Public Disclosure Synopsis
Protocol A6181193 – 20150225 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Sutent® / Sunitinib Malate
PROTOCOL NO.: A6181193
PROTOCOL TITLE: A Phase II Study of Sunitinib in Patients with Progressive
Advanced/Metastatic Well-differentiated Pancreatic Neuroendocrine Tumors
Study Center(s): Four centers in Japan
Study Initiation Date and Primary Completion or Final Completion Dates:
28 July 2010 to 05 November 2013.
Phase of Development: Phase 2
Study Objective(s):Primary objective:
To assess the clinical benefit response (CBR) rate in subjects with unresectable progressive
advanced/metastatic well-differentiated pancreatic neuroendocrine tumors treated withsunitinib at a dose of 37.5 mg once daily in a continuous daily regimen.
Secondary objectives:•

To assess objective response rate (ORR)•

To assess tumor shrinkage in diameter•

To assess progression-free survival (PFS)•To assess overall survival (OS)•To assess safety and tolerability of sunitinib•

To assess pharmacokinetics (trough plasma concentrations) of sunitinib, SU012662(active metabolite) and total drug (sunitinib + SU012662)

Exploratory objective:•

To evaluate biochemical markers (hormone concentrations and a tumor marker,
chromogranin A)

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METHODS
Study Design: This was a multi-center, open-label, uncontrolled, phase II study of sunitinibin subjects with unresectable progressive advanced/metastatic well-differentiated pancreatic
neuroendocrine tumors. Sunitinib was orally given in a continuous daily dosing regimen at adose of 37.5 mg once daily in the morning (regardless of fasting or not) with each cycle
repeated every 4 weeks to evaluate the efficacy and safety. A dose increase to 50 mg/day
after Week 9 was permitted at the discretion of the investigator if there was no response in a
subject within the first 8 weeks of treatment based on the Response Evaluation Criteria in
Solid Tumors (RECIST) version 1.0, if the treatment-related non-hematological toxicity
remained ≤ grade 1, and if the treatment-related hematological toxicity remained ≤ grade 2.

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SCHEDULE OF ACTIVITIES
Screening
Study Procedures≤ 21
Days Prior
to DosingInformed Consent[5]Medical/Oncological History [6]Physical Examination [7]Hematology, Blood Chemistry [8]

X
X
X
X

Coagulation [9]X

Thyroid Function Test [10]Urinalysis [11]Pregnancy Test [12]HIV Test [13]

X
X
(X)
(X)

12-lead Electrocardiogram [14]X

MUGA or Echocardiogram for LVEF assessment

X

Ki-67 [15](X)

Chromogranin A, Pancreatic hormone [16]X

Brain CT or MRI scan, Bone scan [17](X)

Tumor Imaging [18]X

Registration [19]Symptom at baseline
Sunitinib [20]
Study Drug Compliance [21]Adverse Events [22]Concomitant Medications/Treatments [23]X

X
X

Blood sampling for Pharmacokinetics (trough level)[24]Cycle 1
Day 1 [2]Day 15
–1/+0
–3/+3

(X)
(X)

X

Page 3

X
X
X
Every other cycleon and after Cycle 3
X
X

X
X

(X)

(X)

->
X
X
X

X->
X
X
X
X
Up to Cycle 4

End ofTreatment/
Withdrawal [4]On and After
28 Days Posttreatment

X
X

(X)
(X)

X

(X)

X
X
(X)

(X)
(X)

X
X

X
Every other cycleon and after Cycle 3(X)
X
Every other cycleon and after Cycle 3

(X)

X
X->

Post- treatment

Cycle 2 and After
Day 1
Day 15 [3]
–3/+3
–3/+3

X
Every other cycleon and after Cycle 3
X
Every other cycleon and after Cycle 3

X

Post-Study Survival Status [25]
1 cycle = 28 days; (X) = if necessary.

