Letrozole After Tamoxifen in Treating Women With Breast Cancer

September 15, 2020 updated by: NCIC Clinical Trials Group

A Phase III Randomized Double Blind Study of Letrozole Versus Placebo in Women With Primary Breast Cancer Completing Five or More Years of Adjuvant Tamoxifen

RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by reducing the production of estrogen.

PURPOSE: This randomized phase III trial is studying letrozole to see how well it works in treating women with breast cancer who have received tamoxifen for at least 5 years.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

Primary

  • Compare the disease-free survival and overall survival of postmenopausal women with primary breast cancer who have completed at least five years of adjuvant aromatase inhibitor as initial therapy or after tamoxifen treated with letrozole or placebo.

Secondary

  • Compare the incidence of contralateral breast cancer in patients treated with these regimens.
  • Evaluate the long-term clinical and laboratory safety of letrozole, in terms of lipid profile, cardiovascular morbidity and mortality, incidence of bone fractures, change in bone density, and common toxic effects, in this patient population.
  • Compare the quality of life of patients treated with these regimens. Re-randomization

Primary

  • Compare disease-free survival of patients who, after receiving at least 4.5 years of letrozole, are re-randomized to receive an additional 5 years of letrozole vs placebo.

Secondary

  • Determine whether common genetic polymorphisms for genes encoding proteins involved in pharmacokinetic and/or pharmacodynamic pathways for letrozole contribute to individual variation in toxicity and efficacy of letrozole therapy.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to receptor status (positive vs unknown), lymph node status (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), interval between last dose of aromatase inhibitor therapy and randomization (< 6 months vs 6 months-2 years), and duration of prior tamoxifen use (0 years vs < 2 years vs 2-4.5 years vs > 4.5 years). Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive oral letrozole once daily.
  • Arm II: Patients receive oral placebo once daily. In both arms, treatment continues for 5 years in the absence of disease progression or unacceptable toxicity. Patients in arm II may then be offered oral letrozole once daily for up to 5 years.

Quality of life is assessed at baseline, at 6 months, and then annually for 4.5 years.

  • Double-blind, re-randomization:

Patients who complete ≥ 4.5 years of letrozole (arm I) and who did not experience recurrent disease or new primary breast cancer, including ductal carcinoma in situ, may participate in the double-blind, placebo-controlled, re-randomization portion of the study. Patients are stratified according to lymph node status at enrollment (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), and interval between last dose of letrozole and re-randomization (<6 months vs 6 months to 2 years). Common genetic single nucleotide polymorphisms for genes encoding proteins involved in pharmacokinetic and/or pharmacodynamic pathways for letrozole are analyzed in order to determine if these single nucleotide polymorphisms contribute to individual variation in toxicity and efficacy of letrozole therapy.

Quality of life is assessed as during the first randomization.

Patients are followed annually.

PROJECTED ACCRUAL: A total of 4,700 patients will be accrued for this study.

Study Type

Interventional

Enrollment (Actual)

