A Study In Patients With Advanced Solid Tumor

• ClinicalTrials.gov Identifier: NCT00726752
• Recruitment Status: Completed
• First Posted: August 1, 2008
• 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: Neoplasms
• Intervention: Drug: Axitinib (AG-013736)
• Enrollment: 6

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	AG-013736
Arm/Group Description	Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Period Title: Overall Study
Started	6
Completed	0
Not Completed	6
Reason Not Completed
Lack of Efficacy	6

Baseline Characteristics

Arm/Group Title		AG-013736
Arm/Group Description		Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Overall Number of Baseline Participants		6
Baseline Analysis Population Description		[Not Specified]
Age Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	6 participants
		53.8 (15.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	6 participants
	Female	3 50.0%
	Male	3 50.0%

Outcome Measures

1. Primary Outcome

Title	Single Dose: Maximum Observed Plasma Concentration (Cmax)
Description	[Not Specified]
Time Frame	Predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hour postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.

Arm/Group Title	AG-013736
Arm/Group Description:	Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Overall Number of Participants Analyzed	6
Mean (Standard Deviation); Unit of Measure: ng/mL
5 mg Single Dose	20.732 (14.492)
7 mg Single Dose	32.007 (28.223)
10 mg Single Dose	53.123 (60.921)

2. Primary Outcome

Title	Area Under the Plasma Concentration-Time Curve From Time Zero to Time Infinity (AUCinf)
Description	AUCinf is obtained from AUC (0 - t) plus AUC (t - infinity).
Time Frame	Predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hour postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.

Arm/Group Title	AG-013736
Arm/Group Description:	Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Overall Number of Participants Analyzed	6
Mean (Standard Deviation); Unit of Measure: ng*hr/mL
5 mg Single Dose	180.25 (154.90)
7 mg Single Dose	228.45 (183.12)
10 mg Single Dose	379.12 (345.50)

3. Primary Outcome

Title	Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax)
Description	[Not Specified]
Time Frame	Predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hour postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.

Arm/Group Title	AG-013736
Arm/Group Description:	Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Overall Number of Participants Analyzed	6
Median (Full Range); Unit of Measure: hours
5 mg Single Dose	4.1000; (3.950 to 6.020)
7 mg Single Dose	4.0000; (0.983 to 9.880)
10 mg Single Dose	4.0150; (2.050 to 6.000)

4. Primary Outcome

Title	Single Dose: Plasma Decay Half-Life (t1/2)
Description	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time Frame	Predose, 0.5, 1, 2, 4, 6, 8, 10, 24, and 32-hour postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.

Arm/Group Title	AG-013736
Arm/Group Description:	Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Overall Number of Participants Analyzed	6
Mean (Standard Deviation); Unit of Measure: hours
5 mg Single Dose	4.778 (2.815)
7 mg Single Dose	5.088 (2.592)
10 mg Single Dose	5.880 (3.456)

5. Secondary Outcome

Title	Multiple Dose: Maximum Observed Plasma Concentration (Cmax)
Description	Cmax at multiple dosing
Time Frame	Cycle 1 Day 15 predose in the morning, and 0.5, 1, 2, 4, 8 and 12 hour postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.

Arm/Group Title	AG-013736
Arm/Group Description:	Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Overall Number of Participants Analyzed	6
Mean (Standard Deviation); Unit of Measure: ng/mL
	25.933 (21.703)

6. Secondary Outcome

Title	Multiple Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)
Description	The dosing interval was 12 hours in this study.
Time Frame	Cycle 1 Day 15 predose in the morning, and 0.5, 1, 2, 4, 8 and 12 hour postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.

Arm/Group Title	AG-013736
Arm/Group Description:	Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Overall Number of Participants Analyzed	6
Mean (Standard Deviation); Unit of Measure: ng*h/mL
	164.55 (128.15)

7. Secondary Outcome

Title	Multiple Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax)
Description	Tmax at multiple dosing
Time Frame	Cycle 1 Day 15 predose in the morning, and 0.5, 1, 2, 4, 8 and 12 hour postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.

