Axitinib (AG-013736) With Or Without Dose Titration (Increase) In Patients With Kidney Cancer

• ClinicalTrials.gov Identifier: NCT00835978
• Recruitment Status: Completed
• First Posted: February 4, 2009
• Results First Posted: May 26, 2014
• Last Update Posted: May 30, 2017
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Carcinoma, Renal Cell
• Intervention: Drug: axitinib
• Enrollment: 213

Participant Flow

Recruitment Details	This study was conducted at 49 centers in Czech Republic, Germany, Japan, Russian Federation, Spain, and the United States (US).
Pre-assignment Details	Participants were enrolled in a 4-week lead-in period, during which they received axitinib 5 milligram (mg) twice a day (BID). After the lead-in period, participants meeting randomization criteria were then randomized to one of the two treatment arms. Participants, not meeting criteria, continued study without dose titration (non-randomized arm).

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	Discontinued Prior to Randomization
Arm/Group Description	Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.	Participants who discontinued before they were randomized to any of the treatment or non-randomized arms.
Period Title: Overall Study
Started	56	56	91	10
Treated	56	56	91	10
Completed	0 [1]	0 [1]	0 [1]	0 [1]
Not Completed	56	56	91	10
Reason Not Completed
Death	33	40	49	4
Lost to Follow-up	3	4	2	1
Other	5	1	8	0
Objective progression or relapse	2	0	1	0
Adverse Event	1	0	1	0
Withdrawal by Subject	0	3	0	5
Study terminated by sponsor	12	8	30	0
[1] Study Completion: 29 Feb 2016. Treatment discontinued due to objective progression/relapse & death

Baseline Characteristics

Arm/Group Title		Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	Discontinued Prior to Randomization	Total
Arm/Group Description		Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.	Participants who discontinued before they were randomized to any of the treatment or non-randomized arms.	Total of all reporting groups
Overall Number of Baseline Participants		56	56	91	10	213
Baseline Analysis Population Description		The safety analysis (SA) population consists of all participants who received at least one dose of study medication.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	56 participants	56 participants	91 participants	10 participants	213 participants
		59.7 (10.2)	59.6 (10.5)	62.9 (8.9)	62.9 (7.5)	61.2 (9.7)
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	56 participants	56 participants	91 participants	10 participants	213 participants
< 65 Years		38	38	54	6	136
>= 65 Years		18	18	37	4	77
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	56 participants	56 participants	91 participants	10 participants	213 participants
	Female	19 33.9%	11 19.6%	36 39.6%	4 40.0%	70 32.9%
	Male	37 66.1%	45 80.4%	55 60.4%	6 60.0%	143 67.1%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR) - Percentage of Participants With Objective Response
Description	ORR was defined as the proportion of participants with objective response based assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR was defined as complete disappearance of all target lesions and non-target disease. No new lesions. PR was defined as >=30% decrease on study under baseline of the sum of longest diameters of all target lesions. No unequivocal progression of non-target disease. No new lesions.
Time Frame	Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.

Outcome Measure Data

Analysis Population Description

The Full Analysis (FA) population included all randomized participants who received study drug or different drug to which they were randomized. The Safety Analysis (SA) population included all non-randomized patients who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	All Participants
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.	All enrolled participants (randomized and non-randomized)
Overall Number of Participants Analyzed	56	56	91	213
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	53.6; (39.7 to 67.0)	33.9; (21.8 to 47.8)	59.3; (48.5 to 69.5)	48.4; (41.5 to 55.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Titration Arm, Placebo Titration Arm
	Comments	ORR for the 2 treatment arms was compared with the Cochran-Mantel-Haenszel test stratified by ECOG performance status. The relative risk ratio estimator was used to contrast the treatment effects on the endpoint. Both a point estimate and a 2-sided 95% CI were calculated using a normal approximation.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0189
	Comments	A priori defined threshold for statistical significance was: alpha=0.10 (one-sided)
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.578
	Confidence Interval	(2-Sided) 95%; 1.017 to 2.448
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	The time from first dose administration to first documentation of objective tumor progression or to death due to any cause. PFS in each arm was assessed using the Kaplan-Meier method and estimates of the PFS curves from the Kaplan-Meier method were presented.
Time Frame	Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.

Outcome Measure Data

Analysis Population Description

The Full Analysis (FA) population included all randomized participants who received study drug or different drug to which they were randomized. The Safety Analysis (SA) population included all non-randomized patients who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	All Participants
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.	All enrolled participants (randomized and non-randomized)
Overall Number of Participants Analyzed	56	56	91	213
Median (95% Confidence Interval); Unit of Measure: Months
	14.5; (9.2 to 24.5)	15.7; (8.3 to 19.4)	16.6; (11.2 to 22.5)	14.6; (11.5 to 17.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Titration Arm, Placebo Titration Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2444
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.849
	Confidence Interval	(2-Sided) 95%; 0.535 to 1.348
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Duration of Response (DR)
Description	DR was defined as the time from the first documentation of objective tumor response (complete response - CR or Partial response - PR) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. The median values were estimated based on Kaplan-Meier method. 95% confidence interval was based on the Brookmeyer and Crowley method.
Time Frame	Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks

Outcome Measure Data

Analysis Population Description

Subset of Full Analysis (FA) and Safety Analysis (SA) patients who achieved confirmed complete or partial response. FA included all randomized patients and was based on randomized treatment assignment regardless of whether or not study drug was administered. SA included all non randomized patients who received at least one dose of study medication.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib(blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.
Overall Number of Participants Analyzed	30	19	54
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (10.8 to NA)	21.2; (11.1 to 25.8)	23.3; (15.7 to 28.6)

[1]

The median duration of tumor response among responders was not reached in the active treatment group.

4. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from date of the first dose of the study medication to date of death due to any cause. For participants who did not die, their survival times were to be censored at the last date they were known to be alive.
Time Frame	Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.

