Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Raymond E, Dahan L, Raoul J-L, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011;364:

2 CLINICAL PROTOCOL A PHASE III RANDOMIZED, DOUBLE-BLIND STUDY OF SUNITINIB (SU011248, SUTENT ) VERSUS PLACEBO IN PATIENTS WITH PROGRESSIVE ADVANCED/METASTATIC WELL-DIFFERENTIATED PANCREATIC ISLET CELL TUMORS Compound: Compound Name: SU Sunitinib malate US IND Number: 62,382 Protocol Number: Phase: 3 Version and Date: Global Amendment 4 10 July 2008 Page 1 of 68

3 SUMMARY Indication: Treatment of subjects with progressive advanced/metastatic well-differentiated pancreatic islet cell tumors. Rationale: Neuroendocrine tumors (NET), including pancreatic islet cell tumors, are rare malignancies with an incidence of less than 1 case per 100,000 per year in the US. Because of the indolent nature of this disease, the majority of patients are diagnosed with disseminated metastases. For patients with metastatic disease, the 5-year survival rate is low, and cure is not possible. Pancreatic islet cell tumors arise from neuroendocrine cells. These tumors are typically composed of small cells containing regular, well-rounded nuclei with rare mitoses. Despite an often slow rate of tumor progression, patients with metastatic NET ultimately develop significant morbidity. Their indolent nature and resistance to traditional treatment modalities distinguishes neuroendocrine tumors from small-cell carcinoma, for example, a related malignancy that may also possess neuroendocrine features. Poorly-differentiated carcinoma pursues a far more aggressive clinical course, is often responsive to platinum-based chemotherapy regimens, and is characterized histologically by the presence of frequent mitoses and areas of necrosis. Because of the clinical and histological differences between poorly-differentiated carcinoma and more well-differentiated NET, patients with poorly-differentiated carcinoma will be excluded from this trial. With the exception of surgery for localized disease, there is currently a lack of available therapies with proven survival benefit for NET. Available treatment options for unresectable disease include the use of somatostatin analogs, which may relieve symptoms related to hormonal hypersecretion, but there is little evidence to support a direct antitumor effect. The overall benefit of interferon-α (IFN-α), combination chemotherapy, radiotherapy, cryotherapy, and chemoembolization therapy has been questioned, given the resistance of these tumors to traditional treatment modalities and the associated toxicity of many of these treatments. Therefore, newer agents with novel mechanisms of action are desperately needed for the treatment of this disease. Some patients benefit from the use of IFN-α. Toxic effects associated with IFN-α treatment that frequently outweigh therapeutic gains may occur in some patients, but these effects are reversible once treatment has been discontinued and usually do not occur with smaller doses. Anecdotal reports of biologic activity indicate that some patients may respond to combined octreotide and IFN-α treatment. Patients with metastatic NET and symptoms related to excess hormonal secretion may be symptomatically helped by somatostatin analogs. Somatostatin is a 14-amino acid peptide that inhibits secretion of a broad range of hormones, including insulin, glucagon, and gastrin. Somatostatin analogs are effective in relieving the symptoms of hormonal hypersecretion Page 2 of 68

4 associated with pancreatic endocrine tumors. A long-acting depot form of octreotide, which can be administered on a monthly basis, is now commonly used to manage patients with symptoms of hormonal hypersecretion from carcinoid and pancreatic endocrine tumors. Unfortunately, octreotide appears to have a minimal antitumor effect, and objective radiographic tumor regression with octreotide is quite rare. Cytotoxic chemotherapy has only limited efficacy in the treatment of metastatic neuroendocrine tumors. Streptozocin (Zanosar ) is the only approved anticancer drug for the treatment of patients with pancreatic islet cell tumor. Antitumor efficacy and improved survival was reported for the combination of streptozocin and doxorubicin (compared to streptozocin plus fluorouracil) in a randomized study of 105 patients with advanced islet cell tumors. However, authors included hormonal response as well as radiographic response in their measure of response. A subsequent retrospective, single institution analysis of 16 patients with pancreatic endocrine tumors treated with the combination of streptozocin and doxorubicin showed that this combination was associated with a true radiological response rate of 6%. One small study of patients with pancreatic islet cell tumors found a 55% response rate and a median response duration of 15 months using doxorubicin, streptozocin and 5-fluorouracil. Neuroendocrine tumors are characterized by abundant vasculature. Pancreatic islet cell tumors are associated with high levels of plasma vascular endothelial growth factor (VEGF) and tumor angiogenesis. Inhibition of angiogenesis would therefore be expected to result in growth inhibition and regression of these tumors. Several novel angiogenesis inhibitors also appear to be active in neuroendocrine tumors. In one study performed in a mouse model, treatment with the angiogenesis inhibitors angiostatin and endostatin reduced the tumor burden of pancreatic islet cell tumors by 60%. Investigation of novel angiogenesis inhibitors such as sunitinib in patients with pancreatic islet cell tumors is therefore of great interest A number of tumors, including NET, aberrantly express both the vascular endothelial growth factor (VEGF) ligand and its Flk-1/KDR receptor (VEGFR), both of which play critical roles in tumor angiogenesis. The expression of VEGF upregulates intracellular anti-apoptotic proteins, facilitates tumor growth, and is associated with relatively short disease-free and overall survival. In addition to VEGFR, platelet-derived growth factor receptor (PDGFR) is also activated by phosphorylation in a number of tumor types and is also involved in tumor neoangiogenesis. Therefore, targeted inhibition of these receptors provides the opportunity for a novel therapeutic strategy for the treatment of patients with NET. The investigation of proliferation pathways involving tyrosine kinase receptors such as VEGF receptors, c-kit receptor, (KIT) and PDGF receptor, may allow identifying molecular targets for novel therapeutic approaches in patients with digestive endocrine tumors who failed primary locoregional treatment. Several publications in the literature show that VEGF and VEGF receptor expression play a role in neuroendocrine tumor progression. Microvessel density and tumor contrast enhancement on CT scan have been shown to be associated with survival in endocrine tumors further highlighting the importance of vascularization/angiogenesis in tumor control. Page 3 of 68

5 Objectives: Primary Objective: To compare the progression-free survival (PFS) in subjects with pancreatic islet cell tumors treated with sunitinib at a starting dose of 37.5 mg daily (continuous dosing) with those receiving placebo. Secondary Objectives: To compare overall survival (OS) between subjects receiving sunitinib and those receiving placebo To compare objective response (OR) rate between subjects receiving sunitinib and those receiving placebo To compare duration of response (DR) between subjects receiving sunitinib and those receiving placebo among those subjects achieving a response To assess time to tumor response (TTR) for subjects receiving sunitinib and those receiving placebo To assess safety and tolerability of sunitinib To assess patient reported outcomes (PROs) Trial Design: This is a multi-center double-blind randomized Phase III study of sunitinib (continuous daily dosing with a starting dose of 37.5 mg) versus placebo for subjects with progressive advanced/metastatic well-differentiated pancreatic islet cell tumors. The study is designed to investigate the effect of sunitinib compared to placebo on pancreatic islet cell tumors as well as investigating the safety and tolerability of sunitinib. This study will also investigate overall survival, objective response rate, duration of response and time to tumor response. This trial is designed to have an interim efficacy analysis using the Lan and DeMets spending function analog to the O Brien and Fleming boundaries to make sure the overall Type I error is maintained at 0.05 for two-sided tests. An adaptive design with the possibility of an increase in sample size based on the interim analysis is planned. Approximately 340 eligible subjects will be randomized in a 1:1 ratio to either sunitinib or placebo. Randomization will be balanced by country/region. The cutoff date for the primary analysis is when 260 events (progression of disease or death) have occurred. Page 4 of 68

6 Endpoints: Primary: Progression-Free-Survival (PFS): The primary endpoint is PFS, which is defined as the time from date of randomization to first progression of disease (PD) or death for any reason in the absence of documented PD. PFS data will be censored on the date of the last tumor assessment on study for subjects who do not have objective tumor progression and who do not die while on study. Subjects lacking an evaluation of tumor response after randomization will have their PFS time censored on the date of randomization with a duration of 1 day. Additionally, subjects who start a new anti-cancer therapy prior to documented PD will be censored at the date of the last tumor assessment prior to the start of the new therapy. Secondary: Survival time is defined as the time from date of randomization to date of death. In the absence of confirmation of death, survival time will be censored to last date the subject is known to be alive. The objective response (OR) is the overall objective response recorded from randomization until disease progression. A subject will be considered to have achieved an OR if the subject has a sustained complete response (CR) or partial response (PR) according to RECIST definitions for at least 4 weeks, confirmed by repeat tumor assessments. Otherwise, the subject will be considered as not meeting OR criteria. Additionally, subjects with inadequate data for tumor assessment (eg, no baseline assessment or no follow-up assessments) will be considered as not meeting OR criteria. Duration of response (DR) is defined as the time from the first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first. DR data will be censored on the date of the last tumor assessment on study for subjects who do not have objective tumor progression and who do not die due to any cause while on study. DR will only be calculated for the subgroup of subjects with an objective response. Time-to-tumor-response (TTR) is defined as the time from date of randomization to first documentation of objective tumor response that is subsequently confirmed. Patient reported outcomes (PROs), defined as health-related quality of life using the self administered European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire -C30 (EORTC QLQ-C30). Patients will complete the questionnaire at the clinic prior to administration of study medications or other clinical activities on Day 1 and every 4 weeks thereafter as well as at end of treatment/withdrawal. Page 5 of 68

7 Safety endpoints: Safety profile will be characterized by Treatment-Emergent Adverse Events (TEAE), which are defined as all AEs (serious and non-serious) reported from the first day of study treatment through 28 days post last dose of study treatment, vital signs and laboratory abnormalities. Assessment of adverse events will include type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 3.0, dated August 9, 2006), timing, seriousness, and relatedness; and laboratory abnormalities. Baseline tumor-related signs and symptoms will be recorded as adverse events during the trial if they worsen in severity or increase in frequency. Subject Selection: To be eligible for this trial subjects must have progressive advanced/metastatic well-differentiated pancreatic islet cell tumors with measurable disease according to RECIST. Trial Treatments: Subjects will be randomized to sunitinib, starting dose 37.5 mg once a day, (continuous regimen) or matching placebo. Subjects not experiencing a response according to RECIST and experiencing only Grade 1 non-hematological or Grade 2 hematological treatment-related adverse events during the first 8 weeks may dose-escalate to 50 mg daily (at any time after 8 weeks). Intra-patient dose reduction by 1 dose level (to 25 mg/day or 37.5 mg/day) may be required depending on the type and severity of toxicity encountered. If dose is reduced or increased, it will continue to be on a continuous daily dosing schedule. In this clinical trial, study medication refers to either sunitinib or placebo, where sunitinib refers to the investigational agent, SU L-malate salt. Sunitinib will be supplied in hard gelatin capsules containing 12.5 mg, 25 mg or 50 mg of SU Plastic bottles containing 30 of the 12.5-mg capsules, 30 of the 25 mg capsules or 30 of the 50 mg capsules will be sent to the clinic pharmacy by the Sponsor. Study medication must be stored at controlled room temperature (15-30C) and protected from light. Subjects will be treated until death, progression of disease and/or unacceptable toxicity occurs or until the primary analysis is performed (when 260 events (progression of disease or death) have occurred). Subjects randomized to placebo will be offered treatment with sunitinib in a separate open-label extension study, either after progression of disease and unblinding, or if they have remained on study and free of progression as of the time this study is closed (when the primary analysis is performed). Subjects remaining on study and benefiting from sunitinib treatment at the end of this study (when the primary analysis is performed) will also be offered the opportunity to enter an open-label extension study. Subjects on the sunitinib arm who experience progressive disease or unacceptable toxicity will be withdrawn from the study and will not be offered continuation of sunitinib treatment on an extension study. Page 6 of 68

