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A Phase II, 2-stage, 2-arm PIK3CA Mutation Stratified Trial of MK-2206 in Recurrent or Advanced Endometrial Cancer

Phase 2
18 Years
Open (Enrolling)
Endometrial Adenocarcinoma, Endometrial Adenosquamous Cell Carcinoma, Endometrial Clear Cell Carcinoma, Endometrial Papillary Serous Carcinoma, Recurrent Endometrial Carcinoma

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Trial Information

A Phase II, 2-stage, 2-arm PIK3CA Mutation Stratified Trial of MK-2206 in Recurrent or Advanced Endometrial Cancer


I. To assess the activity of MK-2206 in patients with recurrent or persistent endometrial
cancer classified by PIK3CA mutation. Activity will be ascertained by the proportion of
patients who survive progression-free for at least 6 months after initiating therapy or who
have objective tumor response


I. To determine the duration of progression-free survival and overall survival. II. To
determine the nature and degree of toxicity of MK-2206 as assessed by version 4 of the NCI
Common Terminology Criteria For Adverse Events (CTCAE) in these cohorts of patients.

III. To explore the associations between select biomarkers and response to MK-2206 such as
progression-free survival, objective tumor response, and overall survival as well as patient
characteristics such as histological cell type.

IV. To explore the development of feed-back loop activation (post-treatment biopsy biomarker
analysis) and target inhibition using MK-2206 via analysis of pre-treatment and
post-treatment biopsies in select patients enrolled in the trial.


Patients receive Akt inhibitor MK2206 orally (PO) once weekly. 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 years.

Inclusion Criteria:

- Participants must have histologically confirmed recurrent or persistent carcinoma of
endometrial origin, which is refractory to curative therapy or established
treatments; histologic confirmation of the original primary tumor is required;
patients with the following histologic epithelial cell types are eligible:
endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear
cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise
specified (N.O.S.), mucinous adenocarcinoma, squamous cell carcinoma, and
transitional cell carcinoma; tumors of endometrial histotype that arise from
endometriosis are eligible

- All patients must have measurable disease as defined by RECIST 1.1; measurable
disease is defined as at least one lesion that can be accurately measured in at least
one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when
measured by CT, MRI or caliper measurement by clinical exam; or >= 20 mm when
measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured by

- Patients must have had one prior chemotherapeutic regimen for management of
endometrial carcinoma initial treatment may include chemotherapy, chemotherapy and
radiation therapy, and/or consolidation/maintenance therapy; chemotherapy
administered in conjunction with primary radiation as a radio-sensitizer WILL be
counted as a systemic chemotherapy regimen

- Patients are allowed to receive, but are not required to receive, one additional
prior treatment regimen (including a single chemotherapeutic, a combination of
chemotherapeutics, or an anti-angiogenic drug such as bevacizumab) for management of
their recurrent or persistent disease; prior hormonal therapy is allowed and does not
count towards this prior regimen

- Patients must have NOT received any class of drugs targeted to the PI3K pathway (such
has PI3K inhibitors or mTOR inhibitors) for management of recurrent or persistent

- Life expectancy of greater than 6 months

- ECOG performance status =< 2 (Karnofsky >50%)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- AST (SGOT)/ALT (SGPT) =< 2.5 x institutional upper limit of normal

- Creatinine within normal institutional limits or creatinine clearance >= 60
mL/min/1.73 m^2 for subjects with creatinine levels about institutional normal

- HgA1c =< 7.5% and fasting blood glucose less than 130mg/dL

- Availability of a formalin fixed paraffin embedded (FFPE) block of cancer tissue from
the original or most recent biopsy for mutational analysis

- Women of childbearing potential must use two forms of contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation; should a patient become pregnant or suspect she is
pregnant while she is participating in this study, she should inform the treating
physician immediately

- Toxicities of prior therapy (excepting alopecia) should be resolved to =< grade 1 per
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4

- MK-2206 is an oral medication; patients must be able to tolerate oral medications and
not have gastrointestinal illnesses that would preclude absorption of MK-2206

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

Exclusion Criteria:

- Participants 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 to =< grade 1 (excepting alopecia) from adverse events (as per the revised
NCI CTCAE version 4) due to agents administered more than 3 weeks earlier

- Participants may not be receiving any other study agents

- Participants 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; should patients develop brain metastases while on trial and have clinical
benefit from MK-2206 otherwise, patients may continue on drug after clinical
management of the brain metastases with the permission of the principal investigator.
MK-2206 should be restarted between 3 and 6 weeks after the last radiation treatment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK-2206

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

- Preclinical studies demonstrated the potential of MK-2206 for induction of
hyperglycemia in all preclinical species tested; patients with diabetes or in risk
for hyperglycemia should not be excluded from trials with MK-2206, but the
hyperglycemia should be well controlled on oral agents before the patient enters the
trial. HgbA1c > 7.5% or fasting glucose greater than 130mg/dL will exclude patients
from entry on study; patients requiring insulin for control of their hyperglycemia
are excluded from entry on this study

- Preclinical studies indicated transient changes in QTc interval during MK-2206
treatment; prolongation of QTc interval is potentially a safety concern while on
MK-2206 therapy; cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec
(female) will exclude patients from entry on study

- Due to a high incidence of bradycardia by Holter monitor, preexisting bundle branch
block or baseline bradycardia due to cardiac disease will exclude patients from
treatment with MK-2206

- 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

- Pregnant women are excluded from this study; mother with MK-2206 breastfeeding should
be discontinued if the mother is treated with MK-2206; these potential risks may also
apply to other agents used in this study

- MK-2206 is an oral medication; patients who are unable to tolerate oral medication
are not eligible; patients with signs and symptoms of bowel obstruction or with
uncontrolled, persistent diarrhea will be excluded

- Individuals with a history of a different malignancy are ineligible except for the
following circumstances. Individuals with a history of other malignancies are
eligible if they have been disease-free for at least 5 years and are deemed by the
investigator to be at low risk for recurrence of that malignancy. Individuals with
the following cancers are eligible if diagnosed and treated within the past 5 years:
breast cancer in situ, cervical cancer in situ, and basal cell or squamous cell
carcinoma of the skin

- HIV-positive individuals on combination antiretroviral therapy are ineligible

- Patients may not use natural herbal products or other "folk remedies" while
participating in this study

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival according to RECIST

Outcome Time Frame:

From start of treatment to time of objective disease progression, assessed up to 6 months

Safety Issue:


Principal Investigator

Andrea Schoelerman Myers

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

March 2011

Completion Date:

Related Keywords:

  • Endometrial Adenocarcinoma
  • Endometrial Adenosquamous Cell Carcinoma
  • Endometrial Clear Cell Carcinoma
  • Endometrial Papillary Serous Carcinoma
  • Recurrent Endometrial Carcinoma
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Carcinoma
  • Endometrial Neoplasms
  • Carcinoma, Adenosquamous
  • Adenocarcinoma, Clear Cell
  • Adenomyoepithelioma
  • Cystadenocarcinoma, Serous
  • Adenoma



Memorial Sloan Kettering Cancer Center New York, New York  10021
Beth Israel Deaconess Medical Center Boston, Massachusetts  02215
Dana-Farber Cancer Institute Boston, Massachusetts  02115
Brigham and Women's Hospital Boston, Massachusetts  02115
Massachusetts General Hospital Boston, Massachusetts  02114-2617
Newton-Wellesley Hospital Newton, Massachusetts  02462
M D Anderson Cancer Center Houston, Texas  77030