Outcome Measure Data

Analysis Population Description

The Full Analysis (FA) population included all randomized participants who received study drug or different drug to which they were randomized. The Safety Analysis (SA) population included all non-randomized patients who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Active Titration Arm (FA Population)	Placebo Titration Arm (FA Population)	Non-randomized Arm (SA Population)
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.
Overall Number of Participants Analyzed	56	56	91
Median (95% Confidence Interval); Unit of Measure: Months
	42.7 [1]; (24.7 to NA)	30.4; (23.7 to 45.0)	41.6 [1]; (33.0 to NA)

[1]

Upper limit of the confidence interval was not calculable due to the large number of censored event times

5. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Axitinib
Description	Cmax for steady-state axitinib was evaluated on Cycle 2 Day 15. Results were normalized to axitinib 7 mg dose for active titration arm and axitinib 5 mg dose for placebo titration arm. Results were normalized to axitinib 7 mg dose for active titration arm and axitinib 5 mg dose for placebo titration arm.
Time Frame	Cycle 2 Day 15 (C2D15): pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib(blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).
Overall Number of Participants Analyzed	16	20
Geometric Mean (95% Confidence Interval); Unit of Measure: ng/mL
	31.74; (21.63 to 46.58)	23.05; (16.36 to 32.49)

6. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib,
Description	Tmax for steady-state axitinib was evaluated on Cycle 2 Day 15.
Time Frame	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib(blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).
Overall Number of Participants Analyzed	16	20
Median (Full Range); Unit of Measure: hrs
	2.04; (1.00 to 6.00)	2.00; (0.00 to 6.00)

7. Secondary Outcome

Title	Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Axitinib
Description	Area under the plasma concentration time-curve from zero to the last measurable concentration (AUClast). AUClast for steady-state axitinib was evaluated on Cycle 2 Day 15. Results were normalized to axitinib 7 mg dose for active titration arm and axitinib 5 mg dose for placebo titration arm.
Time Frame	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).
Overall Number of Participants Analyzed	16	20
Geometric Mean (95% Confidence Interval); Unit of Measure: ng.hr/mL
	105.33; (70.16 to 158.14)	78.44; (54.53 to 112.82)

8. Secondary Outcome

Title	Area Under the Curve From Time Zero to 24 Hours[AUC(0-24)] for Axitinib
Description	Area under the plasma concentration time-curve from zero 24 hours[AUC(0-24). AUC(0-24) for steady-state axitinib was evaluated on Cycle 2 Day 15. Results were normalized to axitinib 7 mg dose for active titration arm and axitinib 5 mg dose for placebo titration arm.
Time Frame	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).
Overall Number of Participants Analyzed	16	20
Geometric Mean (95% Confidence Interval); Unit of Measure: ng.hr/mL
	258.68; (150.47 to 444.72)	161.38; (102.09 to 255.12)

9. Secondary Outcome

Title	Plasma Decay Half-Life (t1/2) for Axitinib
Description	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Plasma decay half life for steady-state axitinib was evaluated on Cycle 2 Day 15.
Time Frame	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib(blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo[blinded therapy] 5 mg BID).
Overall Number of Participants Analyzed	16	20
Mean (Standard Deviation); Unit of Measure: hr
	2.48 (1.902)	2.81 (1.685)

10. Secondary Outcome

Title	Apparent Oral Clearance (CL/F) of Axitinib
Description	Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed (F). Clearance is defined as the volume of blood from which drug can be completely removed per unit of time. CL/F for steady-state axitinib was evaluated on Cycle 2 Day 15.
Time Frame	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib(blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).
Overall Number of Participants Analyzed	16	20
Geometric Mean (95% Confidence Interval); Unit of Measure: L/hr
	54.15; (31.49 to 93.12)	61.93; (39.17 to 97.91)

11. Secondary Outcome

Title	Apparent Volume of Distribution During the Elimination Phase (Vz/F) for Axitinib
Description	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vz/F is influenced by the fraction absorbed. Vz/F for steady-state axitinb was evaluated on Cycle 2 Day 15.
Time Frame	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib(blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo[blinded therapy] 5 mg BID).
Overall Number of Participants Analyzed	16	20
Geometric Mean (95% Confidence Interval); Unit of Measure: L
	158.18; (98.38 to 254.34)	216.62; (145.00 to 323.60)

12. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure
Description	Value at respective visit minus value at baseline
Time Frame	At screening (D-14 to D-1); lead-in period: Cycle 1 - Day 1 and Day 15; Cycle 2 - Day 1 and Day 15; Cycle 3 & subsequent cycles Day 1; end of study and follow-up 28 days after last dose.

Outcome Measure Data

Analysis Population Description

The SA population consists of all participatns who received at least one dose of study medication.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib(blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.
Overall Number of Participants Analyzed	56	56	91
Mean (Standard Deviation); Unit of Measure: mmHg
Cycle 1 Day 1 (n=52,51,73)	-4.3 (11.1)	-2.9 (9.2)	-1.8 (14.2)
Cycle 1 Day 15 (n=56,56,91)	3.8 (12.2)	4.1 (12.5)	11.5 (18.0)
Cycle 2 Day 1 (n=56,56,91)	1.9 (12.4)	0.9 (13.6)	9.9 (18.7)
Cycle 2 Day 15 (n=55,55,86)	3.6 (13.8)	2.7 (16.6)	5.9 (20.3)
Cycle 3 Day 1 (n=48,49,84)	3.5 (15.1)	8.4 (15.4)	5.2 (20.2)
Cycle 4 Day 1 (n=45,48,79)	4.3 (12.7)	3.5 (13.0)	5.5 (18.2)
End of treatment (n=35,44,51)	2.4 (17.0)	1.7 (14.0)	-2.8 (19.0)
Follow-up (n=16,25,36)	-3.6 (16.9)	-0.4 (16.3)	-0.6 (16.7)

13. Secondary Outcome

Title	Change From Baseline in Diastolic Blood Pressure
Description	Value at respective visit minus value at baseline.
Time Frame	At screening (D-14 to D-1); lead-in period: Cycle 1 - Day 1 and Day 15; Cycle 2 - Day 1 and Day 15; Cycle 3 & subsequent cycles Day 1; end of study and follow-up 28 days after last dose.

Outcome Measure Data

Analysis Population Description

The SA population consists of all participatns who received at least one dose of study medication.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.
Overall Number of Participants Analyzed	56	56	91
Mean (Standard Deviation); Unit of Measure: mmHg
Cycle 1 Day 1 (n=52,51,73)	-1.6 (8.2)	-2.6 (7.4)	0.5 (8.4)
Cycle 1 Day 15 (n=56,56,91)	4.8 (8.5)	3.0 (7.7)	11.5 (10.0)
Cycle 2 Day 1 (n=56,56,91)	4.2 (9.0)	3.5 (8.0)	10.5 (10.5)
Cycle 2 Day 15 (n=55,55,86)	5.5 (10.5)	4.4 (10.7)	9.7 (11.3)
Cycle 3 Day 1 (n=48,49,84)	6.6 (8.3)	5.9 (9.3)	9.1 (13.6)
Cycle 4 Day 1 (n=45,48,79)	7.4 (8.2)	4.6 (8.5)	8.7 (11.8)
End of treatment (n=35,44,51)	0.6 (10.8)	3.5 (6.3)	3.0 (10.5)
Follow-up (n=16,25,36)	-4.5 (10.1)	-1.3 (8.5)	1.8 (9.0)