8 While on study, subjects may be treated with somatostatin analogues for symptomatic control at the discretion of the investigator. This medication will not be provided, as it is not a study treatment, but will be recorded as a concomitant medication in the Case Report Form. Statistical Methods: This study is designed to demonstrate that sunitinib at a starting dose of 37.5 mg given as a continuous daily dose can significantly improve PFS compared with placebo in subjects with progressive advanced/metastatic well-differentiated pancreatic islet cell tumors. The justification for the sample size is based on the following assumptions for the primary analysis. Approximately 340 subjects will be enrolled to observe 260 events (PD/death) in order to achieve 90% power using a log-rank test (two-sided). The study duration will be approximately 44 weeks after the last subject is enrolled. The sample size is calculated on the basis of the following assumptions: Median PFS time for sunitinib-treated subjects is 33 weeks Median PFS time for placebo-treated subjects is 22 weeks Enrollment period is 26 weeks with an accrual rate of 13 subjects per week. 10% dropout on each treatment arm Type I error of the primary analysis will be maintained via pre-specified methods. The study population for all analyses will be defined as follows for each analysis: Intent-to-Treat Population This population will include all subjects who are randomized, with study drug assignment designated according to initial randomization, regardless of whether patients receive any study drug or receive a different drug from that to which they were randomized. This will be the primary population for evaluating all efficacy endpoints as well as patient characteristics. As-Treated Population The as-treated population consists of all subjects who received at least 1 capsule of study medication with treatment assignments designated according to actual study treatment received. This population will be the primary population for evaluating treatment administration/compliance and safety. Page 7 of 68

9 Schedule of Activities Protocol Activities and Forms to be Completed Screening (Day) 21 Days Prior to Dosing Month 1 (Week 1, Week 3) Day 1 [2] 1/+0 Treatment with sunitinib or placebo [1] Day 15 3/+3 Subsequent Months (Week 5, 9, 13, 17, etc.) Day 1 3/+3 Day 15 [3] 3/+3 Only if dose escalated End of Tx or Withdrawal [4] Post-Treatment 28 Days Post- Treatment [21] Informed Consent [5] X Medical/Oncology History and [6] X Demographics Baseline Signs and Symptoms X Physical Examination, ECOG PS, X {X} X X {X} Body Weight, Height, and Vital Signs [7] Urine Protein Dipstick [8] x X [8] Hematology, Blood Chemistry, X {X} X X {X} X {X} Thyroid Testing[ 9] Pregnancy Test [10] X 12-lead ECG [11] X X (week 5 ) X Ki-67 Assessment [16] MUGA or echocardiogram to assess LVEF [12] Study Randomization [13] (X) X X Study Treatment [14] X X Tumor Imaging [15] X X Every 8 weeks, after Week 9 X EORTC QLQ-C30 [17] X X X Adverse Events [18] X X X X X X X Study Drug Compliance [19] X X X Concomitant Medications and X X X X X X X Treatments [20] Post Study Survival Status [21] { } if applicable Survival Follow-Up X Page 8 of 68

