SU011248 Versus Interferon-Alfa As First-Line Systemic Therapy For Patients With Metastatic Renal Cell Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to test whether SU011248 has activity and is safe compared to interferon-alfa as first-line therapy in patients with metastatic renal cell carcinoma (RCC).

Official Title
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A Phase 3, Randomized Study Of SU011248 Versus Interferon-Alfa As First-Line Systemic Therapy For Patients With Metastatic Renal Cell Carcinoma

Conditions
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Carcinoma, Renal Cell

Intervention / Treatment
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* Drug: Interferon-alfa
* Drug: SU011248


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed renal cell carcinoma of clear cell histology with metastases Evidence of measurable disease by radiographic technique Eastern Cooperative Oncology Group [ECOG] performance status of 0 or 1 Exclusion Criteria: Prior systemic (including adjuvant or neoadjuvant) therapy of any kind for RCC History of or known brain metastases Serious acute or chronic illness or recent history of significant cardiac abnormality

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 2<br> | Drug: Interferon-alfa<br>* 3 MIU first week, 6 MIU second week, and 9 MIU thereafter three times a week (non-consecutive days) until progression or unacceptable toxicity<br>* Other names: Roferon;|
| Experimental: 1<br> | Drug: SU011248<br>* 50 mg orally daily for 4 weeks and 2 weeks off treatment until progression or unacceptable toxicity<br>* Other names: Sunitinib, SUTENT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS), Core Radiology Assessment | Progression-free survival (PFS) = time from randomization to first documentation of objective tumor progression or to death due to any cause, whichever occured first. If tumor progression data included more than 1 date, the first date was used. PFS = first event date minus the date of randomization + 1. On study included treatment plus 28-day follow-up periods. | Day 28 of each 6-week cycle: duration of treatment phase | 
| Progression-Free Survival (PFS), Investigator's Assessment | Progression-free survival = time from randomization to first documentation of objective tumor progression or to death due to any cause, whichever occured first. PFS = first event date minus the date of randomization + 1). On study included treatment plus 28-day follow-up periods. | Day 28 of each 6-week cycle: duration of treatment phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response, Core Radiology Assessment | Objective response (OR) = the number of patients with confirmed complete response (CR) and confirmed partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, relative to all randomized patients. CR was defined as the disappearance of all target lesions. 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. Confirmed responses (CR or PR) = those that persisted on repeat imaging study >= 4 weeks after initial documentation of response. | Day 28 of each 6-week cycle: duration of treatment phase | 
| Objective Response, Investigator's Assessment | Objective response (OR) = the number of patients with confirmed complete response (CR) and confirmed partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, relative to all randomized patients. CR was defined as the disappearance of all target lesions. 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. Confirmed responses = those that persist on repeat imaging study >= 4 weeks after initial documentation of response. | Day 28 of each 6-week cycle: duration of treatment phase | 
| Overall Survival (OS) | Overall survival (OS) = time from date of randomization to date of death due to any cause. For patients not expiring, survival time was censored at the last date they were known to be alive. Patients lacking data beyond randomization had their survival times censored at the date of randomization with a duration of 1 day. | Clinic visit or telephone contact every 2 months until death | 
| Time to Tumor Progression (TTP), Core Radiology Assessment | TTP = time from randomization to first documentation of objective tumor progression. TTP data were censored on the day following the date of last on treatment (including 28 day follow-up period) tumor assessment documenting absence of progressive disease for subjects who did not have objective tumor progression while on treatment or who were given anti-tumor treatment other than study treatment prior to documentation of objective tumor progression. Subjects with no tumor assessments after randomization had TTP censored on the date of randomization with a duration of 1 day. | Randomization to first documentation of tumor progression: duration of treatment phase | 
| Time to Tumor Progression (TTP), Investigator's Assessment | TTP = time from randomization to first documentation of objective tumor progression. TTP data were censored on the day following the date of last on treatment (including 28 day follow-up period) tumor assessment documenting absence of progressive disease for subjects who did not have objective tumor progression while on treatment or who were given anti-tumor treatment other than the study treatment prior to documentation of objective tumor progression. Subjects with no tumor assessments after randomization had TTP censored on the date of randomization with a duration of 1 day. | Randomization to first documentation of tumor progression: duration of treatment phase | 