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Treatment with sunitinib

(X)

X
(X)
X

->
X
X

X
X
X

X
X
X

Public Disclosure Synopsis
Protocol A6181193 – 20150225 – Final
Footnotes for Schedule of Assessments

1. During Treatment: All examination and assessments were performed prior to dosing with sunitinib unless otherwise indicated within an allowance in the scheduled visit. One cycle was 28
days. All examination and assessment were to be performed at the calendar days after the first dose of study drug, regardless of treatment delays.
2. Cycle 1 Day 1: Hematology, blood chemistry, and physical examination were not required if acceptable screening assessment had been performed within 7 days prior to the first dose of
the study drug. Subjects were fasted at least for 10 hours before scheduled visit.
3. Day 15 Beyond Cycle 2: On and after Week 9, subjects could have dose escalated from 37.5 mg to 50 mg daily if subjects did not show response at Week 8 after the study drug initiation
with non-hematologic toxicity ≤ grade 1 and hematologic toxicity ≤ grade 2. If dose was escalated to 50 mg daily, scheduled examination and assessment were performed at Day 15.
4. End of Study Treatment/Withdrawal: All procedures had to be performed within 4 weeks after the last dose if they had not been performed at the last dose. The radiological tumor
assessments (brain CT or MRI, bone scan, if necessary) were not required if they had been performed within 6 weeks prior to the last dose or the end of study.
5. Informed Consent: Had to be obtained prior to undergoing any study specific procedure.
6. Medical/Oncology History and Demographics: Included information on prior treatment regimens, dosing and duration of administration, and description of best response observed andtreatment failure.
7. Physical Examination: Physical examination, ECOG performance status, body weight, height (at screening visit only), and vital signs (temperature, blood pressure(seated), pulse). Bloodpressure was to be measured on the same arm at each examination.
8. Hematology, Blood Chemistry: Performed at screening, Cycle 1 Days 1 and 15, Days 1 and 15 (if required) of Cycle 2 and after. Subjects were fasted at least for 10 hours at thescheduled visit.
9. Coagulation test: Prothrombin Time (PT) or International Normalized Ratio (INR) were examined at screening, Cycle 2 Day 1, Cycle 3 Day 1 and every other cycle afterwards. Subjects
were fasted at least for 10 hours at the scheduled visit.
10. Thyroid function test including TSH were required at screening and every 4 weeks after. Subsequent thyroid function testing were performed if required.(recommended: freeT4, total T3
and thyroglobulin). Subjects were fasted at least for 10 hours at the scheduled visit.
11. Urinalysis (Dip stick): In cases of urine protein resulted ≥2+, urine protein/creatinine ratio was measured to assess NCI CTCAE grade and dose interruption or modification were madeaccording to the severity. Repeat as clinically indicated.
12. Pregnancy test was conducted within 7 days of starting study treatment and at the end of study treatment.
13. If patients had a negative HIV test within 6 months prior to the registration, the test did not have to be performed at screening.
14. ECG: Three consecutive 12-lead ECGs approximately 2 minutes apart to determine the mean QTc interval. If the mean QTc interval was prolonged (>500 msec), the ECGs had to be overread by a cardiologist at the site for confirmation. Additional ECGs were performed as clinically indicated and at 14 days (+/-7 days) after sunitinib dose escalation. The ECGs were to be
performed at the time matched (+/- 1 hour) to the screening examination.
15. Ki-67 Assessment: Assessed based on previous tumor biopsy results or previous surgical resections prior to the study participation. No new assessment performed for this study.
16. Chromogranin A, Pancreatic hormones were evaluated at screening, Cycle 2 Day 1, Cycle 3 Day 1, and every other cycle until 6 months had passed since the initiation of the study.
Chromogranin A was evaluated in all subjects and pancreatic hormones were evaluated in subjects with functional pNET. Subjects were fasted at least for 10 hours at the scheduled visit.
17. Brain CT or MRI, bone scans: Brain and/or bone scan was evaluated at screening if brain or bone metastasis were suspected. Subsequent brain or bone scan were performed if clinicalsign/symptoms of disease suggested brain or bone metastases or disease progression.
18. Tumor Imaging: Performed at screening, Cycle 2 Day 1, Cycle 3 Day 1, and every other cycle afterward. CT or MRI scan of chest, abdomen and pelvis in addition to any other applicablesites of disease were assessed. Additional scan were performed whenever disease progression was suspected (eg, symptomatic deterioration), to confirm a partial or complete response (atleast 4 weeks after initial documentation of response), followed by every other cycle assessment. Allowance of Cycle 7 Day 1 visit (Week 25) was +3 days. The assessment was performed
until median PFS or 2 years after the last subject start of the study treatment, whichever was longer
19. Registration: Subjects were registered at least 3 days prior to the planned dosing date
20. Study Treatment: Treatment started on Day 1 after completing all pre-dose assessments at a starting dose of 37.5 mg. The dose was adjusted according to individual patient tolerance.
21. Study Drug Compliance: The study drug medication bottle(s) including any unused capsules were returned to the site for drug accountability.
22. Adverse Events: Subjects were followed for adverse events from initiation of the 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 were determined to be “chronic” or “stable,” whichever was later. If a subject started other anti-cancer medication, non-serious adverse event
monitoring was completed at the point. Serious adverse events including deaths were monitored and reported from the time that the subject provided informed consent. Safety assessment
was continued until the median PFS or 2 years after the last subject study treatment initiation, whichever was longer.
23. Concomitant Medications and Treatments: Concomitant medications and treatments were recorded from 28 days prior to the start of study treatment until 28 days after last treatment.
24. Trough Drug Level Sampling: A blood sample taken at pre-dose on Cycle 1 Day 15 (+/- 1 day) and Day 1 of Cycles 2 to 4.
25. Post-Study Survival Status: After discontinuation of study treatment, post-study survival status was collected every 6 months. The assessment was continued until median OS or 3 years
after the last subject start the study treatment, whichever was shorter. If OS failed to achieve median value, final confirmation of survival status were provided at timing when 3 years had
passed since completion of subject registration. In addition, this was not required if confirmation of survival status had been provided within 2 months before timing when 3 years had
passed since completion of subject registration.