10 Footnotes for Schedule of Activities 1. During Treatment: All assessments should be performed prior to dosing with sunitinib or placebo unless otherwise indicated. Acceptable time windows for performing each assessment are described in the column headings. The term month is taken to mean a 28-day period. 2. Month 1 Day 1: Hematology, blood chemistry, and physical examination not required if acceptable screening assessment is performed within 7 days prior to the start of treatment with sunitinib or placebo. 3. Day 15 Beyond Month 2: Dose may be escalated at any time following 8 weeks as discussed later in the protocol. If dose is escalated from 37.5 mg daily to 50 mg daily, clinic visit is required mid-month for 2 months. 4. End of Study Treatment/Withdrawal: Obtain these assessments if not completed during the previous two weeks on study (during the last 6 weeks on study for radiological tumor assessments). 5. Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 21-day screening period. 6. Medical/Oncology History and Demographics: To include information on prior treatment regimens, including dosing and duration of administration, plus description of best response observed and treatment failure. 7.Physical Examination: Examination of major body systems, height (at screening visit only), ECOG performance status, body weight, and vital signs (temperature, blood pressure, heart rate, respiratory rate). 8.Urinalysis: Dip stick analysis, protein at screening and week 5. For urine analysis in cases of 2+ protein a 24 hour urinalysis to confirm NCI CTCAE grade is required and dose interruption and modification rules as outlined in protocol by grade for non-hematologic toxicity should be applied. Repeat as clinically indicated. 9. Hematology, Blood Chemistry and thyroid function testing: See Appendix 1 of the protocol for required tests. Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) only required once at screening. Thyroid function testing consisting of TSH at screening, Subsequent thyroid tests only as clinically indicated. Recommended follow-up based on institutional standard-free T4, T3 Total, thyroglobulin may be considered. 10. Pregnancy test must be within 7 days of starting study treatment. 11. ECG: Three consecutive 12-lead ECGs approximately 2 minutes apart at screening and on Cycle 2 Day 1 to determine the mean QTc interval. If the mean QTc interval is prolonged (>500 msec), the ECGs should be overread by a cardiologist at the site for confirmation. Additional ECGs may be performed as clinically indicated to include 2 weeks following intrapatient sunitinib dose.additional ECGs may be performed as clinically indicated to include after a new steady state of sunitinib is reached (ie, 2 weeks) following: intrapatient sunitinib dose escalation for any reason; or QTc interval prolongation, significant electrolyte changes, vomiting, diarrhea, or addition of a potent CYP3A4 inhibitor after consultation with the sponsor s medical monitor The Fridericia formula is: QT F = QT/ RR 1/3 12. Subsequent post-screening evaluation of LVEF required only if subject exhibits clinical signs/symptoms of congestive heart failure. 13. Study Randomization: Subject number will be obtained from the sponsor. 14. Study Treatment: Treatment will start on Day 1 after completing all pre-dose assessments. Subjects will receive either sunitinib capsules at a starting dose of 37.5 mg or placebo according to randomization. The dose may be adjusted according to individual patient tolerance as in protocol. 15. Tumor Imaging: CT or MRI scans at screening to include chest, abdomen, pelvis and brain as well as a bone scan. Subsequent scans may include only areas of known or suspected tumors. Additional scans should be performed whenever disease progression is suspected (eg, symptomatic deterioration), to confirm a partial or complete response (at least 4 weeks after initial documentation of response), and at the time of withdrawal from the study (if >6 weeks since last assessment). Subsequent brain scans (after screening) should only be performed if symptoms suggest brain metastases, and bone scans (after screening) only need be performed if patient had bone metastases at screening or if subsequent bone metastases are suspected/documented. Tumor imaging to be done at Screening, Week 5, 9, and then every 8 weeks thereafter. 16. Ki-67 Assessment: Assessment based on previous tumor biopsy results or previous surgical resections to be provided. No new biopsy or surgery need be performed for this study. 17. EORTC QLQ-C30 Questionnaire: The questionnaire is to be self-administered by the patient in the clinic. The questionnaire should be completed before any interventions (eg, laboratory assessments or study drug administration) every month post baseline assessment. 18. Adverse Events: Subjects must be followed for adverse events from the first day of study treatment until at least 28 days after the last on-study treatment administration, or until all serious or study drug-related toxicities have resolved or are determined to be chronic or stable, whichever is later. Serious adverse events should be monitored and reported from the time that the subject provides informed consent as described in the protocol. For adverse events occurring near the end of this study in patients who are entering an extension study the adverse events will be followed as part of the extension study. 19. Study Drug Compliance: The study drug medication bottle(s) including any unused capsules will be returned to the clinic for drug accountability. 20. Concomitant Medications and Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment until 28 days after last treatment. Page 9 of 68

11 Footnotes for Schedule of Activities 21. Post-Study Survival Status: After discontinuation of study treatment, post-study survival status will be collected by telephone contact every 8 weeks until final Overall Survival update or 5 years after all subjects have been enrolled. For patients who enter an extension study follow-up for overall survival will be conducted as part of the extension study. 22. This visit is necessary only for those subjects not entering an extension study. For subjects entering an extension study, all follow-up will be performed as part of the extension study, according to the schedule in that protocol. Page 10 of 68

12 Table of Contents 1. INTRODUCTION Background Receptor Tyrosine Kinase Sunitinib Malate Molecular Formula and Chemical Name Clinical Studies Pharmacokinetics Scope of Clinical Program Rationale for Study OBJECTIVES Primary Objective Secondary Objectives TRIAL DESIGN SUBJECT SELECTION Inclusion Criteria Exclusion Criteria Randomization Criteria Life Style Guidelines TRIAL TREATMENTS Allocation to Treatment Breaking the Blind Drug Supplies Formulation and Packaging Preparation and Dispensing Administration Dose Modification Compliance Overdose Instructions Drug Storage and Drug Accountability Concomitant Medication(s) General Concomitant Medication and Herbal Supplements Considerations Drugs with Proarrhythmic Potential Inhibitors and Inducers of CYP3A Anticoagulants Approved or Experimental Therapy for Cancer Antiemetic and Antidiarrheal Therapy...31 Page 11 of 68

13 5.5.7 Hematopoietic Growth Factors Other Concomitant Medications Concomitant Radiotherapy or Surgery TRIAL PROCEDURES Screening Trial Period End of Study Treatment/Withdrawal Procedures Post-dosing Follow-up Subject Withdrawal ASSESSMENTS Efficacy Assessments Time-To-Event Endpoints Response Endpoints Patient Reported Outcomes EORTC QLQ-C Safety Assessments Adverse Events Laboratory Safety Assessments Other Safety Assessments ADVERSE EVENT REPORTING Adverse Events Reporting Period Definition of an Adverse Event Abnormal Test Findings Serious Adverse Events Hospitalization Severity Assessment Causality Assessment Exposure In Utero Withdrawal Due to Adverse Events (See also Subject Withdrawal, Section 6.5) Eliciting Adverse Event Information Reporting Requirements Serious Adverse Event Reporting Requirements Non-Serious Adverse Event Reporting Requirements DATA ANALYSIS/STATISTICAL METHODS Analysis Populations Efficacy Analysis Analysis of Primary Endpoint...50 Page 12 of 68