14. Secondary Outcome

Title	Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline
Description	CECs are noninvasive marker of vascular damage, remodeling, and dysfunction. Samples were collected and following proteins were analyzed: CD146+/CD105+ CECs, CD146+/CD105+ mean fluorescence intensity (MFI) platelet derived growth factor receptor (PDGFR)-beta, CD146+/CD105+ MFI phospho-PDGFR (pPDGFR)-beta, CD146+/CD105+ phospho-Vascular endothelial growth factor receptor (pVEGFR), CD146+/CD105+ MFI VEGFR. The ratio of plasma levels of the biomarkers at the selected time point vs baseline is reported.
Time Frame	At baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Outcome Measure Data

Analysis Population Description

The Biomarker Analysis Set included participants receiving at least one dose of treatment, with a Cycle 1 Day 1 biomarker result for at least one biomarker.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib(blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.
Overall Number of Participants Analyzed	17	22	20
Mean (Standard Deviation); Unit of Measure: Fluorescent Intensity Unit (FIU)
Baseline CECs Count (n=17,22,20)	23584 (18213.1)	28544 (27694.4)	29663 (30651.0)
Baseline MFI PDGFR-BETA (n=17,22,20)	346815 (179563)	455238 (238157)	327567 (167728)
Baseline MFI pPDGFR-BETA (n=17,22,20)	401226 (195445)	395509 (136933)	397672 (193172)
Baseline MFI pVEGFR (n=16,22,20)	456086 (290174)	436197 (128225)	398754 (188137)
Baseline MFI VEGFR (n=16,22,20)	367799 (181320)	473290 (228619)	359092 (167706)

15. Secondary Outcome

Title	Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline
Description	CECs are noninvasive marker of vascular damage, remodeling, and dysfunction. Samples were collected and following proteins were analyzed: CD146+/CD105+ CECs, CD146+/CD105+ MFI platelet derived growth factor receptor (PDGFR)-beta, CD146+/CD105+ MFI phospho-PDGFR (pPDGFR)-beta, CD146+/CD105+ phospho-VEGFR (pVEGFR), CD146+/CD105+ MFI VEGFR. The ratio of plasma levels of the biomarkers at the selected time point vs baseline is reported.
Time Frame	At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT)

Outcome Measure Data

Analysis Population Description

The Biomarker Analysis Set included participants receiving at least one dose of treatment, with a Cycle 1 Day 1 biomarker result for at least one biomarker.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib(blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.
Overall Number of Participants Analyzed	17	22	20
Mean (Standard Deviation); Unit of Measure: Ratio
C1D15:C1D1 CECs Count (n=11,18,14)	2.3 (2.52)	3.7 (6.92)	2.2 (3.10)
C2D15:C1D1 CECs Count (n=13,16,11)	1.3 (1.43)	4.4 (9.27)	1.3 (1.22)
EOT:C1D1 CECs Count (n=7,9,4)	2.8 (4.81)	8.9 (21.70)	1.2 (1.50)
C1D15:C1D1 MFI PDGFRBETA (n=11,17,13)	1.3 (1.03)	1.5 (1.14)	1.1 (0.73)
C2D15:C1D1 MFI PDGFRBETA (n=13,16,11)	1.4 (1.24)	1.1 (1.14)	2.2 (1.62)
EOT:C1D1 MFI PDGFRBETA (n=7,9,4)	1.5 (1.75)	0.6 (0.52)	1.2 (1.78)
C1D15:C1D1 MFI pPDGFR-BETA (n=11,17,13)	1.1 (0.63)	1.2 (0.77)	1.0 (1.12)
C2D15:C1D1 MFI pPDGFR-BETA (n=13,16,11)	1.0 (0.69)	0.8 (0.45)	1.2 (0.79)
EOT:C1D1 MFI pPDGFRBETA (n=7,9,4)	0.8 (0.71)	0.8 (0.93)	1.9 (1.57)
C1D15:C1D1 MFI pVEGFR (n=10,18,14)	1.0 (0.46)	1.2 (0.88)	1.2 (1.00)
C2D15:C1D1 MFI pVEGFR (n=12,16,11)	1.0 (0.74)	0.9 (0.82)	1.2 (0.80)
EOT:C1D1 MFI pVEGFR (n=7,9,4)	0.8 (0.53)	1.3 (0.96)	3.0 (1.16)
C1D15:C1D1 MFI VEGFR (n=10,18,14)	1.4 (1.25)	1.3 (0.94)	1.0 (0.64)
C2D15:C1D1 MFI VEGFR (n=12,16,11)	1.5 (1.48)	1.3 (0.99)	2.1 (1.72)
EOT:C1D1 MFI VEGFR (n=7,9,4)	1.1 (1.03)	0.7 (0.48)	1.9 (1.63)

16. Secondary Outcome

Title	Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+
Description	CECs are noninvasive marker of vascular damage, remodeling, and dysfunction. Samples were collected and following proteins were analyzed: CD31+/CD146+ CECs, CD31+/CD146+ MFI PDGFR-beta, CD31+/CD146+ MFI pPDGFR-beta, CD31+/CD146+ pVEGFR, CD31+/CD146+ MFI VEGFR. The ratio of plasma levels of the biomarkers at the selected time point vs baseline is reported.
Time Frame	At baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Outcome Measure Data

Analysis Population Description

The Biomarker Analysis Set included participants receiving at least one dose of treatment, with a Cycle 1 Day 1 biomarker result for at least one biomarker.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.
Overall Number of Participants Analyzed	17	22	20
Mean (Standard Deviation); Unit of Measure: Fluorescent Intensity Unit (FIU)
Baseline CECs Count (n=17,22,20)	74668 (50558.9)	76258 (46779.5)	77437 (63419.4)
Baseline MFI PDGFR-BETA (n=17,21,20)	333760 (164604)	380886 (147261)	442642 (267436)
Baseline MFI pPDGFR-BETA (n=17,21,20)	380139 (205600)	355441 (147046)	383202 (211174)
Baseline MFI pVEGFR (n=17,22,20)	385617 (203956)	352644 (128803)	380184 (173578)
Baseline MFI VEGFR (n=17,22,20)	330333 (151710)	401909 (165235)	359097 (146943)

17. Secondary Outcome

Title	Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline
Description	CECs are noninvasive marker of vascular damage, remodeling, and dysfunction. Samples were collected and following proteins were analyzed: CD31+/CD146+ CECs, CD31+/CD146+ MFI PDGFR-beta, CD31+/CD146+ MFI pPDGFR-beta, CD31+/CD146+ pVEGFR, CD31+/CD146+ MFI VEGFR. The ratio of plasma levels of the biomarkers at the selected time point vs baseline is reported.
Time Frame	At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT)