Arm/Group Title	AG-013736
Arm/Group Description:	Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Overall Number of Participants Analyzed	6
Median (Full Range); Unit of Measure: hours
	4.0400; (3.930 to 7.700)

8. Secondary Outcome

Title	Multiple Dose: Accumulation Ratio for Cmax (Rac Cmax) and Accumulation Ratio for AUCtau (Rac AUCtau)
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	Cycle 1 Day 15 predose in the morning, and 0.5, 1, 2, 4, 8 and 12 hour postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacokinetic blood sampling for at least 1 day.

Arm/Group Title	AG-013736
Arm/Group Description:	Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Overall Number of Participants Analyzed	6
Mean (Standard Deviation); Unit of Measure: ratio
Rac Cmax	1.3540 (0.5335)
Rac AUCtau	1.4185 (0.3951)

9. Secondary Outcome

Title	Percent Change From Baseline in Soluble Vascular Endothelial Growth Factor Receptor 1, 2, and 3 (s-VEGFR1, 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., s-VEGFR1, VEGFR2, s-VEGFR3, s-KIT, and VEGF
Time Frame	Prior to the initial dose (baseline) and Day 1 of Cycle 2

Outcome Measure Data

Analysis Population Description

Pharmacodynamic analysis set was defined as all enrolled participants who received at least 1 dose of the study medication and who completed pharmacodynamic blood sampling for at least 1 day.

Arm/Group Title	AG-013736
Arm/Group Description:	Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Overall Number of Participants Analyzed	6
Median (Full Range); Unit of Measure: percent
s-VEGFR1	-29.15; (-31.4 to -25.3)
s-VEGFR2	-33.16; (-58.4 to -26.2)
s-VEGFR3	-56.38; (-66.2 to -42.1)
s-KIT	-14.59; (-23.7 to -5.2)
VEGF	179.52; (37.0 to 1444.6)

10. Secondary Outcome

Title	Number 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 470 days

Outcome Measure Data

Analysis Population Description

Anti-tumor response analysis set was defined as all participants with at least 1 target lesion according to RECIST and who received at least 1 dose of study drug.

Arm/Group Title	AG-013736
Arm/Group Description:	Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Overall Number of Participants Analyzed	6
Measure Type: Number; Unit of Measure: participants
CR	0
PR	0
SD	3
PD	3

11. Secondary 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 (CTCAE) Version 3.0 Grade 3 or higher , serious adverse events, and adverse events resulted in discontinuation.
Time Frame	Up to 470 days of treatment plus 28-days follow-up

Outcome Measure Data

Analysis Population Description

Safety analysis set was defined as all enrolled participants who received the study drug at least once in this study (same as the full analysis set:FAS).

Arm/Group Title	AG-013736
Arm/Group Description:	Single Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
Overall Number of Participants Analyzed	6
Measure Type: Number; Unit of Measure: participants
Any adverse events	6
Any serious adverse events	1
Any Grade-3 or -4 adverse events	4
Any Grade-5 adverse events (= death)	1
Discontinuation due to adverse events	0

