Fulvestrant With or Without AZD6244 in Treating Patients With Advanced Breast Cancer That Progressed After Aromatase Inhibitor Therapy

OBJECTIVES:

Primary

• To assess the efficacy of fulvestrant with versus without MEK inhibitor AZD6244 in patients with advanced stage, endocrine-sensitive breast cancer that progressed after aromatase inhibitor therapy.

Secondary

• To assess the safety and tolerability of this regimen in these patients.
• To examine other outcome parameters.
• To develop a virtual tissue bank for future translational research.

OUTLINE: This is a multicenter study. Patients are stratified according to center, prior treatment with tamoxifen citrate (yes vs no), the setting in which prior aromatase inhibitor was given (adjuvant treatment vs advanced stage treatment), HER-2 disease (positive vs negative), visceral metastasis (present vs absent), performance status (0 vs 1 or 2), and disease (measurable disease vs bone-only disease or small but unequivocal liver or lung metastases). Patients are randomized to 1 of 2 treatment arms.

• Arm I (experimental): Patients receive fulvestrant intramuscularly (IM) on days 1 and 15 of course 1 and on day 1 of each subsequent course. Patients also receive oral AZD6244 twice daily on days 1-28. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.
• Arm II (control): Patients receive fulvestrant as in arm I. Patients also receive oral placebo twice daily on days 1-28. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 1 year and then every 6 months thereafter.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed breast cancer

• Not amenable to curative therapy
• HER-2 positive disease allowed
• Disease relapse or progression after aromatase inhibitor as adjuvant therapy or for advanced stage disease
• Bilateral breast cancer allowed provided tumor endocrine sensitivity has been proven on both sides
• Measurable disease according to RECIST criteria v1.1 or other lesions assessable by radiological exams (i.e., bone-only disease or small but unequivocal liver or lung metastases)
• Received no more than 1 line of chemotherapy for advanced stage disease
• Estrogen receptor- and/or progesterone receptor-positive (≥ 10% tumor cells positive by immunohistochemistry or ≥ 10 fmol/mg cytosol protein by ligand binding assay)
• No known CNS metastases

• Patients with brain metastases treated with radiotherapy and without any sign of brain progression after ≥ 3 months since the end of radiotherapy may be considered eligible after trial chair approval)

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• Postmenopausal
• Hemoglobin ≥ 90 g/L
• Platelet count ≥ 100 x 10^9/L
• Absolute neutrophil count ≥ 1.5 x 10^9/L
• Creatinine clearance ≥ 30 mL/min
• ALT ≤ 2.5 times upper limit of normal (ULN) (≤ 5 times ULN in patients with liver metastases)
• Bilirubin ≤ 1.5 times ULN
• INR < 1.6
• PTT normal
• LVEF ≥ 50%
• Able to swallow AZD6244/placebo capsules
• Capable of understanding information given by the investigator on the trial
• Must adhere to and be geographically proximal to allow for proper staging, treatment, and follow up
• No contraindication for intramuscular injections
• No bleeding diathesis
• No current or prior malignancy other than breast cancer within the past 5 years, except carcinoma in situ of the cervix or basal cell carcinoma of the skin treated curatively
• No serious underlying medical condition that, in the judgment of the investigator, would impair the ability of the patient to participate in the trial (e.g., active autoimmune disease or uncontrolled diabetes)
• No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that preclude adequate absorption
• No psychiatric disorder precluding understanding of information on trial-related topics, giving informed consent, or interfering with adherence for oral drug intake
• No uncontrolled hypertension (systolic BP > 150 mm Hg and/or diastolic BP > 100 mm Hg, measured repeatedly at more than two visits despite adequate treatment with at least two different antihypertensive drugs)
• No clinically significant (i.e., active) cardiovascular disease, including any of the following:

• Cerebrovascular accident/stroke or myocardial infarction within the past 6 months
• Unstable angina
• NYHA class III-IV congestive heart failure
• Serious cardiac arrhythmia or AV-block > 1, requiring medication during the trial and which might interfere with regularity of the trial treatment, or not controlled by medication
• No known hypersensitivity to trial drugs or any other component of the trial drugs

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 30 days since other prior experimental drugs or participation in another clinical trial
• No prior fulvestrant, AZD6244, MEK inhibitors, RAF inhibitors, or endocrine therapies other than aromatase inhibitors (e.g., anastrazole, letrozole, or exemestane) or tamoxifen
• No more than 1 line of aromatase inhibitors (steroidal and nonsteroidal aromatase inhibitors are considered two different lines)
• No concurrent full-dose anticoagulation therapy (e.g., low molecular weight heparin, acenocoumarol, phenprocoumon, or analogues)

• Prophylactic doses of anticoagulation or antiplatelet may be allowed
• No concurrent radiotherapy
• No other concurrent anticancer therapy or experimental drugs
• Concurrent bisphosphonate allowed provided the investigator rules out tumor progression