Outcome Measure Data

Analysis Population Description

The Biomarker Analysis Set included participants receiving at least one dose of treatment, with a Cycle 1 Day 1 biomarker result for at least one biomarker.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo[blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.
Overall Number of Participants Analyzed	17	22	20
Mean (Standard Deviation); Unit of Measure: Ratio
C1D15:C1D1 CECs Count (n=11,18,14)	2.7 (3.17)	1.6 (2.32)	1.5 (2.31)
C2D15:C1D1 CECs Count (n=13,16,11)	1.4 (1.38)	2.2 (3.91)	2.5 (3.98)
EOT:C1D1 CECs COUNT (n=7,9,4)	1.5 (1.95)	1.4 (2.66)	0.6 (0.71)
C1D15:C1D1 MFI PDGFRBETA (n=11,15,13)	1.2 (0.74)	1.3 (0.89)	0.8 (0.51)
C2D15:C1D1 MFI PDGFRBETA (n=13,14,11)	1.4 (1.36)	1.1 (1.03)	2.2 (2.64)
EOT:C1D1 MFI PDGFRBETA (n=6,8,4)	1.2 (1.23)	0.6 (0.51)	1.7 (1.49)
C1D15:C1D1 MFI pPDGFR-BETA (n=11,15,13)	1.2 (1.07)	1.4 (0.81)	1.0 (0.87)
C2D15:C1D1 MFI pPDGFR-BETA (n=13,14,11)	1.2 (0.89)	0.8 (0.38)	1.1 (0.71)
EOT:C1D1 MFI pPDGFRBETA (n=6,8,4)	0.7 (0.63)	0.8 (0.91)	3.0 (0.47)
C1D15:C1D1 MFI pVEGFR (n=11,18,14)	1.1 (0.75)	1.4 (0.74)	1.2 (0.90)
C2D15:C1D1 MFI pVEGFR (n=13,16,10)	1.2 (1.00)	0.9 (0.68)	1.3 (0.70)
EOT:C1D1 MFI pVEGFR (n=7,9,4)	0.7 (0.59)	1.1 (1.24)	3.1 (0.95)
C1D15:C1D1 MFI VEGFR (n=11,18,14)	1.3 (0.93)	1.3 (0.90)	1.0 (0.57)
C2D15:C1D1 MFI VEGFR n=13,16,10)	1.5 (1.44)	1.2 (0.96)	2.1 (1.80)
EOT:C1D1 MFI VEGFR (n=7,9,4)	1.2 (1.27)	1.1 (0.90)	1.5 (1.42)

18. Secondary Outcome

Title	ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms
Description	ORR, defined as proportion of participants with CR or PR according to RECIST, in subgroups that were defined by VEGFA or VEGFR3 polymorphisms.
Time Frame	At baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Outcome Measure Data

Analysis Population Description

The Safety Analysis (SA) population consisted of all participants who received at least one dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.
Overall Number of Participants Analyzed	49	49	79
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
VEGFA/rs699947 Genotype: A/A (n = 7, 9, 14)	85.7; (42.1 to 99.6)	22.2; (2.8 to 60.0)	42.9; (17.7 to 71.1)
VEGFA/rs699947 Genotype: A/C (n = 22, 20, 41)	54.5; (32.2 to 75.6)	35.0; (15.4 to 59.2)	65.9; (49.4 to 79.9)
VEGFA/rs699947 Genotype: C/C (n = 14, 14, 24)	50.0; (23.0 to 77.0)	35.7; (12.8 to 64.9)	66.7; (44.7 to 84.4)
VEGFA/rs1570360 Genotype: G/G (n = 22, 23, 43)	59.1; (36.4 to 79.3)	39.1; (19.7 to 61.5)	67.4; (51.5 to 80.9)
VEGFA/rs1570360 Genotype: G/A (n = 19, 16, 29)	57.9; (33.5 to 79.7)	18.8; (4.0 to 45.6)	58.6; (38.9 to 76.5)
VEGFA/rs1570360 Genotype: A/A (n = 2, 4, 7)	50.0; (1.3 to 98.7)	50.0; (6.8 to 93.2)	42.9; (9.9 to 81.6)
VEGFR3/rs448012 Genotype: G/G (n = 16, 15, 28)	81.3; (54.4 to 96.0)	53.3; (26.6 to 78.7)	60.7; (40.6 to 78.5)
VEGFR3/rs448012 Genotype: G/C (n = 22, 22, 35)	45.5; (24.4 to 67.8)	18.2; (5.2 to 40.3)	57.1; (39.4 to 73.7)
VEGFR3/rs448012 Genotype: C/C (n = 5, 6, 16)	40.0; (5.3 to 85.3)	33.3; (4.3 to 77.7)	75.0; (47.6 to 92.7)
VEGFR3/rs307826 Genotype: A/A (n = 36, 39, 79)	58.3; (40.8 to 74.5)	30.8; (17.0 to 47.6)	64.3; (51.9 to 75.4)
VEGFR3/rs307826 Genotype: A/G (n = 6, 4, 9)	50.0; (11.8 to 88.2)	50.0; (6.8 to 93.2)	44.4; (13.7 to 78.8)
VEGFR3/rs307826 Genotype: G/G (n = 1, 0, 0)	100.0; (2.5 to 100.0)	0; (0.0 to 0.0)	0; (0.0 to 0.0)
VEGFR3/rs307821 Genotype: G/G (n = 36, 38, 79)	55.6; (38.1 to 72.1)	28.9; (15.4 to 45.9)	65.2; (52.8 to 76.3)
VEGFR3/rs307821 Genotype: G/T (n = 6, 5, 10)	66.7; (22.3 to 95.7)	60.0; (14.7 to 94.7)	40.0; (12.2 to 73.8)
VEGFR3/rs307821 Genotype: T/T (n = 1, 0, 0)	100.0; (2.5 to 100.0)	0; (0.0 to 0.0)	0; (0.0 to 0.0)

19. Secondary Outcome

Title	PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms
Description	PFS, defined as the time from randomization to first documentation of objective tumor progression or to death due to any cause, in subgroups that were defined by VEGFA or VEGFR3 polymorphisms. Estimates of the PFS curves from the Kaplan-Meier method were presented.
Time Frame	At baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Outcome Measure Data

