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Letrozole After Tamoxifen in Treating Women With Breast Cancer

This study has been completed.
Sponsor:
Collaborators:
National Cancer Institute (NCI)
North Central Cancer Treatment Group
International Breast Cancer Study Group
Eastern Cooperative Oncology Group
Southwest Oncology Group
Cancer and Leukemia Group B
European Organisation for Research and Treatment of Cancer - EORTC
Information provided by (Responsible Party):
NCIC Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT00003140
First received: November 1, 1999
Last updated: September 20, 2012
Last verified: March 2012
History of Changes

November 1, 1999
September 20, 2012
August 1998
October 2003   (final data collection date for primary outcome measure)
Disease-free survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
Not Provided
Complete list of historical versions of study NCT00003140 on ClinicalTrials.gov Archive Site
Not Provided
Not Provided
Not Provided
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Letrozole After Tamoxifen in Treating Women With Breast Cancer
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.

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.
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Breast Cancer
  • Drug: letrozole
    Given orally
    Other Name: Femara
  • Other: placebo
    Given orally
  • Experimental: Arm I
    Patients receive oral letrozole once daily.
    Intervention: Drug: letrozole
  • Placebo Comparator: Arm II
    Patients receive oral placebo once daily.
    Intervention: Other: placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
5187
December 2010
October 2003   (final data collection date for primary outcome measure)

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
Female
Not Provided
No
Contact information is only displayed when the study is recruiting subjects
Canada,   United Kingdom
 
NCT00003140
MA17, U10CA025224, CAN-NCIC-MA17, CALGB-49805, E-JMA17, EORTC-10983, IBCSG-BIG97-01, NCCTG-JMA17, SWOG-JMA17, JRF-Vor-Int-10, NCCTG-CAN-MA17, SWOG-CAN-MA17, CDR0000065921
Yes
NCIC Clinical Trials Group
NCIC Clinical Trials Group
  • National Cancer Institute (NCI)
  • North Central Cancer Treatment Group
  • International Breast Cancer Study Group
  • Eastern Cooperative Oncology Group
  • Southwest Oncology Group
  • Cancer and Leukemia Group B
  • European Organisation for Research and Treatment of Cancer - EORTC
Study Chair: Paul E. Goss, MD, PhD Massachusetts General Hospital
Study Chair: James N. Ingle, MD Mayo Clinic
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: Silvana Martino, DO John Wayne Cancer Institute at Saint John's Health Center
Study Chair: Hyman B. Muss, MD University of Vermont
Study Chair: Martine J. Piccart-Gebhart, MD, PhD Institut Jules Bordet
NCIC Clinical Trials Group
March 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP