Study Of AG-013736 (Axitinib) In Patients With Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT00447005
• Recruitment Status: Completed
• First Posted: March 13, 2007
• Results First Posted: March 26, 2012
• Last Update Posted: May 23, 2012
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma
• Intervention: Drug: Axitinib (AG-013736)
• Enrollment: 12

Participant Flow

Recruitment Details
Pre-assignment Details	Six participants initially received a single dose of AG-013736 5 mg followed by 5 mg twice daily (BID) multiple dosing. They were monitored for dose limiting toxicity (DLT) up to multiple dosing Cycle 1. Since no more than 1 of the first 6 participants had a DLT, 6 additional participants initiated AG-013736 from multiple dosing per the protocol.

Arm/Group Title	AG-013736
Arm/Group Description	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Period Title: Overall Study
Started	12
Completed	0
Not Completed	12
Reason Not Completed
Adverse Event	1
Lack of Efficacy	11

Baseline Characteristics

Arm/Group Title		AG-013736
Arm/Group Description		Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Overall Number of Baseline Participants		12
Baseline Analysis Population Description		[Not Specified]
Age Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	12 participants
		60.2 (13.1)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	12 participants
	Female	5 41.7%
	Male	7 58.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	Number of participants with any adverse events, adverse events graded as Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE) Grade 3 or higher, serious adverse events, and adverse events resulted in discontinuation.
Time Frame	Up to 795 days of treatment plus 28-days follow-up

Outcome Measure Data

Analysis Population Description

All subjects who received at least 1 dose of the study drug.

Arm/Group Title	AG-013736
Arm/Group Description:	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Overall Number of Participants Analyzed	12
Measure Type: Number; Unit of Measure: participants
Any adverse events	12
Any serious adverse events	5
Any Grade-3 or -4 adverse events	7
Any Grade-5 adverse events (= death)	0
Discontinuation due to adverse events	1

2. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax): Single Dose
Description	[Not Specified]
Time Frame	Single dose: predose, 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose

Outcome Measure Data

Analysis Population Description

Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set). Only the first 6 participants were administered a single dose.

Arm/Group Title	AG-013736
Arm/Group Description:	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Overall Number of Participants Analyzed	6
Mean (Standard Deviation); Unit of Measure: ng/mL
	29.97 (9.97)

3. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax): Single Dose
Description	[Not Specified]
Time Frame	Single dose: predose, 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose

Outcome Measure Data

Analysis Population Description

Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set). Only the first 6 participants were administered a single dose.

Arm/Group Title	AG-013736
Arm/Group Description:	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Overall Number of Participants Analyzed	6
Median (Full Range); Unit of Measure: hours
	4; (2 to 6)

4. Secondary Outcome

Title	Area Under The Plasma Concentration-Time Curve From Time Zero to Time Infinity (AUCinf): Single Dose
Description	AUCinf is obtained from AUC (0 - t) plus AUC (t - infinity).
Time Frame	Single dose: predose, 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose

Outcome Measure Data

Analysis Population Description

Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set). Only the first 6 participants were administered a single dose.

Arm/Group Title	AG-013736
Arm/Group Description:	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Overall Number of Participants Analyzed	6
Mean (Standard Deviation); Unit of Measure: ng*hr/mL
	210.3 (146.5)

5. Secondary Outcome

Title	Terminal Phase Plasma Half-Life (t1/2): Single Dose
Description	t1/2 is the time measured for the plasma concentration to decrease by one half.
Time Frame	Single dose: predose, 0.5, 1, 2, 4, 6, 8, 12, 24, and 32 hours postdose

Outcome Measure Data

Analysis Population Description

Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set). Only the first 6 participants were administered a single dose.

Arm/Group Title	AG-013736
Arm/Group Description:	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Overall Number of Participants Analyzed	6
Mean (Standard Deviation); Unit of Measure: hours
	4.8 (1.146)

6. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax): Multiple Dose
Description	[Not Specified]
Time Frame	Multiple dose Cycle 1 Day 1 and 15: predose, 0.5, 1, 2, 4, 8 and 12 hours postdose

Outcome Measure Data

Analysis Population Description

Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set); n= number of participants assessed.

