Clinical trial NCT01239355: MK2206 in Treating Patients With Advanced Liver Cancer That Did Not Respond to Previous Therapy
Official title: A Phase II Study of MK-2206 in Patients With Advanced Hepatocellular Carcinoma Who Have Failed or Are Intolerant of One Prior Line of Anti-angiogenic Therapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Adult Hepatocellular Carcinoma
Advanced Adult Hepatocellular Carcinoma
Localized Non-Resectable Adult Liver Carcinoma
Recurrent Adult Liver Carcinoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-11-11
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression-free Survival
timeFrame: Until disease progression or death, up to 26 months
Secondary outcomes:
measure: Objective Response
timeFrame: 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
measure: Overall Survival
timeFrame: Until death, up to 26 months
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Tower Cancer Research Foundation
state: California
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Evanston
country: United States
facility: NorthShore University HealthSystem-Evanston Hospital
state: Illinois
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Joliet
country: United States
facility: Joliet Oncology-Hematology Associates Limited
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Peoria
country: United States
facility: Illinois CancerCare-Peoria
state: Illinois
city: Springfield
country: United States
facility: Central Illinois Hematology Oncology Center
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology Inc-Parkview
state: Indiana
city: South Bend
country: United States
facility: Northern Indiana Cancer Research Consortium
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Joseph
country: United States
facility: Oncology Care Associates PLLC
state: Michigan
city: Saint Louis
country: United States
facility: Saint John's Mercy Medical Center
state: Missouri
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
state: Ohio
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: University of Southern California, Norris
name: Anthony El-Khoueiry, MD
role: PRINCIPAL_INVESTIGATOR
References: