A Study of Sunitinib In Young Patients With Advanced Gastrointestinal Stromal Tumor

Study Overview
=================
Brief Summary
-----------------
Children and young adults with gastrointestinal stromal tumors (GIST) will be treated with sunitinib. The safety (including pharmacokinetics) and tolerability of sunitinib will be studied in these patients. In addition, tumor responses and overall survival will be assessed.

Official Title
-----------------
A PHASE I/II STUDY OF SUNITINIB IN YOUNG PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMOR

Conditions
-----------------
Gastrointestinal Stromal Tumors

Intervention / Treatment
-----------------
* Drug: sunitinib malate dose escalation
* Drug: sunitinib malate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histological diagnosis of GIST. Patients must have demonstrated either disease progression or intolerance to imatinib mesylate, have non-mutant Stem Cell Factor Receptor gene (KIT) GIST, or cannot obtain imatinib in their country Measurable by Response Evaluation Criterion in Solid Tumors (RECIST) or evaluable disease. Exclusion Criteria: Current treatment with another investigational agent. Prior sunitinib treatment. Prior therapy with known risk for cardiovascular complications.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Children with GIST<br>children ages 6yrs-<18yrs | Drug: sunitinib malate dose escalation<br>* sunitinib starting dose will be 15mg/m^2 daily on a 4 weeks on/2 weeks off schedule (Schedule 4/2).<br>|
| Experimental: Young adults with GIST<br>young adults ages 18yrs-<21 yrs | Drug: sunitinib malate<br>* sunitinib 50mg daily on Schedule 4/2<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Steady-State Maximum Plasma Concentration (Cmax,ss) of Sunitinib and Its Metabolite | Estimated steady-state maximum plasma concentration (Cmax,ss) of Sunitinib and its metabolite SU012662. Summarized data for all time points was reported. | pre-dose on Day 1, Day 12-18 and Day 25-29 of Cycle 1,2, 3 and 2, 4, 6, 8 hours post-dose on Day 1 Cycle 1 | 
| Estimated Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours Post Dose AUC(0-24) of Sunitinib and Its Metabolite | Estimated area under the plasma concentration versus time curve from time zero to 24 hours post dose (AUC24) of Sunitinib and its metabolite SU012662. Summarized data for all time points was reported. | pre-dose on Day 1, Day 12-18 and Day 25-29 of Cycle 1,2, 3 and 2, 4, 6, 8 hours post-dose on Day 1 Cycle 1 | 
| Estimated Oral Clearance (CL/F) of Sunitinib and Its Metabolite | SU012662 is the metabolite of Sunitinib. Oral clearance (CL/F) is a quantitative measure of the rate at which a drug substance is removed from the blood (CL) normalized by the oral bioavailability of the drug (F). Summarized data for all time points was reported. | pre-dose on Day 1, Day 12-18 and Day 25-29 of Cycle 1,2, 3 and 2, 4, 6, 8 hours post-dose on Day 1 Cycle 1 | 
| Maximum Observed Plasma Concentration (Cmax) of Sunitinib and Its Metabolite | SU012662 is the metabolite of Sunitinib. | Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for Sunitinib and Its Metabolite | SU012662 is the metabolite of Sunitinib. | Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours Post Dose AUC(0-8) for Sunitinib and Its Metabolite | AUC(0-8) was defined as area under the plasma concentration time-curve from time zero to 8 hours post dose. SU012662 is the metabolite of Sunitinib. | Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to end of study (up to Cycle 18) that were absent before treatment or that worsened relative to pretreatment state. AEs included both non-serious adverse events (AEs) and SAEs. | Baseline up to end of study (up to Cycle 18, each cycle was of 42 days) | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) Greater Than or Equal to (>=) Grade 3, Based on National Cancer Institute (NCI) Common Terminology Criteria (CTC) for AEs (CTCAE), Version 4.0 | An AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. As per NCI CTCAE, Grade 3 events =medically significant but not immediately life-threatening, unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment, Grade 4 events =participant to be in imminent danger of death. Grade 5 events =death. Treatment-emergent events are events between first dose of study drug and up to end of study (up to Cycle 18) that were absent before treatment or that worsened relative to pretreatment state. Number of participants with AEs of any of the Grade 3 or above (Grade 4, 5) were reported. | Baseline up to end of study (up to Cycle 18, each cycle was of 42 days) | 
| Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both non-serious adverse events (AEs) and SAEs. | Baseline up to end of study (up to Cycle 18, each cycle was of 42 days) | 
| Number of Participants With Clinically Significant Laboratory Abnormalities | Criteria for clinically significant laboratory abnormalities: Hemoglobin (Hb), hematocrit: less than (<) 0.8*lower limit of normal (LLN), platelet: <75 or greater than (>) 700*10^3/millimeter (mm)^3*upper limit of normal (ULN), leukocyte: <2.5 or >17.5*10^3/mm^3*ULN; total bilirubin 1.5*ULN, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase: >3.0*ULN, total protein, albumin: <0.8*LLN or >1.2*ULN ;blood urea nitrogen, creatinine: >1.3*ULN, uric acid >1.2*ULN; sodium <0.95*LLN or >1.05*ULN, potassium, calcium: <0.9*LLN or >1.1*ULN, albumin, total protein <0.8*LLN or >1.2*ULN; glucose <0.6*LLN or >1.5*ULN, creatine kinase >2.0*ULN; urine (red blood cell, white blood cell >6/high power field). | Baseline up to end of study (up to Cycle 18, each cycle was of 42 days) | 
| Number of Participants With Objective Response | Objective response in participants was defined as the number of participants with confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Confirmed response were those that persisted on repeat imaging study for at least 4 weeks after initial documentation of response. CR was defined as disappearance of all lesions (target and non-target). PR was defined as at least 30 percentage (%) decrease in the sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non-target lesions not increased or absent. | Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days) | 