Analysis Population Description

The Safety Analysis (SA) population consisted of all participants who received at least one dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/Group Description:	Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.
Overall Number of Participants Analyzed	43	43	79
Median (95% Confidence Interval); Unit of Measure: Months
VEGFA/rs699947 Genotype: A/A (n = 7, 9, 14)	NA [1]; (1.74 to NA)	11.50 [2]; (3.58 to NA)	7.33; (5.06 to 13.83)
VEGFA/rs699947 Genotype: A/C (n = 22, 20, 41)	11.07; (3.02 to 17.44)	9.67; (1.91 to 16.59)	16.59 [2]; (10.97 to NA)
VEGFA/rs699947 Genotype: C/C (n = 14, 14, 41)	18.74 [2]; (1.84 to NA)	24.64 [2]; (4.01 to NA)	25.13; (8.28 to 30.45)
VEGFA/rs1570360 Genotype: G/G (n = 22, 23, 43)	14.62 [2]; (7.39 to NA)	19.42; (5.81 to 27.63)	25.13; (11.47 to 30.45)
VEGFA/rs1570360 Genotype: G/A (n = 19, 16, 29)	12.78 [2]; (1.84 to NA)	8.34; (1.91 to 16.59)	13.90; (8.28 to 22.54)
VEGFA/rs1570360 Genotype: A/A (n = 2, 4, 29)	NA [1]; (1.74 to NA)	10.04 [2]; (3.58 to NA)	8.57 [2]; (1.74 to NA)
VEGFR3/rs448012 Genotype: G/G (n = 16, 15, 28)	17.44 [2]; (12.78 to NA)	19.42 [2]; (5.35 to NA)	22.54 [2]; (8.08 to NA)
VEGFR3/rs448012 Genotype: G/C (n = 22, 22, 35)	9.18 [2]; (1.84 to NA)	8.31; (3.58 to 16.52)	13.83; (5.62 to 16.59)
VEGFR3/rs448012 Genotype: C/C (n = 5, 6, 16)	11.07 [2]; (1.84 to NA)	15.67; (1.91 to 27.63)	NA [1]; (8.57 to NA)
VEGFR3/rs307826 Genotype: A/A (n = 36, 39, 70)	13.73; (8.28 to 24.47)	15.67; (8.21 to 22.17)	16.56; (10.28 to 25.13)
VEGFR3/rs307826 Genotype: A/G (n = 6, 4, 9)	16.52 [2]; (1.18 to NA)	7.93; (1.84 to 11.86)	16.26; (2.66 to 30.45)
VEGFR3/rs307826 Genotype: G/G (n = 0, 0, 0)	NA [3]; (NA to NA)	NA [3]; (NA to NA)	NA [3]; (NA to NA)
VEGFR3/rs307821 Genotype: G/G (n = 36, 38, 69)	12.78; (7.39 to 24.47)	15.67; (8.21 to 23.95)	16.59; (10.28 to 28.52)
VEGFR3/rs307821 Genotype: G/T (n = 36, 38, 10)	24.80 [2]; (1.18 to NA)	8.34; (1.84 to 11.86)	13.86; (2.66 to 30.45)
VEGFR3/rs307821 Genotype: T/T (n = 1, 0, 0)	NA [4]; (NA to NA)	NA [3]; (NA to NA)	NA [3]; (NA to NA)

[1]

Values were not calculable due to the large number of censored event times

[2]

Upper limit of the confidence interval was not calculable due to the large number of censored event times

[3]

Number of participants with an event in this category was 0

[4]

