Study of SU011248 in Patients With Advanced Kidney Cancer

Phase II Study Of Single-Agent SU011248 In The Treatment Of Patients With Renal Cell Carcinoma

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00254540

Enrollment

Registered

2005-11-16

Start date

2005-12-31

Completion date

2009-02-28

Last updated

2010-02-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Carcinoma, Renal Cell

Keywords

Ph2, RCC, SU011248, SUNITINIB

Brief summary

To determine the objective tumor response of single-agent SU011248 at a dose of 50 mg orally once daily for 4 consecutive weeks and 2 weeks rest, repeated every 6 weeks in patients with metastatic Renal Cell Cancer (RCC).

Interventions

DRUGSU011248 capsule

50mg, PO on day 28 of each 42 day cycle, until progression or unacceptable toxicity develops

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

20 Years to No maximum

Healthy volunteers

Inclusion criteria

* Histologically proven renal cell carcinoma with metastases with a component of clear cell histology

Exclusion criteria

* Any cellular therapy (LAK, TIL, DC), any vaccine therapy, mini-transplantation, or systemic molecular-targeting therapy for RCC.

Design outcomes

Primary

Measure	Time frame	Description
Number of Subjects With Objective Response	Day 28 of Cycles 1-4	Based on Extramural Review Committee's assessment. Number of subjects with objective response is defined as sum of the subjects with confirmed complete response (CR) and partial response (PR) as the best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed responses were those that persisted on repeat imaging study ≥4 weeks after initial documentation of response. CR = the disappearance of all target lesions. PR = a ≥30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.

Secondary

Measure	Time frame	Description
Progression-Free Survival (PFS)	Day 28 of Cycle 1-4, Day 28 of even cycles after Cycle 5, and at the end of the study. Up to 28 days after the last administration of the study drug.	Progression-free survival (PFS) is defined as the time from the date of first dose of study treatment to the date of the first documentation of progressive disease (PD) or death.
Time To Tumor Progression (TTP)	Day 28 of Cycle 1-4, Day 28 of even cycles after Cycle 5, and at the end of the study. Up to 28 days after the last administration of the study drug.	Time to tumor progression (TTP) is defined as the time from the date of first dose of study treatment to the date of the first documentation of progressive disease (PD).
Duration of Response (DR)	Day 28 of Cycle 1-4, Day 28 of even cycles after Cycle 5, and at the end of the study. Up to 28 days after the last administration of the study drug.	Duration of response (DR) is defined as the period between the day of initial confirmation of complete response (CR) or partial response (PR) and the day of initial confirmation of progressive disease (PD) or death of any cause. For subjects who were not confirmed to have PD or death of any cause during the study (including 28 days after the completion of study treatment) or before the initiation of another antitumor therapy, DR was censored on the final confirmation of progression-free condition during the study.
Time to Tumor Response (TTR)	Day 28 of Cycle 1-4, Day 28 of even cycles after Cycle 5, and at the end of the study.	Time to tumor response (TTR) is defined as the period between the day of initial study treatment and the day of initial confirmation of complete response (CR) or partial response (PR). CR = the disappearance of all target lesions. PR = a ≥30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.
Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Day 28 of Cycle 1; Days 1 and 28 of Cycles 2-4	Change from Baseline: weighted health state index at each observation minus weighted health state index at baseline. The EQ-5D evaluates 5 dimensions of health. The subjects rates the severity of impairment for each dimensions on a 3-point scale (1 to 3). The digits for five dimensions were combined in a five-digit number describing the respondent's health state. Health states were converted into a weighted health state index (Range: 0 to 1). High score is indicating high health.
Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Day 28 of Cycle 1; Days 1 and 28 of Cycles 2-4	Change from Baseline: weighted health state VAS score at each observation minus weighted health state VAS score at baseline. The VAS is a self-completed scale designed to rate the subject's current health state from 0 to 100 where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.
Trough Plasma Concentration (Ctrough) of SU-011248 in First-line Treatment Population	Days 14 and 28 of Cycle 1; Days 1 and 28 of Cycle 2; Day 28 of Cycle 3	Trough Plasma Concentration (Ctrough) means the concentration prior to study drug administration
Overall Survival Time	once year. Up to 3 years after the completion of subject registration.	Overall survival time is defined as the time from the date of first dose of study treatment to the date of the death due to any cause. For subjects whose death had not been confirmed, overall survival time was censored on the last date when the subject was known to be alive.
Trough Plasma Concentration (Ctrough) of SU-012662 in First-line Treatment Population	Days 14 and 28 of Cycle 1; Days 1 and 28 of Cycle 2; Day 28 of Cycle 3	SU-012662 is a metabolite of SU-011248. Trough Plasma Concentration (Ctrough) means the concentration prior to study drug administration
Trough Plasma Concentration (Ctrough) of SU-012662 in Pretreated Population	Days 14 and 28 of Cycle 1; Days 1 and 28 of Cycle 2; Day 28 of Cycle 3	SU-012662 is a metabolite of SU-011248. Trough Plasma Concentration (Ctrough) means the concentration prior to study drug administration
Trough Plasma Concentration (Ctrough) of SU-011248+SU-012662 in First-line Treatment Population	Days 14 and 28 of Cycle 1; Days 1 and 28 of Cycle 2; Day 28 of Cycle 3	SU-012662 is a metabolite of SU-011248. Trough Plasma Concentration (Ctrough) means the concentration prior to study drug administration. The Ctrough for total drug (SU-011248+SU-012662) was calculated as the mean of the Ctrough of total drug from each individual subject.
Trough Plasma Concentration (Ctrough) of SU-011248+SU-012662 in Pretreated Population	Days 14 and 28 of Cycle 1; Days 1 and 28 of Cycle 2; Day 28 of Cycle 3	SU-012662 is a metabolite of SU-011248. Trough Plasma Concentration (Ctrough) means the concentration prior to study drug administration. The Ctrough for total drug (SU011248+SU012662) was calculated as the mean of the Ctrough of total drug from each individual subject.
Plasma Concentrations of Vascular Endothelial Growth Factor (VEGF)	Days 1, 14 and 28 of Cycle 1; Days 1 and 28 of Cycle 2; Day 28 of Cycle 3	Plasma concentrations of potential pharmacodynamic markers; Vascular Endothelial Growth Factor (VEGF)
Plasma Concentrations of Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2)	Days 1, 14 and 28 of Cycle 1; Days 1 and 28 of Cycle 2; Day 28 of Cycle 3	Plasma concentrations of potential pharmacodynamic markers; Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2)
Trough Plasma Concentration (Ctrough) of SU-011248 in Pretreated Population	Days 14 and 28 of Cycle 1; Days 1 and 28 of Cycle 2; Day 28 of Cycle 3	Trough Plasma Concentration (Ctrough) means the concentration prior to study drug administration.

Countries

Japan

Participant flow

Participants by arm

Arm	Count
First-line Treatment Population SU-011248 capsule: Subjects who had not had any prior systemic treatment for renal cell carcinoma. Subjects received SU-011248 in an open-label manner at a starting dose of 50-mg once daily for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. SU-011248 was taken orally in the morning without regard to meals beginning on Day 1 of the study. Subjects were monitored for toxicity, and the SU-011248 dose could be adjusted according to individual subject tolerance. Subjects were allowed to continue to receive SU-011248 until they met any of the study discontinuation criteria.	25
Pretreated Population SU-011248 capsule: Subjects who had previously been treated with one cytokine-based systemic therapy regimen for renal cell carcinoma. Subjects received SU-011248 in an open-label manner at a starting dose of 50-mg once daily for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. SU-011248 was taken orally in the morning without regard to meals beginning on Day 1 of the study. Subjects were monitored for toxicity, and the SU-011248 dose could be adjusted according to individual subject tolerance. Subjects were allowed to continue to receive SU-011248 until they met any of the study discontinuation criteria.	26
Total	51

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	6	7
Overall Study	Death	0	1
Overall Study	Laboratory Test Abnormality	0	1
Overall Study	Lack of Efficacy	13	13

Baseline characteristics

Characteristic	First-line Treatment Population	Pretreated Population	Total
Age, Customized 20-44 years	4 participants	1 participants	5 participants
Age, Customized 45-64 years	14 participants	14 participants	28 participants
Age, Customized >=65 years	7 participants	11 participants	18 participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Score 0	20 participants	22 participants	42 participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Score 1	5 participants	4 participants	9 participants
Region of Enrollment Japan	25 participants	26 participants	51 participants
Sex: Female, Male Female	14 Participants	5 Participants	19 Participants
Sex: Female, Male Male	11 Participants	21 Participants	32 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	51 / 51
serious Total, serious adverse events	28 / 51

Outcome results

Primary

Number of Subjects With Objective Response

Based on Extramural Review Committee's assessment. Number of subjects with objective response is defined as sum of the subjects with confirmed complete response (CR) and partial response (PR) as the best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed responses were those that persisted on repeat imaging study ≥4 weeks after initial documentation of response. CR = the disappearance of all target lesions. PR = 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: Day 28 of Cycles 1-4

Population: Intent-to-Treat (ITT) population defined as all subjects enrolled in study that receive at least 1 dose of study medication.

Arm	Measure	Group	Value (NUMBER)
First-line Treatment Population	Number of Subjects With Objective Response	Total Number of Subjects with CR+PR	12 participants
First-line Treatment Population	Number of Subjects With Objective Response	Complete Response (CR)	1 participants
First-line Treatment Population	Number of Subjects With Objective Response	Partial Response (PR)	11 participants
Pretreated Population	Number of Subjects With Objective Response	Total Number of Subjects with CR+PR	12 participants
Pretreated Population	Number of Subjects With Objective Response	Complete Response (CR)	0 participants
Pretreated Population	Number of Subjects With Objective Response	Partial Response (PR)	12 participants

95% CI: [27.8, 68.7]

95% CI: [26.6, 66.6]

Secondary

Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score

Change from Baseline: weighted health state index at each observation minus weighted health state index at baseline. The EQ-5D evaluates 5 dimensions of health. The subjects rates the severity of impairment for each dimensions on a 3-point scale (1 to 3). The digits for five dimensions were combined in a five-digit number describing the respondent's health state. Health states were converted into a weighted health state index (Range: 0 to 1). High score is indicating high health.

Time frame: Day 28 of Cycle 1; Days 1 and 28 of Cycles 2-4

Population: Intent-to-Treat (ITT) population defined as all subjects enrolled in study that receive at least 1 dose of study medication.~n=Number of subjects with analyzable data.

Arm	Measure	Group	Value (MEAN)	Dispersion
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 2 Day 28 (n=20, 22)	-0.0946 Scores on a scale	Standard Deviation 0.2045
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 3 Day 28 (n=17, 21)	-0.1058 Scores on a scale	Standard Deviation 0.2058
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 2 Day 1 (n=20, 23)	-0.0067 Scores on a scale	Standard Deviation 0.1556
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 4 Day 1 (n=14, 19)	-0.0079 Scores on a scale	Standard Deviation 0.1856
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 3 Day 1 (n=17, 21)	0.0375 Scores on a scale	Standard Deviation 0.1509
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 4 Day 28 (n=14, 21)	-0.1573 Scores on a scale	Standard Deviation 0.1627
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 1 Day 28 (n=25, 24)	-0.0937 Scores on a scale	Standard Deviation 0.2032
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 4 Day 28 (n=14, 21)	-0.0974 Scores on a scale	Standard Deviation 0.1979
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 1 Day 28 (n=25, 24)	-0.0604 Scores on a scale	Standard Deviation 0.1753
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 2 Day 1 (n=20, 23)	0.0513 Scores on a scale	Standard Deviation 0.0906
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 2 Day 28 (n=20, 22)	-0.0957 Scores on a scale	Standard Deviation 0.2127
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 3 Day 1 (n=17, 21)	0.0153 Scores on a scale	Standard Deviation 0.0911
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 3 Day 28 (n=17, 21)	-0.0735 Scores on a scale	Standard Deviation 0.2245
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Health State Index Score	Cycle 4 Day 1 (n=14, 19)	0.0173 Scores on a scale	Standard Deviation 0.1105

Secondary

Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)

Change from Baseline: weighted health state VAS score at each observation minus weighted health state VAS score at baseline. The VAS is a self-completed scale designed to rate the subject's current health state from 0 to 100 where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.

