Study Of SU011248 Plus Gefitinib (Iressa) In Patients With Advanced Renal Cell Carcinoma

• ClinicalTrials.gov Identifier: NCT00113529
• Recruitment Status: Completed
• First Posted: June 9, 2005
• Results First Posted: March 31, 2010
• Last Update Posted: August 29, 2011
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma, Renal Cell
• Intervention: Drug: Gefitinib + Sunitinib
• Enrollment: 42

Participant Flow

Recruitment Details
Pre-assignment Details	There were 11 subjects enrolled in Phase 1. Phase 2 included 4 subjects from Phase 1 (37.5 mg sunitinib Cohort) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib Cohort), for a total of 35 subjects.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description	Phase 2 included 4 subjects from Phase 1 (37.5 milligrams (mg) or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Period Title: Overall Study
Started	35 [1]
Completed	1 [2]
Not Completed	34
Reason Not Completed
Adverse Event	4
Lack of Efficacy	20
Decision of sponsor	6
Withdrawal by Subject	4
[1] Phase 2 included 4 subjects from Phase 1 and 31 from Phase 2, for a total of 35 subjects.; [2] Subject discontinued from the study and continued treatment on commercially available sunitinib.

Baseline Characteristics

Arm/Group Title		Sunitinib + Gefitinib
Arm/Group Description		Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Baseline Participants		35
Baseline Analysis Population Description		[Not Specified]
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	35 participants
< 65 years		19
> = 65 years		16
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	35 participants
	Female	9 25.7%
	Male	26 74.3%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Overall Confirmed Objective Disease Response According to the Response Evaluation Criteria in Solid Tumors (RECIST)
Description	Objective disease response = subjects with confirmed complete response (CR) or partial response (PR) according to RECIST. A CR was defined as the disappearance of all target lesions. A PR was defined as a ≥ 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.
Time Frame	From start of treatment until Day 28 of Cycles 1 to 4, Day 28 of even cycles thereafter

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) = all subjects enrolled in the study that received at least 1 dose of study medication (sunitinib or gefitinib).

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	35
Measure Type: Number; Unit of Measure: participants
	13

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Objective Response Rate (ORR) (percent)
	Estimated Value	37.1
	Confidence Interval	95%; 21.5 to 55.1
	Estimation Comments	ORR=proportion of subjects with confirmed CR or PR, relative to total subjects who received at least 1 dose of study medication, had a baseline disease assessment, and had the correct histological cancer type.

2. Secondary Outcome

Title	Time to Tumor Response (TTR)
Description	TTR was defined as the time from date of the first dose of study medication to first documentation of objective tumor response (CR or PR). For subjects proceeding from PR to CR, the onset of PR was taken as the onset of response. If lesion assessment data included more than 1 date, the first date was used. TTR was calculated as (first event date minus first dose date +1)/7. TTR was calculated based on the subgroup of subjects with a baseline disease assessment, who had the correct histological cancer type, and had a confirmed objective tumor response. Kaplan-Meier method was used.
Time Frame	From start of treatment until Day 28 of Cycles 1 to 4, Day 28 of even cycles thereafter

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = those who had a confirmed response on study.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	13
Median (95% Confidence Interval); Unit of Measure: weeks
	16.0; (4.3 to 21.1)

3. Secondary Outcome

Title	Duration of Response (DR)
Description	DR was defined as the time from start of the first documentation of objective tumor response to the first documentation of objective tumor progression or death due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used. DR was calculated as (the end date for DR minus first CR or PR that was subsequently confirmed +1)/7. DR was calculated for the subgroup of subjects with an objective tumor response (CR or PR).
Time Frame	From start of treatment until Day 28 of Cycles 1 to 4, Day 28 of even cycles thereafter or death due to cancer

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = those who had a response and subsequent progression or death due to any cause while on study.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	4
Median (Full Range); Unit of Measure: weeks
	52.2; (26.6 to 80.1)

4. Secondary Outcome

Title	Time to Tumor Progression (TTP)
Description	TTP was defined as the time from the date of first dose of study medication to first documentation of objective tumor progression. If tumor progression data included more than 1 date, the first date was used. TTP (in weeks) was calculated as (first event date minus first dose date +1)/7. Kaplan-Meier method was used.
Time Frame	From start of treatment until Day 28 of Cycles 1 to 4, Day 28 of even cycles thereafter

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = those who progressed on study.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	19
Median (95% Confidence Interval); Unit of Measure: weeks
	48.4; (28.1 to 84.0)

5. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from date of the first dose of study medication to date of death due to any cause. OS (in weeks) is calculated as (date of death minus first dose date +1)/7. For subjects not expiring, their survival times were censored at the last date of known contact they were known to be alive. Subjects lacking data beyond the day of first dose had their survival times censored at 1 day. Kaplan-Meier method was used.
Time Frame	From start of study treatment until death

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = subjects who died.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	12
Median (Full Range); Unit of Measure: weeks
	49.5; (16.1 to 93.3)

6. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS was defined as the time from the date of first dose of study medication to the date of first documentation of tumor progression or death due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used. PFS (in weeks) was calculated as (first event date minus first dose date +1)/7. Kaplan-Meier method was used.
Time Frame	From start of treatment until Day 28 of Cycles 1 to 4, Day 28 of even cycles thereafter or death

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = those who progressed or died due to any cause while on study.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	19
Median (95% Confidence Interval); Unit of Measure: weeks
	48.4; (28.1 to 84.0)

7. Secondary Outcome

Title	Probability of Survival at One Year
Description	Survival rate was defined as the percentage of subjects alive at 1 year after the date of first administration of study medication. Survival rate was estimated using the Kaplan-Meier method.
Time Frame	From start of treatment until Day 28 of Cycles 1 to 4, Day 28 of even cycles thereafter up until 1 year

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	35
Measure Type: Number; Unit of Measure: probability
	82.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	probability
	Estimated Value	82.4
	Confidence Interval	95%; 64.9 to 91.7
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	VEGF (Vascular Endothelial Growth Factor) Concentration at Baseline
Description	Concentration of VEGF at baseline.
Time Frame	Baseline (Cycle 1, Day 1)

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects with soluble protein biomarkers at baseline.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	31
Mean (Standard Deviation); Unit of Measure: pg/mL
	63.79 (43.437)

9. Secondary Outcome

Title	VEGF Ratio to Baseline at Each Time Point
Description	VEGF concentration at each time point divided by VEGF concentration at baseline (ratio to baseline).
Time Frame	Baseline to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects with soluble protein biomarkers at baseline. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	31
Mean (Standard Deviation); Unit of Measure: ratio
Cycle 1, Day 28 (n=29)	2.29 (1.269)
Cycle 2, Day 1 (n=26)	1.65 (1.951)
Cycle 2, Day 28 (n=23)	2.65 (1.956)
Cycle 3, Day 1 (n=22)	1.93 (1.872)
Cycle 3, Day 28 (n=20)	2.26 (1.195)

10. Secondary Outcome

Title	VEGF-C Concentration at Baseline
Description	Concentration of VEGF-C at baseline.
Time Frame	Baseline (Cycle 1, Day 1)

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects with soluble protein biomarkers at baseline.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	31
Mean (Standard Deviation); Unit of Measure: pg/mL
	725.82 (533.798)

11. Secondary Outcome

Title	VEGF-C Ratio to Baseline at Each Time Point
Description	VEGF-C concentration at each time point divided by VEGF-C concentration at baseline (ratio to baseline).
Time Frame	Baseline to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects with soluble protein biomarkers at baseline. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	31
Mean (Standard Deviation); Unit of Measure: ratio
Cycle 1, Day 28 (n=29)	0.93 (0.433)
Cycle 2, Day 1 (n=26)	0.86 (0.315)
Cycle 2, Day 28 (n=23)	1.01 (0.585)
Cycle 3, Day 1 (n=22)	1.09 (0.573)
Cycle 3, Day 28 (n=20)	0.93 (0.452)

12. Secondary Outcome

Title	Soluble VEGF Receptor 2 (sVEGFR2) Concentration at Baseline
Description	Concentration of sVEGFR2 at baseline.
Time Frame	Baseline (Cycle 1, Day 1)

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects with soluble protein biomarkers at baseline.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	31
Mean (Standard Deviation); Unit of Measure: pg/mL
	10525.0 (2198.017)

13. Secondary Outcome

Title	sVEGFR2 Ratio to Baseline at Each Time Point
Description	sVEGFR2 concentration at each time point divided by sVEGFR2 concentration at baseline (ratio to baseline).
Time Frame	Baseline to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects with soluble protein biomarkers at baseline. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	31
Mean (Standard Deviation); Unit of Measure: ratio
Cycle 1, Day 28 (n=29)	0.64 (0.130)
Cycle 2, Day 1 (n=26)	0.82 (0.181)
Cycle 2, Day 28 (n=23)	0.63 (0.151)
Cycle 3, Day 1 (n=22)	0.75 (0.154)
Cycle 3, Day 28 (n=20)	0.64 (0.217)

14. Secondary Outcome

Title	Soluble VEGF Receptor 3 (sVEGFR3) Concentration at Baseline
Description	Concentration of sVEGFR3 at baseline.
Time Frame	Baseline (Cycle 1, Day 1)

