A Study Of SU011248 As Therapy In Patients With Locally Advanced Or Metastatic Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study is to find out if SU011248 (sunitinib) provides additional benefit when it is given after treatment with two chemotherapy drugs carboplatin and paclitaxel and also if sunitinib is safe for patients with locally advanced and metastatic Non Small Cell Lung Cancer (NSCLC).

Official Title
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Phase 2 Study Of SU011248 As Consolidation Therapy In Patients With Locally Advanced Or Metastatic Non-Small Cell Lung Cancer

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: paclitaxel
* Drug: sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven NSCLC Stage IIIB (locally advanced with malignant effusion) or Stage IV disease No prior therapy for NSCLC Evidence of unidimensionally measurable disease Exclusion Criteria: Previous treatment with systemic chemotherapy for lung cancer History of or known brain metastases NCI CTCAE Grade 3 hemorrhage within 4 weeks of starting study treatment Evidence of hemoptysis within 4 weeks of starting study treatment Serious acute or chronic illness or recent history of significant cardiac abnormality Previous treatment with anti-angiogenesis agents including thalidomide, or inhibitors of EGFR and PDGFR

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: 1<br> | Drug: carboplatin<br>* AUC of 6 mg*min/mL via IV infusion every 21 days for 4 cycles as per institutional practices.<br>* Other names: Paraplatin;Drug: paclitaxel<br>* 175-225 mg/m2 via IV infusion every 21 days for 4 cycles as per institutional practices.<br>* Other names: Taxol;Drug: sunitinib<br>* 50 mg orally daily for 4 weeks followed by 2 weeks off treatment up to 1 year (after completing 1 year of treatment, pts deriving clinical benefit may continue to receive sunitinib in a separate continuation protocol).<br>* Other names: SUTENT, SU011248;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Surviving at One Year | Proportion of those surviving at the end of one year from the first dose of study treatment. In the absence of confirmation of death, survival time was censored at the last date the subject was known to be alive. Patients lacking data beyond the day of first dose had their survival time censored at Day 1 of treatment. | From start of treatment until 1 year or death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the time from start of study treatment to first documentation of objective disease progression or to death on study due to any cause, whichever was first. If tumor progression data included more than 1 date, the first date was used. PFS (in weeks) was calculated as (first event date - first paclitaxel/carboplatin dose date +1)/7.02. | From start of treatment until Day 21 of Cycles 2 and 4 (Carboplatin plus Paclitaxel), Day 28 of Cycles 1, 2, 3, 4, and even cycles thereafter (Sunitinib) or death | 
| Time to Tumor Progression (TTP) | TTP was defined as the time from start of study treatment to first documentation of objective disease progression. If tumor progression data included more than 1 date, the first date was used. TTP (in weeks) was calculated as (first event date - first paclitaxel/carboplatin dose date +1)/7.02. | From start of treatment until Day 21 of Cycles 2 and 4 (Carboplatin plus Paclitaxel), Day 28 of Cycles 1, 2, 3, 4, and even cycles thereafter (Sunitinib) | 
| Duration of Response (DR) | DR=time from the first documentation of objective tumor response (complete response [CR] or partial response [PR]) that was subsequently confirmed to first documentation of objective disease progression or death due to any cause, whichever was first. CR=disappearance of all target lesions. PR=a > = 30% decrease in sum of longest dimensions of target lesions taking as a reference baseline sum longest dimensions. If tumor progression data included more than 1 date, first date was used. DR (in weeks) was calculated as (the end date for DR - first CR or PR that was subsequently confirmed +1)/7.02. | From start of treatment until Day 21 of Cycles 2 and 4 (Carboplatin plus Paclitaxel), Day 28 of Cycles 1, 2, 3, 4, and even cycles thereafter (Sunitinib) or death | 
| Number of Subjects With Overall Confirmed Objective Disease Response | Objective disease response = subjects with confirmed CR or PR according to the Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.0). 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 21 of Cycles 2 and 4 (Carboplatin plus Paclitaxel), Day 28 of Cycles 1, 2, 3, 4, and even cycles thereafter (Sunitinib) | 
| Overall Survival (OS) | OS was defined as the time from start of study treatment to death due to any cause. OS (in months) was calculated as (date of death - date of paclitaxel/carboplatin first dose +1)/30.4. 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 of paclitaxel/carboplatin had their survival time censored at Day 1 of paclitaxel/carboplatin treatment. | From start of study treatment until death | 
