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

Advanced Adult Hepatocellular Carcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01425879
• Other study ID #: NCI-2011-02974
• Secondary ID: NCI-2011-02974OS
• Status: Completed
• Phase: Phase 2
• First received: August 27, 2011
• Last updated: December 22, 2015
• Start date: April 2011
• Est. completion date: May 2014

Study information

• Verified date: December 2015
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. completion date: May 2014
• Est. primary completion date: May 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Advanced Adult Hepatocellular Carcinoma
• Carcinoma
• Carcinoma, Ductal
• Carcinoma, Hepatocellular
• Cholangiocarcinoma
• Gallbladder Neoplasms
• 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

Drug:
• Akt Inhibitor MK2206
Given PO

Other:
• Diagnostic Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies

Locations

Country	Name	City	State
United States	Emory University/Winship Cancer Institute	Atlanta	Georgia
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center	Cleveland	Ohio
United States	Seidman Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center	Cleveland	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	M D Anderson Cancer Center	Houston	Texas
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	MedStar Georgetown University Hospital	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall response rate (complete and partial response) as defined by RECIST 1.1		Up to 4 weeks after completion of study treatment	No
Secondary	Frequency of adverse events related to MK-2206	Severity of adverse events is graded according to the NCI CTCAE 4.0.	Up to 30 days after completion of study treatment	Yes
Secondary	Overall survival	Analyzed using Kaplan-Meier plots.	From study initiation to time of death, assessed up to 4 weeks after completion of study treatment	No
Secondary	Progression-free survival	Analyzed using Kaplan-Meier plots.	From start of treatment to time of documented progression or death whichever occurs first, assessed up to 4 weeks after completion of study treatment	No