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects with soluble protein biomarkers at baseline.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	31
Mean (Standard Deviation); Unit of Measure: pg/mL
	48355.48 (19623.342)

15. Secondary Outcome

Title	sVEGFR3 Ratio to Baseline at Each Time Point
Description	sVEGFR3 concentration at each time point divided by sVEGFR3 concentration at baseline (ratio to baseline).
Time Frame	Baseline to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects with soluble protein biomarkers at baseline. n=number of subjects with levels of soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	31
Mean (Standard Deviation); Unit of Measure: ratio
Cycle 1, Day 28 (n=29)	0.41 (0.185)
Cycle 2, Day 1 (n=26)	0.96 (0.506)
Cycle 2, Day 28 (n=23)	0.52 (0.413)
Cycle 3, Day 1 (n=22)	0.89 (0.453)
Cycle 3, Day 28 (n=20)	0.38 (0.211)

16. Secondary Outcome

Title	Change From Baseline in VEGF by Time Point Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] Versus PD)
Description	Change = median VEGF level at each specified time point for subjects with tumor response (CR or PR or [SD > = 6 weeks] versus PD) minus median VEGF level at Baseline. A measure of dispersion is not included because the Wilcoxon rank sum test is a non-parametric test that makes no assumptions about the distribution of the data (eg, normality).
Time Frame	Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects with soluble protein biomarkers at baseline. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	31
Measure Type: Number; Unit of Measure: pg/mL
Cycle 1, Day 1 (CR or PR or SD, n=22)	40.70
Cycle 1, Day 1 (PD, n=5)	94.50
Cycle 1, Day 28 (CR or PR or SD, n=22)	2.31
Cycle 1, Day 28 (PD, n=4)	1.94
Cycle 2, Day 1 (CR or PR or SD, n=22)	1.05
Cycle 2, Day 1 (PD, n=3)	1.01
Cycle 2, Day 28 (CR or PR or SD, n=21)	2.26
Cycle 2, Day 28 (PD, n=2)	2.30
Cycle 3, Day 1 (CR or PR or SD, n=20)	1.33
Cycle 3, Day 1(PD, n=2)	0.91
Cycle 3, Day 28 (CR or PR or SD, n=20)	1.87

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.075
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.749
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.834
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.332
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

17. Secondary Outcome

Title	Change From Baseline in VEGFC by Time Point Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] Versus PD)
Description	Change = median VEGFC level at each specified time point for subjects with tumor response (CR or PR or [SD > = 6 weeks] versus PD) minus median VEGFC level at Baseline. A measure of dispersion is not included because the Wilcoxon rank sum test is a non-parametric test that makes no assumptions about the distribution of the data (eg, normality).
Time Frame	Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects with soluble protein biomarkers at baseline. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	31
Measure Type: Number; Unit of Measure: pg/mL
Cycle 1, Day 1 (CR or PR or SD, n=22)	561.20
Cycle 1, Day 1 (PD, n=5)	751.30
Cycle 1, Day 28 (CR or PR or SD, n=22)	0.95
Cycle 1, Day 28 (PD, n=4)	0.71
Cycle 2, Day 1 (CR or PR or SD, n=22)	0.90
Cycle 2, Day 1 (PD, n=3)	0.80
Cycle 2, Day 28 (CR or PR or SD, n=21)	0.84
Cycle 2, Day 28 (PD, n=2)	1.19
Cycle 3, Day 1 (CR or PR or SD, n=20)	1.04
Cycle 3, Day 1(PD, n=2)	0.69
Cycle 3, Day 28 (CR or PR or SD, n=20)	0.93

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.473
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.286
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.277
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.956
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.278
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

18. Secondary Outcome

Title	Change From Baseline in VEGFR2 by Time Point Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] Versus PD)
Description	Change = median VEGFR2 level at each specified time point for subjects with tumor response (CR or PR or [SD > = 6 weeks] versus PD) minus median VEGFR2 level at Baseline. A measure of dispersion is not included because the Wilcoxon rank sum test is a non-parametric test that makes no assumptions about the distribution of the data (eg, normality).
Time Frame	Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects with soluble protein biomarkers at baseline. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	31
Measure Type: Number; Unit of Measure: pg/mL
Cycle 1, Day 1 (CR or PR or SD, n=22)	10041.50
Cycle 1, Day 1 (PD, n=5)	9760.00
Cycle 1, Day 28 (CR or PR or SD, n=22)	0.59
Cycle 1, Day 28 (PD, n=4)	0.68
Cycle 2, Day 1 (CR or PR or SD, n=22)	0.79
Cycle 2, Day 1 (PD, n=3)	0.69
Cycle 2, Day 28 (CR or PR or SD, n=21)	0.62
Cycle 2, Day 28 (PD, n=2)	0.62
Cycle 3, Day 1 (CR or PR or SD, n=20)	0.74
Cycle 3, Day 1(PD, n=2)	0.73
Cycle 3, Day 28 (CR or PR or SD, n=20)	0.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.275
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.227
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.029
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