| Trough Plasma Concentration (Ctrough) of Sunitinib | Ctrough = the plasma concentration prior to study drug administration. On Day 28, this parameter provided and idea of the concentration at steady state since no big fluctuation was expected in a 24 hour interval. | predose on Day 28 of Cycles 1, 2, 3, and 5 of Part 2 | 
| Ctrough of SU-012662 (Sunitinib's Metabolite) | Ctrough = the plasma concentration prior to study drug administration. On Day 28, this parameter provided and idea of the concentration at steady state since no big fluctuation was expected in a 24 hour interval. | predose on Day 28 of Cycles 1, 2, 3, and 5 of Part 2 | 
| Ctrough of Total Drug (Sunitinib + SU-012662) | Ctrough = the plasma concentration prior to study drug administration. On Day 28, this parameter provided and idea of the concentration at steady state since no big fluctuation was expected in a 24 hour interval. | predose on Day 28 of Cycles 1, 2, 3, and 5 of Part 2 | 
| Dose-Corrected Ctrough of Sunitinib | Ctrough = the plasma concentration prior to study drug administration. Dose correction was made to the initial intended dose in Cycle 1. This was determined due to potential dose changes throughout the study in different subjects. It was calculated as the observed values multiplied by the reference dose (50 mg) divided by the actual dose. For dose-corrected trough concentration, only trough concentration values from subjects who received sunitinib during at least the last 10 consecutive days of dosing at the same dose level were included. | predose on Day 28 of Cycles 1, 2, 3, and 5 of Part 2 | 
| Dose-Corrected Ctrough of SU-012662 (Sunitinib's Metabolite) | Ctrough = the plasma concentration prior to study drug administration. Dose correction was made to the initial intended dose in Cycle 1. This was determined due to potential dose changes throughout the study in different subjects. It was calculated as the observed values multiplied by the reference dose (50 mg) divided by the actual dose. For dose-corrected trough concentration, only trough concentration values from subjects who received sunitinib during at least the last 10 consecutive days of dosing at the same dose level were included. | predose on Day 28 of Cycles 1, 2, 3, and 5 of Part 2 | 
| Dose-Corrected Ctrough of Total Drug (Sunitinib + SU-012662) | Ctrough = the plasma concentration prior to study drug administration. Dose correction was made to the initial intended dose in Cycle 1. This was determined due to potential dose changes throughout the study in different subjects. It was calculated as the observed values multiplied by the reference dose (50 mg) divided by the actual dose. For dose-corrected trough concentration, only trough concentration values from subjects who received sunitinib during at least the last 10 consecutive days of dosing at the same dose level were included. | predose on Day 28 of Cycles 1, 2, 3, and 5 of Part 2 | 
| Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Concentration at Baseline | Concentration of VEGFR3 at baseline. | Baseline (Cycle 1, Day 1) of Part 2 | 
| VEGFR3 Ratio to Baseline at Each Time Point | VEGFR3 concentration at each time point divided by VEGFR3 concentration at baseline (ratio to baseline). | Baseline to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) of Part 2 | 
| VEGF-C Concentration at Baseline | Concentration of VEGF-C at baseline. | Baseline (Cycle 1, Day 1) of Part 2 | 
| 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 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) of Part 2 | 
| Soluble E-Selectin at Baseline | Concentration of soluble E-Selectin at baseline. | Baseline (Cycle 1, Day 1) of Part 2 | 
| Soluble E-Selectin Ratio to Baseline at Each Time Point | Soluble E-Selectin concentration at each time point divided by soluble E-Selectin concentration at baseline (ratio to baseline). | Baseline to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 4 (Day 28), Cycle 5 (Day 28) of Part 2 | 
| VEGFR3 at Baseline Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] or PD) | Median concentration of VEGFR3 at baseline stratified by tumor response (CR or PR or [SD > = 6 Weeks] or PD). A measure of dispersion is not included because the Wilcoxon rank sum test is a nonparametric test that makes no assumptions about the distribution of the data (eg, normality). | Baseline (Cycle 1, Day 1) of Part 2 | 
| VEGFR3 Ratio to Baseline at Each Time Point Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] or PD) | Median VEGFR3 concentration at each time point divided by median VEGFR3 concentration at baseline (ratio to baseline) for subjects with tumor response (CR or PR or [SD > = 6 weeks] or PD). 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 to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) of Part 2 | 
