Therapeutic Efficacy and Safety of Concurrent FOLFIRINOX Plus HIFU for Locally Advanced/Borderline Resectable Pancreatic Cancer: A Prospective Single-center, Single-arm, Investigator-initiated, Open-labeled, Exploratory Clinical Trial
Phase: NA
Conditions: Pancreatic Cancer Non-resectable, Chemotherapy Effect, Ultrasound Therapy
Sponsor: Seoul National University Hospital

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 1 / 65 
 
Evaluation of therapeutic efficacy and safety of concurrent 
FOLFIRINOX plus high intensity focused ultrasound (ALPIUS 900) 
for locally advanced/borderline resectable pancreatic cancer: A 
prospective single-center, single-arm, investigator-initiated, open-
labeled, exploratory clinical trial 
 
 
NCT number: Not available  
Date of document: Aug. 13, 2021 
 
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 2 / 65 
 
Summary of Clinical Trial Protocol 
Title 
Evaluation of therapeutic efficacy and safety of concurrent FOLFIRINOX 
plus high intensity focused ultrasound (ALPIUS 900) for locally 
advanced/borderline resectable pancreatic cancer: A prospective single-
center, single-arm, investigator-initiated, open-labeled, exploratory 
clinical trial 
Purpose  
Through a number of preclinical studies and our recent preliminary clinical 
study corresponding to phase 1 (Korean FDA approval number No. 584), we 
demonstrated that high-intensity focused ultrasound (HIFU) increases the 
effectiveness of chemotherapy, shows significantly longer survival periods, 
and has safety and potential effectiveness. This clinical study, which 
corresponds to phase 2, is a prospective, single-center, single-arm, 
investigator-initiated, open-label, exploratory clinical trial to be conducted 
to verify the therapeutic effect of high-intensity focused ultrasonography 
(HIFU) and anti-cancer drugs (FOLFIRINOX) in patients with locally advanced 
pancreatic cancer (LAPC)/ borderline resectable pancreatic cancer (BRPC). 
Institute  
Seoul National University Hospital/Prof. Jae Young Lee (Radiology) 
Medical 
Device 
Manager  
Seoul National University Hospital /technician Dong Hyuk Park (Radiology) 
Sponsor  
FUS foundation  
Monitor  
Synex Consulting Ltd. (CEO, Young Kim) 
10F Asia Tower, 430, Nonhyeon-ro, Gangnam-gu, Seoul 06223, Korea 
Monitor personnel : Hyun-Ji Kim, CRA 
Subject  
Patients diagnosed with locally advanced/borderline resectable pancreatic 
cancer through biopsy and CT/MRI imaging and planned to undergo anti-
cancer treatment using FOLFIRINOX 
Subject number 
30 + 30 subjects that can be assessed  
Clinical Trial Device 
'ALPIUS 900' (Subject 14-3227, Manufacturer: Alpine Medical System Co., Ltd.) 
U.S.-guided High Intensity Focused Ultrasound Unit  

