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

Study Overview
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Brief Summary
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The purpose of this study is to confirm the safety and efficacy of sunitinib in subjects with unresectable pancreatic neuroendocrine tumors.

Detailed Description
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This study is being conducted to meet regulatory post-marketing commitments.

Official Title
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A SINGLE-ARM OPEN-LABEL INTERNATIONAL MULTI-CENTER STUDY OF THE EFFICACY AND SAFETY OF SUNITINIB MALATE (SU011248, SUTENT (REGISTERED)) IN PATIENTS WITH PROGRESSIVE ADVANCED METASTATIC WELL-DIFFERENTIATED UNRESECTABLE PANCREATIC NEUROENDOCRINE TUMORS

Conditions
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Well-differentiated Pancreatic Neuroendocrine Tumor

Intervention / Treatment
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* Drug: sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven diagnosis of well-differentiated pancreatic neuroendocrine tumor (according to World Health Organization [WHO 2000] classification). Disease progression within 12 months prior to study enrollment. Disease that is not amenable to surgery, radiation, or combined modality therapy with curative intent. Exclusion Criteria: Patients with poorly differentiated pancreatic neuroendocrine tumors (according to WHO 2000 classification). Prior treatment with any tyrosine kinase inhibitors, anti vascular endothelial growth factor (VEGF) angiogenesis inhibitors, non VEGF targeted angiogenesis inhibitors, or mammalian target of rapamycin (mTOR) inhibitors.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sunitinib<br> | Drug: sunitinib<br>* Sunitinib capsules will be given orally at continuous daily dosing with a starting dose of 37.5 mg. One cycle is equal to 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS): Investigator Assessment | 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. | Baseline until disease progression or death due to any cause (up to 1226 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS): Independent Radiological Review (IRR) Assessment | 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. | Baseline until disease progression or death due to any cause (up to 1226 days) | 
| Time to Tumor Progression (TTP): Investigator Assessment | Investigator assessed TTP was defined as the time (in months) from the date of enrollment in study until the date of first documentation of objective tumor progression. TTP calculated as (first event date minus date of enrollment plus 1)/30.4. Progression as per RECIST 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. The analysis was performed by Kaplan-Meier method. | Baseline until first documented tumor progression (up to 1226 days) | 
| Overall Survival (OS) | 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. | Baseline until death or end of study (up to 1939 days) | 
| Percentage of Participants With Objective Response (OR): Investigator Assessment | 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. | Baseline until disease progression or death due to any cause (up to 1226 days) | 
| Duration of Response (DOR): Investigator 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. | Baseline until disease progression or death due to any cause (up to 1226 days) | 
| Time to Tumor Response (TTR): Investigator Assessment | Investigator assessed TTR was defined as the time (in months) from date of enrollment in study until date of first documentation of objective tumor response (CR or PR) that was subsequently confirmed. TTR was calculated as (first response date minus the date of enrollment plus 1) divided by 30.4. As per RECIST 1.0, CR was defined as disappearance of all target and non-target lesions and 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. | Baseline until first documented objective tumor response (up to 1226 days) | 
| Percentage of Participants With Objective Response (OR): Independent Radiological Review (IRR) Assessment | 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. | Baseline until disease progression or death due to any cause (up to 1226 days) | 
| Duration of Response (DOR): Independent Radiological Review (IRR) Assessment | 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. | Baseline until disease progression or death due to any cause (up to 1226 days) | 
| Time to Tumor Response (TTR): Independent Radiological Review (IRR) Assessment | IRR assessed TTR was defined as the time (in months) from date of enrollment in study until first documentation of objective tumor response (CR or PR) that was subsequently confirmed. TTR was calculated as (first response date minus the date of enrollment plus 1) divided by 30.4. 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. | Baseline until first documented objective tumor response (up to 1226 days) | 
| Percentage of Participants With Chromogranin A (CgA) Response | 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. | Baseline until CgA response or death due to any cause (up to 1226 days) | 
| Quality of Life Measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) | 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. | 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) | 
| Quality of Life Measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Gastrointestinal Related Neuroendocrine Tumours-21 (EORTC QLQ-GI NET 21) | EORTC QLQ-GI-NET 21 was a 21-item questionnaire. These 21 questions assesses endocrine symptoms, gastrointestinal (G.I.) symptoms, treatment related symptoms, social functioning, disease related worries, muscle/bone pain, sexual function, information/communication function and body image. Each item was answered on a 4-point scale: 1 =not at all, 2 =a little, 3 =quite a bit, 4 =very much; where higher scores indicated more severe symptoms/problems. Scores averaged, transformed to 0-100 scale; higher score=more severe symptoms. | 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) | 
| Plasma Concentration of Soluble Protein Biomarker (sKIT) |  | 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) | 
| Minimum Observed Plasma Concentration (Ctrough) of Sunitinib and Its Metabolite SU012662 | Ctrough is the minimum observed plasma concentration of drug. SU012662 is the metabolite of sunitinib. | Pre-dose on Day 15 of Cycle 1, Day 1 of Cycle 2, 3 and 5 | 
| Dose-Corrected Trough Plasma Concentration of Sunitinib and Its Metabolite SU012662 | 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. | Pre dose on Day 15 of Cycle 1, Day 1 of Cycle 2, 3 and 5 | 
| Area Under the Curve (AUC24) of Sunitinib and Its Metabolite SU012662 | Area under the plasma concentration-time profile from time zero (pre-dose) to 24 hours post-dose. SU012662 is the metabolite of sunitinib. | 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) | 
| Oral Clearance (CL/F) of Sunitinib and Its Metabolite SU012662 | Clearance is a quantitative measure of the rate at which a drug substance is removed from the body. | Pre dose on Day 15 of Cycle 1, Day 1 of Cycle 2, 3 and 5 (each cycle 28 days) | 
| Half Maximal Effective Concentration (EC50) of Sunitinib | Concentration of sunitinib in plasma at which 50 percent of the maximum effect was observed. | Pre dose on Day 15 of Cycle 1, Day 1 of Cycle 2, 3 and 5 (each cycle 28 days) | 
| 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. 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. | Baseline up to 1939 days | 
| Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Baseline up to 1939 days | 
| Number of Participants With Adverse Events (AEs) According to Severity | 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. | Baseline up to 1939 days | 
| Number of Participants With Clinically Significant Laboratory Abnormalities | 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. | Baseline up to 1939 days | 
| Number of Participants With Change From Baseline in Vital Signs Abnormalities | Following parameters were analyzed for examination of vital signs: systolic and diastolic blood pressure, body temperature and heart rate. | Baseline up to 1939 days | 
| Number of Participants With Increase From Baseline in Corrected QT Interval (QTc) |  | Baseline up to 1939 days | 
| Number of Participants With Change From Baseline in Physical Examinations Findings | Physical examination included an examination of the general appearance, skin, heart, head, eyes, ears, nose, throat, breasts, abdomen, musculoskeletal, neck, extremities, thyroid and others. | Baseline up to 1939 days | 
| Number of Participants With Change From Baseline in Body Weight | Participants with increase of >=5 percent and decrease of >=5 percent from baseline in body weight were reported in this outcome measure. | Baseline up to 1939 days | 
| Number of Participants With Eastern Co-operative Oncology Group Performance Status (ECOG-PS) | 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. | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neuroendocrine tumors, adenoma islet cells, carcinoma islet cells, pancreatic neoplasms, angiogenesis inhibitors, sunitinib, neoplasms, carcinoma, adenoma