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

Study Overview
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Brief Summary
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This phase II trial is studying how well MD2206 works in treating patients with advanced refractory biliary cancer that cannot be removed by surgery.

Detailed Description
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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.

Official Title
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A Multi-Institutional Phase II Study of the Akt Inhibitor MK-2206 in Refractory Biliary Cancers

Conditions
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Advanced Adult Hepatocellular Carcinoma, Localized Non-Resectable Adult Liver Carcinoma, Recurrent Adult Liver Carcinoma, Recurrent Gallbladder Carcinoma, Stage IV Distal Bile Duct Cancer, Stage IV Gallbladder Cancer, Unresectable Extrahepatic Bile Duct Carcinoma, Unresectable Gallbladder Carcinoma

Intervention / Treatment
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* Drug: Akt Inhibitor MK2206
* Other: Diagnostic Laboratory Biomarker Analysis
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (Akt inhibitor MK2206)<br>Patients receive Akt inhibitor MK2206 PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Akt Inhibitor MK2206<br>* Given PO<br>* Other names: MK2206;Other: Diagnostic Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (Complete and Partial Response) as Defined by RECIST 1.1 | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 4 weeks after completion of study treatment, for total treatment time of up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Adverse Events Related to MK-2206 | Severity of adverse events is graded according to the NCI CTCAE 4.0. | Up to 4 weeks after completion of study treatment, for total treatment time of up to 1 year | 
| Overall Survival | Analyzed using Kaplan-Meier method. | From study initiation to time of death, assessed up to 4 weeks after completion of study treatment | 
| Progression-free Survival | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | From start of treatment to time of documented progression or death whichever occurs first, assessed up to 4 weeks after completion of study treatment |