Arm/Group Title	AG-013736
Arm/Group Description:	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Overall Number of Participants Analyzed	12
Mean (Standard Deviation); Unit of Measure: ng/mL
Cycle 1 Day 1 (n=12)	23.85 (10.94)
Cycle 1 Day 15 (n=11)	32.14 (18.04)

7. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax): Multiple Dose
Description	[Not Specified]
Time Frame	Multiple dose Cycle 1 Day 1 and 15: predose, 0.5, 1, 2, 4, 8 and 12 hours postdose

Outcome Measure Data

Analysis Population Description

Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set); n= number of participants assessed.

Arm/Group Title	AG-013736
Arm/Group Description:	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Overall Number of Participants Analyzed	12
Median (Full Range); Unit of Measure: hours
Cycle 1 Day 1 (n=12)	3; (2 to 4)
Cycle 1 Day 15 (n=11)	4; (1 to 4)

8. Secondary Outcome

Title	Area Under The Plasma Concentration-Time Curve Over Dosing Interval Tau (AUCtau): Multiple Dose
Description	Dosing Interval was 12 hours in this study.
Time Frame	Multiple dose Cycle 1 Day 1 and 15: predose, 0.5, 1, 2, 4, 8 and 12 hours postdose

Outcome Measure Data

Analysis Population Description

Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set); n= number of participants assessed.

Arm/Group Title	AG-013736
Arm/Group Description:	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Overall Number of Participants Analyzed	12
Mean (Standard Deviation); Unit of Measure: ng*h/mL
Cycle 1 Day 1 (n=12)	137.3 (84.3)
Cycle 1 Day 15 (n=11)	187.8 (125.3)

9. Secondary Outcome

Title	Accumulation Ratio for Cmax (Rac Cmax) and Accumulation Ratio for AUCtau (Rac AUCtau): Multiple Dose
Description	Rac Cmax is obtained from Cmax (Cycle 1, Day 15) divided by Cmax (Cycle 1, Day 1) Rac AUCtau is obtained from AUCtau (Cycle 1, Day 15) divided by AUCtau (Cycle 1, Day 1)
Time Frame	Multiple dose Cycle 1 Day 1 and 15: predose, 0.5, 1, 2, 4, 8 and 12 hours postdose

Outcome Measure Data

Analysis Population Description

Participants who received at least one study drug and completed pharmacokinetic blood sampling for at least one day (Pharmacokinetic Analysis Set); n= number of participants assessed.

Arm/Group Title	AG-013736
Arm/Group Description:	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Overall Number of Participants Analyzed	12
Mean (Standard Deviation); Unit of Measure: ratio
Rac Cmax (n=11)	1.449 (0.471)
Rac AUCtau (n=11)	1.541 (0.489)

10. Secondary Outcome

Title	Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 2 and 3 (s-VEGFR2 and s-VEGFR3), Vascular Endothelial Growth Factor (VEGF), Soluble Stem Cell Factor Receptor (s-KIT)
Description	Percent change from baseline is obtained from (observed value minus baseline value) divided by baseline value multiplied by 100 in each parameter, i.e., VEGFR2, s-VEGFR3, s-KIT, and VEGF.
Time Frame	Prior to the initial dose (baseline), Day 1 of Cycle 2 and at the discontinuation

Outcome Measure Data

Analysis Population Description

Participants who received at least one study drug and completed pharmacodynamic blood sampling for at least one day (Pharmacodynamic Analysis Set); n= number of participants assessed.

