MK2206 in Treating Patients With Advanced Refractory Biliary Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To evaluate the objective response rate (complete and partial response), as defined by
the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria, in patients with
advanced refractory biliary cancers (BC) receiving Akt inhibitor MK2206 (MK2206).

SECONDARY OBJECTIVES:

I. To determine the frequency and severity of adverse events and tolerability of the regimen
in patients with advanced refractory BC receiving MK2206.

II. To determine the overall and progression-free survival of patients with advanced
refractory BC receiving MK2206.

III. To determine the presence of genetic mutations of PI3-kinase/ Akt pathway
signaling-pathway genes relevant to BC and how these correlate with objective response to
treatment with MK2206.

IV. To determine the pharmacokinetic and pharmacogenetic profile as a way of assessing
inter-individual variability as well as how these relate to clinical outcomes.

V. To determine genetic variants and mutations in genes encoding drug-metabolizing enzymes
and transporters, and genes involved in tumor biology, and how these may be related to
response to treatment.

OUTLINE: This is a multicenter study.

Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, 15, and 22. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and periodically during study for pharmacokinetic,
pharmacogenetic, and other correlative studies. Previously collected tumor tissue is also
analyzed.

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

Inclusion Criteria:

- Patients must have histologically confirmed biliary tract carcinoma that is
surgically unresectable

- Cytological confirmation is not allowed on this study, as tissue is needed for
correlative science analysis

- Either fresh-frozen tissue (FFT) or paraffin-embedded tissue blocks (PETB) will
be required from patients before enrolling on this study

- No biopsies will be required unless there is insufficient tissue or if the PETB
available is more than 12 months old

- 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) as ≥
10 mm with spiral CT scan (CT scan slice thickness no greater than 5 mm)

- Malignant lymph nodes will be considered measurable if they are ≥ 15 mm in short
axis

- Patients must have received one prior therapy for metastatic disease

- No prior Akt inhibitors allowed

- Patients with known brain metastases should be excluded from this clinical trial

- Life expectancy greater than 12 weeks

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) =<2 (Karnofsky >=
60%)

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelet count >= 100,000/mcL

- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]
=< 2.5 x IULN

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
(measured or calculated using the Cockroft-Gualt formula)

- Women of childbearing potential and men 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

- Not pregnant or nursing

- Able to swallow oral tablets

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to Akt Inhibitor MK2206 (MK2206) or other agents used in the
study

- Patients with diabetes or in risk for hyperglycemia should not be excluded from
trials with MK2206, but the hyperglycemia should be well controlled on oral agents
before the patient enters the trial

- Cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec (female) will
exclude patients from entry on study

- Patients with clinically significant bundle branch block or pre-existing clinically
significant bradycardia will be excluded from the study

- 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 grapefruit or grapefruit juice

- For patients having prior cryotherapy, radiofrequency ablation, ethanol injection,
transarterial chemoembolization (TACE), or photodynamic therapy, the following
criteria must be met:

- 6 weeks has elapsed since that therapy

- Indicator lesion(s) is/are outside the area of prior treatment or, if the only
indicator lesion is inside the prior treatment area, there must be clear
evidence of disease progression associated with that lesion

- Edges of the indicator lesion are clearly distinct on CT scanning

- Prior radiation therapy with or without the use of a fluoropyrimidine as a
radiosensitizer in the adjuvant setting will be allowed on study if > 12 weeks
have elapsed since therapy

- Prior palliative radiation therapy will allowed as long as > 4 weeks have
elapsed since therapy

- No patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or
mitomycin C) prior to entering the study or those who have not recovered from adverse
events due to agents administered more than 4 weeks earlier

- Patients may not be receiving any other investigational agents

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

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