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 3 / 65 
 
Trial Design  
In patients diagnosed with LAPC/BRPC and planned chemotherapy using 
FOLFIRINOX, HIFU/FOLFIRINOX combined treatment is performed on 
patients who agree to this study. The combined treatment group is treated 
in parallel with FOLFIRINOX and HIFU for the first four cycles and then CT 
is taken for reaction evaluation immediately, 2 months, and 4 months after 
the four cycle treatment. For the response assessment, the response rate 
using RECIST ver. 1.1 and operable rate are evaluated, and compared with 
the results of already established FOLFIRINOX single treatment in our 
institute. Time-to-progress and overall survival are calculated.  
Trial Method  
1. Patients diagnosed with pancreatic cancer through biopsy and diagnosed 
with LAPC/BRPC through computed tomography (CT) or magnetic resonance 
imaging (MRI) are referred to this clinical trial. When the referred patients are 
voluntarily signed a written consent form after hearing sufficient explanations 
related to this study, they will be registered for this clinical trial if all criteria 
for selection/exception are met. 
2. A management log will be prepared for all subjects who have signed a 
clinical trial agreement and are registered in the study. These management 
logs are used to assign sequential subject numbers to subjects registered in 
clinical trials, and subject numbers are assigned 'screening numbers' and 
'registration numbers'.  
3. The subjects will visit on the scheduled date to receive chemotherapy and 
HIFU combined therapy, and will be treated in accordance with the following 
treatment procedures and protocols.  
<Visit 1 to Visit 4: Combined Treatment, Cycle 1, Cycle 2, Cycle 3, Cycle 4 
± 14 Days> 
The subjects will receive combined treatments with anticancer drugs 
(FOLFIRINOX) and HIFU (ALPIUS 900) over four cycles over eight weeks. 
Afterwards, CT for reaction evaluation is taken immediately after 4 cycles (i.e., 
2 months after the onset of combined treatment). CT is taken at intervals of 
two months up to 6 months after the onset of combined treatment.  
 At the end of each combined treatment, the patient will be observed about 
adverse events including anticancer drug adverse events and skin change and 
can be back home or hospitalized for one to two days after collecting blood 
for blood tests according to doctor’s opinion.  
 
Schedule and procedures for combined treatment 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 4 / 65 
 
Perform a total of four treatments every two weeks for eight weeks. 
Combined treatment procedure 
① Subjects are hospitalized and given anti-cancer drugs for about 50 
hours in accordance with the standard protocol for anti-cancer 
treatment. 
☞ If the medication is canceled or postponed due to the condition of the 
subject, the HIFU procedure will be canceled or postponed.  
② After the start of chemotherapy, receive HIFU treatment within 48 
hours (30 minutes to 1 hour) and go up to the inpatient ward to 
monitor for 1 to 2 hours. 
☞ If adverse events caused by anticancer drugs have not been recovered 
within 24 hours of administration or adverse events have not been fully 
recovered from previous HIFU procedures, the HIFU procedure may be 
canceled or postponed under the judgment of the investigator.  
③ When combined treatment (anti-cancer drug administration) is 
completed, the subject shall be hospitalized for one to two days or 
return home depending on the physical condition of the subject. 
 
◼ 
Treatment protocol 
⚫ 
Anti-cancer drug administration (one time regimen) 
No. 
FOLFIRINOX regimen 
Daily 
administration 
dose (route) 
Administration schedule 
1 
Oxaliplatin 
 85 
mg/m2 
(Intravenous, IV) 
It is administered at the following 
schedule every two weeks. 
 
Day 
1 
: 
Oxaliplatin, 
Irinotecan, Leocovorin, 5-FU 
(IV-push), 5-FU (IV infusion) 
 
Day 2-3 : 5-FU (IV infusion) 
 
2 
Irinotecan 
 180 mg/m2 
(Intravenous, IV) 
3 
Leucovorin(Folic acid) 
400 mg/m2 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 5 / 65 
 
The administration of anticancer drugs (FOLFIRINOX therapy) is applied 
equally to each treatment group and according to the institution's standard 
procedure.. 
<Table 1> Dose and schedule of FOLFIRINOX therapy 
* The FOLFIRINOX dose and administration cycle (interval) can be adjusted 
by the researcher's judgment depending on the condition and progress of 
the subject. 
e.g. 20% reduction by drug, Oxaliplatin 85mg/m2 -> 60mg/m2, Irinotecan 
180mg/m2->150mg/m2->120mg/m2 
 
* Anti-cancer drugs used in clinical trials are licensed medicines and are used 
within the scope of permission. 
 
