A Phase I/II Study of Sunitinib Malate (SU011248) In Patients With Gastrointestinal Stromal Tumor (GIST)

Study Overview
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Brief Summary
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Phase I;To investigate the clinically recommended dose of Sunitinib malate (SU011248) following multiple oral dosing in the first cycle (4 consecutive weeks and 2 weeks rest) by reviewing the safety and tolerability. Phase II;To determine the objective tumor response and the safety of Sunitinib malate (SU011248) at the clinically recommended dose.

Official Title
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A Phase I/II Study of Sunitinib Malate (SU011248) In The Treatment of Patients With Malignant Gastrointestinal Stromal Tumor (GIST) Previously Treated by Imatinib Mesylate.

Conditions
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Gastrointestinal Stromal Tumors

Intervention / Treatment
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* Drug: Sunitinib malate (SU011248)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically-confirmed metastatic or unresectable gastrointestinal stromal tumor (GIST). Patients previously treated with imatinib mesylate. Exclusion Criteria: Patients who have not recovered from the acute toxic effects of previous antineoplastic therapy or treatment with imatinib mesylate. Any tumor therapy for gastrointestinal stromal tumor (GIST) discontinued less than 4 weeks prior to starting study treatment. Imatinib mesylate discontinued less than 2 weeks prior to starting therapy.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 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: SU011248<br>25 , 50 or 75 mg/day of SU011248 | Drug: Sunitinib malate (SU011248)<br>* SU011248<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Dose Limiting Toxicities (DLT) | Dose Limiting Toxicities(DLT) in the subjects enrolled in Phase 1. | Cycle 1 (Baseline to Week 6) | 
| Maximum Plasma Concentration (Cmax) on Cycle 1 Day 1 | Maximum Plasma Concentration (Cmax) of SU-011248, its active metabolite SU-012662 and Total drug (SU-011248+SU-012662) in the subjects enrolled in Phase 1. The Cmax for total drug (SU-011248+SU-012662) was calculated as the mean of the Cmax of total drug from each individual subject (it is not the simple sum of means of Cmax of SU-011248 and SU-012662). | Day 1 of Cycle 1 | 
| Maximum Plasma Concentration (Cmax) on Cycle 1 Day 28 | Maximum Plasma Concentration (Cmax) of SU-011248, its active metabolite SU-012662 and Total drug (SU-011248+SU-012662) in the subjects enrolled in Phase 1. The Cmax for total drug (SU-011248+SU-012662) was calculated as the mean of the Cmax of total drug from each individual subject (it is not the simple sum of means of Cmax of SU-011248 and SU-012662). | Day 28 of Cycle 1 | 
| Area Under the Plasma Concentration Curve (AUC0-24) on Cycle 1 Day 1 | Area Under the Plasma Concentration Curve (AUC0-24) of SU-011248, its active metabolite SU-012662 and Total drug (SU-011248+SU-012662) in the subjects enrolled in Phase 1. The AUC0-24 for total drug (SU-011248+SU-012662) was calculated as the mean of the AUC0-24 of total drug from each individual subject (it is not the simple sum of means of AUC0-24 of SU-011248 and SU-012662). | Day 1 of Cycle 1 | 
| Area Under the Plasma Concentration Curve (AUC0-24) on Cycle 1 Day 28 | Area Under the Plasma Concentration Curve (AUC0-24) of SU-011248, its active metabolite SU-012662 and Total drug (SU-011248+SU-012662) in the subjects enrolled in Phase 1. The AUC0-24 for total drug (SU-011248+SU-012662) was calculated as the mean of the AUC0-24 of total drug from each individual subject (it is not the simple sum of means of AUC0-24 of SU-011248 and SU-012662). | Day 28 of Cycle 1 | 
| Time to First Occurrence of Cmax (Tmax) on Cycle 1 Day 1 | Time to First Occurrence of Cmax (Tmax) of SU-011248, its active metabolite SU-012662 and Total drug (SU-011248+SU-012662) in the subjects enrolled in Phase 1. The Tmax for total drug (SU-011248+SU-012662) was calculated as the median of the Tmax of total drug from each individual subject (it is not the simple sum of median of Tmax of SU-011248 and SU-012662). | Day 1 of Cycle 1 | 
| Time to First Occurrence of Cmax (Tmax) on Cycle 1 Day 28 | Time to First Occurrence of Cmax (Tmax) of SU-011248, its active metabolite SU-012662 and Total drug (SU-011248+SU-012662) in the subjects enrolled in Phase 1. The Tmax for total drug (SU-011248+SU-012662) was calculated as the median of the Tmax of total drug from each individual subject (it is not the simple sum of medians of Tmax of SU-011248 and SU-012662). | Day 28 of Cycle 1 | 
