Gastrointestinal Stromal Tumors
Conditions
Keywords
Children and young adults with GIST, sunitinib malate, pharmacokinetics, tumor response, overall survival, tumor KIT mutation status
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.
Interventions
DRUGsunitinib malate dose escalation
sunitinib starting dose will be 15mg/m\^2 daily on a 4 weeks on/2 weeks off schedule (Schedule 4/2).
DRUGsunitinib malate
sunitinib 50mg daily on Schedule 4/2
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 20 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Steady-State Maximum Plasma Concentration (Cmax,ss) of Sunitinib and Its Metabolite | 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 steady-state maximum plasma concentration (Cmax,ss) of Sunitinib and its metabolite SU012662. Summarized data for all time points was reported. |
| 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 | 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 (AUC24) of Sunitinib and its metabolite SU012662. Summarized data for all time points was reported. |
| Estimated Oral Clearance (CL/F) of Sunitinib and Its Metabolite | 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 | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Sunitinib and Its Metabolite | Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose | SU012662 is the metabolite of Sunitinib. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for Sunitinib and Its Metabolite | Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose | SU012662 is the metabolite of Sunitinib. |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours Post Dose AUC(0-8) for Sunitinib and Its Metabolite | Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | 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 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). |
| Overall Survival | Baseline until death or discontinuation from the study whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days) | 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. |
| Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Cycle 1 Day 28 up to Cycle 3 (each cycle 42 days) | 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). |
| Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | 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 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. |
| Pearson Correlation Coefficient Between Percent Change From Baseline in Vital Sign Results With Total Drug (Sunitinib + SU012662) Concentration | 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 were calculated on Day 28 of Cycles 1, 2, and 3. Vital signs included systolic blood pressure and diastolic blood pressure. |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to end of study (up to Cycle 18, each cycle was of 42 days) | 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. |
| Progression Free Survival for PK Subgroups | 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 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). |
| Pearson Correlation Coefficient Between Progression Free Survival With Total Drug (Sunitinib + SU012662) Concentration | 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 (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). |
| 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 | — |
| Number of Participants With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups | 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) | 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). |
| 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 | Baseline up to end of study (up to Cycle 18, each cycle was of 42 days) | 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. |
| Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to end of study (up to Cycle 18, each cycle was of 42 days) | 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. |
| Number of Participants With Clinically Significant Laboratory Abnormalities | Baseline up to end of study (up to Cycle 18, each cycle was of 42 days) | 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). |
| Number of Participants With Objective Response | 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) | 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. |
| Duration of Response | 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 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). |
Countries
Czechia, France, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sunitinib Participants received Sunitinib capsules orally at a dose based on body surface area (BSA) (minimum dose of 15 milligram/ meter square \[mg/m\^2\] up to a maximum dose of 30 mg/m\^2) once daily, from Day 1 to 28 in each treatment cycle of 42 days (up to a maximum of 18 cycles) until completion of study treatment, disease progression, unacceptable toxicity, required a treatment rest (greater than \[\>4\] weeks), withdrawal of participant consent, or if other withdrawal criteria were met. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Patient Decision | 1 |
Baseline characteristics
| Characteristic | Sunitinib |
|---|---|
| Age, Continuous | 14.3 years STANDARD_DEVIATION 1.4 |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized White | 5 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
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.
Time frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose
Population: The PK population included all treated participants with at least one PK observation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sunitinib | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours Post Dose AUC(0-8) for Sunitinib and Its Metabolite | Sunitinib | 77.49 nanograms*hour per milliliter (ng*hr)/mL | Geometric Coefficient of Variation 42 |
| Sunitinib | Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours Post Dose AUC(0-8) for Sunitinib and Its Metabolite | SU012662 | 10.11 nanograms*hour per milliliter (ng*hr)/mL | Geometric Coefficient of Variation 37 |
Primary
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.
Time frame: 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
Population: The PK population included all treated participants with at least one PK observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sunitinib | 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 | Sunitinib | 812.59 nanogram*hour per milliliter (ng*hr)/mL | Standard Deviation 273.37 |
| Sunitinib | 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 | SU012662 | 336.78 nanogram*hour per milliliter (ng*hr)/mL | Standard Deviation 74.15 |
Primary
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.
Time frame: 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
Population: The PK population included all treated participants with at least one PK observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sunitinib | Estimated Oral Clearance (CL/F) of Sunitinib and Its Metabolite | Sunitinib | 26.37 Liters per hour (L/hr) | Standard Deviation 7.62 |
| Sunitinib | Estimated Oral Clearance (CL/F) of Sunitinib and Its Metabolite | SU012662 | 12.85 Liters per hour (L/hr) | Standard Deviation 3.11 |
Primary
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.