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 Dosing: Participants received single AG-013736 5 mg, followed by 7 mg, and subsequently 10 mg. After the single dose at each dose level, participants were monitored for at least 48 hours prior to the next dosing. Multiple Dosing (28-day cycle ): After the monitoring period following the 10 mg single dose, participants received multiple doses of AG-013736 at 5 mg twice daily (BID) at approximately 12 hours apart. The treatment was continued until participants experienced intolerable toxicity or progressive disease.
All-Cause Mortality
	AG-013736
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	AG-013736
	Affected / at Risk (%)
Total	1/6 (16.67%)
General disorders
Disease progression † 1 [1]	1/6 (16.67%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 13.0; [1] Caused death.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	AG-013736
	Affected / at Risk (%)
Total	6/6 (100.00%)
Endocrine disorders
Thyroiditis chronic † 1	1/6 (16.67%)
Eye disorders
Eye irritation † 1	1/6 (16.67%)
Gastrointestinal disorders
Abdominal pain upper † 1	1/6 (16.67%)
Ascites † 1	1/6 (16.67%)
Cheilitis † 1	1/6 (16.67%)
Constipation † 1	2/6 (33.33%)
Diarrhoea † 1	3/6 (50.00%)
Nausea † 1	2/6 (33.33%)
Stomatitis † 1	2/6 (33.33%)
General disorders
Chest pain † 1	1/6 (16.67%)
Fatigue † 1	5/6 (83.33%)
Mucosal inflammation † 1	1/6 (16.67%)
Oedema † 1	2/6 (33.33%)
Hepatobiliary disorders
Jaundice cholestatic † 1	1/6 (16.67%)
Infections and infestations
Nasopharyngitis † 1	2/6 (33.33%)
Paronychia † 1	1/6 (16.67%)
Injury, poisoning and procedural complications
Contusion † 1	1/6 (16.67%)
Fracture † 1	1/6 (16.67%)
Investigations
Alanine aminotransferase increased † 1	1/6 (16.67%)
Aspartate aminotransferase increased † 1	2/6 (33.33%)
Blood alkaline phosphatase increased † 1	3/6 (50.00%)
Blood amylase increased † 1	3/6 (50.00%)
Blood cholesterol increased † 1	2/6 (33.33%)
Blood lactate dehydrogenase increased † 1	3/6 (50.00%)
Blood potassium increased † 1	1/6 (16.67%)
Blood thyroid stimulating hormone decreased † 1	2/6 (33.33%)
Blood thyroid stimulating hormone increased † 1	4/6 (66.67%)
Blood urine present † 1	1/6 (16.67%)
Lipase increased † 1	1/6 (16.67%)
Neutrophil count decreased † 1	2/6 (33.33%)
Platelet count decreased † 1	1/6 (16.67%)
Thyroglobulin increased † 1	1/6 (16.67%)
Thyroxine free decreased † 1	2/6 (33.33%)
Thyroxine free increased † 1	1/6 (16.67%)
Tri-iodothyronine free decreased † 1	2/6 (33.33%)
Weight decreased † 1	1/6 (16.67%)
White blood cell count decreased † 1	2/6 (33.33%)
Metabolism and nutrition disorders
Decreased appetite † 1	3/6 (50.00%)
Musculoskeletal and connective tissue disorders
Back pain † 1	1/6 (16.67%)
Myalgia † 1	2/6 (33.33%)
Neck pain † 1	1/6 (16.67%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain † 1	2/6 (33.33%)
Nervous system disorders
Dizziness † 1	1/6 (16.67%)
Headache † 1	2/6 (33.33%)
Neuropathy peripheral † 1	3/6 (50.00%)
Somnolence † 1	1/6 (16.67%)
Renal and urinary disorders
Proteinuria † 1	4/6 (66.67%)
Reproductive system and breast disorders
Menstruation irregular † 1	1/6 (16.67%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	1/6 (16.67%)
Dysphonia † 1	2/6 (33.33%)
Epistaxis † 1	2/6 (33.33%)
Skin and subcutaneous tissue disorders
Dermatitis † 1	1/6 (16.67%)
Dermatitis acneiform † 1	1/6 (16.67%)
Haemorrhage subcutaneous † 1	1/6 (16.67%)
Palmar-plantar erythrodysaesthesia syndrome † 1	4/6 (66.67%)
Pruritus † 1	1/6 (16.67%)
Rash † 1	3/6 (50.00%)
Telangiectasia † 1	1/6 (16.67%)
Urticaria † 1	1/6 (16.67%)
Vascular disorders
Hypertension † 1	5/6 (83.33%)
Hypotension † 1	2/6 (33.33%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 13.0

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

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00726752
• Other Study ID Numbers: A4061044
• First Submitted: July 30, 2008
• First Posted: August 1, 2008
• Results First Submitted: February 25, 2012
• Results First Posted: March 26, 2012
• Last Update Posted: May 23, 2012