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Number of Subjects (Planned and Analyzed): Targeted number of subjects was 10. A
total of 12 subjects were enrolled and analyzed.
Diagnosis and Main Criteria for Inclusion: The study included Japanese patients 20 years
or older with a histologically or cytologically proven diagnosis of well-differentiatedpancreatic neuroendocrine tumor and with local, locally advanced or metastatic disease
documented as having shown progression on a scan (CT or MRI) taken within 12 months
prior to baseline compared to a previous scan (taken at any time in the past) in accordancewith RECIST. Eligible subjects also had to have at least one measurable target lesion forfurther evaluation in accordance with RECIST, disease that was not amenable to surgery,radiation, or combined modality therapy with curative intent, an Eastern Cooperative
Oncology Group Performance Status (ECOG PS) of 0 or 1, and a life expectancy of at least 3
months.
Study Treatment: Sunitinib capsule was orally administered from Day 1 in a continuous
daily dosing regimen at a dose of 37.5 mg once daily with each cycle repeated every 4 weeks.
The starting dose was 37.5 mg/day and sunitinib was administered once daily in the morning
regardless of fasting or not. Dose reductions were allowed depending on the individual
tolerability.
Efficacy Endpoints:
Tumor assessments were performed at baseline, on Day 1 of Cycle 2, on Day 1 of Cycle 3,
and then at 8-week intervals during the study. Additional assessments of disease were
performed when progression of disease was suspected.
Primary Endpoint:•

CBR rate defined as the percentage of subjects with a best overall response of confirmed
complete response (CR), confirmed partial response (PR), or stable disease (SD) ≥ 24
weeks in the analysis population.

Secondary Endpoints:
ORR defined as the percentage of subjects with a best overall response of confirmed CR
or confirmed PR in the analysis population.
• Tumor shrinkage defined as the percent change from baseline in the sum of the longest
diameter of target lesions in subjects calculated as:•

Tumor shrinkage (%) =(Sum of the diameter after treatment) - (Sum of the diameter at baseline)
× 100(Sum of the diameter at baseline)•

PFS defined as the time from registration to first documentation of progressive disease(PD) or to death due to any cause, whichever occurred first.