⚫ 
HIFU treatment (one-time treatment) 
The HIFU procedure is in accordance with the HIFU parameter (Table 2), and 
the details of the pre-procedure, procedure, and post-procedure care of the 
subjects are in accordance with the manufacturer's ALPIUS 900 User Manual 
(see Supplemental material). 
<Table 2> HIFU parameter 
Acoustic Intensity 
Duty cycle 
Exposure time 
PRF 
2.0 kW/cm2 
1% 
3 sec/point 
10 Hz 
 
4. Immediately, 2 months, and 4 months after completion of the 4th cycle 
combined treatment, the subjects visit the hospital to conduct the efficacy 
(Intravenous, IV) 
4 
5-FU 
 400 mg/m2 
(IV push) 
5 
5-FU 
2400 mg/m2 
(Intravenous, IV) 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 6 / 65 
 
and safety assessment. The DLT or ADE assessment will be evaluated on 
each planned visit.  
5. Treatment after the end of combined treatment of HIFU/Anticancer drug 
Subsequent treatment of patients who have completed HIFU/anti-cancer 
combined treatment in the first 4 cycles is determined and performed 
according to findings of CT performed after 4 cycles of combined treatment, 
overall physical condition of patients, and standard care guidelines. The 
implementation of surgery, continuation of FOLFIRINOX chemotherapy, 
conversion to other anticancer drugs, and further radiation therapy can be 
considered as possible treatments. This assessment is conducted after 8 and 
12 cycles of treatment if the treatment continues for FOLFIRINOX 
chemotherapy, and further treatment policies are determined in accordance 
with the standard care guidelines. If surgery is performed after 8 or 12 cycles, 
additional cancer or radiotherapy may be performed after surgery according 
to surgery and pathological findings, and it is required to be determined in 
accordance with the standard care guidelines.  
Clinical trial period  24 months from the date of approval of clinical planning by the FDA 
Inclusion Criteria 
All of the following selection criteria must be met before they can be 
registered for this clinical trial. 
1. Adults over 19–85  
2. Persons with a Karnofsky Performance Scale (KPS) of 70 percent or more; 
3. A person diagnosed as a tubular adenocarcinoma through biopsy.  
4. A person diagnosed with LAPC/BRPC by computed tomography (CT) or 
magnetic resonance imaging (MRI) 
 5. A person willing to voluntarily agree to a clinical trial and comply with the 
test plan 
Exclusion Criteria 
The following exclusion criteria may not be registered in clinical trials. 
1. The presence of a cystic lesion within pancreatic cancer to be treated with 
HIFU or at the pancreas adjacent to the pancreatic cancer.  
2. The presence of a wide range of scar or surgical clips observed in the 
passage through the ultrasonic beam.  
3. In case proper ultrasound images for HIFU procedures are not shown 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 7 / 65 
 
4. A person who cannot lie down in a comfortable position.  
5. A person who has difficulty communicating 
6. A person who has experience in toxic or hypersensitive reactions to 
FOLFIRINOX anticancer drugs. 
7. A person pregnant or breastfeeding 
8. Pancreatic cancer patients who have previously been anti-cancer treatment 
9. If severe side effects such as aortic rupture, duodenum perforation, 
gastrointestinal damage or intestinal necrosis are expected due to HIFU 
procedures.  
10. Other cases where participation in this clinical trial is judged inappropriate 
by the investigator (specific reasons should be recorded in the case report 
form) 
Efficacy Validation 
Variables 
⚫ 
Tumor response on CT taken 2 months, 4 months and 6 months 
after the start of combined treatment  
⚫ 
Percentage of subjects who were subject to surgical resection 4 
months and 6 months after the start of combined treatment  
⚫ 
Time-to-Progression 
⚫ 
Survival time 
Safety 
Validation 
Variables 
All adverse events that occurred to the subject during the clinical trial period 
Methods 
and 
criteria for efficacy 
assessment 
The tumor response and the percentage of subjects that were subject to 
surgical resection are the primary efficacy variable and the rest are the 
secondary efficacy variables.  
1. Tumor response on CT taken 2 months, 4 months and 6 months after the 
start of combined treatment  
Based on the findings of CT taken at screening and 2 months, 4 months, or 
6 months after the start of combined treatment, the tumor response is 
assessed as the complete response (CR), partial response (PR), stable disease 
(SD), or progressive disease (PD) according to Response Evaluation Criteria In 
Solid Tumors(RECIST, Ver. 1.1) below  

