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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01425879
• Collaborator: (none)
• Enrollment: 8
• Locations: 8
• Arm: 1
• Duration (Months): 37
• Patient Per Site: 1
• Patients Per Site Per Month: 0

Study Details

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:

1. 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:

1. To determine the frequency and severity of adverse events and tolerability of the regimen in patients with advanced refractory BC receiving MK2206.

2. To determine the overall and progression-free survival of patients with advanced refractory BC receiving MK2206.

3. 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.

4. To determine the pharmacokinetic and pharmacogenetic profile as a way of assessing inter-individual variability as well as how these relate to clinical outcomes.

5. 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
• 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: Apr 1, 2011
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 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 Names: 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 [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 [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 [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 [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

Criteria

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

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

	Site	City	State	Country	Postal Code
1	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
2	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
3	Emory University/Winship Cancer Institute	Atlanta	Georgia	United States	30322
4	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
5	Seidman Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106
6	Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44195
7	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
8	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01425879
• Other Study ID Numbers: NCI-2011-02974; NCI-2011-02974; OSU-10104; OSU 10104; CDR0000698451; OSU 10104; 8735; N01CM00070; P30CA016058
• First Posted: Aug 30, 2011
• Last Update Posted: Jun 17, 2016
• Last Verified: May 1, 2016

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Gallbladder Neoplasms; Bile Duct Neoplasms; Liver Neoplasms; Recurrence

Study Results

Participant Flow

Recruitment Details	Patients were enrolled between September 2012 and December 2013

Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	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. Akt Inhibitor MK2206: Given PO Diagnostic Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Period Title: Overall Study
STARTED	8
COMPLETED	8
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	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. Akt Inhibitor MK2206: Given PO Diagnostic Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Overall Participants	8
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58
Sex: Female, Male (Count of Participants)
Female	4 50%
Male	4 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 12.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	7 87.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (patients) [Number]
United States	8
Disease site (patients) [Number]
Intrahepatic	6
Gallbladder	0
Extrahepatic	2
ECOG Performance Status (patients) [Number]
PS 0	2
PS 1	6

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (Complete and Partial Response) as Defined by RECIST 1.1
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; Overall Response (OR) = CR + PR.
Time Frame	Up to 4 weeks after completion of study treatment, for total treatment time of up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	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. Akt Inhibitor MK2206: Given PO Diagnostic Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Measure Participants	8
Number [patients]	0

2. Secondary Outcome

Title	Frequency of Adverse Events Related to MK-2206
Description	Severity of adverse events is graded according to the NCI CTCAE 4.0.
Time Frame	Up to 4 weeks after completion of study treatment, for total treatment time of up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	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. Akt Inhibitor MK2206: Given PO Diagnostic Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Measure Participants	8
lymphopenia	75
rash	63
fatigue	50
fever	50
vomiting	50
diarrhea	50

3. Secondary Outcome

Title	Overall Survival
Description	Analyzed using Kaplan-Meier method.
Time Frame	From study initiation to time of death, assessed up to 4 weeks after completion of study treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	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. Akt Inhibitor MK2206: Given PO Diagnostic Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Measure Participants	8
Median (95% Confidence Interval) [months]	3.5

4. Secondary Outcome

Title	Progression-free Survival
Description	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
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	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. Akt Inhibitor MK2206: Given PO Diagnostic Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies
Measure Participants	8
Mean (95% Confidence Interval) [months]	1.7

Adverse Events

Time Frame	All patients were evaluable for toxicity from the time of their first treatment with MK2206
Adverse Event Reporting Description	NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4 was utilized for Adverse Event reporting.
Arm/Group Title	Treatment (Akt Inhibitor MK2206)
Arm/Group Description	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. Akt Inhibitor MK2206: Given PO Diagnostic Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: 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	0/8 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Akt Inhibitor MK2206)
	Affected / at Risk (%)	# Events
Total	8/8 (100%)
Blood and lymphatic system disorders
Anemia	1/8 (12.5%)	1
Thrombocytopenia	2/8 (25%)	2
Fever	4/8 (50%)	4
Lymphopenia	6/8 (75%)	6
Gastrointestinal disorders
Constipation	1/8 (12.5%)	1
Diarrhea	4/8 (50%)	4
Dry Mouth	2/8 (25%)	2
Mucositis	3/8 (37.5%)	3
Nausea	3/8 (37.5%)	3
Vomiting	4/8 (50%)	4
General disorders
Fatigue	4/8 (50%)	4
Investigations
Leukopenia	1/8 (12.5%)	1
Metabolism and nutrition disorders
Hypophosphatemia	2/8 (25%)	2
Hyponatremia	1/8 (12.5%)	1
Skin and subcutaneous tissue disorders
Dry Skin	3/8 (37.5%)	3
Hand Foot Syndrome	3/8 (37.5%)	3
Macular Rash	5/8 (62.5%)	5

Limitations/Caveats

[Not Specified]

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.