•

OS defined as the time from registration to documentation of death due to any cause.

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Pharmacokinetic Endpoints:
For pharmacokinetic analysis, trough plasma concentrations of sunitinib, its active metabolite,
SU012662, and total drug (sunitinib + SU012662) were assessed. Total drug concentrations
were calculated as the sum of sunitinib and SU012662 concentrations. Plasma samples werecollected before sunitinib dosing to determine trough concentrations on Day 15 of Cycle 1
and on day 1 of Cycles 2 to 4. Concentrations of sunitinib and its active metabolite,
SU012662 were assayed using a validated high performance liquid chromatography / tandem
mass spectrometry.
To evaluate biochemical markers in an exploratory manner in sunitinib-treated subjects,
blood hormone concentrations and tumor marker (chromogranin A) concentrations were
measured at screening, on Day 1 of Cycle 2, on Day 1 of Cycle 3, and then at 8-weekintervals until 6-month follow period for all subjects. Chromogranin A was measured in all
subjects. As for blood hormone, the produced hormones were measured only in subjects witha diagnosis of functional pancreatic neuroendocrine tumor.
Safety Evaluations:
Subjects were followed for adverse events from Day 1 of study treatment until the last visit
and for serious adverse events from the time of informed consent until 28 days after the last
on-study treatment. Laboratory tests, vital signs (temperature, blood pressure, pulse, bodyweight), 12-lead electrocardiogram (ECG), left ventricular ejection fraction (LVEF), physicalexamination, and ECOG PS were also used to evaluate subject safety.
Statistical Methods:
Full Analysis Set (FAS) was defined as the population of all enrolled subjects in whom welldifferentiated pancreatic neuroendocrine tumor had been diagnosed and who received at least
one dose of study medication. The FAS was used for efficacy analysis. For the analysis of
the primary endpoint, CBR rate and its exact 95% confidence interval (CI) were calculated.
For the analysis of the secondary endpoints, ORR and its exact 95% CI, and the percent
change from baseline in the sum of the longest diameter of target lesions were calculated.
PFS and OS were summarized by Kaplan-Meier methods.
Pharmacokinetic Analysis Set was defined as the population of subjects who received at least
one dose of study medication and in whom trough concentrations at steady state wereassessed. Trough plasma concentrations of sunitinib, SU012662, and total drug were listed,summarized with descriptive statistics, and plotted.
To evaluate biochemical markers, data of hormone concentrations and tumor marker(chromogranin A) concentrations were listed.
Safety Analysis Set was defined as all subjects enrolled in the study who received at least one
dose of study medication. Safety endpoints were summarized according to Pfizer data
standards (PDS) specifying the sponsor’s standards of reporting clinical study data. Safety
endpoints included adverse events, laboratory abnormalities, vital signs, 12-lead ECG,

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LVEF, physical examination, and ECOG PS. The severity of adverse events was gradedaccording to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
The primary analysis of this study was conducted after all the subjects enrolled in the study
discontinued treatment or completed the 6-month follow period
RESULTS
Subject Disposition and Demography:
Subject disposition was shown in Table 1.
Table 1.

Subject Disposition

Enrolled
Assigned to Treatment
Completed
Discontinued
Tumor progression or recurrence
Study discontinuation initiated by Sponsor
Consent withdrawal not due to adverse event
Others (interruption of study treatment exceeding 4 weeks was required)
Adverse event
Analyzed for Efficacy
Analyzed for Pharmacokinetics
Analyzed for Safety

Number of Subjects
12
12
0
12
8
1
1
1
1
12
11
12

Subjects assigned to treatment were 8 males and 4 females with the mean age of 54.1 years(range: 34 to 79 years).
Efficacy Results:
Primary endpoint
A summary of investigator-assessed CBR rate and ORR values was shown in Table 2.
Table 2.