Time frame: 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
Population: The PK population included all treated participants with at least one PK observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sunitinib | Estimated Steady-State Maximum Plasma Concentration (Cmax,ss) of Sunitinib and Its Metabolite | Sunitinib | 37.98 nanograms per milliliter (ng/mL) | Standard Deviation 12.91 |
| Sunitinib | Estimated Steady-State Maximum Plasma Concentration (Cmax,ss) of Sunitinib and Its Metabolite | SU012662 | 14.55 nanograms per milliliter (ng/mL) | Standard Deviation 3.04 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Sunitinib and Its Metabolite
SU012662 is the metabolite of Sunitinib.
Time frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose
Population: The PK population included all treated participants with at least one PK observation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sunitinib | Maximum Observed Plasma Concentration (Cmax) of Sunitinib and Its Metabolite | Sunitinib | 17.58 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 32 |
| Sunitinib | Maximum Observed Plasma Concentration (Cmax) of Sunitinib and Its Metabolite | SU012662 | 2.342 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 18 |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Sunitinib and Its Metabolite
SU012662 is the metabolite of Sunitinib.
Time frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose
Population: The PK population included all treated participants with at least one PK observation.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sunitinib | Time to Reach Maximum Observed Plasma Concentration (Tmax) for Sunitinib and Its Metabolite | Sunitinib | 8 hours |
| Sunitinib | Time to Reach Maximum Observed Plasma Concentration (Tmax) for Sunitinib and Its Metabolite | SU012662 | 8 hours |
Secondary
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).
Time frame: 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)
Population: Analysis was performed on a subset of FAS which included participants who had a confirmed CR or PR. Since, none of the participants had confirmed CR or PR, hence duration of response was not analyzed.
Secondary
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
Time frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose
Population: Due to low number of enrolled participants (n=6), there was insufficient data to perform any type of pharmacokinetic/pharmacodynamic modeling to obtain EC50 values, hence data is not reported.
Secondary
Estimated Sunitinib Plasma Concentration at Which 50% of the Maximum Effect (EC50) for Each Selected Safety Endpoint (e.g., Absolute Neutrophil Count) Was Observed
Time frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose
Population: Due to low number of enrolled participants (n=6), there was insufficient data to perform any type of pharmacokinetic/pharmacodynamic modeling to obtain EC50 values, hence data is not reported.
Secondary
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).
Time frame: Cycle 1 Day 28 up to Cycle 3 (each cycle 42 days)
Population: The PK subgroup analysis set included all treated participants with at least 1 PK observation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sunitinib | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Nausea | 0 participants |
| Sunitinib | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Vomiting | 0 participants |
| Sunitinib | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Diarrhoea | 0 participants |
| Sunitinib | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Fatigue | 0 participants |
| Sunitinib | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Palmar-Plantar Erythrodysaesthesia Syndrome | 1 participants |
| Sunitinib | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Neutropenia | 2 participants |
| Sunitinib | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Thrombocytopenia | 1 participants |
| Sunitinib | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Lymphopenia | 0 participants |
| Sunitinib | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Hypertension | 0 participants |
| Sunitinib | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Anaemia | 1 participants |
| Sunitinib: Higher Exposure | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Lymphopenia | 0 participants |
| Sunitinib: Higher Exposure | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Nausea | 2 participants |
| Sunitinib: Higher Exposure | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Neutropenia | 1 participants |
| Sunitinib: Higher Exposure | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Vomiting | 1 participants |
| Sunitinib: Higher Exposure | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Anaemia | 0 participants |
| Sunitinib: Higher Exposure | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Diarrhoea | 2 participants |
| Sunitinib: Higher Exposure | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Thrombocytopenia | 1 participants |
| Sunitinib: Higher Exposure | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Fatigue | 1 participants |
| Sunitinib: Higher Exposure | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Hypertension | 0 participants |
| Sunitinib: Higher Exposure | Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups | Palmar-Plantar Erythrodysaesthesia Syndrome | 0 participants |
Secondary
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).
Time frame: Baseline up to end of study (up to Cycle 18, each cycle was of 42 days)
Population: The as-treated population included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib | Number of Participants With Clinically Significant Laboratory Abnormalities | 0 participants |
Secondary
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.
Time frame: 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)
Population: The full analysis set included all enrolled participants regardless of what treatment, if any, was received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sunitinib | Number of Participants With Objective Response | Complete response | 0 participants |
| Sunitinib | Number of Participants With Objective Response | Partial response | 0 participants |
Secondary
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).
