Clinical trial NCT00003140: Letrozole After Tamoxifen in Treating Women With Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: North Central Cancer Treatment Group
name: ETOP IBCSG Partners Foundation
name: Eastern Cooperative Oncology Group
name: SWOG Cancer Research Network
name: Cancer and Leukemia Group B
name: European Organisation for Research and Treatment of Cancer - EORTC
First posted: 2003-01-27
Enrollment: 5187
Sex: FEMALE
Minimum age (years): 0
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Disease-free survival
timeFrame: 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Lethbridge
country: Canada
facility: Lethbridge Cancer Centre
state: Alberta
city: Kelowna
country: Canada
facility: BCCA - Cancer Centre for the Southern Interior
state: British Columbia
city: Nanaimo
country: Canada
facility: NRGH - Nanaimo Cancer Clinic
state: British Columbia
city: Penticton
country: Canada
facility: Penticton Regional Hospital
state: British Columbia
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Centre
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Victoria
country: Canada
facility: BCCA - Vancouver Island Cancer Centre
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Moncton
country: Canada
facility: The Moncton Hospital
state: New Brunswick
city: Moncton
country: Canada
facility: The Vitalite Health Network - Dr. Leon Richard
state: New Brunswick
city: Saint John
country: Canada
facility: Atlantic Health Sciences Corporation
state: New Brunswick
city: St. John's
country: Canada
facility: Dr. H. Bliss Murphy Cancer Centre
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: QEII Health Sciences Center
state: Nova Scotia
city: Barrie
country: Canada
facility: The Royal Victoria Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Cancer Centre of Southeastern Ontario at Kingston
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Markham
country: Canada
facility: Markham Stouffville Hospital
state: Ontario
city: Mississauga
country: Canada
facility: Credit Valley Hospital
state: Ontario
city: Newmarket
country: Canada
facility: Stronach Regional Health Centre at Southlake
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Health Research Institute - General Division
state: Ontario
city: Peterborough
country: Canada
facility: Peterborough Regional Health Centre
state: Ontario
city: Sault Ste. Marie
country: Canada
facility: Algoma District Cancer Program
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health System
state: Ontario
city: Sudbury
country: Canada
facility: Regional Cancer Program of the Hopital Regional
state: Ontario
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Science Centre
state: Ontario
city: Toronto
country: Canada
facility: North York General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto East General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Odette Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: Univ. Health Network-The Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Univ. Health Network-Princess Margaret Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Joseph's Health Centre
state: Ontario
city: Toronto
country: Canada
facility: Trillium Health Centre - West Toronto
state: Ontario
city: Toronto
country: Canada
facility: Humber River Regional Hospital
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Cancer Centre
state: Ontario
city: Charlottetown
country: Canada
facility: PEI Cancer Treatment Centre,Queen Elizabeth Hospital
state: Prince Edward Island
city: Gatineau
country: Canada
facility: Centre de Sante et de services sociaux de Gatineau
state: Quebec
city: Levis
country: Canada
facility: L'Hotel-Dieu de Levis
state: Quebec
city: Montreal
country: Canada
facility: Hopital Maisonneuve-Rosemont
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Hopital Notre-Dame
state: Quebec
city: Montreal
country: Canada
facility: McGill University - Dept. Oncology
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Hotel Dieu du Montreal
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Pavillon Saint-Luc
state: Quebec
city: Montreal
country: Canada
facility: Hopital du Sacre-Coeur de Montreal
state: Quebec
city: Quebec City
country: Canada
facility: CHUQ-Pavillon Hotel-Dieu de Quebec
state: Quebec
city: Quebec City
country: Canada
facility: CHA-Hopital Du St-Sacrement
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre hospitalier universitaire de Sherbrooke
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
city: Quebec
country: Canada
facility: University Institute of Cardiology and
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
city: Manchester
country: United Kingdom
facility: Christie's Hospital NHS Trust
city: Surrey
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust - Sutton
Study officials:
affiliation: Massachusetts General Hospital
name: Paul E. Goss, MD, PhD
role: STUDY_CHAIR
affiliation: Mayo Clinic
name: James N. Ingle, MD
role: STUDY_CHAIR
affiliation: Insel Gruppe AG, University Hospital Bern
name: Monica Castiglione-Gertsch, MD
role: STUDY_CHAIR
affiliation: Fairfax Northern Virginia Hematology Oncology, PC - Fairfax
name: Nicholas J. Robert, MD
role: STUDY_CHAIR
affiliation: Saint John's Cancer Institute
name: Silvana Martino, DO
role: STUDY_CHAIR
affiliation: University of Vermont
name: Hyman B. Muss, MD
role: STUDY_CHAIR
affiliation: Jules Bordet Institute
name: Martine J. Piccart-Gebhart, MD, PhD
role: STUDY_CHAIR
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citation: Abetz L, Barghout V, Thomas S, et al.: Letrozole did not worsen quality of life relative to placebo in post-menopausal women with early breast cancer: results from the US subjects of the MA-17 study. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-2047, 2005.
citation: Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005 Sep 7;97(17):1262-71. doi: 10.1093/jnci/dji250.
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citation: Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802. doi: 10.1056/NEJMoa032312. Epub 2003 Oct 9.
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citation: 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.