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

Study Overview
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Brief Summary
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To assess the maximum tolerated dose and overall safety and tolerability of sunitinib [SU011248] administered in combination with gefitinib (Iressa) for the treatment of patients with metastatic renal cell carcinoma (Phase 1). To assess antitumor activity of the combination of gefitinib and sunitinib (Phase 2).

Official Title
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A Phase 1/2 Safety And Pharmacokinetic Study Of SU011248 In Combination With Gefitinib (Iressa) In Patients With Metastatic Renal Cell Carcinoma

Conditions
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Carcinoma, Renal Cell

Intervention / Treatment
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* Drug: Gefitinib + Sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed renal cell carcinoma with metastases Evidence of unidimensionally measurable disease Failure of 1 prior immunotherapy or no prior systemic therapy for metastatic RCC Exclusion Criteria: RCC without any clear (conventional) cell component History of or known brain metastases Uncontrolled hypertension or other significant cardiac events within the 12 months prior to study entry

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sunitinib + Gefitinib<br>Phase 1 - 37.5 mg Sunitinib 4/2 Schedule + 250 mg Gefitinib; 50 mg Sunitinib + 250 mg Gefitinib Phase 2 - 37.5 mg Sunitinib 4/2 Schedule + 250 mg Gefitinib | Drug: Gefitinib + Sunitinib<br>* Until disease progression or unacceptable toxicity.<br>* Other names: Iressa, SU011248, SUTENT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Overall Confirmed Objective Disease Response According to the Response Evaluation Criteria in Solid Tumors (RECIST) | 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. | From start of treatment until Day 28 of Cycles 1 to 4, Day 28 of even cycles thereafter | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Tumor Response (TTR) | 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. | From start of treatment until Day 28 of Cycles 1 to 4, Day 28 of even cycles thereafter | 
| Duration of Response (DR) | 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). | From start of treatment until Day 28 of Cycles 1 to 4, Day 28 of even cycles thereafter or death due to cancer | 
| Time to Tumor Progression (TTP) | 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. | From start of treatment until Day 28 of Cycles 1 to 4, Day 28 of even cycles thereafter | 
| Overall Survival (OS) | 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. | From start of study treatment until death | 
| Progression-Free Survival (PFS) | 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. | From start of treatment until Day 28 of Cycles 1 to 4, Day 28 of even cycles thereafter or death | 
| Probability of Survival at One Year | 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. | From start of treatment until Day 28 of Cycles 1 to 4, Day 28 of even cycles thereafter up until 1 year | 
| VEGF (Vascular Endothelial Growth Factor) Concentration at Baseline | Concentration of VEGF at baseline. | Baseline (Cycle 1, Day 1) | 
| VEGF Ratio to Baseline at Each Time Point | VEGF concentration at each time point divided by VEGF concentration at baseline (ratio to baseline). | Baseline to Cycle 3, Day 28 inclusive | 
| VEGF-C Concentration at Baseline | Concentration of VEGF-C at baseline. | Baseline (Cycle 1, Day 1) | 
| VEGF-C Ratio to Baseline at Each Time Point | VEGF-C concentration at each time point divided by VEGF-C concentration at baseline (ratio to baseline). | Baseline to Cycle 3, Day 28 inclusive | 
| Soluble VEGF Receptor 2 (sVEGFR2) Concentration at Baseline | Concentration of sVEGFR2 at baseline. | Baseline (Cycle 1, Day 1) | 
| sVEGFR2 Ratio to Baseline at Each Time Point | sVEGFR2 concentration at each time point divided by sVEGFR2 concentration at baseline (ratio to baseline). | Baseline to Cycle 3, Day 28 inclusive | 
| Soluble VEGF Receptor 3 (sVEGFR3) Concentration at Baseline | Concentration of sVEGFR3 at baseline. | Baseline (Cycle 1, Day 1) | 
| sVEGFR3 Ratio to Baseline at Each Time Point | sVEGFR3 concentration at each time point divided by sVEGFR3 concentration at baseline (ratio to baseline). | Baseline to Cycle 3, Day 28 inclusive | 
| Change From Baseline in VEGF by Time Point Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] Versus PD) | 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). | Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive | 
| Change From Baseline in VEGFC by Time Point Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] Versus PD) | 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). | Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive | 
| Change From Baseline in VEGFR2 by Time Point Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] Versus PD) | 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). | Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive | 
| Change From Baseline in VEGFR3 by Time Point Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] Versus PD) | 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). | Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive | 
| Change From Baseline in VEGF by Time Point Stratified by PFS >= Median and PFS < Median | 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). | Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive | 
| Change From Baseline in VEGFC by Time Point Stratified by PFS >= Median and PFS < Median | 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). | Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive | 
| Change From Baseline in VEGFR2 by Time Point Stratified by PFS >= Median and PFS < Median | 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). | Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive | 
| Change From Baseline in VEGFR3 by Time Point Stratified by PFS >= Median and PFS < Median | 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). | Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive | 
| Change From Baseline in VEGF by Time Point Stratified by TTP >= Median and TTP < Median | 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). | Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive | 
| Change From Baseline in VEGFC by Time Point Stratified by TTP >= Median and TTP < Median | 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). | Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive | 
| Change From Baseline in VEGFR2 by Time Point Stratified by TTP >= Median and TTP < Median | 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). | Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive | 
| Change From Baseline in VEGFR3 by Time Point Stratified by TTP >= Median and TTP < Median | 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). | Baseline (Cycle 1, Day 1) to Cycle 3, Day 28 inclusive | 
| Trough Plasma Concentrations (Ctrough) of Sunitinib |  | prior to dosing on Cycle 1 (Days 1, 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28) | 
| Ctrough of SU-012662 (Sunitinib's Metabolite) |  | prior to dosing on Cycle 1 (Days 1, 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28) | 
| Ctrough of Gefitinib |  | prior to dosing on Cycle 1 (Days 1, 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28) |