| Duration of Response (DR), Core Radiology Assessement | Duration of response (DR) = time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause. DR data were censored on the day following the date of the last on treatment (including 28 day follow-up period) tumor assessment documenting absence of progressive disease for subjects without objective tumor progression who did not die due to any cause while on treatment or who were given anti-tumor treatment other than study treatment prior to observing tumor progression. | Day 28 of each cycle: duraton of treatment phase | 
| Duration of Response (DR), Investigator's Assessment | Duration of response (DR) = time from the first documentation of objective tumor response to the first documentaion of objective tumor progression or to death due to any cause. DR data were censored on the day following the date of the last on treatment (including 28 day follow-up period) tumor assessment documenting absence of progressive disease for subjects without objective tumor progression who did not die due to any cause while on treatment or who were given anti-tumor treatment other than study treatment prior to observing tumor progression. | Day 28 of each cycle: duration of treatment phase | 
| FACT-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) Subscale | FACT-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) subscale of the FKSI to measure advanced kidney cancer disease related symptoms. Includes 9 items: lack of energy, pain, losing weight, bone pain, fatigue, short of breath, coughing, bothered by fevers, and hematuria. Each question was answered on a five-point Likert-type scale ranging from 0 (not at all) to 4 (very much). Score = the sum score of the item scores in the subscale; total range: 0 to 36. A score greater than 0 indicates the difference favored sunitinib. | Day 1 & 28 of each cycle: duration of treatment phase | 
| FACT-Kidney Symptom Index (FKSI) Subscale | FACT-Kidney Symptom Index (FKSI) subscale designed to be a stand-alone instrument to measure symptoms and quality of life in patients with advanced kidney cancer. Contains 15 questions; some questions overlap with the FACT-G questions. Each question was answered on a five-point Likert-type scale ranging from 0 to 4 (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). Total FKSI score = sum score of the 15 item scores; total range: 0 - 60; 0 (most severe symptoms and concerns) to 60 (no symptoms or concerns). | Day 1 & 28 of each cycle: duration of treatment phase | 
| Functional Assessment of Cancer Therapy-General (FACT-G) | Functional Assessment of Cancer Therapy-General (FACT-G): core questionnaire of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system that has been validated in a variety of cancer populations. 27 questions grouped into 4 domains that measure a patient's physical, functional, social and family, and emotional well-being. Five-point Likert-type scale ranging from 0 to 4 (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). Score = sum score of item scores in the subscale; total range: 0 to 108 with higher score indicating better quality of life. | Day 1 & 28 of each cycle: duration of treatment phase | 
| Functional Assessment of Cancer Therapy-General (FACT-G): Physical Well Being (PWB) Subscale | Physical well-being (PWB) subscale of the Functional Assessment of Cancer Therapy-General (FACT-G). Each question was answered on a five-point Likert-type scale ranging from 0 to 4 (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). Score = the sum score of the item scores in the subscale; range: 0 to 28; lower score indicates better physical well-being. | Day 1 & 28 of each cycle: duration of treatment phase | 
| Functional Assessment of Cancer Therapy-General (FACT-G): Social/Family Well Being (SWB) Subscale | Social/family well-being (SWB)subscale of the Functional Assessment of Cancer Therapy-General (FACT-G). Each question was answered on a five-point Likert-type scale ranging from 0 to 4 (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). Score = the sum score of the item scores in the subscale; range: 0 to 28; lower score indicates less social/family well-being. | Day 1 & 28 of each cycle: duration of treatment phase | 
| Functional Assessment of Cancer Therapy-General (FACT-G): Emotional Well Being (EWB) Subscale | Emotional well-being (EWB)subscale of the Functional Assessment of Cancer Therapy-General (FACT-G). Each question was answered on a five-point Likert-type scale ranging from 0 to 4 (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). Score = the sum score of the item scores in the subscale; range: 0 to 24; lower score indicates better emotional well-being. | Day 1 & 28 of each cycle: duration of treatment phase | 