Number of participants with an event in this category was 1

Adverse Events

Time Frame	AEs were reported until follow up visit. Non-SAEs: up to 28 days post last dose or upon starting new anticancer treatment, whichever was first. SAEs: up to 28 days post last dose, irrespective of new anticancer treatment.
Adverse Event Reporting Description	The same event may be referred to as (serious and non-serious) AEs. 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	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	Discontinued Prior to Randomization
Arm/Group Description	Participants initially received axitinib 5 mg twice a day (BID) + axitinib(blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).	Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator's clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).	Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.	Participants who were discontinued prior to randomization to either treatment or non-randomization arms.
All-Cause Mortality
	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	Discontinued Prior to Randomization
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--	--/--
Serious Adverse Events
	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	Discontinued Prior to Randomization
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	25/56 (44.64%)	14/56 (25.00%)	39/91 (42.86%)	2/10 (20.00%)
Blood and lymphatic system disorders
Neutropenia * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Anaemia * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Cardiac disorders
Myocardial ischaemia * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Acute myocardial infarction * 1	1/56 (1.79%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Angina pectoris * 1	0/56 (0.00%)	0/56 (0.00%)	2/91 (2.20%)	0/10 (0.00%)
Coronary artery stenosis * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Diastolic dysfunction * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Myocardial infarction * 1	4/56 (7.14%)	0/56 (0.00%)	2/91 (2.20%)	0/10 (0.00%)
Acute coronary syndrome * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Atrial fibrillation * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Cardiac failure * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Coronary artery disease * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Ear and labyrinth disorders
Tinnitus * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Endocrine disorders
Hypothyroidism * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Eye disorders
Cataract * 1	0/56 (0.00%)	0/56 (0.00%)	3/91 (3.30%)	0/10 (0.00%)
Gastrointestinal disorders
Diarrhoea * 1	2/56 (3.57%)	1/56 (1.79%)	1/91 (1.10%)	0/10 (0.00%)
Nausea * 1	2/56 (3.57%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Vomiting * 1	3/56 (5.36%)	1/56 (1.79%)	1/91 (1.10%)	0/10 (0.00%)
Diverticulum intestinal haemorrhagic * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Abdominal distension * 1	1/56 (1.79%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Abdominal pain * 1	1/56 (1.79%)	1/56 (1.79%)	1/91 (1.10%)	0/10 (0.00%)
Abdominal pain upper * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Ascites * 1	0/56 (0.00%)	2/56 (3.57%)	0/91 (0.00%)	0/10 (0.00%)
Crohn's disease * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Enterocolitis * 1	0/56 (0.00%)	1/56 (1.79%)	1/91 (1.10%)	0/10 (0.00%)
Gastrointestinal hypomotility * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/1 (0.00%)
Ileus * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Intestinal obstruction * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Pancreatitis * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Small intestinal obstruction * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
General disorders
Disease progression * 1	1/56 (1.79%)	1/56 (1.79%)	6/91 (6.59%)	0/10 (0.00%)
General physical health deterioration * 1	1/56 (1.79%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Chest pain * 1	1/56 (1.79%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Fatigue * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Pyrexia * 1	0/56 (0.00%)	2/56 (3.57%)	1/91 (1.10%)	0/10 (0.00%)
Hepatobiliary disorders
Cholecystitis chronic * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Biliary colic * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Cholelithiasis * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Infections and infestations
Cystitis * 1	1/56 (1.79%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Lung abscess * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Pneumonia * 1	3/56 (5.36%)	2/56 (3.57%)	1/91 (1.10%)	0/10 (0.00%)
Appendicitis * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Infection * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Lung infection * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Osteomyelitis * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Peritonitis bacterial * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Postoperative wound infection * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Gingivitis * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Injury, poisoning and procedural complications
Lumbar vertebral fracture * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Overdose * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Postoperative hernia * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Postoperative wound complication * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Road traffic accident * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Cervical vertebral fracture * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Incisional hernia * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Postoperative ileus * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Rib fracture * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Investigations
Blood creatinine increased * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Blood sodium decreased * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Metabolism and nutrition disorders
Dehydration * 1	5/56 (8.93%)	0/56 (0.00%)	3/91 (3.30%)	1/10 (10.00%)
Decreased appetite * 1	1/56 (1.79%)	1/56 (1.79%)	2/91 (2.20%)	0/10 (0.00%)
Hypercalcaemia * 1	0/56 (0.00%)	0/56 (0.00%)	0/91 (0.00%)	1/10 (10.00%)
Hypokalaemia * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Hyponatraemia * 1	0/56 (0.00%)	1/56 (1.79%)	1/91 (1.10%)	0/10 (0.00%)
Musculoskeletal and connective tissue disorders
Back pain * 1	2/56 (3.57%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Haemarthrosis * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Pain in extremity * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Breast cancer * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Colon cancer * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Nervous system disorders
Cerebrovascular insufficiency * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Syncope * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Encephalopathy * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Headache * 1	0/56 (0.00%)	1/56 (1.79%)	1/91 (1.10%)	0/10 (0.00%)
Presyncope * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Somnolence * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Cerebrovascular accident * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Monoparesis * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Transient ischaemic attack * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Psychiatric disorders
Delirium * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Renal and urinary disorders
Renal colic * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Postrenal failure * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Renal failure * 1	0/56 (0.00%)	0/56 (0.00%)	0/91 (0.00%)	1/10 (10.00%)
Acute kidney injury * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Urinary retention * 1	0/56 (0.00%)	0/56 (0.00%)	2/91 (2.20%)	0/10 (0.00%)
Reproductive system and breast disorders
Pelvic prolapse * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Respiratory, thoracic and mediastinal disorders
Atelectasis * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Dyspnoea * 1	1/56 (1.79%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Cough * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	0/10 (0.00%)
Pleural effusion * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Pulmonary hypertension * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Pulmonary oedema * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Hypercapnia * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Pulmonary embolism * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Skin and subcutaneous tissue disorders
Dermatitis * 1	1/56 (1.79%)	0/56 (0.00%)	0/91 (0.00%)	0/10 (0.00%)
Surgical and medical procedures
Incisional hernia repair * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Vascular disorders
Circulatory collapse * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Hypertension * 1	0/56 (0.00%)	1/56 (1.79%)	1/91 (1.10%)	0/10 (0.00%)
