MK2206 in Treating Patients With Advanced Liver Cancer That Did Not Respond to Previous Therapy

Phase 2

Terminated

• Conditions: Advanced Adult Hepatocellular Carcinoma; Adult Hepatocellular Carcinoma; Recurrent Adult Liver Carcinoma; Localized Non-Resectable Adult Liver Carcinoma
• Interventions: Drug: Akt Inhibitor MK2206; Other: Laboratory Biomarker Analysis

• Registration Number: NCT01239355
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase II trial is studying how well MK2206 works in treating patients with advanced liver cancer that did not respond to previous therapy. MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

PRIMARY OBJECTIVES:

I. Evaluate the median progression-free survival in patients with advanced hepatocellular carcinoma treated with MK-2206 after failure of one prior line of anti-angiogenic therapy.

SECONDARY OBJECTIVES:

I. Evaluate the objective response rate (CR + PR). II. Evaluate the median overall survival. III. Evaluate the tolerability and toxicity profile of MK-2206 in this patient population.

IV. Explore, in a preliminary fashion, potential molecular predictors of efficacy.

OUTLINE:

Patients receive oral Akt inhibitor MK2206 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 at 4 weeks and then every 3-6 months thereafter.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2010-11-10
• Study First Submitted QC: 2010-11-10
• Study First Posted: 2010-11-11
• Study Start: 2010-12
• Primary Completion: 2013-02
• Study Completion: 2013-02
• Status Verified: 2013-03
• Results First Submitted: 2015-06-10
• Results First Submitted QC: 2015-09-03
• Last Update Submitted: 2015-09-03
• Results First Posted: 2015-10-05
• Last Update Posted: 2015-10-05

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 15

Inclusion Criteria

• Unresectable or metastatic HCC for which standard curative measures do not exist

  • The diagnosis of hepatocellular carcinoma should be based on at least one of the following:

    • The presence of one or more liver lesions, measuring >= 2 cm, with characteristic arterial enhancement and venous washout in the setting of liver cirrhosis and/or hepatitis B or C infection
    • The presence of liver lesion(s) with AFP >= 400
    • Tissue confirmation in the absence of either or both of the above
    • Tissue availability is desired and will be sought, but tissue availability is not mandated for accrual to the study

• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension, and that has not been the target of local or regional therapy including transarterial chemoembolization, intra-arterial chemotherapy, ethanol, or RFA ablation

• One prior line of systemic anti-angiogenic therapy is required; this type of therapy includes, but is not restricted to, sorafenib, bevacizumab, sunitinib, or brivanib given as single agents or in combination with other agents

• No clinically evident ascites (minimal, medically controlled ascites detectable on imaging studies only is allowed)

• No Child-Pugh C cirrhosis or Child-Pugh B cirrhosis with more than 7 points

• No fibrolamellar carcinoma or any mixed variants of HCC with dominant fibrolamellar histology

• Patients with known brain metastases should be excluded from this clinical trial

• ECOG 0-1

• Life expectancy of greater than 3 months

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count > 1,000 mcL

• Platelets >= 70,000/mcL

• Total bilirubin =< 1.5 institutional upper limit of normal

• AST (SGOT)/ALT (SGPT) < 5 x institutional upper limit of normal

• Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min

• Serum albumin >= 2.8 g/dL

• Not pregnant or nursing

• Fertile patients 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

• Must agree to collection of correlative blood samples during the study

• No patients unable to swallow pills or diagnosed with a gastrointestinal disorder that is likely to interfere with the absorption of MK-2206 or with the patient's ability to take regular oral medication

• Patients with hyperglycemia should be well controlled on oral agents before the patient enters the trial

• Patients with HgbA1C levels >= 8% or fasting blood glucose >= 150 mg/dL are not eligible for this study

• Baseline QTcF > 450 msec (male) or QTcF> 470 msec (female) will exclude patients from entry on study

• Patients with hepatitis B infection, defined by a positive hepatitis B surface antigen test, should be on suppressive anti-viral therapy

  • Only the following anti-viral therapies are allowed while a patient is on study: tenofovir disoproxil fumarate and entecavir
  • Patients with hypothyroidism must be on a stable dose of thyroid replacement and be clinically euthyroid

