Phase II Trial of Akt Inhibitor MK2206 in Patients With Advanced Breast Cancer Who Have Tumors With a PIK3CA Mutation and/or PTEN Loss

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed breast cancer, with
diagnosed or suspected metastatic, inoperable locally advanced breast cancer, or
inoperable locally recurrent breast cancer

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as > 20 mm with conventional
techniques or as > 10 mm with spiral computed tomography (CT) scan

- Patients who have failed to respond to at least one line of systemic therapy are
eligible for MK2206 therapy; if the patient has a HER2 positive tumor, it is expected
that they will have received at least one HER2-targeted therapy in the metastatic
setting; if the patient has an ER+ tumor, it is expected that they will have received
at least one ER-targeted therapy in the metastatic setting; patients can be enrolled
for molecular screening while on another therapy if the patient is interested in
MK2206 therapy upon progression

- Archived primary tumor biopsies or surgical specimens, or biopsies of recurrence or
metastasis, will be available for PIK3CA/Akt mutational analysis and PTEN analysis;
patients with surgical samples, or core/punch biopsies available, will be eligible
for testing for PIK3CA/Akt status as well as PTEN testing; the most recent sample
will be preferred (i.e. in patients with metastatic disease, metastases samples are
preferred over archival primary tumor and in patients with local recurrences a biopsy
of the recurrence is preferred over archival primary tumor); NOTE: PIK3CA or Akt
mutation status can be determined on FNA samples, but PTEN status cannot as stroma
and endothelial cells are used as internal controls and PTEN testing has not been
validated on FNA samples; thus patients with only FNA samples and no tissue blocks
available will be considered to be eligible for screening for PIK3CA/Akt mutations
and will be enrolled onto the study only if they are found to have PIK3CA mutations
or Akt mutations; patients whose tumors have already been tested in the CLIA
environment and have been found to have a PIK3CA mutation or Akt mutation or PTEN
loss will be eligible for treatment; patients whose tumors have been tested in the
research environment and found to have a PIK3CA mutation or Akt mutation or PTEN loss
will have their marker status confirmed in the CLIA environment

- Patients whose tumors have already been tested in the Clinical Laboratory Improvement
Amendments (CLIA) environment and have been found to have a PIK3CA mutation or Akt
mutation or PTEN loss or mutation will be eligible for treatment; patients whose
tumors have been tested in the research environment and found to have a PIK3CA
mutation or Akt mutation or PTEN loss or mutation will have their marker status
confirmed in the CLIA environment

- Patient will have a tumor suitable for fine needle aspirate (FNA) and/or core/punch
biopsy for research purposes

- Patient must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Absolute neutrophil count (ANC) >= 1,000 /μL

- Platelets >= 100,000 / μL

- Hemoglobin (Hgb) >= 9 g/dL

- Creatinine =< 1.5 X upper limit of normal (ULN)

- Prothrombin time (PT), partial thromboplastin time (PTT) =< 1.2 X ULN

- Total bilirubin =< 1.5 X ULN

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 X ULN

- Patients of childbearing potential must have a negative serum or urine pregnancy test
beta-human chorionic gonadotropin (hCG) within 72 hours prior to study registration

- The effects of MK2206 on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason, women of childbearing potential and men must use
two forms of contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry, for the duration of study participation and also for 4 weeks
after the end of therapy; should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, the patient should inform
the treating physician immediately

- Patient must have completed any systemic therapy regimens and therapeutic radiation a
minimum of 21 days prior to initiation of study therapy

- Ability to understand and the willingness to sign a written informed consent document

- >= 6 months life expectancy as documented in patient records

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events to grade 1 or less due to agents administered more than
3 weeks earlier

- Patients may have received prior investigational therapies; however, they not be
receiving any other investigational agents concurrent with MK2206; patients must have
completed therapy a minimum of 21 days prior to initiation of study therapy

- Patients may not have received treatment with another inhibitor of PI3K, Akt or
mammalian target of rapamycin (mTOR) in the neoadjuvant, adjuvant or metastatic
setting with the exception of rapalogs; patients with metastatic breast cancer, who
received PI3K/Akt/mTOR inhibitors on short preoperative window trials (treatment for
4 weeks or less), will be eligible if the treatment was over 6 months prior to
registration; patients must have completed therapies a minimum of 21 days prior to
initiation of study therapy

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse
events; patients will not undergo pre-treatment imaging of the brain, unless
clinically indicated

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK2206 or other agents used in the study

- Patients receiving any medications or substances that are potent inhibitors or
inducers of CYP 450 3A4 are ineligible; however, patients will be permitted regular
dietary consumption of caffeine; glyburide will be allowed for the treatment of
hyperglycemia

- Preclinical studies demonstrated the potential of MK2206 for induction of
hyperglycemia in all preclinical species tested; patients with diabetes or in risk
for hyperglycemia should not be excluded from trials with MK2206, but patients with
poorly controlled diabetes (HBA1C > 8%) should be excluded

- Preclinical studies indicated transient changes in QTc interval during MK2206
treatment; prolongation of QTc interval is potentially a safety concern while on
MK2206 therapy; cardiovascular: baseline QTcF > 450 msec (male) or QTcF >470 msec
(female) will exclude patients from entry on study

- 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

- Baseline bradycardia related to cardiac disease, or significant bundle branch block

- Pregnant women are excluded from this study because MK2206 is an agent with the
potential for teratogenic or abortifacient effects; because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with MK2206, breastfeeding should be discontinued if the mother is treated
with MK2206

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
MK2206; in addition, these patients are at increased risk of lethal infections when
treated with marrow-suppressive therapy; appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated

- Patients at high risk for coagulopathy

- Liver disease burden greater or equal to 50 percent

- Need for blood or platelet transfusion within one month from baseline laboratory
testing as well as within treatment initiation