A Study Of The Efficacy And Safety Of Sunitinib In Patients With Advanced Well-Differentiated Pancreatic Neuroendocrine Tumors

Investigator assessed PFS was defined as the time (in months) from the date of enrollment in study to the date of first documented objective tumor progression or death (due to any cause), whichever occurs first. PFS calculated as (first event date minus date of enrollment plus 1)/30.4. If progression or death was not observed, the participant was censored at the date of the participant's last progression-free tumor assessment prior to the study cut-off date. Progression as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria was defined as: greater than or equal to (\>=) 20 percent increase in sum of longest diameter (LD) of target lesions taking as a reference the smallest sum of the LD recorded since the treatment started, or the appearance of one or more new lesions and/or unequivocal progression of existing non target-lesions. The analysis was performed by Kaplan-Meier method.

Time frame: Baseline until disease progression or death due to any cause (up to 1226 days)

Population: FAS included all participants who were enrolled into the study regardless of whether participants received study drug or not.

Area under the plasma concentration-time profile from time zero (pre-dose) to 24 hours post-dose. SU012662 is the metabolite of sunitinib.

Time frame: Pre-dose (0 hour) and at multiple time points (up to 24 hours) post dose on Day 15 of Cycle 1, Day 1 of Cycle 2, 3 and 5 (each cycle 28 days)

Population: Due to insufficient data, there was substantial uncertainty associated with the parameter estimates; therefore, the population PK/PD analyses was not completed. Instead, the exposure response analyses with respect to different safety and efficacy endpoints were carried out and reported.

Dose-corrected plasma trough concentration is calculated as: trough plasma concentration\*(intended dose divided by actual dose). Intended dose was defined as the starting dose in the study and actual dose was defined as the last dose which the participant had received. SU012662 is the metabolite of sunitinib.

Time frame: Pre dose on Day 15 of Cycle 1, Day 1 of Cycle 2, 3 and 5

Population: PK population included all participants who received at least 1 dose of study medication, had baseline and at least 1 post-baseline value for each parameters.

IRR assessed DOR was defined as the time (in months) from the date of first documented objective tumor response (CR or PR) that was subsequently confirmed to the first documented objective tumor progression or death due to any cause, whichever occurred first. According to Choi criteria, CR was defined as disappearance of all target and non-target lesions and no new lesions. PR was defined as a decrease of \>=10 percent in tumor size or a decrease in tumor density (HU) of 15 percent or more on CT with no new lesions and no obvious progression of non-measurable disease.

Time frame: Baseline until disease progression or death due to any cause (up to 1226 days)

Population: Analysis was performed on only those participants who had objective response as per IRR assessment.

Investigator assessed DOR was defined as the time (in months) from the date of first documented objective tumor response (CR or PR), that was subsequently confirmed, to the first documented objective tumor progression or death due to any cause, whichever occurred first. According to RECIST 1.0, CR was defined as disappearance of all target and non-target lesions. PR was defined as \>=30 percent decrease in the sum of the LD of the target lesions taking as a reference the baseline sum LD. Progression as per RECIST version 1.0 was defined as \>=20 percent increase in sum of LD of target lesions taking as a reference the smallest sum of the LD recorded since the treatment started, or the appearance of one or more new lesions and/or unequivocal progression of existing non target-lesions.

Time frame: Baseline until disease progression or death due to any cause (up to 1226 days)

Population: Analysis was performed on only those participants who had objective response as per investigator assessment.

Concentration of sunitinib in plasma at which 50 percent of the maximum effect was observed.

Time frame: Pre dose on Day 15 of Cycle 1, Day 1 of Cycle 2, 3 and 5 (each cycle 28 days)

Population: Due to insufficient data, there was substantial uncertainty associated with the parameter estimates; therefore, the population PK/PD analyses was not completed. Instead, the exposure response analyses with respect to different safety and efficacy endpoints were carried out and reported.

Ctrough is the minimum observed plasma concentration of drug. SU012662 is the metabolite of sunitinib.