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 8 / 65 
 
Table> Solid tumor response indicators by Response Evaluation Criteria In 
Solid Tumors (RECIST, Ver. 1.1)  
  
구분 
내용 
CR 
Complete 
Response 
In case all lesions and pathological lymph nodes are 
completely lost  
PR  
Partial 
Response 
The sum of the lesion diameters is reduced by more 
than 30% from the pre-treatment (Baseline) 
SD  
Stable 
Disease 
PR or PD is not applicable either 
PD 
Progressive 
Disease 
If the sum of the lesion diameters measured during 
the clinical trial is increased by more than 20% from 
the sum of the lesion diameters at the time of the 
smallest and the difference in values is at least 5 mm 
or a new lesion is observed. 
Reference) Watanabe H, Okada M, Kaji Y, Satouchi M, Sato Y, Yamabe Y, Onaya 
H, Endo M, Sone M, Arai Y.New response evaluation criteria in solid tumours-
revised RECIST guideline (version 1.1) Gan To Kagaku Ryoho. 2009 Dec; 
36(13):2495-501. 
2. Percentage of subjects who were subject to surgical resection 4 
months or 6 months after the start of combined treatment 
When surgery is determined according to AJCC (American Joint Committee 
on Cancer, 8 edition) guidelines based on computed tomography (CT) images 
taken 4 months or 6 months after the start of the combined treatment, the 
percentage of subjects who were able to be operated on compared to the 
total number of registered subjects is calculated. 
3. Time-to-Progression  
The time taken from the date of diagnosis of pancreatic cancer or from the 
start date of combined treatment of pancreatic cancer until the date of first 
documented progression, assessed up to 24 months. Judging by RECIST ver. 
1.1 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 9 / 65 
 
4. Survival time 
The time taken from the date of diagnosis of pancreatic cancer or the start 
date of combined treatment of pancreatic cancer until the date of death from 
any cause, assessed up to 24 months. 
Methods 
and 
criteria for safety 
assessment 
The safety assessment is observed for all adverse events that occurred from 
the time of the start of the first cycle of chemotherapy and HIFU combined 
treatment to the end of the clinical trial as follows: 
All undesirable medical findings that are newly observed during clinical trial 
are classified as an adverse event. Side effects predicted according to the 
definitions and criteria described in the section "14. Evaluation Criteria, 
Evaluation Methods, and Reporting Methods for Safety including Side Effects" 
are also classified as adverse events. The degree of adverse events caused by 
medical devices is graded according to the NCI-CTCAE (Version 4.03) criteria, 
and the use of terms in medical coding is based on MedDRA's "Preferred 
Term" and "System organ class". However, in case of an adverse events that 
do not have any applicable items, write 'Other' of the appropriate 'Categories' 
and record the details and select the appropriate grade from grade 1-5 (see 
14.3.1 Severity Degree Assessment Section). 
Observation item  
<Schedule for Clinical Trial> 
anticipated adverse 
events 
◼ 
Expected adverse events due to HIFU treatment 
1. Skin burns, bleeding, or infections in the treatment area; 
2. Subcutaneous fat sclerosis  
3. Abdominal pain 
4. Pancreatitis 
5. Tumor hemorrhage 
6. Peritonitis  
7. Jaundice 
8. Vascular injury (aortic rupture) 
9. Pancreatoduodenal injury and perforation. 
10. Gastric injury and perforation 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 10 / 65 
 
11. Bowel necrosis 
◼ 
Expected adverse events due to anticancer drugs 
1. Thrombocytopenia 
2. Neutropenia 
3. leukopenia 
4. Anemia 
5. Lymphopenia 
6. Febrile neutropenia 
7. Hair loss 
8. Peripheral sensory neuropathy 
9. Lacking appetite 
10. Rash 
11. Nausea  
12. Dullness 
13. Fatigue 
14. Diarrhea 
15. Alanine aminotransferase (ALT) increase 
16. Hyponatremia  
 
 
 
