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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT01239355
• Collaborator: (none)
• Enrollment: 15
• Locations: 22
• Arm: 1
• Duration (Months): 26.1
• Patients Per Site: 0.7
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; Localized Non-Resectable Adult Liver Carcinoma; Recurrent Adult Liver Carcinoma	Drug: Akt Inhibitor MK2206; Other: Laboratory Biomarker Analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. Evaluate the objective response rate (CR + PR). II. Evaluate the median overall survival.

2. Evaluate the tolerability and toxicity profile of MK-2206 in this patient population.

3. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Dec 1, 2010
• Actual Primary Completion Date: Feb 1, 2013
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (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.	Drug: Akt Inhibitor MK2206; Given PO; Other Names: MK2206 ; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. 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

1. 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

2. Overall Survival [Until death, up to 26 months]

   Survival will be estimated by the product-limit (Kaplan-Meier) estimator.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tower Cancer Research Foundation	Beverly Hills	California	United States	90211-1850
2	City of Hope Medical Center	Duarte	California	United States	91010
3	USC Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
4	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
5	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
6	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
7	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois	United States	60201
8	Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
9	Joliet Oncology-Hematology Associates Limited	Joliet	Illinois	United States	60435
10	Loyola University Medical Center	Maywood	Illinois	United States	60153
11	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
12	Central Illinois Hematology Oncology Center	Springfield	Illinois	United States	62702
13	Southern Illinois University	Springfield	Illinois	United States	62702
14	Fort Wayne Medical Oncology and Hematology Inc-Parkview	Fort Wayne	Indiana	United States	46845
15	Northern Indiana Cancer Research Consortium	South Bend	Indiana	United States	46628
16	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
17	University of Michigan	Ann Arbor	Michigan	United States	48109
18	Oncology Care Associates PLLC	Saint Joseph	Michigan	United States	49085
19	Saint John's Mercy Medical Center	Saint Louis	Missouri	United States	63141
20	Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center	Columbus	Ohio	United States	43210
21	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
22	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15232

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Anthony El-Khoueiry, MD, University of Southern California, Norris

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01239355
• Other Study ID Numbers: NCI-2011-02549; NCI-2011-02549; CDR0000688549; CHNMC-PHII-105; PHII-105; 8752; P30CA033572; N01CM00038
• First Posted: Nov 11, 2010
• Last Update Posted: Oct 5, 2015
• Last Verified: Mar 1, 2013

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms

Study Results

Participant Flow

Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	Patients receive 200mg 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. Akt Inhibitor MK2206: Given PO Laboratory Biomarker Analysis: Correlative studies
Period Title: Overall Study
STARTED	15
COMPLETED	15
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	Patients receive 200mg 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. Akt Inhibitor MK2206: Given PO Laboratory Biomarker Analysis: Correlative studies
Overall Participants	15
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	3 20%
Male	12 80%
Region of Enrollment (participants) [Number]
United States	15 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	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.
Time Frame	Until disease progression or death, up to 26 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	Patients receive 200mg 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. Akt Inhibitor MK2206: Given PO Laboratory Biomarker Analysis: Correlative studies
Measure Participants	15
Median (95% Confidence Interval) [Months]	1.7

2. Secondary Outcome

Title	Objective Response
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; Objective Response (OR) = CR + PR
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	Patients receive 200mg 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. Akt Inhibitor MK2206: Given PO Laboratory Biomarker Analysis: Correlative studies
Measure Participants	15
Number [participants]	0 0%

3. Secondary Outcome

Title	Overall Survival
Description	Survival will be estimated by the product-limit (Kaplan-Meier) estimator.
Time Frame	Until death, up to 26 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	Patients receive 200mg 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. Akt Inhibitor MK2206: Given PO Laboratory Biomarker Analysis: Correlative studies
Measure Participants	15
Median (95% Confidence Interval) [Months]	6.1

