A Phase 1 Trial of MK-2206 in Combination With Anastrozole, Fulvestrant, or Anastrozole Plus Fulvestrant in Postmenopausal Women With Estrogen Receptor Positive Metastatic Breast Cancer

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed invasive breast cancer
that is metastatic stage IV or recurrent metastatic (histologic/cytologic
confirmation of recurrence preferred, but not required)

- Either the primary or the metastatic tumor must be positive for estrogen-receptor (>
1% tumor cell staining by immunohistochemistry or an Allred Score of >= 3 by
immunohistochemistry)

- Patient must have measurable or non-measurable lesions (defined by Response
Evaluation Criteria In Solid Tumors [RECIST] 1.1 criteria)

- To be eligible for the positron emission tomography
2-[18F]fluoro-2-deoxy-D-glucose (FDG PET) imaging studies in Phase IA, the
presence of measurable lesions of at least 1.5 cm or the presence of bone
lesions is required

- Patients may not have had disease progression on anastrozole (Arm A and Arm B),
letrozole (Arm C), exemestane (Arm D), or fulvestrant (Arm E) in either the
neoadjuvant, adjuvant (defined as disease recurrence identified within 6 months of
adjuvant discontinuation), or metastatic setting

- Patients with known brain metastases are eligible if stable (no evidence of local
progression) > 3 months after local therapy and are off steroids

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (Karnofsky PS
70-100%)

- Patients must be postmenopausal as defined by one of the following:

- Women > 60 years

- Women =< 60 years with spontaneous cessation of menses > 12 months prior to
registration

- Women =< 60 years with cessation of menses of duration < 12 months or secondary
to hysterectomy AND an FSH (follicle-stimulating hormone) level in the
postmenopausal range according to institutional standards (or > 34.4 IU/L if
institutional range is not available) prior to registration

- Women =< 60 years on hormonal replacement therapy who have discontinued hormonal
therapy AND an FSH level in the postmenopausal range according to institutional
standards (or > 34.4 IU/L if institutional range is not available) prior to
registration

- Status post bilateral surgical oophorectomy

- Premenopausal women on a gonadotropin-releasing hormone (GnRH) analog

- Patients must have a life expectancy greater than 4 months

- Leukocytes >= 3,000/mm^3

- Absolute neutrophil count (ANC) >= 1,5000/mm^3

- Platelet count >= 100,000/mm^3

- Total bilirubin normal

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 times upper
limit of normal

- Creatinine normal OR creatinine clearance >= 60 mL/min

- If patients have diabetes mellitus, fasting glucose must be =< 120 mg/dL and
hemoglobin (Hb)A1c =< 8%

- Patients may not have a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to Akt inhibitor MK2206 (MK-2206) or other
agents used in the study

- Baseline QTcF > 450 msec (male) or QTcF > 470 msec (female) will exclude patients
from entry on study

- Patients may not have uncontrolled intercurrent illness including, but not limited
to; ongoing or active infection, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements

- Patients with known human immunodeficiency virus (HIV)-positive status are excluded
from this study

- Patients may not have had grade 3 or intolerable grade 2 adverse events during run-in
AI or fulvestrant therapy prior to starting MK-2206

- See Disease Characteristics

- Patients may have undergone any number of prior lines of chemotherapy or endocrine
regimens but must not have a history of disease progression on anastrozole (Arm A and
Arm B), letrozole (Arm C), exemestane (Arm D), or fulvestrant (Arm E)

- Patients on Arm A and Arm B must meet one of the following criteria:

- Currently being treated with anastrozole with no evidence of disease
progression

- Currently being treated with letrozole or exemestane with no evidence of
disease progression and willing to switch to anastrozole for study

- Considering switching to anastrozole due to disease progression from the
most recent anti-cancer therapy

- Patients on Arm C must meet one of the following criteria:

- Currently being treated with letrozole with no evidence of disease
progression

- Currently being treated with anastrozole or exemestane with no evidence of
disease progression and willing to switch to letrozole for study

- Considering switching to letrozole due to disease progression from the most
recent anti-cancer therapy

- Patients on Arm D must meet one of the following criteria:

- Currently being treated with exemestane with no evidence of disease
progression

- Currently being treated with anastrozole or letrozole with no evidence of
disease progression and willing to switch to exemestane for study
enrollment

- Considering switching to exemestane due to disease progression from the
most recent anti-cancer therapy

- Patients on Arm E must meet one of the following criteria:

- Currently being treated with fulvestrant with no evidence of disease
progression

- Considering switching to fulvestrant due to disease progression from the
most recent anti-cancer therapy

- Patients may not have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study

- Patient must have recovered from adverse events due to agents administered more
than 4 weeks earlier

- Patients may not have had prior therapy with a PI3K/Akt/mTOR inhibitor

- Patients may not be receiving any other investigational agent

- Patients receiving any medications or substances that are strong inhibitors or
inducers of CYP 450 3A4 are ineligible

- One-week washout period is required for patients who were previously taking
strong inhibitors or inducers of CYP450 3A4

- Patients who are currently taking moderate inhibitors or inducers of CYP450 3A4
are encouraged to switch to other medications that do not interact with CYP450
3A4