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 11 / 65 
 
Clinical Trial Progress Schedule 
Screening 
Period of combined treatment and follow-up observation 
Visits  
V1  
(Cycle1**) 
V2 
(Cycle2) 
V3 
(Cycle3) 
V4 
(Cycle4) 
V5 
 V6 
V7 
Days elapsed 
≤ -4W 
Day1 
Day15 
Day29 
Day43 
After four-
cycle 
treatment 
(Month 2) 
Two 
months 
after four-
cycle 
treatment 
(Month 4) 
Four 
months 
after four-
cycle 
treatment 
(Month 6) 
Visit window 
 
-* 
± 14 days ± 14 days ± 14 days ± 14 days ±28 days ±28 days 
Observation Form 
Visiting 
hospitaliza
tion 
hospitaliza
tion 
hospitaliza
tion 
hospitaliza
tion 
outpatient/
hospitaliza
tion 
outpatient
/hospitaliz
ation 
outpatient
/hospitaliz
ation 
Consent 
acquisition 
√ 
 
 
 
 
 
 
 
Inclusion/Exclusio
n Criteria 
√ 
 
 
 
 
 
 
 
Demographic 
Survey1) 
√ 
 
 
 
 
 
 
 
Pregnancy Test2) 
√ 
 
 
 
 
 
 
 
Vital Signs3) 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Physical 
Examination4) 
√ 
 
 
 
 
 
 
 
Medical History5) 
√ 
 
 
 
 
 
 
 
Ultrasound6) 
√ 
 
 
 
 
 
 
 
KPS evaluation7) 
√ 
 
 
 
 
√ 
 
 
CT Imaging8) 
√ 
 
 
 
 
√† 
√† 
√† 
Blood Test9) 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 12 / 65 
 
CA-19-910) 
√ 
 
 
 
 
√ 
√ 
√ 
NRS Pain 
Assessment(11) 
√ 
 
 
 
 
√ 
√ 
√ 
Survival rate12) 
 
 
 
 
 
√ 
√ 
√ 
Co
mbi
ned 
trea
tme
nt 
Anticancer 
drug 
medication13) 
 
√ 
√ 
√ 
√ 
 
 
 
 
HIFU 
treatment14) 
 
√ 
√ 
√ 
√ 
 
 
 
Adverse 
events/Serious 
adverse event15) 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Concurrent 
medication and 
treatment16) 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Immune analysis 
 
√ 
√ 
√ 
 
√ 
 
 
 
* Based on the first date of chemotherapy 
** Cycle: Anti-cancer drug administration interval according to FOLFIRINOX standard treatment 
protocol, FOLFIRINOX is administered every two weeks, so it becomes a cycle of two weeks. 
The first anti-cancer drug administration cycle will be one cycle and the next two weeks later. 
Visit 5: Visit for CT scanning and other examinations immediately after completion of 4 cycles 
of cancer. 
Visit 6: Visit for CT scanning and other examinations 2 months after Visit 5. Subject's visit is 
terminated with Visit 5 if surgery is performed based on the findings of CT performed on Visit 
5. 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 13 / 65 
 
Visit 7: Visit for CT scanning and other examinations 4 months after Visit 5. Subject's visit is 
terminated with Visit 6 if surgery is performed based on the findings of CT performed on Visit 
6. 
† CT scan: CT for response assessment is usually performed during an outpatient visit before 
the next chemotherapy treatment, but if he/she is a local resident or there are any special 
circumstances, CT is performed during hospitalization for the next chemotherapy treatment. 
 