Arm/Group Title	AG-013736
Arm/Group Description:	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Overall Number of Participants Analyzed	12
Median (Full Range); Unit of Measure: percent change
s-VEGFR2: Cycle 2 Day 1 (n=12)	-41.73; (-53.2 to -10.1)
s-VEGFR2: At discontinuation (n=11)	-40.57; (-53.0 to -8.4)
s-VEGFR3: Cycle 2 Day 1 (n=12)	-52.50; (-93.7 to -15.6)
s-VEGFR3: At discontinuation (n=11)	-65.48; (-81.2 to 39.4)
s-KIT: Cycle 2 Day 1 (n=12)	-0.26; (-23.8 to 33.5)
s-KIT: At discontinuation (n=11)	4.66; (-31.2 to 12.9)
VEGF: Cycle 2 Day 1 (n=12)	266.92; (14.9 to 1030.4)
VEGF: At discontinuation (n=11)	43.48; (-15.5 to 423.1)

11. Secondary Outcome

Title	The Numbers of Participants With Best Overall Response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progression of Disease (PD) According to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0)
Description	CR was defined as the disappearance of all target and nontarget lesions and no appearance of new lesions. PR was defined as at least a 30% decrease in the sum of the longest diameters (SLD) of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as PD being demonstrated during the first 8 weeks. PD was defined as at least a 20% increase in the SLD of target lesions compared to the smallest SLD since the study treatment started.
Time Frame	Up to 795 days

Outcome Measure Data

Analysis Population Description

Participants with at least 1 target lesion according to RECIST and who received at least 1 dose of study drug (Anti-tumor Response Analysis Set).

Arm/Group Title	AG-013736
Arm/Group Description:	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
Overall Number of Participants Analyzed	12
Measure Type: Number; Unit of Measure: participants
CR	0
PR	0
SD	10
PD	2

