This phase I trial studies the side effects and the best dose of MK 2206 (Akt inhibitor MK2206) when given with anastrozole, fulvestrant, or anastrozole and fulvestrant in treating postmenopausal women with breast cancer that has spread to other parts of the body. Estrogen can cause the growth of breast cancer cells. Hormone therapy using anastrozole or fulvestrant may fight breast cancer by lowering the amount of estrogen the body makes. Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving Akt inhibitor MK2206 together with anastrozole, fulvestrant, or anastrozole and fulvestrant may kill more tumor cells.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of MK-2206 in combination with anastrozole based on toxicities observed during cycle 1 therapy. (Phase IA) II. To evaluate the tolerability of prolonged administration (3 months) of MK-2206 in combination with anastrozole at the MTD defined in Phase IA. (Phase IB) III. To determine the recommended phase II treatment dosing (RPTD) of MK-2206 in combination with anastrozole based on toxicities observed with prolonged drug administration. (Phase IB) IV. To determine the tolerability of fulvestrant (Arm C), or fulvestrant plus anastrozole (Arm D), respectively, in combination with MK-2206 (at the RPTD defined in Phase 1B). (Arms C and D) V. To determine the recommended phase II treatment dose (RPTD) of fulvestrant (Arm C) or fulvestrant plus anastrozole (Arm D), respectively, in combination with MK-2206 based on toxicities observed with prolonged drug administration (3 months). (Arms C and D) VI. To evaluate the toxicity profile of MK-2206 in combination with fulvestrant (Arm C) or fulvestrant plus anastrozole (Arm D), respectively, with prolonged drug administration. (Arms C and D) SECONDARY OBJECTIVES: I. To evaluate the toxicity profile of MK-2206 in combination with anastrozole, or fulvestrant, or anastrozole plus fulvestrant. II. To evaluate the clinical benefit rate (CBR: complete response \[CR\]+partial response \[PR\]+stable disease \[SD\] \> 6 months), response rate (CR+PR), and percent of patients progression free at 6 months with the treatment of MK-2206 in combination with anastrozole, or fulvestrant or anastrozole plus fulvestrant in patients with estrogen receptor positive (ER+) metastatic breast cancer. III. To examine serum levels of estradiol prior to and following 1 cycle of MK-2206 therapy. TERTIARY OBJECTIVES: I. To examine baseline tumor specimens for alterations in phosphatidylinositol 3 kinase (PI3K) and other pathway genes and to explore their relationship with treatment response. II. To evaluate the effect of MK-2206 on tumor cell v-akt murine thymoma viral oncogene homolog 1 (AKT) signaling, proliferation, and apoptosis using serially collected tumor samples in available cases. III. To examine changes in tumor cell glucose uptake by positron emission tomography (PET) with 2-\[18F\]fluoro-2-deoxy-D-glucose (FDG) at baseline and 24 h post day 1 MK-2206. (Phase IA) IV. To examine the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation status in circulating deoxyribonucleic acid (DNA) at baseline and following study therapy and to correlate with tumor tissue PIK3CA status and treatment response. OUTLINE: This is a phase I, dose-escalation study of Akt inhibitor MK2206 followed by a recommended phase II dose (RPTD) study. Patients are assigned to the treatment arm that is currently open. ARM A: Patients receive anastrozole orally (PO) on days 1-28. Beginning in course 2, patients receive Akt inhibitor MK-2206 PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: The RPTD of Akt inhibitor MK2206 with anastrozole is determined after 3 courses, administered as in Arm A. ARM C: Patients receive Akt inhibitor MK2206 PO on days 1, 8, 15, and 22, fulvestrant intramuscularly (IM) on day 1 and day 15 of course 1 and then on day 1 of each course in each subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM D: Patients receive Akt inhibitor MK2206 PO as in Arm A, anastrozole PO on days 1-28 and fulvestrant IM on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. NOTE: As of 8/19/2015, in all Arms, patients no longer receive Akt inhibitor MK2206. After completion of study therapy, patients are followed up for 30 days.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
31
Washington University School of Medicine
St Louis, Missouri, United States
MTD of Akt inhibitor MK-2206 in combination with anastrozole determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) (Phase IA)
Data analysis for the study will be descriptive in nature. Demographic and clinical characteristics of the subjects, toxicity by grade, adverse events, serious adverse events and death will be listed and summarized using descriptive statistics for each dose level.
Time frame: 4 weeks
RPTD of Akt inhibitor MK-2206 in combination with anastrozole evaluated by the tolerability of prolonged administration at the MTD assessed by CTCAE v4.0 (Phase IB)
Data analysis for the study will be descriptive in nature. Demographic and clinical characteristics of the subjects, toxicity by grade, adverse events, serious adverse events and death will be listed and summarized using descriptive statistics for each dose level.
Time frame: 3 months
RPTD of fulvestrant in combination with Akt inhibitor MK-2206 assessed by CTCAE v4.0 (ARM C)
Data analysis for the study will be descriptive in nature. Demographic and clinical characteristics of the subjects, toxicity by grade, adverse events, serious adverse events and death will be listed and summarized using descriptive statistics for each dose level.
Time frame: 3 months
RPTD of anastrozole plus fulvestrant in combination with Akt inhibitor MK-2206 assessed by CTCAE v4.0 (ARM D)
Data analysis for the study will be descriptive in nature. Demographic and clinical characteristics of the subjects, toxicity by grade, adverse events, serious adverse events and death will be listed and summarized using descriptive statistics for each dose level.
Time frame: 3 months
Incidence of toxicity, assessed by CTCAE v4.0
Time frame: Up to 30 days post-treatment
Clinical benefit rate (CR+PR+SD for more than 6 months)
Time frame: Up to 30 days post-treatment
Serum levels of estradiol prior to and following 1 course of Akt inhibitor MK-2206 therapy
Time frame: Up to day 28
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