19. Secondary Outcome

Title	Change From Baseline in VEGFR3 by Time Point Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] Versus PD)
Description	Change = median VEGFR3 level at each specified time point for subjects with tumor response (CR or PR or [SD > = 6 weeks] versus PD) minus median VEGFR3 level at Baseline. A measure of dispersion is not included because the Wilcoxon rank sum test is a non-parametric test that makes no assumptions about the distribution of the data (eg, normality).
Time Frame	Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects with soluble protein biomarkers at baseline. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	31
Measure Type: Number; Unit of Measure: pg/mL
Cycle 1, Day 1 (CR or PR or SD, n=22)	43325.00
Cycle 1, Day 1 (PD, n=5)	57300.00
Cycle 1, Day 28 (CR or PR or SD, n=22)	0.41
Cycle 1, Day 28 (PD, n=4)	0.34
Cycle 2, Day 1 (CR or PR or SD, n=22)	0.87
Cycle 2, Day 1 (PD, n=3)	0.71
Cycle 2, Day 28 (CR or PR or SD, n=21)	0.41
Cycle 2, Day 28 (PD, n=2)	1.32
Cycle 3, Day 1 (CR or PR or SD, n=20)	0.85
Cycle 3, Day 1(PD, n=2)	1.84
Cycle 3, Day 28 (CR or PR or SD, n=20)	0.37

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.435
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.722
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.645
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.140
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.046
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

20. Secondary Outcome

Title	Change From Baseline in VEGF by Time Point Stratified by PFS >= Median and PFS < Median
Description	Change = median VEGF level at each specified time point for subjects with tumor response PFS >= Median or PFS < Median minus median VEGF level at Baseline. A measure of dispersion is not included because the Wilcoxon rank sum test is a non-parametric test that makes no assumptions about the distribution of the data (eg, normality).
Time Frame	Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects evaluable for PFS (ie, those who died or had tumor progression) with baseline biomarker values. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	16
Measure Type: Number; Unit of Measure: pg/mL
Cycle 1, Day 1 (PFS >= Median, n=5)	59.30
Cycle 1, Day 1 (PFS < Median, n=11)	44.70
Cycle 1, Day 28 (PFS >= Median, n=5)	2.32
Cycle 1, Day 28 (PFS < Median, n=10)	2.28
Cycle 2, Day 1 (PFS >= Median, n=5)	0.75
Cycle 2, Day 1 (PFS < Median, n=9)	1.06
Cycle 2, Day 28 (PFS >= Median, n=5)	1.91
Cycle 2, Day 28 (PFS < Median, n=8)	2.66
Cycle 3, Day 1 (PFS >= Median, n=5)	1.04
Cycle 3, Day 1 (PFS < Median, n=8)	1.60
Cycle 3, Day 28 (PFS >= Median, n=5)	1.79
Cycle 3, Day 28 (PFS < Median, n=6)	2.31

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.734
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.854
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.230
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.067
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.164
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.121
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

21. Secondary Outcome

Title	Change From Baseline in VEGFC by Time Point Stratified by PFS >= Median and PFS < Median
Description	Change = median VEGFC level at each specified time point for subjects with tumor response PFS >= Median or PFS < Median minus median VEGFC level at Baseline. A measure of dispersion is not included because the Wilcoxon rank sum test is a non-parametric test that makes no assumptions about the distribution of the data (eg, normality).
Time Frame	Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects evaluable for PFS (ie, those who died or had tumor progression) with baseline biomarker values. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	16
Measure Type: Number; Unit of Measure: pg/mL
Cycle 1, Day 1 (PFS >= Median, n=5)	650.80
Cycle 1, Day 1 (PFS < Median, n=11)	532.70
Cycle 1, Day 28 (PFS >= Median, n=5)	0.76
Cycle 1, Day 28 (PFS < Median, n=10)	0.99
Cycle 2, Day 1 (PFS >= Median, n=5)	0.80
Cycle 2, Day 1 (PFS < Median, n=9)	1.00
Cycle 2, Day 28 (PFS >= Median, n=5)	0.84
Cycle 2, Day 28 (PFS < Median, n=8)	1.17
Cycle 3, Day 1 (PFS >= Median, n=5)	0.70
Cycle 3, Day 1 (PFS < Median, n=8)	1.05
Cycle 3, Day 28 (PFS >= Median, n=5)	0.90
Cycle 3, Day 28 (PFS < Median, n=6)	1.22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.734
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.462
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.423
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.510
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.608
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.121
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

