- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00754845
Letrozole in Breast Cancer Who Have Received 5 Years of Aromatase Inhibitor Therapy
A Double Blind Randomization to Letrozole or Placebo for Women Previously Diagnosed With Primary Breast Cancer Completing Five Years of Adjuvant Aromatase Inhibitor Either as Initial Therapy or After Tamoxifen (Including Those in The MA.17 Study)
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether letrozole is more effective than a placebo in treating in women with breast cancer who have already received 5 years of aromatase inhibitor therapy.
PURPOSE: This randomized phase III trial is studying letrozole to see how well it works compared with a placebo in treating women with primary breast cancer who have received 5 years of aromatase inhibitor therapy.
Study Overview
Detailed Description
OBJECTIVES:
Primary
- To compare the disease-free survival of women with primary breast cancer treated with letrozole vs placebo after completing approximately 5 years (i.e., 4½ - 6 years) of aromatase inhibitor therapy (e.g., letrozole, anastrozole, or exemestane).
Secondary
- To compare the effect of these drugs on overall (all cause specific) mortality of these patients.
- To compare the incidence of contralateral breast cancer in patients treated with these drugs.
- To evaluate the long-term clinical and laboratory safety of aromatase inhibitor therapy, particularly cardiovascular morbidity and mortality (e.g., significant coronary artery disease, including myocardial infarction and angina requiring percutaneous transluminal coronary angioplasty or coronary artery bypass graft, fatal and nonfatal strokes, and all vascular deaths); incidence of all bone fractures (with particular emphasis on hip and wrist fractures as indicators of osteoporosis); changes in bone density; and common toxicities.
- To compare overall quality of life (QOL) and menopausal-specific QOL of patients treated with these drugs.
OUTLINE: This is a multicenter study. Patients are stratified according to lymph node status at diagnosis (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), interval between last dose of aromatase inhibitor therapy and study randomization (< 6 months vs 6 months to 2 years), and duration of prior tamoxifen citrate use (0 vs < 2 years vs 2 - 4½ years vs > 4½ years). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive oral letrozole once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
- Arm II: Patients receive oral placebo once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
Patients undergo bone mineral density measurement by DEXA scan at baseline (if not done within 12 months of study entry), at 24 and 48 months during study therapy, and at the completion of study therapy. Some patients also complete quality-of-life questionnaires at baseline and at 12, 24, 36, 48, and 60 months.
After completion of study therapy, patients are followed annually.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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British Columbia
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Kelowna, British Columbia, Canada, V1Y 5L3
- BCCA - Cancer Centre for the Southern Interior
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Surrey, British Columbia, Canada, V3V 1Z2
- BCCA - Fraser Valley Cancer Centre
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Vancouver, British Columbia, Canada, V5Z 4E6
- BCCA - Vancouver Cancer Centre
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Victoria, British Columbia, Canada, V8R 6V5
- BCCA - Vancouver Island Cancer Centre
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Manitoba
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Winnipeg, Manitoba, Canada, R3E 0V9
- CancerCare Manitoba
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New Brunswick
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Moncton, New Brunswick, Canada, E1C 6Z8
- The Moncton Hospital
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Moncton, New Brunswick, Canada, E1C 8X3
- The Vitalite Health Network - Dr. Leon Richard
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Saint John, New Brunswick, Canada, E2L 4L2
- Atlantic Health Sciences Corporation
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Newfoundland and Labrador
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St. John's, Newfoundland and Labrador, Canada, AIB 3V6
- Dr. H. Bliss Murphy Cancer Centre
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Nova Scotia
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Halifax, Nova Scotia, Canada, B3H 1V7
- QEII Health Sciences Center
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Ontario
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Hamilton, Ontario, Canada, L8V 5C2
- Juravinski Cancer Centre at Hamilton Health Sciences
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Kingston, Ontario, Canada, K7L 5P9
- Cancer Centre of Southeastern Ontario at Kingston
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London, Ontario, Canada, N6A 4L6
- London Regional Cancer Program
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Mississauga, Ontario, Canada, L5M 2N1
- Credit Valley Hospital
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Newmarket, Ontario, Canada, L3Y 2P9
- Stronach Regional Health Centre at Southlake
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Oshawa, Ontario, Canada, L1G 2B9
- Lakeridge Health Oshawa
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Sault Ste. Marie, Ontario, Canada, P6B 0A8
- Algoma District Cancer Program
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St. Catharines, Ontario, Canada, L2R 7C6
- Niagara Health System
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Sudbury, Ontario, Canada, P3E 5J1
- Northeast Cancer Center Health Sciences
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Thunder Bay, Ontario, Canada, P7B 6V4
- Thunder Bay Regional Health Science Centre
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Toronto, Ontario, Canada, M5B 1W8
- St. Michael's Hospital
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Toronto, Ontario, Canada, M4C 3E7
- Toronto East General Hospital