Time frame: Day 28 of Cycle 1; Days 1 and 28 of Cycles 2-4

Population: Intent-to-Treat (ITT) population defined as all subjects enrolled in study that receive at least 1 dose of study medication.~n=Number of subjects with analyzable data.

Arm	Measure	Group	Value (MEAN)	Dispersion
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 2 Day 28 (n=20, 22)	-7.85 Scores on a scale	Standard Deviation 18.31
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 3 Day 28 (n=17, 21)	-12.35 Scores on a scale	Standard Deviation 23.69
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 2 Day 1 (n=20, 23)	-2.10 Scores on a scale	Standard Deviation 13.49
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 4 Day 1 (n=14, 19)	-1.86 Scores on a scale	Standard Deviation 17.81
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 3 Day 1 (n=17, 21)	2.71 Scores on a scale	Standard Deviation 12.88
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 4 Day 28 (n=14, 21)	-11.43 Scores on a scale	Standard Deviation 19.7
First-line Treatment Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 1 Day 28 (n=25, 24)	-11.12 Scores on a scale	Standard Deviation 16.29
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 4 Day 28 (n=14, 21)	-6.43 Scores on a scale	Standard Deviation 19.48
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 1 Day 28 (n=25, 24)	-10.54 Scores on a scale	Standard Deviation 15.97
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 2 Day 1 (n=20, 23)	4.17 Scores on a scale	Standard Deviation 13.12
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 2 Day 28 (n=20, 22)	-11.82 Scores on a scale	Standard Deviation 24.36
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 3 Day 1 (n=17, 21)	1.10 Scores on a scale	Standard Deviation 9.14
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 3 Day 28 (n=17, 21)	-7.67 Scores on a scale	Standard Deviation 18.53
Pretreated Population	Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires Visual Analog Scale (VAS)	Cycle 4 Day 1 (n=14, 19)	-0.79 Scores on a scale	Standard Deviation 19.81

Secondary

Duration of Response (DR)

Duration of response (DR) is defined as the period between the day of initial confirmation of complete response (CR) or partial response (PR) and the day of initial confirmation of progressive disease (PD) or death of any cause. For subjects who were not confirmed to have PD or death of any cause during the study (including 28 days after the completion of study treatment) or before the initiation of another antitumor therapy, DR was censored on the final confirmation of progression-free condition during the study.

Time frame: Day 28 of Cycle 1-4, Day 28 of even cycles after Cycle 5, and at the end of the study. Up to 28 days after the last administration of the study drug.

Population: Among Intent-To-Treat population, the number of subjects with objective tumor response based on investigator's assessment was 13 and 14 for the First-line treatment and the Pretreated populations, respectively.

Arm	Measure	Value (MEDIAN)
First-line Treatment Population	Duration of Response (DR)	111.6 Weeks
Pretreated Population	Duration of Response (DR)	38.1 Weeks

Secondary

Overall Survival Time

Overall survival time is defined as the time from the date of first dose of study treatment to the date of the death due to any cause. For subjects whose death had not been confirmed, overall survival time was censored on the last date when the subject was known to be alive.

Time frame: once year. Up to 3 years after the completion of subject registration.

Population: Intent-to-Treat (ITT) population defined as all subjects enrolled in study that receive at least 1 dose of study medication.

Arm	Measure	Value (MEDIAN)
First-line Treatment Population	Overall Survival Time	143.4 Weeks
Pretreated Population	Overall Survival Time	141.0 Weeks

Secondary

Plasma Concentrations of Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2)

Plasma concentrations of potential pharmacodynamic markers; Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2)

Time frame: Days 1, 14 and 28 of Cycle 1; Days 1 and 28 of Cycle 2; Day 28 of Cycle 3

Population: All enrolled subjects who received at least 1 dose of study medication and who had at least 1 plasma concentration data for Pharmacodynamic analysis.~n=Number of subjects with analyzable data.