Clinical Benefit Rate (CBR)

Number of Evaluable Subjects
Best overall responseCR
PR
SD ≥24 weeks (168 days)
The number of subjects with CBR (CBR rate)［95%CI］a)The number of subjects with objective response (ORR) ［95%CI］a)12
Number of subjects (%)
0
6 (50.0)
3 (25.0)9 (75.0) [42.8 to 94.5]
6 (50.0) [21.1 to 78.9]

CBR = Clinical benefit response, ORR = Objective response rate, CR = Complete response,
PR = Partial response, SD = Stable disease, CI = Confidence intervala) Two-sided 95% CIs were calculated using exact method based on binomial F-distribution.

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Secondary endpoints
Secondary endpoints are summarized in Table 3.
Of best overall response in accordance with RECIST, ORR defined as the percentage ofsubjects with a best overall response of confirmed complete response (CR) or confirmed PR
was 50.0% (95% CI: 21.1% to 78.9%).
During the study (including 28 days after the last on-study treatment), 8 of 12 subjects(66.7%) had progressive disease (PD). Of 4 subjects in whom event did not occur, 3 haddiscontinued study treatment prior to PD, and 1 had received other anti-cancer agent prior toPD, and thus, they were censored. No death occurred during the study.
The probability of progression-free survival (PFS) at 6-month, 12-month, and 24-month was
91.7%, 71.3%, and 35.6%, respectively; the median PFS was estimated to be 16.8 months(95% CI: 9.3 to 26.2 months).
In survival follow-up, 4 deaths (33.3%) due to progression of underlying disease, and 1 death(8.3%) due to other reason (multiple organ failure caused by infectious enteritis) werereported. Of 7 subjects whose investigation was censored at the end of the study, survival of
6 subjects were confirmed, but 1 was no longer being followed for survival. The probabilityof OS at 6-month, 12-month, 24-month, and 36-month was 90.9%, 90.9%, 81.8%, and54.5%, respectively; the median OS could not be estimated due to lack of sufficient numberof events.

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Table 3.

Secondary Endpoints

Number of Evaluable Subjects
Best Overall Response
CR
PR
SD
PD
The number of subjects with ORR ［95%CI］a)Percent changes from baseline to each assessment time pointin sum of the longest diameter of target lesions

12
Number of subjects (%)
0
6 (50.0)
5 (41.7)
1 ( 8.3)
6 (50.0) [21.1 to 78.9]
Mean ± SD

Cycle 1 (n=1)
Cycle 2 (n=11)
Cycle 3 (n=12)
Cycle 5 (n=9)
Cycle 7 (n=9)
Cycle 9 (n=9)
Cycle 11 (n=9)
Cycle 13 (n=9)
Cycle 14 (n=1)
Cycle 15 (n=7)
Cycle 16 (n=1)
Cycle 17 (n=5)
Cycle 18 (n=1)
Cycle 19 (n=4)
Cycle 21 (n=4)
Cycle 23 (n=4)
Cycle 25 (n=4)
Cycle 27 (n=3)
Cycle 28 (n=2)
Cycle 29 (n=1)
Maximum Reduction (n=12)
Progression-free Survival (PFS)(Months)
Overall Survival (OS)(Months)-20.0 ± NA
-14.4 ± 13.43-18.0 ± 17.70-26.0 ± 10.03-28.5 ± 11.86-31.8 ± 17.20-36.4 ± 30.11-28.8 ± 16.92
1.7 ± NA
-32.5 ± 17.29-34.7 ± NA
-38.7 ± 15.41-43.1 ± NA
-37.8 ± 19.21-35.8 ± 19.19-35.1 ± 22.82-32.6 ± 19.64-30.8 ± 26.68-40.4 ± 9.72
3.3 ± NA
-34.8 ± 28.76
Median ［95%CI］
16.8 ( 9.3 to 26.2 )Median ［95%CI］
NA ( 22.0 to NA )CI = Confidence interval, CR = Complete response, NA = not applicable, ORR = Objective response rate, PR = Partial
response, PD = Progressive Disease, SD = Stable diseasea) Two-sided 95% CIs were calculated using exact method based on binomial F-distribution.

