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

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