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

Primary Purpose

Advanced Adult Hepatocellular Carcinoma, Localized Non-Resectable Adult Liver Carcinoma, Recurrent Adult Liver Carcinoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Akt Inhibitor MK2206
Diagnostic Laboratory Biomarker Analysis
Pharmacological Study
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Adult Hepatocellular Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • USC / Norris Comprehensive Cancer Center
  • MedStar Georgetown University Hospital
  • Emory University/Winship Cancer Institute
  • University of North Carolina at Chapel Hill
  • Seidman Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center
  • Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
  • Ohio State University Comprehensive Cancer Center
  • M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (Akt inhibitor MK2206)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Frequency of Adverse Events Related to MK-2206
Severity of adverse events is graded according to the NCI CTCAE 4.0.
Overall Survival
Analyzed using Kaplan-Meier method.
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

Full Information

First Posted
August 27, 2011
Last Updated
May 16, 2016
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01425879
Brief Title
MK2206 in Treating Patients With Advanced Refractory Biliary Cancer That Cannot Be Removed by Surgery
Official Title
A Multi-Institutional Phase II Study of the Akt Inhibitor MK-2206 in Refractory Biliary Cancers
Study Type
Interventional

2. Study Status

Record Verification Date
May 2016
Overall Recruitment Status
Completed
Study Start Date
April 2011 (undefined)
Primary Completion Date
May 2013 (Actual)
Study Completion Date
May 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
8 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (Akt inhibitor MK2206)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Akt Inhibitor MK2206
Other Intervention Name(s)
MK2206
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Diagnostic Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Overall Response Rate (Complete and Partial Response) as Defined by RECIST 1.1
Description
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.
Time Frame
Up to 4 weeks after completion of study treatment, for total treatment time of up to 1 year
Secondary Outcome Measure Information:
Title
Frequency of Adverse Events Related to MK-2206
Description
Severity of adverse events is graded according to the NCI CTCAE 4.0.
Time Frame
Up to 4 weeks after completion of study treatment, for total treatment time of up to 1 year
Title
Overall Survival
Description
Analyzed using Kaplan-Meier method.
Time Frame
From study initiation to time of death, assessed up to 4 weeks after completion of study treatment
Title
Progression-free Survival
Description
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
Time Frame
From start of treatment to time of documented progression or death whichever occurs first, assessed up to 4 weeks after completion of study treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tanios Bekaii-Saab
Organizational Affiliation
Ohio State University Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
USC / Norris Comprehensive Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
MedStar Georgetown University Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States
Facility Name
Emory University/Winship Cancer Institute
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
University of North Carolina at Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Seidman Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

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

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