22. Secondary Outcome

Title	Change From Baseline in VEGFR2 by Time Point Stratified by PFS >= Median and PFS < Median
Description	Change = median VEGFR2 level at each specified time point for subjects with tumor response PFS >= Median or PFS < Median minus median VEGFR2 level at Baseline. A measure of dispersion is not included because the Wilcoxon rank sum test is a non-parametric test that makes no assumptions about the distribution of the data (eg, normality).
Time Frame	Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects evaluable for PFS (ie, those who died or had tumor progression) with baseline biomarker values. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	16
Measure Type: Number; Unit of Measure: pg/mL
Cycle 1, Day 1 (PFS >= Median, n=5)	9100.00
Cycle 1, Day 1 (PFS < Median, n=11)	10145.00
Cycle 1, Day 28 (PFS >= Median, n=5)	0.56
Cycle 1, Day 28 (PFS < Median, n=10)	0.69
Cycle 2, Day 1 (PFS >= Median, n=5)	0.79
Cycle 2, Day 1 (PFS < Median, n=9)	0.78
Cycle 2, Day 28 (PFS >= Median, n=5)	0.56
Cycle 2, Day 28 (PFS < Median, n=8)	0.64
Cycle 3, Day 1 (PFS >= Median, n=5)	0.74
Cycle 3, Day 1 (PFS < Median, n=8)	0.75
Cycle 3, Day 28 (PFS >= Median, n=5)	0.52
Cycle 3, Day 28 (PFS < Median, n=6)	0.62

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.910
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.020
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.509
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.883
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.582
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

23. Secondary Outcome

Title	Change From Baseline in VEGFR3 by Time Point Stratified by PFS >= Median and PFS < Median
Description	Change = median VEGFR3 level at each specified time point for subjects with tumor response PFS >= Median or PFS < Median minus median VEGFR3 level at Baseline. A measure of dispersion is not included because the Wilcoxon rank sum test is a non-parametric test that makes no assumptions about the distribution of the data (eg, normality).
Time Frame	Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects evaluable for PFS (ie, those who died or had tumor progression) with baseline biomarker values. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	16
Measure Type: Number; Unit of Measure: pg/mL
Cycle 1, Day 1 (PFS >= Median, n=5)	55100.00
Cycle 1, Day 1 (PFS < Median, n=11)	47500.00
Cycle 1, Day 28 (PFS >= Median, n=5)	0.29
Cycle 1, Day 28 (PFS < Median, n=10)	0.44
Cycle 2, Day 1 (PFS >= Median, n=5)	0.86
Cycle 2, Day 1 (PFS < Median, n=9)	0.73
Cycle 2, Day 28 (PFS >= Median, n=5)	0.30
Cycle 2, Day 28 (PFS < Median, n=8)	0.47
Cycle 3, Day 1 (PFS >= Median, n=5)	0.65
Cycle 3, Day 1 (PFS < Median, n=8)	0.91
Cycle 3, Day 28 (PFS >= Median, n=5)	0.32
Cycle 3, Day 28 (PFS < Median, n=6)	0.49

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.428
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.075
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.019
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.124
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.055
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

24. Secondary Outcome

Title	Change From Baseline in VEGF by Time Point Stratified by TTP >= Median and TTP < Median
Description	Change = median VEGF level at each specified time point for subjects with tumor response TTP >= Median and TTP < Median minus median VEGF level at Baseline. A measure of dispersion is not included because the Wilcoxon rank sum test is a non-parametric test that makes no assumptions about the distribution of the data (eg, normality).
Time Frame	Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects evaluable for TTP (ie, those who died or had tumor progression) with baseline biomarker values. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	16
Measure Type: Number; Unit of Measure: pg/mL
Cycle 1, Day 1 (TTP >= Median, n=5)	59.30
Cycle 1, Day 1 (TTP < Median, n=11)	44.70
Cycle 1, Day 28 (TTP >= Median, n=5)	2.32
Cycle 1, Day 28 (TTP < Median, n=10)	2.28
Cycle 2, Day 1 (TTP >= Median, n=5)	0.75
Cycle 2, Day 1 (TTP < Median, n=9)	1.06
Cycle 2, Day 28 (TTP >= Median, n=5)	1.91
Cycle 2, Day 28 (TTP < Median, n=8)	2.66
Cycle 3, Day 1 (TTP >= Median, n=5)	1.04
Cycle 3, Day 1 (TTP < Median, n=8)	1.60
Cycle 3, Day 28 (TTP >= Median, n=5)	1.79
Cycle 3, Day 28 (TTP < Median, n=6)	2.31