Hypertensive crisis * 1	0/56 (0.00%)	0/56 (0.00%)	0/91 (0.00%)	1/10 (10.00%)
Hypotension * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
Orthostatic hypotension * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	0/10 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 19.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	Discontinued Prior to Randomization
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	55/56 (98.21%)	51/56 (91.07%)	91/91 (100.00%)	9/10 (90.00%)
Blood and lymphatic system disorders
Anaemia * 1	5/56 (8.93%)	4/56 (7.14%)	9/91 (9.89%)	1/10 (10.00%)
Lymphopenia * 1	0/56 (0.00%)	0/56 (0.00%)	2/91 (2.20%)	1/10 (10.00%)
Thrombocytopenia * 1	5/56 (8.93%)	3/56 (5.36%)	15/91 (16.48%)	0/10 (0.00%)
Cardiac disorders
Sinus tachycardia * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	2/10 (20.00%)
Ear and labyrinth disorders
Tinnitus * 1	0/56 (0.00%)	3/56 (5.36%)	4/91 (4.40%)	0/10 (0.00%)
Endocrine disorders
Hypothyroidism * 1	18/56 (32.14%)	13/56 (23.21%)	41/91 (45.05%)	2/10 (20.00%)
Gastrointestinal disorders
Abdominal pain * 1	9/56 (16.07%)	9/56 (16.07%)	11/91 (12.09%)	1/10 (10.00%)
Abdominal pain upper * 1	6/56 (10.71%)	2/56 (3.57%)	11/91 (12.09%)	0/10 (0.00%)
Constipation * 1	11/56 (19.64%)	7/56 (12.50%)	27/91 (29.67%)	3/10 (30.00%)
Diarrhoea * 1	34/56 (60.71%)	35/56 (62.50%)	58/91 (63.74%)	1/10 (10.00%)
Dry Mouth * 1	7/56 (12.50%)	2/56 (3.57%)	7/91 (7.69%)	0/10 (0.00%)
Dyspepsia * 1	7/56 (12.50%)	5/56 (8.93%)	18/91 (19.78%)	0/10 (0.00%)
Flatulence * 1	7/56 (12.50%)	3/56 (5.36%)	4/91 (4.40%)	0/10 (0.00%)
Haemorrhoids * 1	2/56 (3.57%)	1/56 (1.79%)	4/91 (4.40%)	1/10 (10.00%)
Nausea * 1	24/56 (42.86%)	19/56 (33.93%)	33/91 (36.26%)	2/10 (20.00%)
Stomatitis * 1	10/56 (17.86%)	4/56 (7.14%)	17/91 (18.68%)	0/10 (0.00%)
Vomiting * 1	18/56 (32.14%)	12/56 (21.43%)	25/91 (27.47%)	2/10 (20.00%)
Abdominal distension * 1	1/56 (1.79%)	3/56 (5.36%)	3/91 (3.30%)	0/10 (0.00%)
Gastritis * 1	3/56 (5.36%)	2/56 (3.57%)	9/91 (9.89%)	0/10 (0.00%)
Gastrooesophageal reflux disease * 1	2/56 (3.57%)	3/56 (5.36%)	6/91 (6.59%)	0/10 (0.00%)
Abdominal discomfort * 1	2/56 (3.57%)	0/56 (0.00%)	6/91 (6.59%)	0/10 (0.00%)
Dysphagia * 1	0/56 (0.00%)	2/56 (3.57%)	2/91 (2.20%)	1/10 (10.00%)
Proctalgia * 1	2/56 (3.57%)	0/56 (0.00%)	5/91 (5.49%)	0/10 (0.00%)
Toothache * 1	1/56 (1.79%)	3/56 (5.36%)	5/91 (5.49%)	0/10 (0.00%)
General disorders
Asthenia * 1	6/56 (10.71%)	5/56 (8.93%)	6/91 (6.59%)	0/10 (0.00%)
Fatigue * 1	27/56 (48.21%)	26/56 (46.43%)	49/91 (53.85%)	4/10 (40.00%)
Mucosal inflammation * 1	12/56 (21.43%)	8/56 (14.29%)	13/91 (14.29%)	0/10 (0.00%)
Oedema peripheral * 1	4/56 (7.14%)	3/56 (5.36%)	14/91 (15.38%)	0/10 (0.00%)
Pain * 1	4/56 (7.14%)	3/56 (5.36%)	6/91 (6.59%)	0/10 (0.00%)
Chest pain * 1	5/56 (8.93%)	2/56 (3.57%)	6/91 (6.59%)	0/10 (0.00%)
Chills * 1	4/56 (7.14%)	1/56 (1.79%)	5/91 (5.49%)	0/10 (0.00%)
General physical health deterioration * 1	0/56 (0.00%)	0/56 (0.00%)	0/91 (0.00%)	1/10 (10.00%)
Pyrexia * 1	6/56 (10.71%)	3/56 (5.36%)	4/91 (4.40%)	0/10 (0.00%)
Hepatobiliary disorders
Hepatic function abnormal * 1	3/56 (5.36%)	1/56 (1.79%)	5/91 (5.49%)	0/10 (0.00%)
Infections and infestations
Rhinitis * 1	3/56 (5.36%)	6/56 (10.71%)	4/91 (4.40%)	0/10 (0.00%)
Upper respiratory tract infection * 1	4/56 (7.14%)	3/56 (5.36%)	6/91 (6.59%)	0/10 (0.00%)
Nasopharyngitis * 1	4/56 (7.14%)	3/56 (5.36%)	19/91 (20.88%)	0/10 (0.00%)
Respiratory tract infection * 1	2/56 (3.57%)	3/56 (5.36%)	0/91 (0.00%)	0/10 (0.00%)
Sinusitis * 1	4/56 (7.14%)	2/56 (3.57%)	2/91 (2.20%)	0/10 (0.00%)
Urinary tract infection * 1	3/56 (5.36%)	1/56 (1.79%)	10/91 (10.99%)	1/10 (10.00%)
Investigations
Alanine aminotransferase increased * 1	6/56 (10.71%)	9/56 (16.07%)	12/91 (13.19%)	0/10 (0.00%)
Aspartate aminotransferase increased * 1	6/56 (10.71%)	10/56 (17.86%)	12/91 (13.19%)	0/10 (0.00%)
Blood creatinine increased * 1	4/56 (7.14%)	8/56 (14.29%)	14/91 (15.38%)	1/10 (10.00%)
Blood glucose increased * 1	4/56 (7.14%)	7/56 (12.50%)	10/91 (10.99%)	2/10 (20.00%)
Fibrin D dimer increased * 1	0/56 (0.00%)	1/56 (1.79%)	0/91 (0.00%)	1/10 (10.00%)
Weight decreased * 1	16/56 (28.57%)	12/56 (21.43%)	25/91 (27.47%)	1/10 (10.00%)
Blood alkaline phosphatase increased * 1	4/56 (7.14%)	4/56 (7.14%)	6/91 (6.59%)	2/10 (20.00%)
Blood glucose decreased * 1	3/56 (5.36%)	5/56 (8.93%)	1/91 (1.10%)	0/10 (0.00%)
Blood potassium increased * 1	4/56 (7.14%)	3/56 (5.36%)	4/91 (4.40%)	0/10 (0.00%)
Blood thyroid stimulating hormone increased * 1	8/56 (14.29%)	7/56 (12.50%)	9/91 (9.89%)	0/10 (0.00%)
Blood albumin decreased * 1	1/56 (1.79%)	3/56 (5.36%)	1/91 (1.10%)	0/10 (0.00%)
Blood sodium decreased * 1	2/56 (3.57%)	3/56 (5.36%)	1/91 (1.10%)	0/10 (0.00%)
Blood triglycerides increased * 1	2/56 (3.57%)	2/56 (3.57%)	5/91 (5.49%)	0/10 (0.00%)
Haemoglobin decreased * 1	1/56 (1.79%)	1/56 (1.79%)	5/91 (5.49%)	0/10 (0.00%)
Metabolism and nutrition disorders
Decreased appetite * 1	21/56 (37.50%)	16/56 (28.57%)	37/91 (40.66%)	3/10 (30.00%)
Hyponatraemia * 1	4/56 (7.14%)	1/56 (1.79%)	4/91 (4.40%)	1/10 (10.00%)
Hyperkalaemia * 1	6/56 (10.71%)	1/56 (1.79%)	5/91 (5.49%)	0/10 (0.00%)
Hyperlipidaemia * 1	0/56 (0.00%)	0/56 (0.00%)	7/91 (7.69%)	0/10 (0.00%)
Hyperuricaemia * 1	1/56 (1.79%)	0/56 (0.00%)	9/91 (9.89%)	0/10 (0.00%)
Hypoalbuminaemia * 1	3/56 (5.36%)	1/56 (1.79%)	2/91 (2.20%)	0/10 (0.00%)
Hypophosphataemia * 1	2/56 (3.57%)	2/56 (3.57%)	4/91 (4.40%)	1/10 (10.00%)
Dehydration * 1	3/56 (5.36%)	4/56 (7.14%)	5/91 (5.49%)	0/10 (0.00%)
Hyperglycaemia * 1	4/56 (7.14%)	3/56 (5.36%)	6/91 (6.59%)	0/10 (0.00%)
Hypoglycaemia * 1	0/56 (0.00%)	3/56 (5.36%)	2/91 (2.20%)	0/10 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	13/56 (23.21%)	11/56 (19.64%)	17/91 (18.68%)	0/10 (0.00%)
Back pain * 1	13/56 (23.21%)	8/56 (14.29%)	17/91 (18.68%)	0/10 (0.00%)
Groin pain * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	1/10 (10.00%)
Musculoskeletal pain * 1	8/56 (14.29%)	4/56 (7.14%)	15/91 (16.48%)	0/10 (0.00%)
Bone pain * 1	3/56 (5.36%)	2/56 (3.57%)	5/91 (5.49%)	0/10 (0.00%)
Muscular weakness * 1	3/56 (5.36%)	2/56 (3.57%)	2/91 (2.20%)	0/10 (0.00%)
Musculoskeletal stiffness * 1	1/56 (1.79%)	4/56 (7.14%)	3/91 (3.30%)	0/10 (0.00%)
Myalgia * 1	4/56 (7.14%)	3/56 (5.36%)	8/91 (8.79%)	0/10 (0.00%)
Neck pain * 1	4/56 (7.14%)	4/56 (7.14%)	5/91 (5.49%)	0/10 (0.00%)
Pain in extremity * 1	8/56 (14.29%)	9/56 (16.07%)	23/91 (25.27%)	2/10 (20.00%)
Flank pain * 1	1/56 (1.79%)	3/56 (5.36%)	4/91 (4.40%)	0/10 (0.00%)
Muscle spasms * 1	3/56 (5.36%)	3/56 (5.36%)	6/91 (6.59%)	0/10 (0.00%)
Musculoskeletal chest pain * 1	3/56 (5.36%)	3/56 (5.36%)	3/91 (3.30%)	0/10 (0.00%)
Nervous system disorders
Dysgeusia * 1	9/56 (16.07%)	5/56 (8.93%)	21/91 (23.08%)	1/10 (10.00%)
Headache * 1	9/56 (16.07%)	15/56 (26.79%)	27/91 (29.67%)	0/10 (0.00%)
Hypoaesthesia * 1	2/56 (3.57%)	0/56 (0.00%)	4/91 (4.40%)	1/10 (10.00%)
Paraesthesia * 1	5/56 (8.93%)	3/56 (5.36%)	3/91 (3.30%)	1/10 (10.00%)
Dizziness * 1	8/56 (14.29%)	10/56 (17.86%)	14/91 (15.38%)	1/10 (10.00%)
Transient ischaemic attack * 1	0/56 (0.00%)	0/56 (0.00%)	1/91 (1.10%)	1/10 (10.00%)
Dyskinesia * 1	0/56 (0.00%)	0/56 (0.00%)	0/91 (0.00%)	1/10 (10.00%)
Peripheral sensory neuropathy * 1	4/56 (7.14%)	1/56 (1.79%)	3/91 (3.30%)	0/10 (0.00%)
Psychiatric disorders
Confusional state * 1	1/56 (1.79%)	1/56 (1.79%)	0/91 (0.00%)	2/10 (20.00%)
Insomnia * 1	3/56 (5.36%)	4/56 (7.14%)	8/91 (8.79%)	1/10 (10.00%)
Anxiety * 1	3/56 (5.36%)	3/56 (5.36%)	7/91 (7.69%)	0/10 (0.00%)
Delirium * 1	0/56 (0.00%)	0/56 (0.00%)	0/91 (0.00%)	1/10 (10.00%)
Depression * 1	4/56 (7.14%)	4/56 (7.14%)	6/91 (6.59%)	0/10 (0.00%)
Renal and urinary disorders
Haemoglobinuria * 1	2/56 (3.57%)	3/56 (5.36%)	5/91 (5.49%)	1/10 (10.00%)
Proteinuria * 1	12/56 (21.43%)	12/56 (21.43%)	40/91 (43.96%)	2/10 (20.00%)
Dysuria * 1	3/56 (5.36%)	0/56 (0.00%)	3/91 (3.30%)	0/10 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	7/56 (12.50%)	8/56 (14.29%)	19/91 (20.88%)	0/10 (0.00%)
Dysphonia * 1	18/56 (32.14%)	20/56 (35.71%)	44/91 (48.35%)	3/10 (30.00%)
Dyspnoea * 1	6/56 (10.71%)	8/56 (14.29%)	27/91 (29.67%)	1/10 (10.00%)
Epistaxis * 1	4/56 (7.14%)	3/56 (5.36%)	12/91 (13.19%)	0/10 (0.00%)
Oropharyngeal pain * 1	4/56 (7.14%)	2/56 (3.57%)	8/91 (8.79%)	0/10 (0.00%)
Skin and subcutaneous tissue disorders
Dry skin * 1	7/56 (12.50%)	3/56 (5.36%)	7/91 (7.69%)	0/10 (0.00%)
Palmar-plantar erythrodysaesthesia syndrome * 1	18/56 (32.14%)	10/56 (17.86%)	40/91 (43.96%)	0/10 (0.00%)
Pruritus * 1	2/56 (3.57%)	6/56 (10.71%)	13/91 (14.29%)	0/10 (0.00%)
Rash * 1	5/56 (8.93%)	8/56 (14.29%)	19/91 (20.88%)	0/10 (0.00%)
Alopecia * 1	2/56 (3.57%)	3/56 (5.36%)	14/91 (15.38%)	0/10 (0.00%)
Erythema * 1	1/56 (1.79%)	2/56 (3.57%)	6/91 (6.59%)	0/10 (0.00%)
Hyperkeratosis * 1	2/56 (3.57%)	4/56 (7.14%)	5/91 (5.49%)	0/10 (0.00%)
Surgical and medical procedures
Tooth extraction * 1	0/56 (0.00%)	3/56 (5.36%)	1/91 (1.10%)	0/10 (0.00%)
Vascular disorders
Hypertension * 1	35/56 (62.50%)	24/56 (42.86%)	76/91 (83.52%)	5/10 (50.00%)
Hypotension * 1	0/56 (0.00%)	8/56 (14.29%)	9/91 (9.89%)	0/10 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 19.1