14 Analysis of Secondary Endpoints Analysis of Other Endpoints Patient Reported Outcomes (PROs): EORTC QLQ-C Subject Disposition Baseline Characteristics Treatment Administration Safety Analysis Analysis of Clinical Laboratory Data Concomitant Medications and Non-drug Treatments/Procedures ECOG Performance Status Lead ECG Interim Analysis Timing of the Interim Analysis Distribution of Results of Interim Analysis Endpoints Analyzed and Analyses to be Performed During the Interim Analysis Futility Analysis Sample Size Re-estimation Control of the Overall Type I Error Data Monitoring Committee QUALITY CONTROL AND QUALITY ASSURANCE DATA HANDLING AND RECORD KEEPING Case Report Forms/Electronic Data Record Record Retention ETHICS Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Ethical Conduct of the Trial Subject Information and Consent DEFINITION OF END OF TRIAL End of Trial in a Member State (If Applicable) End of Trial in all Participating Countries (If Applicable) SPONSOR DISCONTINUATION CRITERIA PUBLICATION OF TRIAL RESULTS REFERENCES...58 FIGURES Figure 1. Molecular Formula and Chemical Name...17 Page 13 of 68

15 APPENDICES Appendix 1. Required Laboratory Tests...61 Appendix 2. ECOG Performance Status...62 Appendix 3. RECIST Tumor Assessment Criteria...63 Appendix 4. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)...66 Appendix 5. EORTC QLQ-C30 Questionnaire...67 Page 14 of 68

16 1. INTRODUCTION Neuroendocrine tumors (NET), including pancreatic islet cell tumors, are rare malignancies with an incidence of less than 1 case per 100,000 per year in the US. Because of the indolent nature of this disease, the majority of patients are diagnosed with disseminated metastases. For patients with metastatic disease, the 5-year survival rate is very low, and cure is not possible. Pancreatic islet cell tumors arise from neuroendocrine cells. These tumors are typically composed of small cells containing regular, well-rounded nuclei with rare mitoses. Despite an often slow rate of tumor progression, patients with metastatic NET ultimately develop significant morbidity. Their indolent nature and resistance to traditional treatment modalities distinguishes neuroendocrine tumors from small-cell carcinoma, for example, a related malignancy that may also possess neuroendocrine features. Poorly-differentiated carcinoma pursues a far more aggressive clinical course, is often responsive to platinum-based chemotherapy regimens, and is characterized histologically by the presence of frequent mitoses and areas of necrosis. Because of the clinical and histological differences between poorly-differentiated carcinoma and more well-differentiated NET, patients with poorly-differentiated carcinoma will be excluded from this trial Background With the exception of surgery for localized disease, there is presently a lack of available therapies with proven survival benefit for NET. 1 Available treatment options for unresectable disease include the use of somatostatin analogs, which may relieve symptoms related to hormonal hypersecretion, but there is little evidence to support a direct antitumor effect. The palliative benefit of interferon-α (IFN-α), combination chemotherapy, radiotherapy, cryotherapy, and chemoembolization therapy has been questioned, given the resistance of these tumors to traditional treatment modalities and the associated toxicity of many of these treatments. Therefore, newer agents with novel mechanisms of action are desperately needed for the treatment of this disease. Some patients benefit from the use of IFN-α. 2 Toxic effects associated with interferon treatment that frequently outweigh therapeutic gains may occur in some patients, but these effects are reversible once treatment has been discontinued and usually do not occur with smaller doses. Anecdotal reports of biologic activity indicate that some patients may respond to combined octreotide and IFN-α treatment. 2 Patients with metastatic NET and symptoms related to excess hormonal secretion may be helped symptomatically by somatostatin analogs. Somatostatin is a 14-amino acid peptide that inhibits secretion of a broad range of hormones, including insulin, glucagon, and gastrin. Somatostatin analogs are effective in relieving the symptoms of hormonal hypersecretion associated with pancreatic endocrine tumors. 3 A long-acting depot form of octreotide, which can be administered on a monthly basis, is now commonly used to manage patients with symptoms of hormonal hypersecretion from carcinoid and pancreatic endocrine tumors. Page 15 of 68