| Functional Assessment of Cancer Therapy-General (FACT-G): Functional Well Being (FWB) Subscale | Functional well-being (FWB) subscale of the Functional Assessment of Cancer Therapy-General (FACT-G). Each question was answered on a five-point Likert-type scale ranging from 0 to 4 (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). Score = the sum score of the item scores in the subscale; range: 0 to 28; higher score indicates greater functional well-being. | Day 1 & 28 of each cycle: duration of treatment phase | 
| EuroQoL Five Dimension (EQ-5D) Health State Index | EQ-5D Health State Index: a brief, self-administered generic health status instrument. Respondents were asked to describe their current health state on each of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety or depression) on a three-level scale (1=no problem, 2=some problem, and 3=extreme problem). A maximum score of 1 can be derived from these 5 dimensions by score conversion; range: -0.39 (worst health state)to 1.00 (best health state). This descriptive system classifies respondents into one of 243 possible distinct health states (EQ-5D descriptive system). | Day 1 & 28 of each cycle: duration of treatment phase | 
| Euro-QoL Visual Analog Scale (EQ-VAS) | EQ-VAS: overall self-rating rating of the patient's current health state using a 20 cm Visual Analog Scale (EQ-VAS), also called the health state thermometer) is a metric measurement (in 2 mm interval) from the visual analog scale which ranges between 0 (worse imaginable health state) and 100 (best imaginable health state). | Day 1 & 28 of each cycle: duration of treatment phase | 
| Plasma Concentrations of Soluble Proteins: Plasma VEGF-A, Plasma VEGF-C, Plasma sVEGFR-3, PLASMA IL-8, and PLASMA bFGF That May be Associated With Tumor Proliferation or Angiogenesis | Plasma concentrations of soluble proteins that may be associated with tumor proliferation or angiogenesis collected from a subset of patients were analyzed by enzyme-linked immunosorbent assay (ELISA) analysis. Soluble protein values: Baseline concentration (pM) and ratio to Baseline at each timepoint; ratio = plasma concentration of soluble protein (picograms per milliliter [pg/ml]) at timepoint / concentration of soluble protein (pg/ml) at baseline. Samples below the limit of quantitation and samples with insufficient volume available were excluded. | Day 1 & Day 28, Cycle 1 to Cycle 4 | 
| Plasma Concentrations of Soluble Proteins: Plasma Basic Fibroblast Growth Factor (bFGF) That May be Associated With Tumor Proliferation or Angiogenesis | Plasma concentrations of soluble proteins that may be associated with tumor proliferation or angiogenesis collected from a subset of patients were analyzed by enzyme-linked immunosorbent assay (ELISA) analysis. Soluble protein values: Baseline concentration (pM) and ratio to Baseline at each timepoint; ratio = plasma concentration of soluble protein (picograms per milliliter [pg/ml]) at timepoint / concentration of soluble protein (pg/ml) at baseline. Samples below the limit of quantitation and samples with insufficient volume available were excluded. | Day 1 & Day 28, Cycle 1 to Cycle 4 | 
| Incremental Cost Effectiveness Ratio (ICER) | Incremental cost effectiveness ratio (ICER) of sunitinib compared to IFN-a as first-line treatment for MRCC, defined as the ratio of the incremental cost of treatment over the incremental effectiveness; effectiveness measured as quality adjusted life year (QALY) gain. This objective was not addressed in the clinical study report, but an interim analysis of cost-effectiveness was presented separately. These results were not available for inclusion at the time of this posting. | post study measurement | 
| Ctrough Concentrations of SU011248 | Subject observed Ctrough (trough drug) concentrations of SU011248 per cycle and study day determined by plasma trough samples collected from a subset of patients. Steady-state observed trough concentrations were dose corrected to the starting dose (reference dose) where appropriate. Concentrations below the limits of quantitation (BLQ) were set to 0. Ctrough = minimum (trough) plasma concentration (nanograms per milliliter [ng/mL]). | Day 28 of Cycle 1 to Cycle 4 | 
| Ctrough Concentrations of Metabolite SU012662 | Subject observed Ctrough (trough drug) concentrations of active metabolite SU012662 per cycle and study day determined by plasma trough samples collected from a subset of patients. Steady-state observed trough concentrations were dose corrected to the starting dose (reference dose) where appropriate. Concentrations below the limits of quantitation (BLQ) were set to 0. Ctrough = minimum (trough) plasma concentration (nanograms per milliliter [ng/mL]). | Day 28 of Cycle 1 to Cycle 4 | 
| Ctrough Concentrations of SU011248 and Active Metabolite SU012662 | Subject observed Ctrough (trough drug) concentrations of total drug (SU011248 and its active metabolite SU012662) per cycle and study day determined by plasma trough samples collected from a subset of patients. Steady-state observed trough concentrations were dose corrected to the starting dose (reference dose) where appropriate. Concentrations below the limits of quantitation (BLQ) were set to 0. Ctrough = minimum (trough) plasma concentration (nanograms per milliliter [ng/mL]). | Day 28 of Cycle 1 to Cycle 4 |