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Toronto, Ontario, Canada, M5G 1X5
- Mount Sinai Hospital
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Toronto, Ontario, Canada, M4N 3M5
- Odette Cancer Centre
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Toronto, Ontario, Canada, M5G 2M9
- Univ. Health Network-Princess Margaret Hospital
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Toronto, Ontario, Canada, M2K 1E1
- North York General Hospital
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Toronto, Ontario, Canada, M6R 1B5
- St. Joseph's Health Centre
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Toronto, Ontario, Canada, M9C 1A5
- Trillium Health Centre - West Toronto
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Toronto, Ontario, Canada, M9N 1N8
- Humber River Regional Hospital
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Windsor, Ontario, Canada, N8W 2X3
- Windsor Regional Cancer Centre
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Prince Edward Island
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Charlottetown, Prince Edward Island, Canada, C1A 8T5
- PEI Cancer Treatment Centre,Queen Elizabeth Hospital
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Quebec
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Gatineau, Quebec, Canada, J8P 7H2
- Centre de Sante et de services sociaux de Gatineau
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Greenfield Park, Quebec, Canada, J4V 2H1
- Hopital Charles LeMoyne
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Levis, Quebec, Canada, G6V 3Z1
- L'Hotel-Dieu de Levis
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Montreal, Quebec, Canada, H4J 1C5
- Hopital du Sacre-Coeur de Montreal
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Montreal, Quebec, Canada, H2W 1S6
- McGill University - Dept. Oncology
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Montreal, Quebec, Canada, H1T 2M4
- Hopital Maisonneuve-Rosemont
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Montreal, Quebec, Canada, H2W 1T8
- CHUM - Hotel Dieu du Montreal
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Quebec City, Quebec, Canada, G1S 4L8
- CHA-Hopital Du St-Sacrement
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Sherbrooke, Quebec, Canada, J1H 5N4
- Centre Hospitalier Universitaire de Sherbrooke
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Saskatchewan
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Regina, Saskatchewan, Canada, S4T 7T1
- Allan Blair Cancer Centre
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Saskatoon, Saskatchewan, Canada, S7N 4H4
- Saskatoon Cancer Centre
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Manchester, United Kingdom, M23 9LT
- Wythenshawe Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
DISEASE CHARACTERISTICS:
- Previously diagnosed with primary breast cancer
Must have received 4½ - 6 years of aromatase inhibitor therapy (e.g., letrozole, anastrozole, or exemestane), either as initial therapy or after prior tamoxifen citrate, including treatment received as part of clinical trial CAN-NCIC-MA17
- Completed aromatase inhibitor therapy ≤ 2 years ago
No metastatic or recurrent disease, contralateral breast cancer, or ductal carcinoma in situ in either breast, as determined by the following:
- Clinical examination of the breast area, axillae, and neck within the past 60 days
- Mammogram within the past 12 months*
- Chest x-ray within the past 60 days
- Bone scan, if alkaline phosphatase > 2 times normal and/or there are symptoms of metastatic disease AND confirmatory x-ray, if bone scan results are questionable, within the past 60 days
- Abdominal ultrasound, liver scan, or CT scan of the abdomen within the past 60 days, if ALT, AST, or alkaline phosphatase > 2 times normal NOTE: *A baseline mammogram is not required for patients who have undergone bilateral complete mastectomy
Hormone-receptor status:
- Estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) primary tumor at the time of diagnosis, defined as a tumor receptor content of > 10 fmol/mg protein or receptor positive by immunocytochemical assay (for patients not previously enrolled on clinical trial CAN-NCIC-MA17)
- ER+ and/or PR+ primary tumor OR hormone receptor status of primary tumor unknown (for patients previously enrolled on clinical trial CAN-NCIC-MA17)
PATIENT CHARACTERISTICS:
- Menopausal status not specified
- ECOG performance status 0-2
- Life expectancy ≥ 5 years
- WBC > 3.0 x 10^9/L OR granulocyte count (polymorphs + bands) ≥ 1.5 times 10^9/L
- Platelet count > 100 x 10^9/L
- AST and/or ALT < 2 times upper limit of normal (ULN)*
- Alkaline phosphatase < 2 times ULN*
Able (i.e. sufficiently fluent) and willing to complete quality-of-life questionnaires in either English or French (NCIC CTG participating centers)
- Inability to complete questionnaires due to illiteracy in English or French, loss of sight, or other equivalent reason allowed
- Accessible for treatment and follow-up
- No other prior or concurrent malignancy except adequately treated, superficial squamous cell or basal cell skin cancer, carcinoma in situ of the cervix, or other cancer treated > 5 years ago that is presumed cured NOTE: *Elevated levels allowed provided imaging examinations have ruled out metastatic disease
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- No concurrent selective estrogen receptor modulator (e.g., raloxifene, idoxifene)
- No other concurrent anticancer therapy
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Letrozole
Patients receive oral letrozole once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
|
Given orally
Other Names:
|
Placebo Comparator: Placebo
Patients receive oral placebo once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
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Given orally
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Disease-free Survival (DFS)
Time Frame: Unitil the end of study with a median follow up of 75 months
|
It is defined as the months from the day of randomization to the earliest date when a recurrence of the primary disease (recurrence in the breast, chest wall and nodal sites or the development of metastatic disease) or a contralateral breast cancer was observed.
