Official Title: “A Phase III Randomized Double Blind Study of Vorozole 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 Type: Interventional

Study Design: Treatment, Randomized, Double-Blind, Placebo Control

Study Primary Completion Date: September 2002

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.

Intervention(s) in this Clinical Trial

• Drug: letrozole
  • Given orally
• Other: placebo
  • Given orally

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Arm I
  • Patients receive oral letrozole once daily.
• Placebo Comparator: Arm II
  • Patients receive oral placebo once daily.

Primary Measures

• Disease-free survival
  • Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Cancer Institute of Canada

Overall Clinical Trial Officials and Contacts

Paul E. Goss, MD, PhD Study Chair Massachusetts General Hospital  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00003140

Study ID Number: CDR0000065921

ClinicalTrials.gov Identifier: NCT00003140

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database