Adverse Events

Time Frame	Adverse events recorded over a period of 1 year and 5 months.
Adverse Event Reporting Description	"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	Patients receive 200mg 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. Akt Inhibitor MK2206: Given PO Laboratory Biomarker Analysis: Correlative studies
All Cause Mortality
	Treatment (Akt Inhibitor MK2206)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Akt Inhibitor MK2206)
	Affected / at Risk (%)	# Events
Total	6/15 (40%)
Gastrointestinal disorders
Ascites	1/15 (6.7%)	1
Mucositis oral	1/15 (6.7%)	1
Oral pain	1/15 (6.7%)	1
General disorders
Fever	1/15 (6.7%)	1
Pain	1/15 (6.7%)	1
Investigations
Alanine aminotransferase increased	1/15 (6.7%)	1
Aspartate aminotransferase increased	1/15 (6.7%)	1
Blood bilirubin increased	2/15 (13.3%)	2
Neutrophil count decreased	1/15 (6.7%)	1
White blood cell decreased	1/15 (6.7%)	1
Metabolism and nutrition disorders
Hyponatremia	2/15 (13.3%)	2
Musculoskeletal and connective tissue disorders
Bone pain	1/15 (6.7%)	1
Nervous system disorders
Movements involuntary	1/15 (6.7%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/15 (6.7%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Akt Inhibitor MK2206)
	Affected / at Risk (%)	# Events
Total	15/15 (100%)
Blood and lymphatic system disorders
Anemia	11/15 (73.3%)	17
Cardiac disorders
Sinus tachycardia	1/15 (6.7%)	1
Gastrointestinal disorders
Abdominal distension	1/15 (6.7%)	1
Abdominal pain	1/15 (6.7%)	2
Bloating	1/15 (6.7%)	1
Constipation	4/15 (26.7%)	6
Diarrhea	6/15 (40%)	6
Dry mouth	5/15 (33.3%)	6
Gastrointestinal pain	1/15 (6.7%)	3
Mucositis oral	3/15 (20%)	3
Nausea	3/15 (20%)	4
Rectal hemorrhage	1/15 (6.7%)	1
Stomach pain	1/15 (6.7%)	1
Toothache	1/15 (6.7%)	1
Vomiting	1/15 (6.7%)	1
General disorders
Chills	1/15 (6.7%)	1
Edema limbs	2/15 (13.3%)	2
Edema trunk	1/15 (6.7%)	1
Fatigue	9/15 (60%)	14
Fever	2/15 (13.3%)	3
Flu like symptoms	2/15 (13.3%)	2
Pain	2/15 (13.3%)	2
Infections and infestations
Mucosal infection	1/15 (6.7%)	1
Investigations
Activated partial thromboplastin time pr	1/15 (6.7%)	1
Alanine aminotransferase increased	7/15 (46.7%)	14
Alkaline phosphatase increased	8/15 (53.3%)	21
Aspartate aminotransferase increased	11/15 (73.3%)	26
Blood bilirubin increased	3/15 (20%)	11
Creatinine increased	3/15 (20%)	3
Electrocardiogram QT corrected interval	3/15 (20%)	6
INR increased	1/15 (6.7%)	1
Lymphocyte count decreased	3/15 (20%)	7
Neutrophil count decreased	4/15 (26.7%)	6
Platelet count decreased	6/15 (40%)	17
Weight gain	1/15 (6.7%)	1
White blood cell decreased	3/15 (20%)	11
Metabolism and nutrition disorders
Anorexia	4/15 (26.7%)	5
Hypercalcemia	1/15 (6.7%)	1
Hyperglycemia	9/15 (60%)	19
Hyperkalemia	2/15 (13.3%)	2
Hypoalbuminemia	7/15 (46.7%)	10
Hypokalemia	1/15 (6.7%)	1
Hyponatremia	1/15 (6.7%)	1
Hypophosphatemia	3/15 (20%)	4
Musculoskeletal and connective tissue disorders
Back pain	1/15 (6.7%)	4
Flank pain	1/15 (6.7%)	4
Generalized muscle weakness	1/15 (6.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/15 (6.7%)	1
Nervous system disorders
Dysgeusia	1/15 (6.7%)	2
Headache	2/15 (13.3%)	4
Presyncope	1/15 (6.7%)	1
Somnolence	1/15 (6.7%)	1
Psychiatric disorders
Depression	1/15 (6.7%)	1
Insomnia	1/15 (6.7%)	1
Renal and urinary disorders
Urinary tract obstruction	1/15 (6.7%)	1
Urine discoloration	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/15 (6.7%)	2
Cough	1/15 (6.7%)	1
Dyspnea	2/15 (13.3%)	2
Pleuritic pain	1/15 (6.7%)	2
Skin and subcutaneous tissue disorders
Alopecia	1/15 (6.7%)	1
Dry skin	3/15 (20%)	3
Periorbital edema	1/15 (6.7%)	1
Pruritus	4/15 (26.7%)	11
Rash maculo-papular	5/15 (33.3%)	12
Vascular disorders
Hypertension	1/15 (6.7%)	1

Limitations/Caveats

Study was terminated early after the first stage of a two-stage design, allowing for early termination for discouraging results

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.