MK2206 in Treating Patients With Stage I, Stage II, or Stage III Breast Cancer

PRIMARY OBJECTIVES:

I. Assess for a decrease in phospho-Akt (Ser^473) levels in tissue after a pre-surgical
trial of weekly Akt inhibitor MK2206 (MK2206) (2 doses) in patients with operable invasive
breast cancer.

SECONDARY OBJECTIVES:

I. Evaluate the effects of MK2206 on the immunohistochemical expression of other PI3K/AKT
pathway biomarkers on pre-and post-MK2206 tumor tissue, such as phospho-S6 kinase.

II. Assess modulation of PI3K/AKT signaling following MK2206 use with reverse-phase protein
microarray analysis.

III. Explore whether PIK3CA mutations demonstrate different modulation of PI3K/Akt-pathway
signaling as compared to tumors with loss of PTEN.

IV. Explore whether MK2206 alters PI3K/Akt pathway signaling differently in hormone
receptor-positive/HER2-negative tumors, as compared to triple-negative or HER2-positive
breast cancers.

V. Evaluate whether tumor proliferation, as measured by Ki-67 staining of breast tumor
cells, is reduced in patients taking MK2206 pre-surgically and correlate Ki-67 modulation
with changes in PI3K/AKT signaling.

VI. Determine safety and tolerability of MK2206 in patients with early-stage breast cancer.

VII. Collect fasting blood for evaluation of predictive markers of drug effect, such as
markers in the insulin growth-factor receptor pathway (i.e., fasting insulin, c-peptide,
IGF-1, and IGFBP-1 and 3), as well as modulation of phospho-markers in peripheral blood
mononuclear cells.

OUTLINE: This is a multicenter study.

Patients receive Akt inhibitor MK2206 orally on days -9 and -2, and undergo segmental
resection or total mastectomy on day 0.

Blood is collected at baseline and before surgery for fasting insulin, c-peptide, IGF-1,
IGFBP-1 and 3, pharmacokinetics, and the pharmacodynamic effects of MK2206 on peripheral
blood mononuclear cells by western blotting and reverse-phase protein microarray (RPPA).
Tumor tissue samples are also collected at baseline and during surgery for PI3K/AKT pathway
and Ki-67 modulation by IHC and RPPA analysis.

After completion of therapy, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients must have histologically confirmed operable, invasive adenocarcinoma of the
breast and haveundergone core-needle biopsy with an anticipated surgical resection
for residual diseaseafter enrollment

- Clinical stage IB-IIIC invasive breast (invasive tumor must be ≥ T1c by radiograph or
palpation)

- Patients must have available tissue from core biopsies for biomarker assessment

- It is recommended that at least 4 cores be performed with 12-gauge (or smaller
gauge) needles, including cores underneath ultrasound-guidance

- Patients planning to undergo surgical treatment with either segmental resection or
total mastectomy required

- Patients may have a history of contralateral breast cancer, provided there is no
evidenceof recurrence of the initial primary breast cancer

- Patients must agree to biomarker assessment of pre-treatment diagnostic corebiopsy
tissue and the surgical resection tissue (i.e., excision or mastectomy) and also
agree to pre- and post-treatment fasting blood biomarker collection

- Patients may not have any known evidence of distant metastatic disease (i.e., lung,
liver,bone, or brain metastases) or locally recurrent breast cancer

- No inflammatory breast cancer

- Estrogen receptor, progesterone receptor, and HER2 positive or negative

- ECOG performance status (PS) 0-1 (Karnofsky PS 80-100%)

- Menopausal status not specified

- WBC ≥ 3,000/μL

- Platelet count ≥ 100,000/μL

- Hemoglobin ≥ 9 g/dL

- Creatinine ≤ 1.5 times upper limit of normal (ULN)

- PT, PTT ≤ 1.2 times ULN

- Total bilirubin ≤ 1.5 times ULN

- ALT and AST < 2.5 times ULN

- Negative pregnancy test

- Women of childbearing potential must use two forms of contraception (hormonal,
barrier method of birth control, or abstinence) prior to study entry and for the
duration of study participation

- Not pregnant or nursing

- Patient must be able to swallow oral tablets

- No history of allergic reactions attributed to compounds of similarchemical or
biologic composition to Akt inhibitor MK2206 used in the study

- No known diabetes that ispoorly controlled (HBA1C ≥ 8%)

- No baseline QTc > 470 msec

- No baseline bundle branch block

- No 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

- No concurrent combination antiretroviral therapy for HIV-positive patients

- More than 6 months since prior chemotherapy or radiotherapy

- Concurrent metformin allowed provided patient has been taking it for > 3 months

- No prior neoadjuvant therapy

- No other concurrent investigational agents, including other inhibitors of PI3K, Akt,
or mTOR