted: January 27, 2003
• Study Start: November 1, 2000
• Primary Completion: January 1, 2015
• Study Completion: August 1, 2016
• Last Updated: September 16, 2016
• Results First Posted: December 11, 2015

Record last verified: 2016-08

Locations

ZA (1); CL (5); CH (8); PE (1); BR (1); HU (1); AU (6); BE (1); RO (1); NG (1); IT (10)