5187

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
      • Quebec, Canada, G1V 4G5
        • University Institute of Cardiology and
    • Alberta
      • Lethbridge, Alberta, Canada, T1J 1W5
        • Lethbridge Cancer Centre
    • British Columbia
      • Kelowna, British Columbia, Canada, V1Y 5L3
        • BCCA - Cancer Centre for the Southern Interior
      • Nanaimo, British Columbia, Canada, V9S 2B7
        • NRGH - Nanaimo Cancer Clinic
      • Penticton, British Columbia, Canada, V2A 3G6
        • Penticton Regional Hospital
      • Surrey, British Columbia, Canada, V3V 1Z2
        • BCCA - Fraser Valley Cancer Centre
      • Vancouver, British Columbia, Canada, V5Z 4E6
        • BCCA - Vancouver Cancer Centre
      • Victoria, British Columbia, Canada, V8R 6V5
        • BCCA - Vancouver Island Cancer Centre
    • Manitoba
      • Winnipeg, Manitoba, Canada, R3E 0V9
        • CancerCare Manitoba
    • New Brunswick
      • Moncton, New Brunswick, Canada, E1C 6Z8
        • The Moncton Hospital
      • Moncton, New Brunswick, Canada, E1C 8X3
        • The Vitalite Health Network - Dr. Leon Richard
      • Saint John, New Brunswick, Canada, E2L 4L2
        • Atlantic Health Sciences Corporation
    • Newfoundland and Labrador
      • St. John's, Newfoundland and Labrador, Canada, AIB 3V6
        • Dr. H. Bliss Murphy Cancer Centre
    • Nova Scotia
      • Halifax, Nova Scotia, Canada, B3H 1V7
        • QEII Health Sciences Center
    • Ontario
      • Barrie, Ontario, Canada, L4M 6M2
        • The Royal Victoria Hospital
      • Hamilton, Ontario, Canada, L8V 5C2
        • Juravinski Cancer Centre at Hamilton Health Sciences
      • Kingston, Ontario, Canada, K7L 5P9
        • Cancer Centre of Southeastern Ontario at Kingston
      • London, Ontario, Canada, N6A 4L6
        • London Regional Cancer Program
      • Markham, Ontario, Canada, L6B 1A1
        • Markham Stouffville Hospital
      • Mississauga, Ontario, Canada, L5M 2N1
        • Credit Valley Hospital
      • Newmarket, Ontario, Canada, L3Y 2P9
        • Stronach Regional Health Centre at Southlake
      • Oshawa, Ontario, Canada, L1G 2B9
        • Lakeridge Health Oshawa
      • Ottawa, Ontario, Canada, K1H 8L6
        • Ottawa Health Research Institute - General Division
      • Peterborough, Ontario, Canada, K9H 7B6
        • Peterborough Regional Health Centre
      • Sault Ste. Marie, Ontario, Canada, P6B 0A8
        • Algoma District Cancer Program
      • St. Catharines, Ontario, Canada, L2R 7C6
        • Niagara Health System
      • Sudbury, Ontario, Canada, P3E 5J1
        • Regional Cancer Program of the Hopital Regional
      • Thunder Bay, Ontario, Canada, P7B 6V4
        • Thunder Bay Regional Health Science Centre
      • Toronto, Ontario, Canada, M5B 1W8
        • St. Michael's Hospital
      • Toronto, Ontario, Canada, M4C 3E7
        • Toronto East General Hospital
      • Toronto, Ontario, Canada, M5G 1X5
        • Mount Sinai Hospital
      • Toronto, Ontario, Canada, M4N 3M5
        • Odette Cancer Centre
      • Toronto, Ontario, Canada, M5G 2M9
        • Univ. Health Network-Princess Margaret Hospital
      • Toronto, Ontario, Canada, M2K 1E1
        • North York General Hospital
      • Toronto, Ontario, Canada, M6R 1B5
        • St. Joseph's Health Centre
      • Toronto, Ontario, Canada, M9C 1A5
        • Trillium Health Centre - West Toronto
      • Toronto, Ontario, Canada, M9N 1N8
        • Humber River Regional Hospital
      • Toronto, Ontario, Canada, M5G 2C4
        • Univ. Health Network-The Toronto General Hospital
      • Windsor, Ontario, Canada, N8W 2X3
        • Windsor Regional Cancer Centre
    • Prince Edward Island
      • Charlottetown, Prince Edward Island, Canada, C1A 8T5
        • PEI Cancer Treatment Centre,Queen Elizabeth Hospital
    • Quebec
      • Gatineau, Quebec, Canada, J8P 7H2
        • Centre de Sante et de services sociaux de Gatineau
      • Levis, Quebec, Canada, G6V 3Z1
        • L'Hotel-Dieu de Levis
      • Montreal, Quebec, Canada, H4J 1C5
        • Hôpital du Sacré-Coeur de Montreal
      • Montreal, Quebec, Canada, H2L 4M1
        • CHUM - Hopital Notre-Dame
      • Montreal, Quebec, Canada, H2W 1S6
        • McGill University - Dept. Oncology
      • Montreal, Quebec, Canada, H1T 2M4
        • Hopital Maisonneuve-Rosemont
      • Montreal, Quebec, Canada, H2W 1T8
        • CHUM - Hotel Dieu du Montreal
      • Montreal, Quebec, Canada, H3X 3J4
        • CHUM - Pavillon Saint-Luc
      • Quebec City, Quebec, Canada, G1R 2J6
        • CHUQ-Pavillon Hotel-Dieu de Quebec
      • Quebec City, Quebec, Canada, G1S 4L8
        • CHA-Hopital Du St-Sacrement
      • Sherbrooke, Quebec, Canada, J1H 5N4
        • Centre Hospitalier Universitaire de Sherbrooke
    • Saskatchewan
      • Regina, Saskatchewan, Canada, S4T 7T1
        • Allan Blair Cancer Centre
      • Saskatoon, Saskatchewan, Canada, S7N 4H4
        • Saskatoon Cancer Centre
  • United Kingdom
      • London, United Kingdom, SW3 6JJ
        • The Royal Marsden NHS Foundation Trust
      • Manchester, United Kingdom, M23 9LT
        • Wythenshawe Hospital
      • Manchester, United Kingdom, M2O 4BX
        • Christie's Hospital NHS Trust
      • Surrey, United Kingdom, SM2 5PT
        • The Royal Marsden Nhs Foundation Trust - Sutton

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 118 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

DISEASE CHARACTERISTICS:

  • Histologically or cytologically confirmed primary invasive breast carcinoma resected at time of original diagnosis

    • No ductal carcinoma in situ
  • Axillary lymph node negative, positive, or unknown
  • No evidence of metastases
  • No localized or distant breast cancer recurrence
  • Not registered on protocol NCCTG-893052, any other IBCSG protocol, or protocol SWOG-S9623

  • Hormone receptor status:

