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Pre-surgical Evaluation of MK-2206 in Patients With Operable Invasive Breast Cancer

Phase 2
18 Years
Not Enrolling
Estrogen Receptor-negative Breast Cancer, Estrogen Receptor-positive Breast Cancer, HER2-negative Breast Cancer, HER2-positive Breast Cancer, Progesterone Receptor-negative Breast Cancer, Progesterone Receptor-positive Breast Cancer, Stage IB Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Triple-negative Breast Cancer

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Trial Information

Pre-surgical Evaluation of MK-2206 in Patients With Operable Invasive Breast Cancer


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


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 phosphatase and tensin homolog(PTEN).

IV. Explore whether MK2206 alters PI3K/Akt pathway signaling differently in hormone
receptor-positive/human epidermal growth factor receptor (HER)2-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,
insulin-like growth factor (IGF)-1, and IGF binding protein (BP)-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 (PO) on days -9 and -2, and undergo segmental
resection or total mastectomy on day 0.

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 have undergone core-needle biopsy with an anticipated surgical resection
for residual disease after 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
evidence of recurrence of the initial primary breast cancer

- Patients must agree to biomarker assessment of pre-treatment diagnostic core-biopsy
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 human epidermal growth factor (HER)2
positive or negative

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

- Menopausal status not specified

- White blood cell count (WBC) >= 3,000/μL

- Platelet count >= 100,000/μL

- Hemoglobin >= 9 g/dL

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

- Prothrombin time (PT) and partial thromboplastin time (PTT) =< 1.2 times ULN

- Total bilirubin =< 1.5 times ULN

- Alanine aminotransferase (ALT) and aspartate aminotransferase (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 similar chemical or
biologic composition to Akt inhibitor MK2206 used in the study

- No known diabetes that is poorly controlled (glycosylated hemoglobin [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 human immunodeficiency virus
(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 mammalian target of rapamycin (mTOR)

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Change in phospho-Akt (Ser473) levels

Outcome Description:

A Wilcoxon signed-rank matched-pairs test will be used to compare expression levels in paired pre- and post-MK-2206 tissue.

Outcome Time Frame:

Baseline and day 0

Safety Issue:


Principal Investigator

Kevin Kalinsky

Investigator Role:

Principal Investigator

Investigator Affiliation:

Montefiore Medical Center


United States: Food and Drug Administration

Study ID:




Start Date:

April 2011

Completion Date:

Related Keywords:

  • Estrogen Receptor-negative Breast Cancer
  • Estrogen Receptor-positive Breast Cancer
  • HER2-negative Breast Cancer
  • HER2-positive Breast Cancer
  • Progesterone Receptor-negative Breast Cancer
  • Progesterone Receptor-positive Breast Cancer
  • Stage IB Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Triple-negative Breast Cancer
  • Breast Neoplasms



Montefiore Medical Center Bronx, New York  10467-2490