Low-dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-negative Early Breast Cancer (22-00)

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Methotrexate

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.

• Study Type: Interventional
• Enrollment (Actual): 1086
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Christchurch, Australia, 1
    • Christchurch Hospital
  • New South Wales
    • Tweed Heads, New South Wales, Australia, 2485
      • Tweed Heads Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5011
      • Queen Elizabeth Hospital
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Box Hill Hospital
    • East Ringwood, Victoria, Australia, 3135
      • Maroondah Hospital
    • Wodonga, Victoria, Australia, 3690
      • Murray Valley Private Hospital and Cancer Treatment Centre
• Belgium
  • Liege, Belgium, B-4000
    • CHU Liege - Domaine Universitaire du Sart Tilman
• Brazil
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90035-003
      • Hospital de Clinicas de Porto Alegre
• Chile
  • Santiago, Chile
    • Hospital Clinico Universidad de Chile
  • Santiago, Chile
    • Hospital Clinico San Borja Arriarán
  • Santiago, Chile, 29
    • Fundacion Arturo Lopez Perez
  • Santiago, Chile
    • Centro de Estudios Oncologicos Santiago
  • Valparaiso, Chile
    • Hospital Carlos Van Buren
• Hungary
  • Budapest, Hungary, 1122
    • National Institute of Oncology - Budapest
• Italy
  • Bergamo, Italy, 24100
    • Ospedali Riuniti di Bergamo
  • Biella, Italy, 13900
    • Ospedale degli Infermi - ASL 12
  • Carpi, Italy, 41012
    • Ospedale Civile Ramazzini
  • Lecco, Italy, 23900
    • Ospedale Alessandro Manzoni
  • Milan, Italy, 20142
    • Ospedale San Paolo
  • Milano, Italy, 20141
    • European Institute of Oncology
  • Padova, Italy, 35128
    • Azienda Ospedaliera di Padova
  • Rimini, Italy, 47900
    • Ospedale Civile Rimini
  • Rome, Italy, 00144
    • Ospedale Sant' Eugenio
  • Udine, Italy, 33100
    • Policlinico Universitario Udine
• Nigeria
  • Ibadan, Nigeria
    • University of Ibadan Health Center
• Peru
  • Lima, Peru, 34
    • Instituto Nacional de Enfermedades Neoplasicas
• Romania
  • Cluj-Napoca, Romania, 3400
    • Institutul Oncologic - Universitatea de Medicina
• South Africa
  • Johannesburg, South Africa, 2121
    • Sandton Oncology Centre
• Switzerland
  • Aarau, Switzerland, CH-5001
    • Kantonsspital Aarau
  • Bellinzona, Switzerland, CH-6500
    • Istituto Oncologico della Svizzera Italiana - Ospedale San Giovanni
  • Bern, Switzerland, CH-3010
    • Inselspital Bern
  • Chur, Switzerland, CH-7000
    • Kantonsspital Graubuenden
  • Rheinfelden, Switzerland, 4310
    • FMH Onkologie/Haematologie
  • St. Gallen, Switzerland, CH-9007
    • Kantonsspital - St. Gallen
  • Thun, Switzerland, 3600
    • Regionalspital
  • Zurich, Switzerland, CH-8091
    • UniversitaetsSpital Zuerich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
NO_INTERVENTION: No-CM; No further chemotherapy following standard adjuvant chemotherapy.
EXPERIMENTAL: 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)	Drug: Cyclophosphamide; 50 mg/day orally continuously for 1 year; Other Names: Cytoxan; Endoxan; Drug: Methotrexate; 2.5 mg twice/day orally days 1 and 2 of every week for 1 year; Other Names: Trexall

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	5-year estimates, reported at a median follow-up of 6.9 years
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.	5-year estimates, reported at a median follow-up of 6.9 years
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.	5-year estimates, reported at a median follow-up of 6.9 years

Collaborators and Investigators

• Sponsor: ETOP IBCSG Partners Foundation
• Investigators: Study Chair: Marco Colleoni, MD, European Institute of Oncology

Publications and helpful links

General 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.
• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2000
• Primary Completion (ACTUAL): January 1, 2015
• Study Completion (ACTUAL): August 1, 2016

Study Registration Dates

• First Submitted: August 10, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (ESTIMATE): January 27, 2003

Study Record Updates

• Last Update Posted (ESTIMATE): September 16, 2016
• Last Update Submitted That Met QC Criteria: August 5, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; stage II breast cancer; angiogenesis; stage IA 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
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Cyclophosphamide; Methotrexate
• Other Study ID Numbers: CDR0000068827; IBCSG-22-00 (OTHER: IBCSG); 2005-005666-36 (EudraCT Number); EU-20119 (REGISTRY: NCI Liaison Office, Brussels)