    • Estrogen or progesterone receptor positive as defined by tumor receptor content at least 10 fmol/mg protein or receptor positive by ERICA or PgRICA
    • Unknown status allowed if effort to determine status has been made by immunocytochemistry
  • No contralateral breast cancer

PATIENT CHARACTERISTICS:

Age:

  • Postmenopausal

Sex:

  • Female

Menopausal status:

  • Postmenopausal defined by one of the following:

    • Age 50 or over at start of adjuvant tamoxifen
    • Under age 50 and considered postmenopausal by treating physician at start of adjuvant tamoxifen
    • Under age 50 at start of adjuvant tamoxifen and had bilateral oophorectomy (surgical or radiation)
    • Under age 50 and premenopausal at start of adjuvant tamoxifen, but became amenorrheic during tamoxifen and remained amenorrheic for at least 1 year
    • Considered postmenopausal by physician with LH/FSH levels under the treatment center's postmenopausal limits

Performance status:

  • ECOG 0-2

Life expectancy:

  • At least 5 years

Hematopoietic:

  • WBC ≥ 3,000/mm^3 OR
  • Granulocyte count ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3

Hepatic:

  • AST and/or ALT < 2 times upper limit of normal (ULN) (unless imaging examinations have ruled out metastatic disease)
  • Alkaline phosphatase < 2 times ULN (unless imaging examinations have ruled out metastatic disease)

Renal:

  • Not specified

Other:

  • No concurrent medical or psychiatric condition that would preclude study participation
  • No other malignancy within the past 5 years except adequately treated superficial squamous cell or basal cell skin cancer or carcinoma in situ of the cervix
  • Able to swallow study drug
  • Adequate oral intake

PRIOR CONCURRENT THERAPY:

Biologic therapy:

  • Not specified

Chemotherapy:

  • Prior adjuvant chemotherapy allowed
  • No concurrent chemotherapy

Endocrine therapy:

  • Completed at least 4.5 but no more than 6 years of adjuvant tamoxifen after resection
  • Completed at least 4.5-6 years of adjuvant aromatase inhibitor as initial therapy or after tamoxifen
  • No more than 3 months since prior adjuvant tamoxifen
  • No concurrent hormone replacement therapy (e.g., megestrol)
  • No concurrent selective estrogen-receptor modulators (e.g., raloxifene or idoxifene)
  • Concurrent intermittent vaginal estrogens (e.g., Estring) allowed if other local measures for intractable vaginal atrophy are insufficient
  • No other concurrent aromatase inhibitors
  • No more than 2 years since prior aromatase inhibitor therapy (re-randomization)

Radiotherapy:

  • Prior radiotherapy allowed

Surgery:

  • See Disease Characteristics

Other:

  • At least 1 month since prior investigational drugs
  • Prior treatment on a clinical trial for breast cancer allowed if permission has been obtained from the sponsors of the original study for their patient to participate on MA.17/JMA.17/BIG-97-01
  • No prior placebo on core protocol
  • No concurrent anticancer therapy
  • Concurrent thyroid medication, calcium, vitamin D, and bisphosphonates allowed

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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
Placebo Comparator: Arm II
Patients receive oral placebo once daily.
Other: placebo
Given orally
Experimental: Arm I
Patients receive oral letrozole once daily.
Drug: letrozole
Given orally
Other Names:
  • Femara

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Disease-free survival
Time Frame: 5 years
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

NCIC Clinical Trials Group

Collaborators

National Cancer Institute (NCI)
European Organisation for Research and Treatment of Cancer - EORTC
Eastern Cooperative Oncology Group
Southwest Oncology Group
Cancer and Leukemia Group B
ETOP IBCSG Partners Foundation
North Central Cancer Treatment Group

Investigators

  • Study Chair: Silvana Martino, DO, Saint John's Cancer Institute
  • Study Chair: Monica Castiglione-Gertsch, MD, University Hospital Inselspital, Berne
  • Study Chair: Nicholas J. Robert, MD, Fairfax Northern Virginia Hematology Oncology, PC - Fairfax
  • Study Chair: Hyman B. Muss, MD, University of Vermont

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 24, 1998

Primary Completion (Actual)

August 22, 2003

Study Completion (Actual)

October 1, 2003

Study Registration Dates

First Submitted

November 1, 1999

First Submitted That Met QC Criteria

January 26, 2003

First Posted (Estimate)

January 27, 2003

Study Record Updates

Last Update Posted (Actual)

September 16, 2020

Last Update Submitted That Met QC Criteria

September 15, 2020

Last Verified

March 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MA17
  • U10CA025224 (U.S. NIH Grant/Contract)
  • CAN-NCIC-MA17 (Registry Identifier: PDQ)
  • CALGB-49805
  • E-JMA17
  • EORTC-10983
  • IBCSG-BIG97-01
  • NCCTG-JMA17
  • SWOG-JMA17
  • JRF-Vor-Int-10
  • NCCTG-CAN-MA17
  • SWOG-CAN-MA17
  • CDR0000065921 (Other Identifier: PDQ)

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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