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

• ClinicalTrials.gov Identifier: NCT01425879
• Recruitment Status: Completed
• First Posted: August 30, 2011
• Results First Posted: April 15, 2016
• Last Update Posted: June 17, 2016
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

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.

Condition or disease	Intervention/treatment	Phase
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	Drug: Akt Inhibitor MK2206; Other: Diagnostic Laboratory Biomarker Analysis; Other: Pharmacological Study	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-Institutional Phase II Study of the Akt Inhibitor MK-2206 in Refractory Biliary Cancers
• Study Start Date: April 2011
• Actual Primary Completion Date: May 2013
• Actual Study Completion Date: May 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment (Akt inhibitor MK2206); 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; Given PO; Other Name: MK2206; Other: Diagnostic Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies

Outcome Measures

Primary Outcome Measures :

1. Overall Response Rate (Complete and Partial Response) as Defined by RECIST 1.1 [ Time Frame: Up to 4 weeks after completion of study treatment, for total treatment time of up to 1 year ]
   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 :

1. Frequency of Adverse Events Related to MK-2206 [ Time Frame: Up to 4 weeks after completion of study treatment, for total treatment time of up to 1 year ]
   Severity of adverse events is graded according to the NCI CTCAE 4.0.
2. Overall Survival [ Time Frame: From study initiation to time of death, assessed up to 4 weeks after completion of study treatment ]
   Analyzed using Kaplan-Meier method.
3. Progression-free Survival [ 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 ]
   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

USC / Norris Comprehensive Cancer Center

Los Angeles, California, United States, 90033

United States, District of Columbia

MedStar Georgetown University Hospital

Washington, District of Columbia, United States, 20007

United States, Georgia

Emory University/Winship Cancer Institute

Atlanta, Georgia, United States, 30322

United States, North Carolina

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States, 27599

United States, Ohio

Seidman Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center

Cleveland, Ohio, United States, 44106

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Cleveland, Ohio, United States, 44195

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States, 43210

United States, Texas

M D Anderson Cancer Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Tanios Bekaii-Saab; Ohio State University Comprehensive Cancer Center

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01425879
• Other Study ID Numbers: NCI-2011-02974; NCI-2011-02974 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); OSU-10104; OSU 10104; CDR0000698451; OSU 10104 ( Other Identifier: Ohio State University Comprehensive Cancer Center ); 8735 ( Other Identifier: CTEP ); N01CM00070 ( U.S. NIH Grant/Contract ); P30CA016058 ( U.S. NIH Grant/Contract )
• First Posted: August 30, 2011
• Results First Posted: April 15, 2016
• Last Update Posted: June 17, 2016
• Last Verified: May 2016

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Hepatocellular; Gallbladder Neoplasms; Bile Duct Neoplasms; Liver Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Biliary Tract Neoplasms; Biliary Tract Diseases; Gallbladder Diseases; Bile Duct Diseases