17 Unfortunately, octreotide appears to have a minimal antitumor effect, and objective radiographic tumor regression with octreotide is quite rare. Cytotoxic chemotherapy has only limited efficacy in the treatment of metastatic neuroendocrine tumors. Streptozocin (Zanosar ) is the only approved anticancer drug for the treatment of patients with pancreatic islet cell tumor. Antitumor efficacy and improved survival was reported for the combination of streptozocin and doxorubicin (compared to streptozocin plus fluorouracil) in a randomized study of 105 patients with advanced islet cell tumors. 4 However, authors included hormonal response as well as radiographic response in their measure of response. A subsequent retrospective, single institution analysis of 16 patients with pancreatic endocrine tumors treated with the combination of streptozocin and doxorubicin showed that this combination was associated with a true radiological response rate of 6%. 5 One small study of patients with islet cell tumors found a 55% response rate and a median response duration of 15 months using doxorubicin, streptozocin and 5-fluorouracil. 6 Neuroendocrine tumors are characterized by abundant vasculature. Pancreatic islet cell tumors are associated with high levels of plasma vascular endothelial growth factor (VEGF) and tumor angiogenesis. 7 Inhibition of angiogenesis would therefore be expected to result in growth inhibition and regression of these tumors. Several novel angiogenesis inhibitors also appear to be active in neuroendocrine tumors. In one study performed in a mouse model, treatment with the angiogenesis inhibitors angiostatin and endostatin reduced the tumor burden of pancreatic islet cell tumors by 60%. 8 Investigation of novel angiogenesis inhibitors such as sunitinib in patients with pancreatic islet cell tumors is therefore of great interest A number of tumors, including NET, aberrantly express both the vascular endothelial growth factor (VEGF) ligand and its Flk-1/KDR receptor (VEGFR), both of which play critical roles in tumor angiogenesis. The expression of VEGF up regulates intracellular anti-apoptotic proteins, facilitates tumor growth, and is associated with relatively short disease-free and overall survival. In addition to VEGFR, platelet-derived growth factor receptor (PDGFR) is also activated by phosphorylation in a number of tumor types and is also involved in tumor neoangiogenesis. Therefore, targeted inhibition of these receptors provides the opportunity for a novel therapeutic strategy for the treatment of patients with NET. The investigation of proliferation pathways involving tyrosine kinase receptors such as VEGF receptors, c-kit receptor, (KIT) and PDGF receptor, may allow identifying molecular targets for novel therapeutic approaches in patients with digestive endocrine tumors who have failed primary loco-regional treatment. Several publications in the literature show that VEGF and VEGF receptor expression play a role in neuroendocrine tumor progression. 9,10,11 Microvessel density and tumor contrast enhancement on CT scan have been shown to be associated with survival in endocrine tumors, 12 further highlighting the importance of vascularization/angiogenesis in tumor control. Page 16 of 68

18 Receptor Tyrosine Kinase Receptor tyrosine kinases (RTKs) are transmembrane proteins containing extracellular ligand-binding domains and intracellular catalytic domains. RTKs are activated following binding of their cognate ligands and many of the processes involved in tumor growth, progression, and metastases are mediated by signaling molecules acting downstream from these proteins. 13,14 Several members of the split-kinase domain family of RTKs are implicated in deregulated/ autocrine proliferation and survival of solid and hematologic cancer cells. These include the platelet-derived growth factor receptors (PDGFR and); vascular endothelial growth factor receptors (VEGFR) Type 1 and 2 (FLT1 and FLK1/KDR); the stem cell factor (SCF) receptor, KIT; and the FLT3-ligand receptor. In addition, PDGFR and VEGFR are implicated in tumor-dependent angiogenesis. 15 Sunitinib malate is an orally administered small molecule that inhibits the tyrosine kinase enzymatic activities of the receptors for VEGF and PDGF, and also blocks signalling through the KIT, FLT3 and RET pathways. Therefore, sunitinib malate may provide an opportunity for a novel therapeutic strategy for the treatment of subjects with pancreatic islet cell tumors. For further details refer to the sunitinib malate Investigator Brochure (IB) Sunitinib Malate Molecular Formula and Chemical Name Sunitinib is a small molecule with the molecular formula C 22 H 27 FN 4 O 2. The free base has a molecular weight of and the L-malate salt, the form used in clinical trials (Figure 1), has a molecular weight of The chemical name of the L-malate salt is (Z)-N-[2-(Diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (S)-2-hydroxysuccinate. Figure 1. Molecular Formula and Chemical Name O N N H F N H O N H. HOOC OH H COOH Sunitinib malate SU drug substance has been identified by NMR spectroscopy as the (Z)-isomer. Page 17 of 68

19 Clinical Studies Pharmacokinetics Single- and multiple-dose clinical pharmacokinetic studies of sunitinib over a range of 25 to 100 mg daily have been performed. Regimens have included either a repeated 4-week cycle comprising daily treatment for 2 weeks followed by a 2-week rest period (2/2 regimen) or a repeated 6-week cycle comprising daily treatment for 4 weeks followed by a 2-week rest period (4/2 regimen). The Cmax and AUC of sunitinib increase in proportion to dose across the range of doses studied. No dose-dependent changes in Tmax or T1/2 have been observed. Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce the active N-desethyl metabolite, SU To date, no other major metabolite has been identified. The terminal elimination half-life of sunitinib and SU are approximately 40 hours and 80 hours, respectively. Trough plasma drug concentrations plateau during the first 2 weeks of dosing. Accumulation across multiple cycles of treatment has not been observed. Sunitinib may be administered without regard to meals Scope of Clinical Program To date, over 7000 patients with advanced malignancies have been treated with sunitinib. Multiple phase 1, 2 and 3 studies have been conducted or are underway. The majority of studies have administered sunitinib at the starting dose of 50 mg once per day for 4 weeks followed by a 2-week period off-drug, repeated at 6-week intervals (Schedule 4/2). Preclinical investigations have indicated that total drug (sunitinib parent drug + SU active metabolite) plasma concentrations of 50 ng/ml or greater are required in order to achieve inhibition of receptor phosphorylation. At the 50 mg daily dose, mean steady state plasma trough concentrations of 80 ng/ml of total drug are achieved; pharmacokinetic modeling of a once daily 37.5 mg dose indicates that the steady state trough concentrations of total drug will be in the region of 60 ng/ml. Several clinical studies investigating the safety and anti-tumor activity of sunitinib administered at a starting dose of 37.5 mg/day have been initiated. The protocols include the possibility of insertion of 1-week treatment breaks in the event of grade 3 toxicity, with dose reduction to 25 mg daily at the discretion of the investigator for a recurring Grade 3 toxicity or for grade 4 toxicity. Patients experiencing minimal toxicity during 8 weeks of treatment may dose escalate to 50 mg/day at any time after that. The safety profile for sunitinib administered in the continuous regimen appears to be comparable to that for the currently registered regimen of 50 mg/day administered on Schedule 4/2. The study having the longest continuous dose administration experience is a Phase II trial of single agent sunitinib in subjects having advanced, cytokine-refractory renal cell carcinoma (Study A ). A total of 107 subjects were enrolled and as of February 2007, have been on study for a median of 6.9 months (range ). Patients were randomized to a sunitinib dose of 37.5 mg once daily given in the AM (n=54) or PM (n=53). Based on tolerability, individual doses were subsequently titrated to 25 or 50 mg/d. RECIST-defined ORR was the primary endpoint. Secondary endpoints included PFS, adverse events (AEs) Page 18 of 68

20 and quality of life (QoL) measures. 70 patients have discontinued, 50 (47%) due to progression, 19 (18%) due to AEs, and 1 due to consent withdrawal. Continuous dosing at 37.5 mg/d has been maintained in 38 patients (36%). Dosing was reduced to 25 mg/d in 47 patients (44%). The most commonly reported ( 5 % of pts) grade 3/4 AEs were hypertension (10%), asthenia (9%), hand-foot-syndrome (9%), anorexia (8%), and diarrhea (5%). No differences were observed in AM vs. PM dosing. RECIST ORR was 20% by investigator assessment, with 43 pts (40%) achieving clinical benefit of 6mos stable disease. Median PFS is 8.3 months. A second Phase 2 study, Protocol A , is investigating the continuous dosing regimen of sunitinib in patients having GIST who are refractory to or intolerant of imatinib. Sixty-one patients were enrolled between September 2005 and May As of May 2007, results are available for 60 patients, median number of cycles (28 days) started were 11 (range 1-21) with 254 days as the median number of days drug was administered. There were 2 dose escalations to 50 mg/d with 1 reduction back to 37.5 mg/d and 14 dose reductions to 25 mg/d and 8 re-escalations to 37.5 mg/d. There are 8 pts (13%) ongoing, 16 pts (27%) completed and continued to a rollover study, 36 pts (60%) discontinued. Discontinuation was due to progression 23 (38%), death 7 (12%)- death due to disease progression 4 (7%),AEs 2 (3%) 1 (2%) unknown. Response measured by RECIST criteria was reported as 7 (12%) PR and 38 (63%) SD of which 25 (42%) was 24 weeks. Median PFS of 35.1 weeks and an OS not yet reached for 60 patients was the latest data reported at ECCO Safety As of September 2007, approximately 7000 patients with solid tumors have been treated with sunitinib in clinical trials. Overall, the most frequent adverse events associated with sunitinib treatment have been constitutional symptoms (fatigue/asthenia), gastrointestinal effects (nausea, diarrhea, stomatitis, dyspepsia), myelosuppression (eg, neutropenia, thrombocytopenia), and dermatologic effects (eg, dermatitis, skin discoloration, hair depigmentation). Clinically significant neutropenia has been observed in very few solid tumor patients and febrile neutropenia has rarely been observed in this patient population. The severity of adverse events has correlated with higher drug exposure and/or lower patient performance status for both patients treated with previous chemotherapy and chemotherapy-naïve patients. As of September 2007, treatment-emergent adverse events of note in these 7000 patients treated with sunitinib were: Hypertension was reported in 806 (18.7%) with 236 (5.5%) Grade 3 and 1 patient (0%) Grade 4. No risk factors have been identified. Presumably patients with uncontrolled hypertension may be at higher risk of developing severe hypertension. Page 19 of 68

21 Severe treatment-related hemorrhagic adverse events (including tumor, GI, lung, brain, urinary, gum, and liver hemorrhages) were reported in 74 (1.7%) Grade 3, 14 (0.3%) Grade 4, and 11 (0.26%) Grade 5 cases. Tissues with tumor involvement appear to be more likely to hemorrhage than uninvolved areas. Treatment of severe thrombocytopenia can be expected to help prevent hemorrhages; however, hemorrhages are not necessarily associated with thrombocytopenia. Cases of serious infection (with or without neutropenia), in some cases with fatal outcome, have also been reported. The incidence of Grade 3-4 QTc prolongation was rarely reported (0.1%). Safety data from Study A (thorough QT study) indicated that QT prolongation was an identified risk in subjects exposed to sunitinib. Torsade de pointes has been reported in one case (Study A ). Hypothyroidism has been reported in 190 (4.4%) of patients with severe treatment-related hypothyroidism reported in 0.2% of patients. Published literature involving 159 evaluable patients report the incidence of abnormal laboratory thyroid studies (TSH and T4) as high as 30-65% with up to one-third of these patients requiring supplemental synthetic thyroid therapy. Therefore, baseline laboratory measurement of thyroid function is recommended, and patients with hypothyroidism should be treated prior to the start of SUTENT treatment. Out of 1303 patients in whom creatine kinase measurements were reported, 22 (1.7%) patients reported Grade 3 results, and 3 (0.2%) patients reported Grade 4 results that were increased since baseline. Included in this cohort is one report of rhabdomyolysis or muscle necrosis, one report of myopathy, and 2 reports of myositis. Recent reports from the Health Canada Office of Clinical Trials have identified 8 cases of rhabdomyolysis, 3 with confirmed death, in association with Sutent during the period of September 2006 and June As of 03Sep2007 there were a total of 8221 cases in the sunitinib safety database and reports of rhabdomyolysis comprise <0.1% of these cases Rationale for Study Sunitinib is an orally administered small molecule that inhibits the tyrosine kinase enzymatic activities of the receptors for VEGF and PDGF, and also blocks signalling through the KIT, FLT3 and RET pathways. Therefore, sunitinib may provide an opportunity for a novel therapeutic strategy for the treatment of subjects with neuroendocrine tumors. Two patients with advanced unresectable carcinoid tumors were treated within the context of the Phase I program with sunitinib. Both patients achieved a sustained partial response, one of which was complicated by intestinal-bladder fistula and pelvic abscesses secondary to tumor necrosis, but without unacceptable toxicity in the other. 16 These responses, together with the acceptable safety profile of sunitinib at the recommended dose schedule of 50 mg daily 4 weeks on/2 weeks off, provided the clinical justification to further investigate the Phase II efficacy and safety of sunitinib in patients with NET at this dose level and administration schedule. Page 20 of 68