Subjects who died without recurrence of the primary disease or the development of the contralateral breast cancer were censored at their death date.
If a patient has not recurred, developed a contralateral breast cancer, or died, disease-free survival was censored on the date of the last day the patient was known to be alive.
Probability of disease free survival at 5 years is estimated and reported.
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Unitil the end of study with a median follow up of 75 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of Contralateral Breast Cancer
Time Frame: 10 years
|
The annual incidence rate was estimated based on the time to the development of contralateral breast cancer, which was calculated in months from the day of randomization to the diagnosis date of contralateral breast cancer for subjects who had developed the contralateral breast cancer, to the time of death for the patient who died, or to the last day the patient was known alive for subjects without contralateral breast cancer
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10 years
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Overall Survival (OS)
Time Frame: Until the end of study with a median follow-up of 75 months
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For subjects who died, overall survival was calculated in months from the day of randomization to the date of death.
Otherwise, survival was censored at the last day the patient was known to be alive.
Probability of overall survival at 5 years is estimated and reported.
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Until the end of study with a median follow-up of 75 months
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Change From Baseline in Role Function- Physical Scale on SF(Short Form)-36 Health Survey
Time Frame: 8 years
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Difference between post baseline scores and baseline score of role function-physical scale on SF-36 Health Survey (scale range between 0 and 100 with higher score indicating better quality of life).
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8 years
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Chair: Paul E. Goss, MD, PhD, Massachusetts General Hospital
Publications and helpful links
General Publications
- Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, Gelmon K, Whelan T, Strasser-Weippl K, Rubin S, Sturtz K, Wolff AC, Winer E, Hudis C, Stopeck A, Beck JT, Kaur JS, Whelan K, Tu D, Parulekar WR. Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. N Engl J Med. 2016 Jul 21;375(3):209-19. doi: 10.1056/NEJMoa1604700. Epub 2016 Jun 5.
- Li Y, Zheng X, Tu D, Ingle JN, Goss PE, Parulekar WR, Qin G. Predicting the clinical outcomes and benefit from letrozole after 5 years of treatment with aromatase inhibitors for early breast cancer: analysis from CCTG MA.17R. Breast Cancer Res Treat. 2022 Feb;191(3):523-533. doi: 10.1007/s10549-021-06448-5. Epub 2021 Nov 26.
- Ethier JL, Anderson GM, Austin PC, Clemons M, Parulekar W, Shepherd L, Summers Trasiewicz L, Tu D, Amir E. Influence of the competing risk of death on estimates of disease recurrence in trials of adjuvant endocrine therapy for early-stage breast cancer: A secondary analysis of MA.27, MA.17 and MA.17R. Eur J Cancer. 2021 May;149:117-127. doi: 10.1016/j.ejca.2021.02.034. Epub 2021 Apr 11.
- Lemieux J, Brundage MD, Parulekar WR, Goss PE, Ingle JN, Pritchard KI, Celano P, Muss H, Gralow J, Strasser-Weippl K, Whelan K, Tu D, Whelan TJ. Quality of Life From Canadian Cancer Trials Group MA.17R: A Randomized Trial of Extending Adjuvant Letrozole to 10 Years. J Clin Oncol. 2018 Feb 20;36(6):563-571. doi: 10.1200/JCO.2017.75.7500. Epub 2018 Jan 12. Erratum In: J Clin Oncol. 2018 May 20;36(15):1540.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Skin Diseases
- Neoplasms
- Neoplasms by Site
- Breast Diseases
- Breast Neoplasms
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Hormone Antagonists
- Aromatase Inhibitors
- Steroid Synthesis Inhibitors
- Estrogen Antagonists
- Letrozole
Other Study ID Numbers
- MA17R
- CAN-NCIC-MA17R (Registry Identifier: NCI US - Physician Data Query)
- CDR0000614819 (Other Identifier: PDQ)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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