Clinical Drug Experience Knowledgebase

Criteria

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