Pharmacokinetic Endpoint
Dose-corrected Trough Plasma Concentrations of Sunitinib, SU012662 and Total Drug
(Sunitinib + SU012662) is summarized in Table 4.

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Table 4.

Dose-corrected Trough Plasma Concentrations of Sunitinib, SU012662 andTotal Drug (Sunitinib + SU012662)

Number of Participants Analyzed
Mean ± Standard Deviation (ng/mL)
Sunitinib (Cycle 1 Day 15, n=10)
Sunitinib (Cycle 2 Day 1, n=2)
Sunitinib (Cycle 3 Day 1, n=8)
Sunitinib (Cycle 4 Day 1, n=5)SU012662 (Cycle 1 Day 15, n=10)SU012662 (Cycle 2 Day 1, n=2)
SU012662 (Cycle 3 Day 1, n=8)SU012662 (Cycle 4 Day 1, n=5)
Total drug (Cycle 1 Day 15, n=10)
Total drug (Cycle 2 Day 1, n=2)
Total drug (Cycle 3 Day 1, n=8)
Total drug (Cycle 4 Day 1, n=5)11
53.9 ± 17.6
41.7 ± 21.9
49.9 ± 19.7
53.5 ± 24.6
23.7 ± 7.00
21.2 ± 6.36
25.7 ± 9.14
19.6 ± 7.44
77.5 ± 20.9
62.9 ± 28.3
75.5 ± 26.5
73.0 ± 28.8

Safety Results:
All 12 subjects (100%) had a total of 198 all-causality adverse events, and a total of 169
treatment-related adverse events. Summary of adverse events are presented in Table 5.
Table 5.

Summary of Adverse Events

Causality with study treatment
Number of Evaluable Subjects
Number of subjects with AE
Number of AEs
Number of subjects with SAE a)
Number of subjects with AE of Grade 3 or 4
Number of subjects with AE of Grade 5 a)
Number of subjects who discontinued study due to adverse event
Number of subjects with dose reduction due to AE b)
Number of subjects with dose interruption due to AE c)

All-causality1212 (100)198
3 (25.0)
12 (100)0
1 (8.3)1 (8.3)12 (100)

Treatment-related12
12 (100)169
2 (16.7)
11 (91.7)
0
1 (8.3)1 (8.3)11 (91.7)a) Number of subjects reported during the study (including 28 days after the last on-study treatment)(%)b) Subjects who needed only dose reduction but did not need treatment interruptionc) Subjects who needed treatment interruption only, and those who needed both treatment interruption and dose reduction

No deaths occurred during the study. Serious adverse events are summarized in Table 6.

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Table 6.

Serious Adverse Events

System Organ Class/Preferred Term
MedDRA (v14.0)
Total, serious adverse events
Gastrointestinal disorders
Enterocolitis
Hepatobiliary disorders
Cholangitis
Cholecystitis acute
Nervous system disorders
Convulsion
Loss of consciousness
MedDRA = ICH Medical Dictionary for Regulatory Activities

All-causality12
3 (25.0)

Treatment-related12
2 (16.7)

1 (8.3)1 (8.3)1 (8.3)1 (8.3)00

1 (8.3)1 (8.3)1 (8.3)1 (8.3)
Number of subjects (%)

All-causality and treatment related adverse events are summarized in Table 7. The mostcommon all-causality adverse events included diarrhea in 10 subjects (83.3%), palmarplantar erythrodysaesthesia syndrome, and hypertension in 8 subjects each (66.7%),
headache and fatigue in 7 subjects each (58.3%), nausea, vomiting, pyrexia, nasopharyngitis,and dysgeusia in 5 subjects each (41.7%).

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Table 7.