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.734
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.854
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.230
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.067
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.164
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.121
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

25. Secondary Outcome

Title	Change From Baseline in VEGFC by Time Point Stratified by TTP >= Median and TTP < Median
Description	Change = median VEGFC level at each specified time point for subjects with tumor response TTP >= Median and TTP < Median minus median VEGFC level at Baseline. A measure of dispersion is not included because the Wilcoxon rank sum test is a non-parametric test that makes no assumptions about the distribution of the data (eg, normality).
Time Frame	Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects evaluable for TTP (ie, those who died or had tumor progression) with baseline biomarker values. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	16
Measure Type: Number; Unit of Measure: pg/mL
Cycle 1, Day 1 (TTP >= Median, n=5)	650.80
Cycle 1, Day 1 (TTP < Median, n=11)	532.70
Cycle 1, Day 28 (TTP >= Median, n=5)	0.76
Cycle 1, Day 28 (TTP < Median, n=10)	0.99
Cycle 2, Day 1 (TTP >= Median, n=5)	0.80
Cycle 2, Day 1 (TTP < Median, n=9)	1.00
Cycle 2, Day 28 (TTP >= Median, n=5)	0.84
Cycle 2, Day 28 (TTP < Median, n=8)	1.17
Cycle 3, Day 1 (TTP >= Median, n=5)	0.70
Cycle 3, Day 1 (TTP < Median, n=8)	1.05
Cycle 3, Day 28 (TTP >= Median, n=5)	0.90
Cycle 3, Day 28 (TTP < Median, n=6)	1.22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.734
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.462
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.423
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.510
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.608
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.121
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

26. Secondary Outcome

Title	Change From Baseline in VEGFR2 by Time Point Stratified by TTP >= Median and TTP < Median
Description	Change = median VEGFR2 level at each specified time point for subjects with tumor response TTP >= Median and TTP < Median minus median VEGFR2 level at Baseline. A measure of dispersion is not included because the Wilcoxon rank sum test is a non-parametric test that makes no assumptions about the distribution of the data (eg, normality).
Time Frame	Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects evaluable for TTP (ie, those who died or had tumor progression) with baseline biomarker values. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	16
Measure Type: Number; Unit of Measure: pg/mL
Cycle 1, Day 1 (TTP >= Median, n=5)	9100.00
Cycle 1, Day 1 (TTP < Median, n=11)	10145.00
Cycle 1, Day 28 (TTP >= Median, n=5)	0.56
Cycle 1, Day 28 (TTP < Median, n=10)	0.69
Cycle 2, Day 1 (TTP >= Median, n=5)	0.79
Cycle 2, Day 1 (TTP < Median, n=9)	0.78
Cycle 2, Day 28 (TTP >= Median, n=5)	0.56
Cycle 2, Day 28 (TTP < Median, n=8)	0.64
Cycle 3, Day 1 (TTP >= Median, n=5)	0.74
Cycle 3, Day 1 (TTP < Median, n=8)	0.75
Cycle 3, Day 28 (TTP >= Median, n=5)	0.52
Cycle 3, Day 28 (TTP < Median, n=6)	0.62

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.910
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.020
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.509
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.883
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.582
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

27. Secondary Outcome

Title	Change From Baseline in VEGFR3 by Time Point Stratified by TTP >= Median and TTP < Median
Description	Change = median VEGFR3 level at each specified time point for subjects with tumor response TTP >= Median and TTP < Median minus median VEGFR3 level at Baseline. A measure of dispersion is not included because the Wilcoxon rank sum test is a non-parametric test that makes no assumptions about the distribution of the data (eg, normality).
Time Frame	Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive

Outcome Measure Data

Analysis Population Description

ITT. Number of participants analyzed = number of subjects evaluable for TTP (ie, those who died or had tumor progression) with baseline biomarker values. n=number of subjects with soluble protein biomarkers at baseline and at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	16
Measure Type: Number; Unit of Measure: pg/mL
Cycle 1, Day 1 (TTP >= Median, n=5)	55100.00
Cycle 1, Day 1 (TTP < Median, n=11)	47500.00
Cycle 1, Day 28 (TTP >= Median, n=5)	0.29
Cycle 1, Day 28 (TTP < Median, n=10)	0.44
Cycle 2, Day 1 (TTP >= Median, n=5)	0.86
Cycle 2, Day 1 (TTP < Median, n=9)	0.73
Cycle 2, Day 28 (TTP >= Median, n=5)	0.30
Cycle 2, Day 28 (TTP < Median, n=8)	0.47
Cycle 3, Day 1 (TTP >= Median, n=5)	0.65
Cycle 3, Day 1 (TTP < Median, n=8)	0.91
Cycle 3, Day 28 (TTP >= Median, n=5)	0.32
Cycle 3, Day 28 (TTP < Median, n=6)	0.49