Time frame: Pre-dose on Day 15 of Cycle 1, Day 1 of Cycle 2, 3 and 5

Population: Pharmacokinetic (PK) population included all participants who received at least 1 dose of study medication, had baseline and at least 1 post-baseline value for each parameters.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to severity grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Grade 1 =mild; Grade 2 =moderate; within normal limits, Grade 3 =severe or medically significant but not immediately life-threatening; Grade 4 =life-threatening or disabling; urgent intervention indicated; Grade 5 =death.

Time frame: Baseline up to 1939 days

Population: Safety analysis set included all participants who received at least 1 dose of study medication. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

Participants with increase of \>=5 percent and decrease of \>=5 percent from baseline in body weight were reported in this outcome measure.

Time frame: Baseline up to 1939 days

Population: Safety analysis set included all participants who received at least 1 dose of study medication.

Physical examination included an examination of the general appearance, skin, heart, head, eyes, ears, nose, throat, breasts, abdomen, musculoskeletal, neck, extremities, thyroid and others.

Time frame: Baseline up to 1939 days

Population: Safety analysis set included all participants who received at least 1 dose of study medication.

Following parameters were analyzed for examination of vital signs: systolic and diastolic blood pressure, body temperature and heart rate.

Time frame: Baseline up to 1939 days

Population: Safety analysis set included all participants who received at least 1 dose of study medication.

Following parameters were analyzed for laboratory examination: hematology (hemoglobin, red blood cell count, platelet count, white blood cell count, total neutrophils, basophils, lymphocytes); liver function (aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein); renal function (blood urea nitrogen, creatinine); electrolytes (sodium, potassium, chloride, calcium, magnesium, phosphate); urinalysis (urine protein), miscellaneous (pregnancy test, Chromogranin A). Clinically significant laboratory abnormalities were identified by the Investigator.

Time frame: Baseline up to 1939 days

Population: Safety analysis set included all participants who received at least 1 dose of study medication.

ECOG-PS performance status is used to assess how the disease affects the daily living abilities of the participant. It was measured on 6-point scale ranging from 0-5, where 0= fully active/able to carry on all pre-disease activities without restriction; 1= restricted in physically strenuous activity but ambulatory/able to carry out light or sedentary work; 2= ambulatory for more than 50 percent of waking hours and capable of all self-care but unable to carry out any work activities; 3= capable of limited self-care, confined to bed or chair \>50 percent of waking hours; 4= completely disabled, not capable of any self-care, totally confined to bed or chair; 5= dead. A higher score indicated greater functional impairment. Only those ECOG-PS categories, in which at least one participant had data at any indicated time point were reported in this outcome measure. Not reported (NR) category included participants with unavailable ECOG performance status.

Time frame: Day 1 of Cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, End of treatment (up to maximum duration of 1226 days)

Population: Safety analysis set included all participants who received at least 1 dose of study medication. Here, 0 participants in the number analyzed field signifies none of the participants were evaluable in the given group at this time point, hence data was not reported.

Time frame: Baseline up to 1939 days

Population: Safety analysis set included all participants who received at least 1 dose of study medication.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. 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 are events between first dose of study drug and up to 1939 days that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-SAEs.

Time frame: Baseline up to 1939 days

Population: Safety analysis set included all participants who received at least 1 dose of study medication.

Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. 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 1939 days that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator.

Time frame: Baseline up to 1939 days

Population: Safety analysis set included all participants who received at least 1 dose of study medication.

Clearance is a quantitative measure of the rate at which a drug substance is removed from the body.

Time frame: Pre dose on Day 15 of Cycle 1, Day 1 of Cycle 2, 3 and 5 (each cycle 28 days)

Population: Due to insufficient data, there was substantial uncertainty associated with the parameter estimates; therefore, the population PK/PD analyses was not completed. Instead, the exposure response analyses with respect to different safety and efficacy endpoints were carried out and reported.

OS was defined as the time (in months) from date of enrollment in study to the date of death due to any cause. If death was not observed, the participant was censored at the earliest of the last date the participant was known to be alive or the end of study. The analysis was performed by Kaplan-Meier method.