Adverse Eventsa

System Organ Class/Preferred Term
MedDRA (v14.0)
Number (%) of Subjects with adverse events
Blood and lymphatic system disorders
Anaemia
Disseminated intravascular coagulation
Neutropenia
Thrombocytopenia
Cardiac disorders
Left ventricular dysfunction
Endocrine disorders
Hypothyroidism
Eye disorders
Conjunctival haemorrhage
Diplopia
Eyelash discolouration
Ocular hyperaemia
Gastrointestinal disorders
Abdominal distension
Abdominal pain
Ascites
Constipation
Diarrhoea
Dyspepsia
Dysphagia
Gastritis
Gingivitis
Glossitis
Haemorrhoids
Hypoaesthesia oral
Loose tooth
NauseaOral dysaesthesia
Periodontitis
Reflux oesophagitis
Stomatitis
Toothache
Vomiting
General disorders and administration site
conditions
Face oedema
Fatigue
Malaise
Mucosal inflammation
OedemaOedema peripheral
Pyrexia
Hepatobiliary disorders
Cholangitis
Hepatic failure

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All-causality1212 (100)

Treatment Related12
12 (100)

2 (16.7)
1 (8.3)2 (16.7)
1 (8.3)2 (16.7)
02 (16.7)
1 (8.3)2 (16.7)

2 (16.7)

4 (33.3)

4 (33.3)

1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)0
1 (8.3)1 (8.3)1 (8.3)1 (8.3)2 (16.7)
1 (8.3)10 (83.3)
1 (8.3)1 (8.3)1 (8.3)2 (16.7)
1 (8.3)1 (8.3)1 (8.3)1 (8.3)5 (41.7)
2 (16.7)
1 (8.3)2 (16.7)
2 (16.7)
1 (8.3)5 (41.7)

1 (8.3)1 (8.3)2 (16.7)
10 (83.3)
1 (8.3)0
1 (8.3)2 (16.7)
1 (8.3)1 (8.3)1 (8.3)0
4 (33.3)
2 (16.7)
1 (8.3)2 (16.7)
2 (16.7)
1 (8.3)4 (33.3)

1 (8.3)7 (58.3)
2 (16.7)
3 (25.0)
4 (33.3)
2 (16.7)
5 (41.7)

1 (8.3)5 (41.7)
2 (16.7)
3 (25.0)
4 (33.3)
2 (16.7)
5 (41.7)

1 (8.3)1 (8.3)0
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Table 7.

Adverse Eventsa

System Organ Class/Preferred Term
MedDRA (v14.0)
Infections and infestations
Encephalitis herpes
Enteritis infectiousEnterocolitis infectious
Hordeolum
Infected epidermal cyst
Nasopharyngitis
Oral herpes
Pharyngitis
Pneumonia
Pyoderma
Skin candida
Trichophytosis
Injury, poisoning and procedural
complications
Contusion
Fall
Wound
Investigations
Blood alkaline phosphatase increased
Blood urine presentElectrocardiogram QT prolonged
Gamma-glutamyltransferase increased
Lipase increased
Lymphocyte count decreased
Neutrophil count decreased
Platelet count decreased
Protein urine present
Urine output decreased
White blood cell count decreased
Metabolism and nutrition disorders
Decreased appetite
Hyperamylasaemia
Hypercholesterolaemia
Hypoalbuminaemia
Musculoskeletal and connective tissue
disorders
Arthralgia
Back pain
Muscle spasms
Neoplasms benign, malignant and unspecified(incl cysts and polyps)
Skin papilloma
Nervous system disorders
Dysaesthesia
Dysgeusia
HeadacheHypoaesthesia

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All-causality
12

Treatment Related
12

1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)5 (41.7)
1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)2 (16.7)

1 (8.3)0
1 (8.3)1 (8.3)0
4 (33.3)
1 (8.3)1 (8.3)1 (8.3)0
1 (8.3)1 (8.3)2 (16.7)
1 (8.3)1 (8.3)000

1 (8.3)1 (8.3)3 (25.00)
1 (8.3)2 (16.7)
1 (8.3)4 (33.3)
2 (16.7)
2 (16.7)
1 (8.3)3 (25.00)

0
1 (8.3)3 (25.00)
0
2 (16.7)
1 (8.3)4 (33.3)
2 (16.7)
2 (16.7)
03 (25.00)

4 (33.3)
1 (8.3)1 (8.3)1 (8.3)4 (33.3)
1 (8.3)1 (8.3)1 (8.3)1 (8.3)2 (16.7)
3 (25.0)

1 (8.3)1 (8.3)3 (25.0)

1 (8.3)0

1 (8.3)5 (41.7)
7 (58.3)
1 (8.3)1 (8.3)5 (41.7)
6 (50.0)
1 (8.3)

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Protocol A6181193 – 20150225 – Final

Table 7.