• No esophageal or gastric variceal bleeding within the last 6 months

  • Patients with prior history of variceal bleeding must have had an upper endoscopy (EGD) with appropriate treatment of varices within 6 months prior to study entry

• No uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness/social situations that would limit compliance with study requirements

• None of the following:

  • Uncontrolled hypertension (systolic BP > 150 or diastolic BP > 100 on two occasions within two weeks of beginning therapy on this protocol)
  • Myocardial infarction within 6 months
  • NYHA class > II
  • Clinically significant bradycardia related to underlying cardiac disease
  • Clinically significant bundle branch block related to underlying cardiac disease

• No patients with second primary cancer (except adequately treated nonmelanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors including lymphomas without bone marrow involvement curatively treated with no evidence of disease for ≥ 5 years)

  • The exception to this criterion is prostate cancer treated definitively with surgery and/or radiation with normal PSA and no clinical evidence of residual or recurrent prostate cancer

• HIV-positive patients on combination antiretroviral therapy are ineligible

• No history of allergic reactions attributed to compounds of similar chemical orbiologic composition to MK-2206 or other agents used in the study

• No medications that cause QTc interval prolongation

• Any number of prior regional therapies with transarterial chemoembolization, intra-arterial chemotherapy, or ablative therapy is allowed

  • No more than 1 prior line of systemic therapy for advanced and/or unresectable disease

• No patients who have had anti-angiogenic therapy, chemotherapy, radiotherapy or regional therapy (such as transarterial chemoembolization, intra-arterial 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

  • Localized radiation for palliation (i.e., bony metastasis, etc.) given for < 3 days is allowed before therapy and is not subject to the 4-week waiting requirement
  • Local ablative therapy such as radiofrequency ablation or cryotherapy must have been completed more than 2 weeks prior to study entry

• Patients may not be receiving any other investigational or non-investigational agents or therapies directed at treating their hepatocellular carcinoma

• Patients may not be receiving any other investigational agents for any condition

• Patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 are ineligible

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (Akt inhibitor MK2206)	Akt Inhibitor MK2206	Patients receive oral Akt inhibitor MK2206 on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Treatment (Akt inhibitor MK2206)	Laboratory Biomarker Analysis	Patients receive oral Akt inhibitor MK2206 on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival	Until disease progression or death, up to 26 months	Estimated using the product-limit method of Kaplan and Meier. 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 (the sum must also demonstrate an absolute increase of at least 5 mm), or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

Name	Time	Method
Objective Response	Evaluated for response every 2 cycles (8 weeks) with confirmatory evaluation at least 4 weeks following initial documentation of objective response, up to 26 months	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; Objective Response (OR) = CR + PR
Overall Survival	Until death, up to 26 months	Survival will be estimated by the product-limit (Kaplan-Meier) estimator.

Trial Locations

Locations (22)

NorthShore University HealthSystem-Evanston Hospital; 🇺🇸 Evanston, Illinois, United States

USC Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center; 🇺🇸 Columbus, Ohio, United States

Tower Cancer Research Foundation; 🇺🇸 Beverly Hills, California, United States

Joliet Oncology-Hematology Associates Limited; 🇺🇸 Joliet, Illinois, United States

City of Hope Medical Center; 🇺🇸 Duarte, California, United States

Penn State Milton S Hershey Medical Center; 🇺🇸 Hershey, Pennsylvania, United States

Illinois CancerCare-Peoria; 🇺🇸 Peoria, Illinois, United States

Fort Wayne Medical Oncology and Hematology Inc-Parkview; 🇺🇸 Fort Wayne, Indiana, United States

University of Maryland/Greenebaum Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Southern Illinois University; 🇺🇸 Springfield, Illinois, United States

Northern Indiana Cancer Research Consortium; 🇺🇸 South Bend, Indiana, United States

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States

Decatur Memorial Hospital; 🇺🇸 Decatur, Illinois, United States

Ingalls Memorial Hospital; 🇺🇸 Harvey, Illinois, United States

Central Illinois Hematology Oncology Center; 🇺🇸 Springfield, Illinois, United States

Oncology Care Associates PLLC; 🇺🇸 Saint Joseph, Michigan, United States

Loyola University Medical Center; 🇺🇸 Maywood, Illinois, United States

Saint John's Mercy Medical Center; 🇺🇸 Saint Louis, Missouri, United States

University of California Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States