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.428
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 1, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.075
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.000
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 2, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.019
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.124
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Sunitinib + Gefitinib
	Comments	Cycle 3, Day 28
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.055
	Comments	[Not Specified]
	Method	Wilcoxon Rank Sum Test
	Comments	[Not Specified]

28. Secondary Outcome

Title	Trough Plasma Concentrations (Ctrough) of Sunitinib
Description	[Not Specified]
Time Frame	prior to dosing on Cycle 1 (Days 1, 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) = the ITT population of subjects who had completed PK blood sampling for at least one day. n=number of subjects with trough plasma concentrations at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	35
Mean (Standard Deviation); Unit of Measure: ng/mL
Cycle 1, Day 1 (n=35)	1.57 (9.263)
Cycle 1, Day 28 (n=33)	33.16 (13.915)
Cycle 2, Day 1 (n=28)	3.25 (3.209)
Cycle 2, Day 28 (n=27)	35.50 (11.957)
Cycle 3, Day 1 (n=25)	3.71 (3.335)
Cycle 3, Day 28 (n=24)	35.97 (12.462)

29. Secondary Outcome

Title	Ctrough of SU-012662 (Sunitinib's Metabolite)
Description	[Not Specified]
Time Frame	prior to dosing on Cycle 1 (Days 1, 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28)

Outcome Measure Data

Analysis Population Description

PK = the ITT population of subjects who had completed PK blood sampling for at least one day. n=number of subjects with trough plasma concentrations at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	35
Mean (Standard Deviation); Unit of Measure: ng/mL
Cycle 1, Day 1 (n=35)	1.16 (6.846)
Cycle 1, Day 28 (n=33)	16.21 (9.381)
Cycle 2, Day 1 (n=28)	3.03 (2.227)
Cycle 2, Day 28 (n=27)	15.25 (6.310)
Cycle 3, Day 1 (n=25)	3.18 (3.564)
Cycle 3, Day 28 (n=24)	14.56 (8.019)

30. Secondary Outcome

Title	Ctrough of Gefitinib
Description	[Not Specified]
Time Frame	prior to dosing on Cycle 1 (Days 1, 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28)

Outcome Measure Data

Analysis Population Description

PK = the ITT population of subjects who had completed PK blood sampling for at least one day. n=number of subjects with trough plasma concentrations at the specified time point.

Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description:	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
Overall Number of Participants Analyzed	35
Mean (Standard Deviation); Unit of Measure: ng/mL
Cycle 1, Day 1 (n=35)	0.00 (0.000)
Cycle 1, Day 28 (n=33)	254.74 (191.631)
Cycle 2, Day 1 (n=24)	328.91 (280.286)
Cycle 2, Day 28 (n=27)	263.23 (210.287)
Cycle 3, Day 1 (n=26)	293.14 (277.288)
Cycle 3, Day 28 (n=24)	211.43 (102.670)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Sunitinib + Gefitinib
Arm/Group Description	Phase 2 included 4 subjects from Phase 1 (37.5 mg or 50 mg sunitinib [administered on Cycle 1, Days 1, 9, 10, 20, 21, 28; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28] + 250 mg gefitinib [administered on Cycle 1, Days 10, 20, 21, 28, 42; Cycles 2 to 4, Days 1, 28; Cycles 5 plus, Days 1, 28]) and 31 from Phase 2 (37.5 mg sunitinib + 250 mg gefitinib [both administered on Cycle 1, Days 1, 14, 28; Cycles 2 to 4, Days 1, 28; Cycle 5 plus, Days 1, 28]), for a total of 35 subjects. A cycle = sunitinib given daily for 4 weeks followed by a 2-week off-treatment period.
All-Cause Mortality
	Sunitinib + Gefitinib
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Sunitinib + Gefitinib
	Affected / at Risk (%)
Total	11/35 (31.43%)
Cardiac disorders
Ventricular tachycardia † 1	1/35 (2.86%)
Myocardial ischaemia †	1/35 (2.86%)
Gastrointestinal disorders
Gastrointestinal haemorrhage †	2/35 (5.71%)
Rectal haemorrhage †	1/35 (2.86%)
Hepatobiliary disorders
Cholecystitis †	1/35 (2.86%)
Investigations
Blood magnesium decreased †	1/35 (2.86%)
Blood calcium increased †	1/35 (2.86%)
Nervous system disorders
Syncope †	1/35 (2.86%)
Renal and urinary disorders
Haematuria †	1/35 (2.86%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion †	1/35 (2.86%)
Epistaxis †	1/35 (2.86%)
Dyspnoea †	1/35 (2.86%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (v8.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Sunitinib + Gefitinib
	Affected / at Risk (%)
Total	35/35 (100.00%)
Blood and lymphatic system disorders
Anaemia † 1	3/35 (8.57%)
Neutropenia †	2/35 (5.71%)
Thrombocytopenia †	3/35 (8.57%)
Gastrointestinal disorders
Constipation †	8/35 (22.86%)
Diarrhoea †	34/35 (97.14%)
Dyspepsia †	15/35 (42.86%)
Flatulence †	2/35 (5.71%)
Gastrooesophageal reflux disease †	3/35 (8.57%)
Haemorrhoids †	2/35 (5.71%)
Nausea †	16/35 (45.71%)
Oral pain †	2/35 (5.71%)
Rectal haemorrhage †	2/35 (5.71%)
Stomatitis †	15/35 (42.86%)
Vomiting †	10/35 (28.57%)
General disorders
Fatigue †	30/35 (85.71%)
Oedema peripheral †	7/35 (20.00%)
Pyrexia †	4/35 (11.43%)
Infections and infestations
Sinusitis †	2/35 (5.71%)
Upper respiratory tract infection †	3/35 (8.57%)
Urinary tract infection †	3/35 (8.57%)
Investigations
Alanine aminotransferase increased †	3/35 (8.57%)
Aspartate aminotransferase increased †	2/35 (5.71%)
Blood phosphorus decreased †	2/35 (5.71%)
Blood pressure increased †	3/35 (8.57%)
Ejection fraction decreased †	2/35 (5.71%)
Weight decreased †	3/35 (8.57%)
White blood cell count decreased †	4/35 (11.43%)
Metabolism and nutrition disorders
Anorexia †	8/35 (22.86%)
Decreased appetite †	5/35 (14.29%)
Hyperglycaemia †	2/35 (5.71%)
Hypophosphataemia †	2/35 (5.71%)
Musculoskeletal and connective tissue disorders
Back pain †	2/35 (5.71%)
Flank pain †	3/35 (8.57%)
Muscular weakness †	2/35 (5.71%)
Pain in extremity †	5/35 (14.29%)
Nervous system disorders
Dizziness †	2/35 (5.71%)
Dysgeusia †	12/35 (34.29%)
Headache †	4/35 (11.43%)
Hypoaesthesia †	3/35 (8.57%)
Neuropathy †	2/35 (5.71%)
Paraesthesia †	3/35 (8.57%)
Peripheral sensory neuropathy †	3/35 (8.57%)
Syncope †	2/35 (5.71%)
Renal and urinary disorders
Dysuria †	2/35 (5.71%)
Nocturia †	2/35 (5.71%)
Pollakiuria †	3/35 (8.57%)
Respiratory, thoracic and mediastinal disorders
Cough †	6/35 (17.14%)
Dysphonia †	2/35 (5.71%)
Dyspnoea †	2/35 (5.71%)
Dyspnoea exertional †	10/35 (28.57%)
Epistaxis †	8/35 (22.86%)
Wheezing †	2/35 (5.71%)
Skin and subcutaneous tissue disorders
Acne †	4/35 (11.43%)
Alopecia †	4/35 (11.43%)
Blister †	3/35 (8.57%)
Dermatitis acneiform †	5/35 (14.29%)
Dry skin †	12/35 (34.29%)
Erythema †	4/35 (11.43%)
Hyperkeratosis †	2/35 (5.71%)
Night sweats †	2/35 (5.71%)
Palmar—plantar erythrodysaesthesia syndrome †	11/35 (31.43%)
Rash †	20/35 (57.14%)
Skin exfoliation †	3/35 (8.57%)
Skin lesion †	2/35 (5.71%)
Vascular disorders
Hypertension †	5/35 (14.29%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (v8.0)

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 < 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), < 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.govCallCenter@pfizer.com

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

Motzer RJ, Hudes GR, Ginsberg MS, Baum MS, Harmon CS, Kim ST, Chen I, Redman BG. Phase I/II trial of sunitinib plus gefitinib in patients with metastatic renal cell carcinoma. Am J Clin Oncol. 2010 Dec;33(6):614-8. doi: 10.1097/COC.0b013e3181c4454d.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00113529
• Other Study ID Numbers: A6181038
• First Submitted: June 8, 2005
• First Posted: June 9, 2005
• Results First Submitted: March 1, 2010
• Results First Posted: March 31, 2010
• Last Update Posted: August 29, 2011