Official Title: “Phase II Pilot of Aromatase Inhibitor Therapy With Femara® (Letrozole) and Ovarian Suppression in Premenopausal Estrogen Receptor Positive Women With Stage IV Carcinoma of the Breast”

RATIONALE: Aromatase inhibitors, such as letrozole, prevent the formation of estradiol, a female hormone. Giving letrozole together with goserelin, leuprolide, or surgery may be an effective treatment in women with hormone-dependent breast cancer.

PURPOSE: This phase II trial is studying how well giving letrozole together with goserelin or leuprolide works in treating premenopausal estrogen receptor-positive patients with stage IV breast cancer.

Study Type: Interventional

Study Design: Treatment, Open Label

Study Primary Completion Date: December 2010

OBJECTIVES:

Primary - To measure overall response rate (ORR) in premenopausal women treated with an aromatase inhibitor (AI) and ovarian suppression (OS).

Secondary - To measure time to treatment failure (TTF) in premenopausal women treated with an AI and OS. - To measure time to progression (TTP) in premenopausal women treated with an AI and OS. - To measure time to death in premenopausal women treated with an AI and OS. - To assess the clinical benefit rate (CBR) in premenopausal women treated with an AI and OS. - To measure the qualitative and quantitative toxicity of an AI and OS. - To determine whether ORR, TTP, and CBR are similar to what is seen in postmenopausal women treated with an AI. - To determine whether ORR, TTP, and CBR are similar to what is seen in premenopausal women treated with tamoxifen and OS. - To determine if levels of estrogen (i.e., estradiol or estrone) are adequately suppressed in premenopausal women on an AI and OS.

OUTLINE: This is a pilot, open-label study.

Patients undergo surgical ovarian suppression (OS) or medical OS with luteinizing hormone-releasing hormone (LHRH) agonist (i.e., goserelin or leuprolide acetate, intramuscularly once monthly for 3 months and then every 2 months thereafter for the duration of study therapy). Beginning on day 14 after initiation of LHRH-agonist therapy or surgery, patients receive oral letrozole once daily. Treatment continues in the absence of disease progression or unacceptable toxicity.

Menopausal status is tested periodically during study by measuring serum estradiol levels.

Patients not converting to a menopausal state after the first month of study therapy, receive a higher dose of LHRH and undergo repeat estradiol testing in the second month. If the patient continues to be premenopausal, they are then considered for bilateral salpingo-oophorectomy or removed from study.

After completion of study therapy, patients are followed every 3 months for 2 years, every 6 months for 2 years, and annually thereafter.

Intervention(s) in this Clinical Trial

• Drug: goserelin
• Drug: letrozole
• Drug: leuprolide acetate
• Procedure: conventional surgery

Primary Measures

• Overall response rate as measured by RECIST
  • Safety Issue?: No

Secondary Measures

• Time to treatment failure
  • Safety Issue?: No
• Time to progression
  • Safety Issue?: No
• Time to death
  • Safety Issue?: No
• Clinical benefit rate
  • Safety Issue?: No
• Qualitative and quantitative toxicity as assessed by NCI CTCAE v3.0
  • Safety Issue?: Yes
• Disease-free survival
  • Safety Issue?: No
• Overall survival
  • Safety Issue?: No
• Safety
  • Safety Issue?: Yes
• Comparison of response with results of previous studies of postmenopausal women treated with aromatase inhibitor (AI) therapy and of premenopausal women treated with ovarian suppression (OS) and tamoxifen
  • Safety Issue?: No
• Determination of adequacy of estrogen suppression by AI therapy and OS
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically confirmed carcinoma of the breast
• Metastatic disease
• Measurable disease (i.e., unidimensional by RECIST)
• No rapidly progressing visceral involvement (e.g., liver or lymphangitic lung disease)
• No known marrow involvement as evidenced by diffuse uptake by imaging studies or bone marrow biopsy or aspirate
• No evidence of CNS metastases
• Estrogen- and/or progesterone-receptor positive status confirmed in primary breast tumor or in recent biopsy of metastatic site

PATIENT CHARACTERISTICS:

• Female
• Premenopausal*, as defined by the following criteria:
• Less than 12 months from last menstrual period or premenopausal estradiol within the past 12 months
• No prior bilateral oophorectomy
• 45 years old or younger with intact ovaries and not a candidate for aromatase inhibitor therapy alone due to the potential for recurrent ovarian function NOTE:
• *Women are considered premenopausal after prior hysterectomy if they have intact ovaries and follicular hormone levels consistent with the institutional normal values for the premenopausal state
• Women meeting premenopausal criteria prior to receiving ovarian suppression are eligible
• ECOG performance status 0-2
• Life expectancy ≥ 3 months
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective nonhormonal contraception during and for 12 weeks after discontinuation of study therapy
• ANC ≥ 500 cells/mm³
• Platelet count ≥ 50,000 cells/mm³
• Hematocrit ≥ 28%
• In the absence of liver metastases:
• AST and ALT ≤ 2.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 2.5 times ULN
• In the presence of liver metastases:
• AST and ALT ≤ 5 times ULN
• Alkaline phosphatase ≤ 5 times ULN
• In the presence of bone metastases:
• AST and ALT ≤ 10 times ULN
• Alkaline phosphatase ≤ 10 times ULN
• Total bilirubin ≤ 2 times ULN
• No significant comorbid conditions, including any of the following:
• Clinically significant cardiac disease not well controlled with medication (e.g., congestive heart failure, symptomatic coronary artery disease, or cardiac arrhythmias)
• Myocardial infarction within the past 12 months
• Serious concurrent infection
• No lack of physical integrity of the upper gastrointestinal tract
• No inability to swallow or malabsorption syndrome
• No other carcinoma within the past 5 years except nonmelanoma skin cancer and treated in situ cervical cancer
• No mental illness
• No known hypersensitivity to luteinizing hormone-releasing hormone (LHRH), LHRH-agonist analogues, or any of the components in goserelin

PRIOR CONCURRENT THERAPY:

• No concurrent chemotherapy and/or additional hormonal therapy
• Concurrent trastuzumab (Herceptin®) for patients with HER2 overexpression allowed

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Fred Hutchinson Cancer Research Center

Overall Clinical Trial Officials and Contacts

Hannah M. Linden, MD Principal Investigator University of Washington  

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00498901

Study ID Number: CDR0000553612

ClinicalTrials.gov Identifier: NCT00498901

Health Authority: Unspecified

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