| VEGF-C at Baseline Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] or PD) | Median concentration of VEGF-C at baseline stratified by tumor response (CR or PR or [SD > = 6 Weeks] or PD). A measure of dispersion is not included because the Wilcoxon rank sum test is a nonparametric test that makes no assumptions about the distribution of the data (eg, normality). | Baseline (Cycle 1, Day 1) of Part 2 | 
| VEGF-C Ratio to Baseline at Each Time Point Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] or PD) | Median VEGF-C concentration at each time point divided by median VEGF-C concentration at baseline (ratio to baseline) for subjects with tumor response (CR or PR or [SD > = 6 weeks] or PD). 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 to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) of Part 2 | 
| Soluble E-Selectin at Baseline Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] or PD) | Median concentration of soluble E-selectin at baseline stratified by tumor response (CR or PR or [SD > = 6 Weeks] or PD). A measure of dispersion is not included because the Wilcoxon rank sum test is a nonparametric test that makes no assumptions about the distribution of the data (eg, normality). | Baseline (Cycle 1, Day 1) of Part 2 | 
| Soluble E-Selectin Ratio to Baseline at Each Time Point Stratified by Tumor Response (CR or PR or [SD > = 6 Weeks] or PD) | Median soluble E-selectin concentration at each time point divided by median soluble E-selectin concentration at baseline (ratio to baseline) for subjects with tumor response (CR or PR or [SD > = 6 weeks] or PD). 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 to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 4 (Day 28), Cycle 5 (Day 28) of Part 2 | 
| Comparison of Kaplan-Meier PFS Curves After Stratification by < or > = Median Levels of VEGFR3 at Baseline and Changes From Baseline | PFS = time from start of study treatment to first documentation of objective disease progression or to death on study due to any cause, whichever was 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 sunitinib dose date +1)divided by 7.02. Groups are defined by < or > = median levels of VEGFR3 at Baseline and after Stratification by < or > = median changes from Baseline in VEGFR3 at each time point. | Baseline to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) of Part 2 | 
| Comparison of Kaplan-Meier PFS Curves After Stratification by < or > = Median Levels of VEGF-C at Baseline and Changes From Baseline | PFS = time from start of study treatment to first documentation of objective disease progression or to death on study due to any cause, whichever was 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 sunitinib dose date +1) divided by 7.02. Groups are defined by < or > = median levels of VEGF-C at Baseline and after stratification by < or > = median changes from Baseline in VEGF-C at each time point. | Baseline to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) of Part 2 | 
| Comparison of Kaplan-Meier PFS Curves After Stratification by < or > = Median Levels of Soluble E-Selectin at Baseline and Changes From Baseline | PFS = time from start of study treatment to first documentation of objective disease progression or to death on study due to any cause, whichever was 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 sunitinib dose date +1) divided by 7.02. Groups are defined by < or > = median levels of soluble E-selectin at Baseline and after stratification by < or > = median changes from Baseline in soluble E-selectin at each time point. | [Baseline to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 4 (Day 28), Cycle 5 (Day 28) of Part 2 | 
| Comparison of Kaplan-Meier TTP Curves After Stratification by < or > = Median Levels of VEGFR3 at Baseline and Changes From Baseline | TTP = time from start of study treatment to first documentation of objective disease 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 sunitinib dose date +1) divided by 7.02. Groups are defined by < or > = median levels of VEGFR3 at Baseline and after stratification by < or > = median changes from baseline in VEGFR3 at each time point. | Baseline to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) of Part 2 | 
| Comparison of Kaplan-Meier TTP Curves After Stratification by < or > = Median Levels of VEGF-C at Baseline and Changes From Baseline | TTP = time from start of study treatment to first documentation of objective disease 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 sunitinib dose date +1) divided by 7.02. Groups are defined by < or > = median levels of VEGF-C at Baseline and after stratification by < or > = median changes from Baseline in VEGF-C at each time point. | Baseline to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) of Part 2 | 
| Comparison of Kaplan-Meier TTP Curves After Stratification by < or > = Median Levels of Soluble E-Selectin at Baseline Changes From Baseline | TTP = time from start of study treatment to first documentation of objective disease 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 sunitinib dose date +1) divided by 7.02. Groups are defined by < or > = median levels of soluble E-selectin at Baseline and after stratification by < or > = median changes from Baseline in soluble E-selectin at each time point. | Baseline to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 4 (Day 28), Cycle 5 (Day 28) of Part 2 | 
| Comparison of Kaplan-Meier OS Curves After Stratification by < or > = Median Levels of VEGFR3 at Baseline Changes From Baseline | OS = time from start of study treatment to death due to any cause. OS (in months) was calculated as (date of death minus date of sunitinib first dose +1)divided by 30.4. 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 of sunitinib had their survival time censored at Day 1 of sunitinib treatment. Groups are defined by < or > = median levels of VEGFR3 at Baseline and after stratification by < or > = median changes from Baseline in VEGFR3 at each time point. | Baseline to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) of Part 2 | 
| Comparison of Kaplan-Meier OS Curves After Stratification by < or > = Median Levels of VEGF-C at Baseline and Changes From Baseline | OS = time from start of study treatment to death due to any cause. OS (in months) was calculated as (date of death minus date of sunitinib first dose +1) divided by 30.4. 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 of sunitinib had their survival time censored at Day 1 of sunitinib treatment. Groups are defined by < or > = median levels of VEGF-C at Baseline and after stratification by < or > = median changes from Baseline in VEGF-C at each time point. | Baseline to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 5 (Day 28) of Part 2 | 
| Comparison of Kaplan-Meier OS Curves After Stratification by < or > = Median Levels of Soluble E-Selectin at Baseline and Changes From Baseline | OS=time from start of study treatment to death due to any cause. OS (in months) calculated as (date of death minus date of sunitinib first dose +1) divided by 30.4. For subjects not expiring their survival times were censored at last date of known contact they were known to be alive. Subjects lacking data beyond day of first dose of sunitinib had their survival time censored at Day 1 of sunitinib treatment. Groups are defined by < or > = median levels of soluble E-selectin at Baseline and after stratification by < or > = median changes from Baseline in soluble E-selectin at each time point. | Baseline to Cycle 1 (Day 28), Cycle 2 (Days 1, 28), Cycle 3 (Days 1, 28), Cycle 4 (Day 28), Cycle 5 (Day 28) of Part 2 | 
| Immunohistochemical Staining of Paraffin Embedded Tumor Tissue | Previously collected tumor paraffin block (or 12-20 10-micron slides prepared for the paraffin block) for correlative laboratory analysis. | Screening | 
| Correlation of Polymorphisms in c-Kit, Flt-3 and c-Fms to Safety of Sunitinib | A blood sample (6 mL) was collected and used to isolate DNA. These samples were not anonymized. | Within 7 days of Day 1 | 
| Change From Baseline in Health Related Quality of Life (HRQOL) and Lung Cancer Related Symptoms as Assessed With the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30) | EORTC QLQ-C30 scales: global health/QoL, functional domains (physical, role, cognitive, emotional, social), and symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea). Recall period: past week; response range: not at all to very much, global/QOL range: very poor to excellent. Scale score range: 0 to 100. Higher functional/global QoL score = better functioning and higher symptom score = greater degree of symptoms. Change: score at each visit in Part 2 minus baseline score in Part 1. | Baseline (Part 1) to Cycle1 (Days 1 [baseline], 28), Cycles 2 and 3 (Days 1, 28), and Cycle 4 (Day 1) in Part 2 | 
| Change From Baseline in HRQOL and Lung Cancer Related Symptoms as Assessed With the EORTC QLQ Lung Cancer Module (QLQ-LC13) | QLQ-LC13 assessed lung cancer symptoms (dyspnea, coughing, dysphasia, hemoptysis, sore mouth, peripheral neuropathy, alopecia, chest pain, arm pain, shoulder pain, and pain in other parts). Recall period: past week; response range: not at all to very much. Scale score range: 0 to 100. Higher symptom score = greater degree of symptoms. Change: score at each visit in Part 2 minus baseline score in Part 1. | Baseline (Part 1) to Cycle1 (Days 1 [baseline], 28), Cycles 2 and 3 (Days 1, 28), and Cycle 4 (Day 1) in Part 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung Neoplasms