Time frame: Baseline until death or end of study (up to 1939 days)

Population: FAS included all participants who were enrolled into the study regardless of whether participants received study drug or not.

CgA response in participants was defined as having confirmed CgA CR or CgA PR, relative to the population with an elevated baseline CgA value in the blood. CgA CR was defined as decrease from a high baseline value of CgA in the blood to one that fell within the normal range. CgA PR was defined as a decrease of greater than or equal to 50 percent from a high baseline value of CgA. Normal baseline value of CgA in blood was 39.0 ng/mL. Confirmed responses were those that persisted for at least 4 weeks after initial documentation of response. Blood levels of CgA were assessed and percentage of participants with CgA response were reported.

Time frame: Baseline until CgA response or death due to any cause (up to 1226 days)

Population: FAS included all participants who were enrolled into the study regardless of whether participants received study drug or not.

IRR assessed OR in participants was defined as having a CR or PR according to Choi criteria and sustained for at least 4 weeks. According to Choi criteria, CR was defined as disappearance of all target and non-target lesions and no new lesions. PR was defined as a decrease of \>=10 percent in tumor size or a decrease in tumor density (HU) of 15 percent or more on Computed tomography (CT) with no new lesions and no obvious progression of non-measurable disease. Percentage of participants with objective response were reported in this outcome measure.

Time frame: Baseline until disease progression or death due to any cause (up to 1226 days)

Population: FAS included all participants who were enrolled into the study regardless of whether participants received study drug or not.

Investigator assessed OR in participants was defined as having a complete response (CR) or partial response (PR) according to RECIST 1.0 and sustained for at least 4 weeks. CR was defined as disappearance of all target and non-target lesions. PR was defined as \>=30 percent decrease in the sum of the LD of the target lesions taking as a reference the baseline sum LD. Percentage of participants with investigator assessed OR were reported.

Time frame: Baseline until disease progression or death due to any cause (up to 1226 days)

Population: FAS included all participants who were enrolled into the study regardless of whether participants received study drug or not.

Time frame: Pre-dose on Day 1 and 15 of Cycle 1, Day 1 of Cycle 2, 3 and every 2 cycles thereafter (Cycle 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43), End of Treatment (up to maximum duration of 1226 days)

Population: sKIT analysis set: enrolled participants who received at least 1 dose of study drug, had at least 1 biomarker parameter from corresponding assay sample with both baseline and post-treatment assessment. Here, 0 participants in number analyzed field=none of the participants were evaluable in given group at this time point, hence data not reported

IRR assessed PFS was defined as the time (in months) from the date of enrollment in study until the date of first documented objective tumor progression or death (due to any cause), whichever occurs first. PFS calculated as (first event date minus date of enrollment plus 1)/30.4. If progression or death was not observed, the participant was censored at the date of the participant's last progression-free tumor assessment prior to the study cut-off date. Progression as per RECIST 1.0 criteria was defined as: \>=20 percent increase in sum of LD of target lesions taking as a reference the smallest sum of the LD recorded since the treatment started, or the appearance of one or more new lesions and/or unequivocal progression of existing non target-lesions. The analysis was performed by Kaplan-Meier method.

Time frame: Baseline until disease progression or death due to any cause (up to 1226 days)

Population: FAS included all participants who were enrolled into the study regardless of whether participants received study drug or not.

EORTC QLQ-C30 is a cancer-specific instrument with 30 questions to assess the participant quality of life. First 28 questions used for evaluating 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, nausea and vomiting, pain) and other single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties). Each question was assessed on 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much); high score represented high level of symptomatology/problem. Last 2 questions used for evaluating global health status (GHS)/quality of life. Each question was assessed on 7-point scale (1=very poor to 7=excellent). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning.

Time frame: Day 1 of Cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, End of treatment (up to maximum duration of 1226 days)

Population: FAS included all participants who were enrolled into the study regardless of whether participants received study drug or not. Here, 0 participants in the number analyzed field signifies none of the participants were evaluable in the given group at this time point, hence data was not reported.