22 A subsequent Phase II study of sunitinib (4/2 schedule) enrolled 43 patients with unresectable carcinoid tumors and 66 patients with unresectable pancreatic islet cell tumors. 17 Nine percent of patients (2% of carcinoids and 13% of islet tumors) had a partial response (according to RECIST criteria). 82% had stable disease (93% of carcinoids, 75% of pancreatic islet cell tumors). The median time to tumor response was 16 weeks and the median duration of tumor response was not reached. Median time to tumor progression was 40 weeks (42 weeks carcinoid, 33 weeks pancreatic cell islet) and median survival was not reached. It was concluded that sunitinib has modest single agent activity in patients with advanced unresectable neuroendocrine tumors. The high incidence of stable disease in this study may be in part attributable to treatment effect, but must be interpreted with caution given the indolent natural history of this disease. In support of continuous dosing, pharmacokinetic modeling of a once daily continuous 37.5 mg dose indicates that the steady state trough concentrations of total drug will be in the region of 60 ng/ml, which is sufficient to expect a therapeutic effect (data on file). Modeling was based on preclinical investigations which indicated that total drug (sunitinib + SU012662) concentrations of 50 ng/ml or greater are required to achieve inhibition of receptor phosphorylation. By comparison, at the 50 mg daily dose, mean steady state plasma trough concentrations of 80 ng/ml of total drug are achieved. The estimate for 37.5 mg trough concentrations is also supported by preliminary data (not presented) from a Phase I study in which daily sunitinib doses of 37.5 mg were given. Thus, the preliminary safety and pharmacokinetic results of a continuous daily dosing regimen are encouraging and justify the use of the 37.5 mg daily for the proposed study. 2. OBJECTIVES 2.1. Primary Objective To compare the progression-free survival (PFS) in subjects with pancreatic islet cell tumors treated with sunitinib at a starting dose of 37.5 mg daily (continuous dosing) with those receiving placebo Secondary Objectives To compare overall survival (OS) between subjects receiving sunitinib and those receiving placebo To compare objective response (OR) rate between subjects receiving sunitinib and those receiving placebo To compare duration of response (DR) between subjects receiving sunitinib and those receiving placebo among those subjects achieving a response To assess time to tumor response (TTR) for subjects receiving sunitinib and those receiving placebo Page 21 of 68

23 To assess safety and tolerability of sunitinib Assess patient reported outcomes (PROs) 3. TRIAL DESIGN This is a multinational, multi center, randomized, double blind, Phase III clinical trial comparing the efficacy and safety of sunitinib versus placebo in subjects with progressive advanced/metastatic well-differentiated pancreatic islet cell tumors. Subjects must have experienced documented progression of disease within a year prior to the start of the study. Subjects will be randomized to sunitinib, starting dose 37.5 mg once a day, (continuous regimen) or matching placebo. Subjects not experiencing a response (CR or PR) according to RECIST and experiencing only grade 1 non-hematological or grade 2 hematological treatment-related adverse events during the first 8 weeks may dose-escalate to 50 mg daily at any time following 8 weeks. Approximately 340 eligible subjects will be randomized in a 1:1 ratio to either sunitinib or placebo. Randomization will be balanced by country/region. Subjects will be treated until death, progression of disease, unacceptable toxicity, or until the primary analysis for the study is performed - when approximately 260 events (progressive disease or death) have occurred. Subjects randomized to placebo will be offered treatment with sunitinib in a separate open-label extension study, either after progression of disease and unblinding, or if they have remained on this study and remained free of progression as of the time this study is closed (when the primary analysis is performed). Subjects receiving sunitinib who remain on this study until the study is closed (when the primary analysis is performed) and who have benefited from treatment will also be offered the opportunity to enter an open-label extension study. Subjects on the sunitinib arm who experience progressive disease or unacceptable toxicity will be withdrawn from the study and will not be offered continuation of sunitinib treatment on an extension study. If an investigator has evidence that the patient is deriving clinical benefit even in the face of objective progression of disease, this may be discussed with the sponsor on an individual case basis. This trial is designed to have an interim efficacy analysis using the Lan and DeMets spending function analog to the O Brien and Fleming boundaries 18 to make sure the overall type I error is maintained at 0.05 for two-sided tests. An adaptive design with the possibility of an increase in sample size based on the interim analysis is planned. The cut-off date for the primary analysis is when 260 events (progression of disease or death) have occurred. Subjects may be treated with somatostatin analogues for symptomatic control. This medication will not be provided as it is not a study treatment, but is a concomitant medication and will be recorded as such in the case report form. Page 22 of 68