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

Study Overview
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Brief Summary
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RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. AZD6244 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether fulvestrant is more effective with or without AZD6244 in treating patients with advanced breast cancer. PURPOSE: This randomized phase II trial is studying how well fulvestrant works with or without AZD6244 in treating patients with advanced breast cancer that progressed after aromatase inhibitor therapy.

Detailed Description
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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.

Official Title
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Fulvestrant With or Without AZD6244, a Mitogen-Activated Protein Kinase Kinase (MEK) ½ Inhibitor, in Advanced Stage Breast Cancer Progressing After Aromatase Inhibitor: A Randomized Placebo-Controlled Double-Blind Phase II Trial

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: fulvestrant
* Drug: selumetinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Fulvestrant / AZD6244<br>Fulvestrant 500mg i.m. day 1, 15, day 1 of cycle 2, then every 28 +/- 3 days AZD6244 75 mg p.o. bid | Drug: fulvestrant<br>* Arm A: Fulvestrant 500mg i.m. day 1, 15, day 1 of cycle 2, then every 28 +/- 3 days Arm B: Fulvestrant 500mg i.m. day 1, 15, day 1 of cycle 2, then every 28 +/- 3 days<br>* Other names: ZD9238;Drug: selumetinib<br>* AZD6244 75 mg p.o. bid<br>* Other names: AZD6244;|
| Placebo Comparator: Arm B: Fulvestrant / Placebo<br>Fulvestrant 500mg i.m. day 1, 15, day 1 of cycle 2, then every 28 +/- 3 days Placebo 3 caps p.o. bid (same appearance as AZD6244) | Drug: fulvestrant<br>* Arm A: Fulvestrant 500mg i.m. day 1, 15, day 1 of cycle 2, then every 28 +/- 3 days Arm B: Fulvestrant 500mg i.m. day 1, 15, day 1 of cycle 2, then every 28 +/- 3 days<br>* Other names: ZD9238;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control (sum of complete response, partial response, and stable disease) at 24 weeks or more according to RECIST 1.1 criteria |  | at 24 weeks or more according to RECIST 1.1 criteria | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events |  | according to NCI CTCAE v 4.0 | 
| Overall response |  | according to RECIST 1.1 | 
| Progression-free survival |  | will be calculated from randomization until documented tumor progression or death, whichever occurs first. | 
| Time to treatment failure |  | will be calculated from randomization to discontinuation of all trial treatment due to any reason | 
| Duration of response |  | will be calculated from the time that measurement criteria are met for the first time until documented tumor progression. | 
| Overall survival |  | Overall survival will be calculated from registration until death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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estrogen receptor-positive breast cancer, HER2-positive breast cancer, HER2-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer