| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PROGRESSIVE ADVANCED METASTATIC WELL DIFFERENTIATED UNRESECTABLE PANCREATIC NEUROENDOCRINE TUMORS |
|
| E.1.1.1 | Medical condition in easily understood language |
| progressive, advanced/metastatic well-differentiated, unresectable pancreatic neuroendocrine tumors |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068916 |
| E.1.2 | Term | Pancreatic neuroendocrine tumor metastatic |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To confirm sunitinib treatment effect on progression-free survival (PFS) per investigator assessment in subjects with advanced/metastatic, well differentiated, unresectable, pancreatic neuroendocrine tumors per Response Evaluation Criteria in Solid Tumors (RECIST). |
|
| E.2.2 | Secondary objectives of the trial |
• To assess PFS per independent radiological review;
• To assess time to tumor progression (TTP);
• To assess overall survival (OS);
• To assess objective response rate (ORR);
• To assess duration of response (DR);
• To assess time to tumor response (TTR);
• To evaluate the use of Choi criteria;
• To evaluate Chromogranin A response;
• To assess the safety and tolerability of sunitinib;
• To assess patient reported outcomes (PROs);
• To explore the potential relationship between plasma soluble KIT levels and measures of efficacy including PFS;
• To assess sunitinib and SU12662 (active metabolite of sunitinib) plasma trough concentrations (Ctrough) and to potentially explore the relationship between Ctrough and safety, biomarker, and efficacy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Histologically or cytologically proven diagnosis of well differentiated pancreatic neuroendocrine tumor (according to WHO 2000 classification) with available Ki-67 index.
4. Unresectable (as assessed by the investigator) or metastatic disease documented on a scan (CT, MRI, or Octreoscan) taken within 28 days of study enrollment. Disease progression (per RECIST 1.0) within 12 months prior to study enrollment.
5. Disease that is not amenable to surgery, radiation, or combined modality therapy with curative intent.
6. Presence of at least one measurable target lesion for further evaluation according to RECIST 1.0 (contrast enhancing lesion with the largest diameter ≥20 mm, based on conventional CT scan (or ≥10 mm with spiral CT scan) done within 3 weeks before the start of treatment).
7. Adequate organ function as defined by the following:
• Serum aspartate aminotransferase (AST; serum glutamate oxalate transferase [SGOT]) and serum alanine aminotransferase (ALT; serum glutamate pyruvate transferase [SGPT]) ≤2.5 x upper limit of normal (ULN). If liver function abnormalities are due to liver metastases, then AST and ALT may be ≤5 x ULN;
• Total serum bilirubin ≤1.5 x ULN;
• Absolute neutrophil count (ANC) ≥1500/μL;
• Platelets ≥100,000/μL;
• Hemoglobin ≥9.0 g/dL.
8. ECOG Performance status 0 or 1.
9. Life expectancy ≥3 months.
10. Age ≥18 years.
11. Able to swallow oral compound.
12. Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 3 months after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active. |
|
| E.4 | Principal exclusion criteria |
1. Subjects who are investigational site staff members or relatives of those site staff members or subjects who are Pfizer employees directly involved in the conduct of the trial.
2. Patients with poorly-differentiated pancreatic neuroendocrine tumors (according to WHO 2000 classification).
3. Prior treatment with any tyrosine kinase inhibitors, anti-VEGF angiogenesis inhibitors, non-VEGF-targeted angiogenesis inhibitors, or mTOR inhibitors.
4. Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri.
5. Treatment with strong CYP3A4 inhibitors and inducers within 7 and 12 days, respectively, prior to study drug administration.
6. Pre existing abnormality of thyroid function with TSH that cannot be maintained in the normal range with medication.
7. Concomitant treatment with therapeutic doses of anticoagulants. Low dose warfarin (Coumadin) up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed.
8. Unstable systemic diseases including uncontrolled hypertension (>150/100 mmHg despite optimal medical therapy) or active uncontrolled infections.
9. Participation in other studies within 4 weeks before baseline scans (ie, screening) before the current study begins and/or during study participation.
10. Any of the following within the 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism.
11. Abnormal cardiac function with abnormal 12 lead electrocardiogram. Ongoing cardiac dysrhythmias of NCI CTC grade ≥2, atrial fibrillation of any grade, or prolongation of the QTc interval to >450 msec for males or >470 msec for females.
12. Symptomatic brain metastases, spinal cord compression, or new evidence of brain or leptomeningeal disease.
13. Left ventricular ejection fraction (LVEF) ≤50% as measured by either multigated acquisition (MUGA) scan or echocardiogram (ECHO).
14. Pregnant females; breastfeeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 3 months after the last dose of the investigational product.
15. Positive test for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness (testing not required in the absence of clinical suspicion).
16. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigationl product administration, or may interfere with the interpretation of study results, and in the judgment of the investigator, would make the subject inappropriate for entry into this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival (PFS): The primary endpoint is investigator assessed PFS according to RECIST 1.0. PFS is defined as the time from date of enrollment 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 enrollment will have their PFS time censored on the date of enrollment with a duration of 1 day. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression-Free-Survival (PFS): at Cycle 2 Day 1, Cycle 3 Day 1 and then every 2 cycles thereafter, and at EOT visit. |
|
| E.5.2 | Secondary end point(s) |
• Progression free survival will also be assessed by independent radiological review per RECIST.
• To assess time-to-tumor-progression (TTP) is defined as the time from enrollment to first documentation of objective tumor progression.
• Survival time is defined as the time from date of enrollment 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 enrollment 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 1.0 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.
• Time to tumor response (TTR) is defined as the time from date of enrollment to first documentation of objective tumor response that is subsequently confirmed.
• ORR, DR, and TTR will also be assessed using Choi criteria for response.
• Chromogranin A response rate.
• 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) and EORTC QLQ-GI.NET21. Subjects 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, at end of treatment/withdrawal, as well as 28 days post treatment.
• Plasma samples for soluble KIT analysis will be collected before dosing at specified timepoints indicated in the Schedule of Activities.
• Observed and dose corrected trough concentrations, estimated pharmacokinetic parameters such as steady state area under the curve (AUC24) and oral clearance (CL/F) for sunitinib and its active metabolite SU012662, as well as pharmacokinetic-pharmacodynamic parameters such as sunitinib concentration at which 50% of the maximum sunitinib effect is observed (EC50) with respect to selected safety, biomarker, and efficacy endpoints.
• Type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 3.0), timing, seriousness, and relatedness of adverse events, laboratory abnormalities, physical examination findings, vital signs, weight and ECOG performance status. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• progression-free survival is assessed in Cycle 2 Day 1, Cycle 3 Day 1, then every 2 cycles and at EOT visit
• survival time: each Day 1 of each cycle, EOT, 28 days post treatment visit, at each phone contact during post-study survival follow-up
• The Objective Response (OR): at Cycle 2 Day 1, Cycle 3 Day 1, then every 2 cycles thereafter, at EOT visit
• DR: at Cycle 2 Day 1, Cycle 3 Day 1, then every 2 cycles, at EOT visit
• TTR: at Cycle 2 Day 1, Cycle 3 Day 1, then every 2 cycles, at EOT visit
• ORR, DR, and TTR also assessed at Cycle 2 Day 1, Cycle 3 Day 1, then every 2 cycles, at EOT visit
• Chromogranin A response rate: at Cycle 1 Day 1 and Day 15, Cycle 2 Day 1, Cycle 3 Day 1, then every 2 cycles, at EOT visit
for more details please refer to protocol section 7 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| historical comparator group |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| historical comparator group |
|
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Brazil |
| Czech Republic |
| Estonia |
| France |
| Hungary |
| India |
| Italy |
| Japan |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Romania |
| Slovakia |
| South Africa |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of Trial in all participating countries is defined as collection of the final data point in the study. Because this clinical trial includes a survival endpoint, the last point is anticipated to be the last survival follow up (ie, date of last known alive or of death) prior to the cut off date for database lock for the Supplemental Clinical Study Report for Overall Survival. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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