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A Multicenter Phase II Study of the Combination of AZD6244 Hydrogen Sulfate and MK-2206 in Patients With Refractory Advanced Biliary Cancers

Phase 2
18 Years
Not Enrolling
Adenocarcinoma of the Gallbladder, Adenocarcinoma With Squamous Metaplasia of the Gallbladder, Adult Primary Cholangiocellular Carcinoma, Advanced Adult Primary Liver Cancer, Cholangiocarcinoma of the Extrahepatic Bile Duct, Localized Unresectable Adult Primary Liver Cancer, Metastatic Extrahepatic Bile Duct Cancer, Recurrent Adult Primary Liver Cancer, Recurrent Extrahepatic Bile Duct Cancer, Stage II Gallbladder Cancer, Stage IIIA Gallbladder Cancer, Stage IIIB Gallbladder Cancer, Stage IVA Gallbladder Cancer, Stage IVB Gallbladder Cancer, Unresectable Extrahepatic Bile Duct Cancer

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Trial Information

A Multicenter Phase II Study of the Combination of AZD6244 Hydrogen Sulfate and MK-2206 in Patients With Refractory Advanced Biliary Cancers


I. To evaluate the objective response rate (complete response [CR] + partial response [PR]),
as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, in
patients with refractory advanced biliary cancers receiving the combination of AZD6244
hydrogen sulfate (selumetinib) and MK-2206 (Akt inhibitor MK-2206).


I. To determine the overall and progression-free survival in patients with refractory
advanced biliary cancer receiving MK-2206 and AZD6244 hydrogen sulfate.

II. To determine the frequency and severity of adverse events and tolerability of AZD6244
hydrogen sulfate + MK-2206 in patients with advanced refractory biliary cancer receiving
this regimen.

III. To evaluate the effects of AZD6244 hydrogen sulfate plus MK-2206 on the inflammatory
cytokine and immune cell profiles as well as on cancer cachexia.

IV. To determine the presence of genetic mutations of phosphatidylinositol 3 kinase
(PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signaling pathway
genes (other than v-raf murine sarcoma viral oncogene homolog [BRAF] V600E) relevant to
biliary cancer and how these correlate with and may predict objective response to treatment
with AZD6244 hydrogen sulfate and MK-2206.

V. To assess and validate target inhibition in patients with refractory advanced biliary
cancer receiving the combination of MK-2206 plus AZD6244 hydrogen sulfate.

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

VII. 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.

VIII. To evaluate the effect of combined MAPK and PI3K/Akt inhibition on skeletal muscle
anabolism in patients receiving treatment with AZD6244 hydrogen sulfate and MK-2206.

IX. To conduct quality of life analyses in patients receiving the combination of AZD6244
hydrogen sulfate plus MK-2206.


Patients receive Akt inhibitor MK-2206 orally (PO) on days 1, 8, 15, and 22 (days 8, 15, and
22 of course 1) and selumetinib 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 4 weeks.

Inclusion Criteria:

- Patients must have surgically unresectable histologically confirmed biliary tract
adenocarcinoma (defined as gallbladder cancer, extrahepatic and intrahepatic
cholangiocarcinoma; this definition excludes ampullary cancers and all tumors of
mixed histology); cytological confirmation is not allowed on this study, as tissue is
needed for correlative science; fresh tissue (mandatory) AND paraffin embedded tissue
(positron emission tomography [PET]) from tumor blocks (if available) will be
required from patients before enrolling on this study

- Patients will be required to undergo a biopsy prior to enrolling on the study and
will be given the option to have another biopsy around 4 weeks from initiation of

- Patients must have measurable disease by RECIST 1.1 criteria, 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 computed tomography (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

- All of the following:

- Patients must have received only one prior line of systemic therapy for
recurrent or advanced disease

- Prior adjuvant therapy (chemotherapy +/- radiation) completed within 6 months of
diagnosis of recurrence/metastases is equivalent to one line of prior therapy
for metastatic disease

- For patients who completed adjuvant therapy > 6 months prior to diagnosis of
recurrence/metastases, progression on 1 prior line of systemic therapy for
metastatic disease is required

- No prior Akt inhibitors or mitogen-activated protein kinase kinase (MEK)
inhibitors allowed

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

- 6 weeks must have 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 be allowed as long as > 2 weeks have
elapsed since therapy

- Life expectancy of greater than 12 weeks

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

- Leukocytes>= 3,000/µL

- Absolute neutrophil count >= 1,500/µL

- Platelets >= 100,000/µL

- Total bilirubin =< 1.5 X institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal OR =< 5 X institutional upper limit of
normal for intrahepatic cholangiocarcinoma if thought to be related to disease

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- The effects of MK-2206 and AZD6244 hydrogen sulfate on the developing human fetus at
the recommended therapeutic dose are unknown; for this reason and because AZD6244
hydrogen sulfate and MK-2206 is known to be teratogenic, 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; 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

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

- Ability to swallow oral tablets and capsules

Exclusion Criteria:

- Patients who have had chemotherapy, biologic therapy, or immunotherapy, within 4
weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those
who have not recovered from adverse events to a grade 1 or less due to agents
administered more than 4 weeks earlier

- Patients may not be receiving any other investigational agents

- Patients 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

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK-2206 or AZD6244 hydrogen sulfate or other agents used in the study

- 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

- Preclinical studies indicated transient changes in corrected QT (QTc) interval during
MK-2206 treatment; prolongation of QTc interval is potentially a safety concern while
on MK-2206 therapy; cardiovascular: baseline corrected QT by Fridericia's formula
(QTcF) > 450 msec (male) or QTcF > 470 msec (female) will exclude patients from entry
on study; a list of medications that may cause QTc interval prolongation should be
avoided by patients entering on trial

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

- History of any other malignancy other than biliary cancer in the last 3 years, except
for adequately treated basal cell carcinoma, and squamous cell carcinoma of the skin
or cervix

- 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; developmental and reproductive toxicity
studies of MK-2206 and AZD6244 hydrogen sulfate have not been performed thus far;
women of child-bearing potential and men participating in clinical studies of AZD6244
hydrogen sulfate and MK-2206 must use appropriate contraception, including abstinence
and double-barrier methods, throughout AZD6244 hydrogen sulfate and MK-2206 therapy;
in preclinical mutagenicity studies, ADZ6244 hydrogen sulfate and MK-2206 were
neither genotoxic or mutagenic; because there is an unknown but potential risk for
adverse events in nursing infants secondary to treatment of the mother with AZD6244
hydrogen sulfate and MK-2206, breastfeeding should be discontinued if the mother is
treated with AZD6244 hydrogen sulfate and MK 2206

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
AZD6244 hydrogen sulfate and MK-2206; in addition, these patients are at increased
risk of lethal infections when treated with marrow-suppressive therapy; appropriate
studies will be undertaken in patients receiving combination antiretroviral therapy
when indicated

- Patients requiring strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) or
those receiving any medications or substances that are inhibitors or inducers of CYP
450 3A4 are ineligible

Type of Study:


Study Design:

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

Outcome Measure:

Proportion of patients who have a response (PR or CR), assessed by the RECIST v1.1

Outcome Description:

Calculated with corresponding 95% binomial confidence intervals.

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Tanios Bekaii-Saab

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University


United States: Food and Drug Administration

Study ID:




Start Date:

January 2013

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Gallbladder
  • Adenocarcinoma With Squamous Metaplasia of the Gallbladder
  • Adult Primary Cholangiocellular Carcinoma
  • Advanced Adult Primary Liver Cancer
  • Cholangiocarcinoma of the Extrahepatic Bile Duct
  • Localized Unresectable Adult Primary Liver Cancer
  • Metastatic Extrahepatic Bile Duct Cancer
  • Recurrent Adult Primary Liver Cancer
  • Recurrent Extrahepatic Bile Duct Cancer
  • Stage II Gallbladder Cancer
  • Stage IIIA Gallbladder Cancer
  • Stage IIIB Gallbladder Cancer
  • Stage IVA Gallbladder Cancer
  • Stage IVB Gallbladder Cancer
  • Unresectable Extrahepatic Bile Duct Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Carcinoma
  • Liver Neoplasms
  • Metaplasia
  • Gallbladder Neoplasms
  • Bile Duct Neoplasms
  • Cholangiocarcinoma



Ohio State University Medical CenterColumbus, Ohio  43210