Arm	Measure	Group	Value (MEDIAN)	Dispersion
First-line Treatment Population	Plasma Concentrations of Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2)	Cycle 1 Day 1 (n=51)	9311.00 pg/mL	Full Range 1630.73
First-line Treatment Population	Plasma Concentrations of Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2)	Cycle 1 Day 14 (n=42)	4673.50 pg/mL	Full Range 1402.34
First-line Treatment Population	Plasma Concentrations of Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2)	Cycle 1 Day 28 (n=16)	3650.00 pg/mL	Full Range 1442.21
First-line Treatment Population	Plasma Concentrations of Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2)	Cycle 2 Day 1 (n=18)	7276.50 pg/mL	Full Range 1756.36
First-line Treatment Population	Plasma Concentrations of Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2)	Cycle 2 Day 28 (n=8)	3535.00 pg/mL	Full Range 927.9
First-line Treatment Population	Plasma Concentrations of Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2)	Cycle 3 Day 28 (n=6)	3312.50 pg/mL	Full Range 831.61

Secondary

Plasma Concentrations of Vascular Endothelial Growth Factor (VEGF)

Plasma concentrations of potential pharmacodynamic markers; Vascular Endothelial Growth Factor (VEGF)

Time frame: Days 1, 14 and 28 of Cycle 1; Days 1 and 28 of Cycle 2; Day 28 of Cycle 3

Arm	Measure	Group	Value (MEDIAN)	Dispersion
First-line Treatment Population	Plasma Concentrations of Vascular Endothelial Growth Factor (VEGF)	Cycle 1 Day 1 (n=51)	54.90 pg/mL	Full Range 84.99
First-line Treatment Population	Plasma Concentrations of Vascular Endothelial Growth Factor (VEGF)	Cycle 1 Day 14 (n=42)	186.60 pg/mL	Full Range 267.19
First-line Treatment Population	Plasma Concentrations of Vascular Endothelial Growth Factor (VEGF)	Cycle 1 Day 28 (n=16)	259.90 pg/mL	Full Range 263.44
First-line Treatment Population	Plasma Concentrations of Vascular Endothelial Growth Factor (VEGF)	Cycle 2 Day 1 (n=18)	57.35 pg/mL	Full Range 94.18
First-line Treatment Population	Plasma Concentrations of Vascular Endothelial Growth Factor (VEGF)	Cycle 2 Day 28 (n=8)	264.75 pg/mL	Full Range 115.19
First-line Treatment Population	Plasma Concentrations of Vascular Endothelial Growth Factor (VEGF)	Cycle 3 Day 28 (n=6)	194.15 pg/mL	Full Range 111.2

Secondary

Progression-Free Survival (PFS)

Progression-free survival (PFS) is defined as the time from the date of first dose of study treatment to the date of the first documentation of progressive disease (PD) or death.

Time frame: Day 28 of Cycle 1-4, Day 28 of even cycles after Cycle 5, and at the end of the study. Up to 28 days after the last administration of the study drug.

Population: Intent-to-Treat (ITT) population defined as all subjects enrolled in study that receive at least 1 dose of study medication.

Arm	Measure	Value (MEDIAN)
First-line Treatment Population	Progression-Free Survival (PFS)	53.0 Weeks
Pretreated Population	Progression-Free Survival (PFS)	46.0 Weeks

Secondary

Time To Tumor Progression (TTP)

Time to tumor progression (TTP) is defined as the time from the date of first dose of study treatment to the date of the first documentation of progressive disease (PD).

Time frame: Day 28 of Cycle 1-4, Day 28 of even cycles after Cycle 5, and at the end of the study. Up to 28 days after the last administration of the study drug.

Population: Intent-to-Treat (ITT) population defined as all subjects enrolled in study that receive at least 1 dose of study medication.

Arm	Measure	Value (MEDIAN)
First-line Treatment Population	Time To Tumor Progression (TTP)	53.0 Weeks
Pretreated Population	Time To Tumor Progression (TTP)	46.0 Weeks

Secondary

Time to Tumor Response (TTR)

Time to tumor response (TTR) is defined as the period between the day of initial study treatment and the day of initial confirmation of complete response (CR) or partial response (PR). CR = the disappearance of all target lesions. PR = 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: Day 28 of Cycle 1-4, Day 28 of even cycles after Cycle 5, and at the end of the study.

Arm	Measure	Value (MEDIAN)
First-line Treatment Population	Time to Tumor Response (TTR)	10.0 Weeks
Pretreated Population	Time to Tumor Response (TTR)	10.5 Weeks

Secondary