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):

Tomita Y, Uemura H, Oya M, Shinohara N, Habuchi T, Fujii Y, Kamei Y, Umeyama Y, Bair AH, Rini BI. Patients with metastatic renal cell carcinoma who benefit from axitinib dose titration: analysis from a randomised, double-blind phase II study. BMC Cancer. 2019 Jan 7;19(1):17. doi: 10.1186/s12885-018-5224-6.

de Velasco G, McKay RR, Lin X, Moreira RB, Simantov R, Choueiri TK. Comprehensive Analysis of Survival Outcomes in Non-Clear Cell Renal Cell Carcinoma Patients Treated in Clinical Trials. Clin Genitourin Cancer. 2017 Dec;15(6):652-660.e1. doi: 10.1016/j.clgc.2017.03.004. Epub 2017 Mar 21.

Grunwald V, Lin X, Kalanovic D, Simantov R. Early Tumour Shrinkage: A Tool for the Detection of Early Clinical Activity in Metastatic Renal Cell Carcinoma. Eur Urol. 2016 Dec;70(6):1006-1015. doi: 10.1016/j.eururo.2016.05.010. Epub 2016 May 26.

Rini BI, Melichar B, Ueda T, Grunwald V, Fishman MN, Arranz JA, Bair AH, Pithavala YK, Andrews GI, Pavlov D, Kim S, Jonasch E. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol. 2013 Nov;14(12):1233-42. doi: 10.1016/S1470-2045(13)70464-9. Epub 2013 Oct 18. Erratum In: Lancet Oncol. 2014 Jun;15(7):e253.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00835978
• Other Study ID Numbers: A4061046; 2008-007786-23 ( EudraCT Number )
• First Submitted: February 2, 2009
• First Posted: February 4, 2009
• Results First Submitted: October 11, 2013
• Results First Posted: May 26, 2014
• Last Update Posted: May 30, 2017