Akt Inhibitor MK2206 in Treating Patients With Advanced Breast Cancer

PRIMARY OBJECTIVES:

I. To determine whether v-akt murine thymoma viral oncogene (Akt) inhibitor MK2206 achieves
objective tumor responses (complete response [CR], partial response [PR]) in advanced breast
cancer patients who have a phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA)
or Akt mutation and/or phosphatase and tensin homolog (PTEN) loss or mutation.

SECONDARY OBJECTIVES:

I. To determine the 6 month progression-free survival on MK2206. II. To determine baseline
molecular markers that may predict clinical outcome. III. To determine pharmacodynamic
markers in blood and tumor tissue that may predict a decrease in proliferation-related Ki-67
antigen (Ki-67) and clinical outcome.

IV. To determine safety and tolerability of MK2206 in previously treated patients with
advanced breast cancer.

V. To determine if decrease in Ki-67 at 2 weeks correlates with anti-tumor effect (CR, PR, or
stable disease [SD] > 6 months).

VI. To determine concordance of PIK3CA and PTEN status between primary tumor and distant
metastasis.

VII. To determine concordance of PIK3CA status of circulating free deoxyribonucleic acid
(DNA) and distant metastasis.

OUTLINE:

Patients receive Akt Inhibitor MK-2206 orally (PO) on days 1, 8, 15, and 22. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 weeks.

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 human epidermal growth factor
receptor 2 (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 estrogen
receptor positive (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 fine needle aspirate (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
Clinical Laboratory Improvement Amendments (CLIA) environment and have been found to
have a PIK3CA mutation or Akt mutation or PTEN loss by immunohistochemistry (IHC) or
PTEN 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 PTEN mutation will have their marker status confirmed in the CLIA
environment

- 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 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 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/uL

- Platelets >= 100,000/uL

- 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

- 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
phosphatidylinositol 3 kinase (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;
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 cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP 450 3A4) are
ineligible; however, patients will be permitted regular dietary consumption of
caffeine; glyburide will be allowed for the treatment of hyperglycemia

- Patients with diabetes or in risk for hyperglycemia should not be excluded, but
patients with poorly controlled diabetes (glycated hemoglobin [HBA1C] > 8%) should be
excluded

- Baseline corrected QT by Fridericia's formula (QTcF) > 450 msec (male) or QTcF >b470
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; breastfeeding should be discontinued if
the mother is treated with MK2206

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- 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