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 14 / 65 
 
< Terminology > 
① 
ADE: Adverse Device Effect 
② 
AE: Adverse Event 
③ 
CRC: Clinical Research Coordinator 
④ 
DVT: Deep Vein Thrombosis 
⑤ 
FAS: Full Analysis Set 
⑥ 
HIFU: High Intensity Focused Ultrasound 
⑦ 
IRB: Institutional Review Board 
⑧ 
KGCP: Korea Good Clinical Practice 
⑨ 
MRgHIFU: Magnetic Resonance Imaging-Guided High Intensity Focused Ultrasound  
⑩ 
MRI: Magnetic Resonance Imaging 
⑪ 
PP: Per-Protocol 
⑫ 
SAE: Serious Adverse Event 
⑬ 
SSS: Symptom Severity Score 
⑭ 
USgHIFU: Ultrasound-Guided High Intensity Focused Ultrasound 
⑮ 
VAS: Visual Analogue Scale 
 
 
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 15 / 65 
 
< Table of Contents > 
Summary of clinical trial protocol ………………………………………………………………..………..……………………………2 
Clinical trial progress schedule………………………………………………………………………….……………………………….11 
Terminology ……………………………………………………………………………………………………………………………………….14 
1. Title of clinical trial ...……………………………………………………………………………………………………….……………..19 
2. Name and location of the institution conducting clinical trial…...………….....……………….…………………19 
3. Name and title of principal investigator, sub-investigator, and co-investigator….……………..…….…19 
4. Name and title of clinical trial medical device manager.……………………………………………….………..……20 
5. Name and title of clinical trial monitor…………………….. …..……………………………………………………………..20 
6. Goal and background of clinical trials ………………………………………………………………………….………………20 
6.1 Goal…………………………………………………………………………………………………………………………..........…………20 
6.2 Background…..………………………………………………………………………………………………………………...…………20 
7. Overview of clinical trial medical device ………………………………………………………………...…………………….25 
7.1 Name of medical device, item classification, and prior permission ………………….…………..……….25 
7.2 Composition …………………………………………….……………………………………………………………….………………25 
7.3 Specification …….………….……………………………………………………………………………..…………………………….26 
7.4 How to use  …….………….……………………………………………………………………….…………………….…………….28 
7.5 Technical Features and Performance …….……………………..……………………..………………….……………….29 
  7.6 Purpose of Use …….……………………………………………………..………………………..………………………………….30 
7.7 Target diseases and indications ………………………………..………………………..…………………..……………….30 
8. Inclusion criteria, exclusion criteria, and target population number and its reasoning.....……….….30 
8.1 Inclusion and exclusion criteria…..……………………………..………………………..…………………..………….…….30 
 8.1.1 Inclusion criteria….…….…………………………………………..………………………..…………………..………….…….30 
 8.1.2 Exclusion criteria….………………………………………………………………………………………………………….…….31 
8.2 Estimation of target population number and its reasoning …………………………………………………..32 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 16 / 65 
 
9. Clinical trial period …..………….…………………………………………………………………………………………………….…..32 
10. Clinical trial method .……………………………………………………………………………………………………………………32 
10.1. Research design ….…………………………………………………………………………………………………………………32 
10.2 Clinical trial procedure ……...……………………………………………………………………….…………………………..32 
10.2.1 Subject numbering ……….……………..…………………………..………………………………….….….……………32 
10.2.2 Screening…………………………….……..….……….…………………………………………….…………………………..33 
10.2.3 Visit 1~ Visit 4…………………………………….…….………………………………..………….…………….…………..34 
10.2.4 Visit 5~ Visit 7……………………..…….…………….………………..………………..…………………….………….…..37 
10.3 Prohibition and Permission in Concomitant medication or therapy..…………………….………….….38 
10.4 Therapy after ending combined HIFU/chemotherapy treatment ….……………………………………..39 
11. Observation items, clinical examination items, and observational inspection methods ……….….39 
12. Expected adverse events ………………………………………….……….….……………………………………………….…….44 
12.1 Expected adverse events by HIFU …………….……………………………………………………………………….….44 
12.2 Expected adverse events by anticancer drugs …..….……………………………………………..…………….…45 
13. Clinical trial suspension and termination criteria …………………………………………………………………….…45 
13.1. Suspension criteria….…………………………………………………………………………………………………………….45 
13.2 Termination criteria ……………………………………………………………………………………………….………….….46 
13.3 Suspension process ………………………………………………………………………………….…….…………..….…….46 
13.4 Termination process….…………………………………………………………………………………………………………..46 
14. Efficacy and Safety: evaluation criteria, evaluation methods and reporting methods…………..…. 47 
   14.1 Efficacy evaluation..…………………………………………………………………………...………………………….…..…. 47 
14.1.1 Efficacy variables ………………………………………………………………………………………………….……….….47 
14.1.2 Evaluation criteria and methods………………………………………………………………………………………47 
14.2 Safety evaluation……………………………………………………………………………….……………………………………49 
14.2.1 Safety variables…………………………………………………………………………………….…………….…………….49 
14.2.2 Evaluation criteria and methods ..…………………………………………………….……………………………..49 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 17 / 65 
 