Time frame: 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)
Population: The PK population included all treated participants with at least 1 PK observation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sunitinib | Number of Participants With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups | Stable Disease | 1 participants |
| Sunitinib | Number of Participants With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups | Partial Response | 0 participants |
| Sunitinib | Number of Participants With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups | Complete Response | 0 participants |
| Sunitinib | Number of Participants With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups | Progressive Disease | 2 participants |
| Sunitinib: Higher Exposure | Number of Participants With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups | Progressive Disease | 1 participants |
| Sunitinib: Higher Exposure | Number of Participants With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups | Stable Disease | 2 participants |
| Sunitinib: Higher Exposure | Number of Participants With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups | Complete Response | 0 participants |
| Sunitinib: Higher Exposure | Number of Participants With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups | Partial Response | 0 participants |
Secondary
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.
Time frame: Baseline up to end of study (up to Cycle 18, each cycle was of 42 days)
Population: The as-treated population included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sunitinib | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 6 participants |
| Sunitinib | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
Secondary
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.
Time frame: Baseline up to end of study (up to Cycle 18, each cycle was of 42 days)
Population: The as-treated population included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib | 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 | 5 participants |
Secondary
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.
Time frame: Baseline up to end of study (up to Cycle 18, each cycle was of 42 days)
Population: The as-treated population included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sunitinib | Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 6 participants |
| Sunitinib | Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
Secondary
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.
Time frame: Baseline until death or discontinuation from the study whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days)
Population: The full analysis set included all enrolled participants regardless of what treatment, if any, was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sunitinib | Overall Survival | NA months |
Secondary
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.
Time frame: Baseline, Day 28 of Cycle 1, Cycle 2 and Cycle 3 (each cycle was of 42 days)
Population: The PK population included all treated participants with at least one PK observation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Absolute Neutrophil Count: Cycle 1 Day 28 | -0.1870 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Absolute Neutrophil Count: Cycle 2 Day 28 | -0.5914 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Absolute Neutrophil Count: Cycle 3 Day 28 | -0.5536 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Platelet Count: Cycle 1 Day 28 | 0.0329 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Platelet Count: Cycle 2 Day 28 | -0.6424 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Platelet Count: Cycle 3 Day 28 | -0.6604 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Lymphocyte Count: Cycle 1 Day 28 | 0.1509 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Lymphocyte Count: Cycle 2 Day 28 | -0.4815 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Lymphocyte Count: Cycle 3 Day 28 | -0.2931 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Hemoglobin: Cycle 1 Day 28 | 0.9107 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Hemoglobin: Cycle 2 Day 28 | 0.4368 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration | Hemoglobin: Cycle 3 Day 28 | 0.2095 correlation coefficient |
Secondary
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.
Time frame: Baseline, Day 28 of Cycle 1, Cycle 2 and Cycle 3 (each cycle was of 42 days)
Population: The PK population included all treated participants with at least one PK observation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Vital Sign Results With Total Drug (Sunitinib + SU012662) Concentration | Systolic Blood Pressure: Cycle 1 Day 28 | -0.3730 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Vital Sign Results With Total Drug (Sunitinib + SU012662) Concentration | Systolic Blood Pressure: Cycle 2 Day 28 | -0.8146 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Vital Sign Results With Total Drug (Sunitinib + SU012662) Concentration | Systolic Blood Pressure: Cycle 3 Day 28 | 0.2768 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Vital Sign Results With Total Drug (Sunitinib + SU012662) Concentration | Diastolic Blood Pressure: Cycle 1 Day 28 | 0.6854 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Vital Sign Results With Total Drug (Sunitinib + SU012662) Concentration | Diastolic Blood Pressure: Cycle 2 Day 28 | -0.3638 correlation coefficient |
| Sunitinib | Pearson Correlation Coefficient Between Percent Change From Baseline in Vital Sign Results With Total Drug (Sunitinib + SU012662) Concentration | Diastolic Blood Pressure: Cycle 3 Day 28 | 0.2634 correlation coefficient |
Secondary
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).
Time frame: 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
Population: The PK population included all treated participants with at least one PK observation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib | Pearson Correlation Coefficient Between Progression Free Survival With Total Drug (Sunitinib + SU012662) Concentration | 0.5904 correlation coefficient |
Secondary
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).
Time frame: 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)
Population: The full analysis set included all enrolled participants regardless of what treatment, if any, was received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sunitinib | Progression-Free Survival | 5.8 months |
Secondary
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).
Time frame: 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)
Population: The PK population included all treated participants with at least one PK observation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sunitinib | Progression Free Survival for PK Subgroups | 2.6 months |
| Sunitinib: Higher Exposure | Progression Free Survival for PK Subgroups | 9.0 months |