RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by blocking the uptake of estrogen. Drugs used in chemotherapy such as CCI-779 use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether letrozole is more effective with or without CCI-779 in treating patients with breast cancer.

PURPOSE: Randomizedphase II trial to compare the effectiveness of letrozole with or without CCI-779 in treating postmenopausal women who have locally advanced or metastatic breast cancer.

Condition	Treatment or Intervention	Phase
stage IIIB breast cancer stage IIIC breast cancer stage IV breast cancer recurrent breast cancer	Drug: CCI-779  Drug: letrozole  Procedure: antiestrogen therapy  Procedure: aromatase inhibition  Procedure: chemotherapy  Procedure: endocrine therapy  Procedure: hormone therapy	Phase II

Further Study Details: 

OBJECTIVES:

• Compare the objective response rate of postmenopausal women with locally advanced or metastatic breast cancer treated with letrozole with vs without CCI-779.
• Compare the overall response rate, including stable disease lasting at least 6 months, time to progression, and time to treatment failure, in patients treated with these regimens.
• Compare the pharmacokinetics of these regimens in these patients.
• Compare the safety of these regimens in these patients.
• Correlate the pharmacodynamics of these regimens with clinical response in these patients.
• Compare the impact of these regimens on patient-reported health outcomes.
• Compare progression-free rates at various intervals in patients treated with these regimens.
• Compare duration of response and overall survival of patients treated with these regimens.

OUTLINE: This is an open-label, randomized, multicenter study. Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive oral letrozole and oral CCI-779 daily.
• Arm II: Patients receive oral letrozole on days 1-14 and oral CCI-779 on days 1-5. Courses repeat every 14 days.
• Arm III: Patients receive oral letrozole daily on days 1-5. Courses repeat every 14 days. Patients with disease progression may cross over to oral CCI-779 alone on days 1-5 every 14 days. In all arms, treatment continues for up to 24 months in the absence of disease progression or unacceptable toxicity.

Patients are followed at 30 days and then every 3 months thereafter.

PROJECTED ACCRUAL: Approximately 108 patients (36 per treatment arm) will be accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed breast cancer
• Locally advanced disease
• Not amenable to curative surgery and/or radiotherapy OR
• Metastatic disease
• Stage IIIB, IIIC, or IV
• Measurable disease
• Presenting with de novo advanced or metastatic cancer OR tumor progression in 1 of the following ways:
• During or after completing adjuvant tamoxifen therapy
• During first-line metastatic therapy with tamoxifen
• Disease limited to the bone allowed provided at least 2 bone metastases exist (including at least 1 osteolytic lesion), each having a unilateral dimension of at least 1 cm
• No CNS metastases
• No hepatic metastases that constitute extensive visceral disease or are acutely life threatening
• No symptomatic pulmonary lymphangitic metastases
• No prior inflammatory breast cancer
• Must be appropriate to receive endocrine therapy as treatment for advanced disease
• Hormone receptor status:
• Estrogen and/or progesterone receptor positive

PATIENT CHARACTERISTICS: Age

• 18 and over

Sex

• Female

Menopausal status

• Postmenopausal defined by 1 of the following:
• Radiation-induced menopause or surgical bilateral oophorectomy
• Intact uterus and any of the following:
• Older than 55 years of age
• No menses for the past 5 years
• 55 years of age or younger and no menses for at least the past 12 months (but has had menses in the past 5 years) and postmenopausal levels of follicle-stimulating hormone (FSH) (i.e., concentration greater than the lower limit of normal)
• No intact uterus and either of the following:
• Older than 55 years of age
• 55 years of age or younger and has FSH levels in the postmenopausal range

Performance status

• ECOG 0-2

Life expectancy

• At least 6 months

Hematopoietic

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 8.5 g/dL

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST and ALT no greater than 3 times ULN (5 times ULN if liver metastases are present)
• Hepatitis B surface antigen negative
• Hepatitis C virus negative

Renal

• Creatinine no greater than 1.5 times ULN
• Calcium no greater than 11 mg/dL (2.75 mmol/L)

Cardiovascular

• No myocardial infarction within the past 6 months
• No unstable angina
• No known pulmonary hypertension

Other

• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 12 weeks after study participation
• Cholesterol no greater than 350 mg/dL (9.0 mmol/L)
• Triglycerides no greater than 400 mg/dL (4.56 mmol/L)
• Able to swallow whole tablets
• HIV negative
• Not immunocompromised
• No other malignancy within the past 5 years except appropriately treated carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, or contralateral breast cancer
• No other serious concurrent illness
• No known hypersensitivity to any of the components in letrozole or CCI-779
• No other major illness that would increase the risk associated with study participation

PRIOR CONCURRENT THERAPY: Biologic therapy

• At least 6 months since prior trastuzumab (Herceptin)
• At least 3 weeks since prior biologic therapy
• At least 3 weeks since prior immunologic therapy
• No concurrent immunotherapy
• No concurrent prophylactic use of growth factors except erythropoietic agents

Chemotherapy

• At least 6 months since prior adjuvant chemotherapy
• No prior chemotherapy for locally advanced disease or in the metastatic setting
• No concurrent cytotoxic chemotherapy
• No prior CCI-779

Endocrine therapy

• See Disease Characteristics
• At least 3 weeks since prior hormonal therapy (adjuvant or metastatic setting)
• Prior adjuvant antiestrogens allowed
• No prior aromatase inhibitors
• No other concurrent aromatase inhibitors
• No concurrent hormonal agents
• Concurrent corticosteroids for physiologic replacement allowed

Radiotherapy

• See Disease Characteristics
• At least 3 weeks since prior local radiotherapy
• No prior radiotherapy to more than 25% of the marrow
• Concurrent radiotherapy allowed with the following criteria:
• Palliative radiotherapy allowed for pain control or other reasons with no curative intent
• Tumor progression should be ruled out before therapy
• No radiotherapy to more than 25% of the bone marrow
• No radiotherapy including all of the target lesions

Surgery

• At least 3 weeks since prior surgery

Other

• At least 3 weeks since prior immunosuppressive agents
• No ongoing maintenance therapy for life-threatening ventricular arrhythmia
• No other concurrent anticancer therapy
• No other concurrent investigational therapy
• No concurrent immunosuppressive therapy
• No concurrent ketoconazole
• No concurrent phenobarbitol, carbamazepine, or phenytoin
• No concurrent Hypericum perforatum (St. John's wort)

Ohio
      Ireland Cancer Center, Cleveland,  Ohio,  44106-5055,  United States

Study chairs or principal investigators

Beth A. Overmoyer, MD,  Study Chair,  Ireland Cancer Center   

Study ID Numbers:  CDR0000302567; CWRU-080234; CWRU-WAGM01102; WYETH-C-3066A1-204-WW
Record last reviewed:  August 2004
Last Updated:  October 13, 2004
Record first received:  June 5, 2003
ClinicalTrials.gov Identifier:  NCT00061971
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08