| SU-011248 Clearance on Cycle 1 Day 28 | SU-011248 Clearance in the subjects enrolled in Phase 1. Clearance was calculated by dividing a SU-011248 dose(mg) by AUC0-24(ng•h/mL). | Day 28 of Cycle 1 | 
| Accumulation Ratio (Rac) on Cycle 1 Day 28 | Accumulation Ratio (Rac) of SU-011248, its active metabolite SU-012662 and Total drug (SU-011248+SU-012662) on Cycle 1 Day 28 in the subjects enrolled in Phase 1. Rac was the ratio of Day 28 to Day 1. | Day 28 of Cycle 1 | 
| Number of Subjects With Clinical Benefit Response (CBR) Based on the Extramural Review Committee Assessment in Recommended Dose Group | Clinical Benefit Response is defined as sum of subjects confirmed with complete response (CR), partial response (PR), or stable disease (SD)>= 22 weeks on study according to Response Evaluation Criteria in Solid Tumors (RECIST). | Day 28 of Cycles 1-4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of Vascular Endothelial Growth Factor (VEGF) | Plasma concentrations of potential pharmacodynamic markers; Vascular Endothelial Growth Factor (VEGF) | Day 1, 14, 28 of Cycles 1-4 | 
| 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) | Day 1, 14, 28 of Cycles 1-4 | 
| Plasma Concentrations of Soluble Stem Cell Factor Receptor (sKIT) | Plasma concentrations of potential pharmacodynamic markers; Soluble Stem Cell Factor Receptor (sKIT) | Day 1, 14, 28 of Cycles 1-4 | 
| Trough Plasma Concentration (Ctrough) of SU-011248 | Trough Plasma Concentration (Ctrough) means the concentration prior to study drug administration | Day 14, 28 of Cycle 1; Day 1, 14, 28 of Cycles 2-4 | 
| Trough Plasma Concentration (Ctrough) of SU-012262 | Trough Plasma Concentration (Ctrough) means the concentration prior to study drug administration | Day 14, 28 of Cycle 1; Day 1, 14, 28 of Cycles 2-4 | 
| Trough Plasma Concentration (Ctrough) of SU-011248+SU-012662 | Trough Plasma Concentration (Ctrough) means the concentration prior to study drug administration | Day 14, 28 of Cycle 1; Day 1, 14, 28 of Cycles 2-4 | 
| Changes From Baseline of Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Questionnaires | Patient-reported outcome: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaires (version 4A). The questionnaire consists of a 13-item subscale which covers specific fatigue questions. The subject rates the intensity of fatigue and its related symptoms on a five-point scale(0 to 4). High score is indicating low fatigue. The total score of the 13 items was evaluated. Change from Baseline: Score at each observation minus score at baseline | Day 7, 14, 28, 35 of Cycle 1; Day 1, 7, 14, 28, 35 of Cycles 2-4 | 
| Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires | The EQ-5D questionnaires 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. High score is indicating high health. Change from Baseline: weighted health state index at each observation minus weighted health state index at baseline | Day 28 of Cycle 1; Day 1, 28 of Cycles 2-4 | 
| Number of Subjects With Disease Controlled Based on the Extramural Review Committee Assessment in Recommended Dose Group | Number of subjects with Disease Controlled is defined as sum of the subjects confirmed with complete response (CR), partial response (PR), or stable disease (SD)>= 10 weeks on study according to Response Evaluation Criteria in Solid Tumors (RECIST). | Day 28 of Cycles 1-4 | 
| Number of Subjects With Objective Response Based on the Extramural Review Committee Assessment in Recommended Dose Group | Number of subjects with Objective Response is defined as sum of the subjects confirmed with complete response (CR) and partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). | Day 28 of Cycles 1-4 | 
| 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). | From the first dose to Progressive Disease | 
| 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. | From the first dose to Progressive Disease or Death | 
| Time To Failure (TTF) | Time To Failure (TTF) 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), the date of treatment discontinuation except completion of treatment, or date of death due to cancer. | From the first dose to Progressive Disease, Treatment discontinuation except completion of treatment, or Death due to cancer. | 
| 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 patient was known to be alive. Survival was surveyed once a year from the registration day of the first subject, for all the subjects who received the study drug at least once. | From the first dose to death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Evaluate of RTD for Japanese GIST patients