| Duration of Response | Duration of response was defined as time (in months) from the first documentation of objective tumor response (confirmed CR or PR) to the first documentation of disease progression or death due to any cause. Confirmed response were those that persisted on repeat imaging study for at least 4 weeks after initial documentation of response. CR was defined as disappearance of all lesions (target and non-target). PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non-target lesions not increased or absent. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). | Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days) | 
| Progression-Free Survival | Progression free survival was defined as time (in months) from date of enrollment to the first documentation of disease progression or to death (due to any cause), whichever occurred first. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). | Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days) | 
| Overall Survival | Overall survival was defined as time (in months) from enrollment to the date of death due to any cause. Analysis was performed using Kaplan-Meier method. | Baseline until death or discontinuation from the study whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days) | 
| Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI CTCAE version 4.0, Grade1= asymptomatic or mild symptoms, Grade 2= Moderate;local or noninvasive intervention indicated; Grade 3 events =medically significant but not immediately life-threatening, unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment, Grade 4 events =participant to be in imminent danger of death. Grade 5 events =death. Participants with any of the Grade 1 to Grade 5 AEs were reported. The PK evaluable participants were divided into 2 PK subgroups on Day 28 of Cycle 1: those with total drug (sunitinib + SU012662) trough plasma concentration (Ctrough) value less than (<) the median Ctrough value(lower exposure) and those with total drug (sunitinib + SU012662) Ctrough values greater than or equal to (>=) the median Ctrough value(higher exposure). | Cycle 1 Day 28 up to Cycle 3 (each cycle 42 days) | 
| Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Pearson correlation coefficient between percent change from baseline in laboratory parameters with total drug (Sunitinib + SU012662) concentration were calculated on Day 28 of Cycles 1, 2, and 3. Laboratory parameters included absolute neutrophil count, platelet count, lymphocyte count and hemoglobin. | Baseline, Day 28 of Cycle 1, Cycle 2 and Cycle 3 (each cycle was of 42 days) | 
| Pearson Correlation Coefficient Between Percent Change From Baseline in Vital Sign Results With Total Drug (Sunitinib + SU012662) Concentration | Pearson correlation coefficient between percent change from baseline in vital sign results with total drug (Sunitinib + SU012662) concentration were calculated on Day 28 of Cycles 1, 2, and 3. Vital signs included systolic blood pressure and diastolic blood pressure. | Baseline, Day 28 of Cycle 1, Cycle 2 and Cycle 3 (each cycle was of 42 days) | 
| Number of Participants With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups | SD:when there is no sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR: as at least 30% decrease in the sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non-target lesions not increased or absent. CR: disappearance of all lesions (target and non-target). PD:at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Participants with SD, PR, CR and PD responses were assessed according to 2 PK subgroups created on Day 28 of Cycle 1: those with total drug (sunitinib + SU012662) trough plasma concentration (Ctrough) value less than (<) the median Ctrough value(lower exposure) and those with total drug (sunitinib + SU012662) Ctrough values greater than or equal to (>=) the median Ctrough value(higher exposure). | Baseline until disease progression or discontinuation from the study, or death, whichever occurred first(maximum duration: up to Cycle 18; each cycle was of 42 days) | 
| Progression Free Survival for PK Subgroups | Progression free survival was defined as time (in months) from date of enrollment to the first documentation of disease progression or to death (due to any cause), whichever occurred first. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The PK evaluable participants were assessed according to 2 PK subgroups created on Day 28 of Cycle 1: those with total drug (sunitinib + SU012662) trough plasma concentration (Ctrough) value less than (<) the median Ctrough value(lower exposure) and those with total drug (sunitinib + SU012662) Ctrough values greater than or equal to (>=) the median Ctrough value(higher exposure). | Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days) | 
| Pearson Correlation Coefficient Between Progression Free Survival With Total Drug (Sunitinib + SU012662) Concentration | Pearson correlation coefficient between Progression Free Survival (PFS) with total drug (Sunitinib + SU012662) concentration at Day 28 of Cycle 1 was calculated. PFS was defined as time (in months) from date of enrolment to the first documentation of disease progression or to death (due to any cause), whichever occurred first. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). | Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days | 
| Estimated Sunitinib Plasma Concentration at Which 50% of the Maximum Effect (EC50) for Each Selected Efficacy Parameter (e.g., Sum of Largest Diameters for Target Tumors) Was Observed |  | Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose | 
| Estimated Sunitinib Plasma Concentration at Which 50% of the Maximum Effect (EC50) for Each Selected Safety Endpoint (e.g., Absolute Neutrophil Count) Was Observed |  | Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Children and young adults with GIST, sunitinib malate, pharmacokinetics, tumor response, overall survival, tumor KIT mutation status