Clinical trial NCT01160718: Fulvestrant With or Without AZD6244 in Treating Patients With Advanced Breast Cancer That Progressed After Aromatase Inhibitor Therapy
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: 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
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2010-07-12
Enrollment: 46
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility 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

Primary outcomes:
measure: Disease control (sum of complete response, partial response, and stable disease) at 24 weeks or more according to RECIST 1.1 criteria
timeFrame: at 24 weeks or more according to RECIST 1.1 criteria
Secondary outcomes:
measure: Adverse events
timeFrame: according to NCI CTCAE v 4.0
measure: Overall response
timeFrame: according to RECIST 1.1
measure: Progression-free survival
timeFrame: will be calculated from randomization until documented tumor progression or death, whichever occurs first.
measure: Time to treatment failure
timeFrame: will be calculated from randomization to discontinuation of all trial treatment due to any reason
measure: Duration of response
timeFrame: will be calculated from the time that measurement criteria are met for the first time until documented tumor progression.
measure: Overall survival
timeFrame: Overall survival will be calculated from registration until death
Other outcomes:
Locations:
city: Ghent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Baden
country: Switzerland
facility: Kantonsspital Baden
city: Basel
country: Switzerland
facility: Universitaetsspital-Basel
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Biel
country: Switzerland
facility: Spitalzentrum Biel
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden
city: Frauenfeld
country: Switzerland
facility: Brustzentrum Thurgau at Kantonsspital Frauenfeld
city: Geneva
country: Switzerland
facility: Hopitaux Universitaires de Geneve
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Luzerne
country: Switzerland
facility: Kantonsspital Luzern
city: Mendrisio
country: Switzerland
facility: Oncology Institute of Southern Switzerland - Mendrisio
city: Morges
country: Switzerland
facility: Hopital de Morges
city: St. Gallen
country: Switzerland
facility: Kantonsspital - St. Gallen
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: City Hospital Triemli
Study officials:
affiliation: Centre Hospitalier Universitaire Vaudois
name: Khalil Zaman, MD
role: STUDY_CHAIR
affiliation: Hopital de Morges
name: Lucien Perey, MD
role: STUDY_CHAIR
affiliation: University Hospital, Gasthuisberg
name: Patrick Neven, MD, PhD
role: STUDY_CHAIR
References:
citation: Zaman K, Winterhalder R, Mamot C, Hasler-Strub U, Rochlitz C, Mueller A, Berset C, Wiliders H, Perey L, Rudolf CB, Hawle H, Rondeau S, Neven P. Fulvestrant with or without selumetinib, a MEK 1/2 inhibitor, in breast cancer progressing after aromatase inhibitor therapy: a multicentre randomised placebo-controlled double-blind phase II trial, SAKK 21/08. Eur J Cancer. 2015 Jul;51(10):1212-20. doi: 10.1016/j.ejca.2015.03.016. Epub 2015 Apr 16.