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Arm/Group Title	AG-013736
Arm/Group Description	Single dose (first 6 participants only): Single AG-013736 5 mg was administered orally. Multiple dose (all participants): AG-013736 5 mg twice daily (BID) was administered orally in fed state, 12 hours apart at approximately the same time each day. AG-013736 dose was titrated or reduced based on the dose modification criteria: the available dose was 2, 3, 5, 7, or 10 mg at a time. One cycle length was 28 days and participants continued the study treatment until intolerable toxicity or disease progression occurred.
All-Cause Mortality
	AG-013736
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	AG-013736
	Affected / at Risk (%)
Total	5/12 (41.67%)
Cardiac disorders
Cardiac tamponade † 1	1/12 (8.33%)
Gastrointestinal disorders
Intestinal obstruction † 1	2/12 (16.67%)
General disorders
Pyrexia † 1	2/12 (16.67%)
Infections and infestations
Liver abscess † 1	1/12 (8.33%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 12.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	AG-013736
	Affected / at Risk (%)
Total	12/12 (100.00%)
Blood and lymphatic system disorders
Lymphopenia † 1	1/12 (8.33%)
Neutropenia † 1	1/12 (8.33%)
Cardiac disorders
Palpitations † 1	1/12 (8.33%)
Ear and labyrinth disorders
Ear discomfort † 1	1/12 (8.33%)
Endocrine disorders
Hyperthyroidism † 1	1/12 (8.33%)
Gastrointestinal disorders
Abdominal discomfort † 1	1/12 (8.33%)
Abdominal pain † 1	5/12 (41.67%)
Constipation † 1	6/12 (50.00%)
Diarrhoea † 1	10/12 (83.33%)
Dyspepsia † 1	2/12 (16.67%)
Nausea † 1	4/12 (33.33%)
Proctalgia † 1	1/12 (8.33%)
Stomatitis † 1	9/12 (75.00%)
Toothache † 1	2/12 (16.67%)
General disorders
Face oedema † 1	1/12 (8.33%)
Fatigue † 1	10/12 (83.33%)
Generalised oedema † 1	1/12 (8.33%)
Pyrexia † 1	1/12 (8.33%)
Thirst † 1	1/12 (8.33%)
Infections and infestations
Herpes zoster † 1	1/12 (8.33%)
Nasopharyngitis † 1	3/12 (25.00%)
Onychomycosis † 1	1/12 (8.33%)
Tinea infection † 1	1/12 (8.33%)
Investigations
Alanine aminotransferase increased † 1	3/12 (25.00%)
Aspartate aminotransferase increased † 1	6/12 (50.00%)
Blood albumin decreased † 1	1/12 (8.33%)
Blood alkaline phosphatase increased † 1	6/12 (50.00%)
Blood amylase increased † 1	1/12 (8.33%)
Blood bilirubin increased † 1	3/12 (25.00%)
Blood creatinine increased † 1	1/12 (8.33%)
Blood glucose increased † 1	5/12 (41.67%)
Blood thyroid stimulating hormone decreased † 1	4/12 (33.33%)
Blood thyroid stimulating hormone increased † 1	9/12 (75.00%)
Blood urea increased † 1	1/12 (8.33%)
Blood urine present † 1	7/12 (58.33%)
Haemoglobin decreased † 1	1/12 (8.33%)
Lipase increased † 1	5/12 (41.67%)
Platelet count decreased † 1	5/12 (41.67%)
Thyroxine free decreased † 1	1/12 (8.33%)
Thyroxine free increased † 1	3/12 (25.00%)
Tri-iodothyronine free increased † 1	3/12 (25.00%)
Urine bilirubin increased † 1	2/12 (16.67%)
Weight decreased † 1	4/12 (33.33%)
White blood cell count decreased † 1	3/12 (25.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	11/12 (91.67%)
Hypoalbuminaemia † 1	1/12 (8.33%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/12 (8.33%)
Back pain † 1	3/12 (25.00%)
Musculoskeletal pain † 1	2/12 (16.67%)
Musculoskeletal stiffness † 1	1/12 (8.33%)
Myalgia † 1	1/12 (8.33%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever † 1	1/12 (8.33%)
Tumour pain † 1	2/12 (16.67%)
Nervous system disorders
Dysgeusia † 1	1/12 (8.33%)
Headache † 1	3/12 (25.00%)
Lacunar infarction † 1	1/12 (8.33%)
Post herpetic neuralgia † 1	1/12 (8.33%)
Somnolence † 1	2/12 (16.67%)
Psychiatric disorders
Insomnia † 1	2/12 (16.67%)
Renal and urinary disorders
Proteinuria † 1	6/12 (50.00%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	4/12 (33.33%)
Dysphonia † 1	7/12 (58.33%)
Dyspnoea † 1	2/12 (16.67%)
Dyspnoea exertional † 1	1/12 (8.33%)
Epistaxis † 1	3/12 (25.00%)
Haemoptysis † 1	1/12 (8.33%)
Nasal mucosal disorder † 1	1/12 (8.33%)
Skin and subcutaneous tissue disorders
Alopecia † 1	1/12 (8.33%)
Erythema † 1	1/12 (8.33%)
Palmar-plantar erythrodysaesthesia syndrome † 1	8/12 (66.67%)
Rash † 1	3/12 (25.00%)
Vascular disorders
Hypertension † 1	6/12 (50.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 12.1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

• Name/Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.
• Phone: 1-800-718-1021
• EMail: ClinicalTrials.gov_Inquiries@pfizer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mukohara T, Nakajima H, Mukai H, Nagai S, Itoh K, Umeyama Y, Hashimoto J, Minami H. Effect of axitinib (AG-013736) on fatigue, thyroid-stimulating hormone, and biomarkers: a phase I study in Japanese patients. Cancer Sci. 2010 Apr;101(4):963-8. doi: 10.1111/j.1349-7006.2009.01465.x. Epub 2009 Dec 9.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00447005
• Other Study ID Numbers: A4061022
• First Submitted: March 12, 2007
• First Posted: March 13, 2007
• Results First Submitted: February 25, 2012
• Results First Posted: March 26, 2012
• Last Update Posted: May 23, 2012