Adverse Eventsa

System Organ Class/Preferred Term
MedDRA (v14.0)
Psychiatric disorders
Insomnia
Renal and urinary disorders
Haematuria
Nephrotic syndrome
Pollakiuria
Proteinuria
Reproductive system and breast disorders
Scrotal haematocoele
Respiratory, thoracic and mediastinal
disorders
Cough
Epistaxis
Pleural effusion
Pneumomediastinum
Skin and subcutaneous tissue disorders
Dermatitis acneiform
Dry skinEczemaHair colour changes
Nail disorder
Onychomadesis
Palmar-plantar erythrodysaesthesia
syndrome
Pruritus
Rash
Skin discolouration
Skin reaction
Vascular disorders
Hypertension

All-causality
12

Treatment Related
12

1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)2 (16.7)

1 (8.3)1 (8.3)1 (8.3)2 (16.7)

1 (8.3)0

1 (8.3)2 (16.7)
1 (8.3)1 (8.3)1 (8.3)2 (16.7)
1 (8.3)0

1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)8 (66.7)

8 (66.7)

2 (16.7)
2 (16.7)
1 (8.3)1 (8.3)2 (16.7)
2 (16.7)
1 (8.3)1 (8.3)8 (66.7)

8 (66.7)

MedDRA = ICH Medical Dictionary for Regulatory Activities

a. Not including serious adverse events

One subject discontinued the study due to an adverse event (Table 8).
Table 8.
Serialnumber1

Adverse Event Resulted in Discontinuation of the Study
Serious adverse event
MedDRA v14.0 Preferred Term
Enterocolitis

Causality
RelatedDay of onset/
Intervention to Outcome
Day of recovery a study treatment
403/426
Discontinued
Resolved

MedDRA = ICH Medical Dictionary for Regulatory Activities
a. Day relative to start of study treatment. First day of study treatment = day 1.

CONCLUSIONS:
Conclusions from the primary analysis are as follows.

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Protocol A6181193 – 20150225 – Final•

Sunitinib orally administered to Japanese patients with pancreatic neuroendocrine tumor
was effective in a continuous daily dosing regimen at a dose of 37.5 mg once daily witheach cycle repeated every 4 weeks. CBR rate was 75.0% (95% CI, 42.8% to 94.5%) andORR was 41.7% (95% CI, 15.2% to 72.3%).

•

Following a continuous daily dosing with sunitinib, the steady state sunitinib, SU012662
and total drug concentrations were reached by Day 15 of Cycle 1 without
disproportionate accumulation after that.

•

Adverse events reported in this study were manageable with dose interruption/reduction
or palliative care and were generally tolerable. Common adverse events were consistent
with the known safety profiles of sunitinib.

Conclusions from the final efficacy and safety analysis were mostly the same as that of the
primary analysis. The updated conclusions based on the final analysis are as follows.
•••

In Japanese patients with pancreatic neuroendocrine tumor orally given sunitinib in acontinuous daily dose regimen at a dose of 37.5 mg once daily with each cycle
repeated every 4 weeks, the CBR rate was the same as Primary Analysis, which was
75.0% (95% CI, 42.8% to 94.5%). Meanwhile ORR was 50.0% (95% CI, 21.1% to78.9%) since PR increased by 1 subject.
The probability of PFS at 12-month was 71.3%, and median PFS was estimated to be
16.8 months. The probability of OS at 12-month and 36-month was 90.9% and 54.5%,
respectively. The median OS could not be estimated due to lack of sufficient numberof events.
Enteritis was newly reported in 1 subject as a treatment-related serious adverse event.

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