14.3. Data collection and statistical analysis…………….……………………………………………….……………………49 
14.3.1 Definition of analysis group ....…………………………………………………………………….………….……….49 
14.3.2 Statistical analysis methods…..…………………………………………..……………………………….…...………..50 
15. Evaluation criteria, methods and reporting of adverse events………………………………..…….……………52 
15.1. Definition of adverse events……………………………………………………………………………………….………..52 
15.2. Serious adverse events/adverse device effect: definition…..……………………………………….………52 
15.3. Evaluation of adverse events………………………………………………………………………………………………..52 
15.3.1. Severity evaluation..………………………………………………………………………………………………………….52 
15.3.2. Evaluation of causal relationships with medical device ………...………………………………………53 
15.3.3 Evaluation criteria……………………………………………………………………………………………………………..54 
15.3.5 Serious adverse events/adverse device effect reporting.………………………………………………..54 
16. Informed consent….………..……………………………….……………………………………………………..…………………….55 
17. Protocol for compensation for victims…..……….……………………………………………………..…………………….56 
18. Matters concerning treatment of subjects after clinical trial…..……………………..…………………….…….56 
19. Measures for safety protection of subjects .……………………………………………………………………….….…..56 
19.1. Good clinical practice for medical devices (KGCP) and Helsinki Declaration …..……………….56 
19.2. Institutional Review Board (IRB)………………..………………………………………………………………….………56 
19.3. Measures for safety protection of subjects ….…………………………………………………………………….57 
19.4 Clinical trial institution……………………………………………………………………………………………….………….57 
19.5 Investigator……………………………………………………………………………………………………………………………57 
20. Others: matters necessary for conducting clinical trial safely and scientifically. ……………………….58 
20.1. Confidentiality……………………………………………………………………………………………………………………….58 
20.1.1. Data………………………………………………………………………………………………………………….…………58 
20.1.2. Anonymity of subjects ………………………………………………………………………………………………58 
20.1.3 Privacy protection methods………………………………………………………………………………………..58 
20.2 Compliance and change in clinical trial protocol…………………………….…………………………………....58 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 18 / 65 
 
20.3 Clinical trial monitoring………………………………………………………………….………………………………….……59 
20.4 Record and use of trial results………………………………..………………………………………………………………60 
   20.4.1 Case report form and source document…..………………………………………………………….…….60 
   20.4.2 Storage of clinical research data ……………………………………………………………………...………..61 
 
References……………………………………………………………………………………………………………………………………………62 
 
 
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 19 / 65 
 
1. Title of Clinical Trial 
Evaluation of therapeutic efficacy and safety of concurrent FOLFIRINOX plus high intensity focused 
ultrasound (ALPIUS 900) for locally advanced/borderline resectable pancreatic cancer: A prospective 
single-center, single-arm, investigator-initiated, open-labeled, exploratory clinical trial 
2. Name and Location of the Institution conducting Clinical Trial 
◼ Seoul National University Hospital  
Daehak-ro 101, Jongro-gu, Seoul (110-744) Tel: 02-2072-2114 
3. Name and Title of Principal Investigator, Sub-investigator, and 
Co-investigator 
◼ Seoul National University Hospital or Seoul National University College of Medicine.  
Role  
Name & Title 
Affiliation 
Tel.  
PI 
Jae Young Lee, Prof. 
Radiology  
822-2072-3073 
Co-Investigator 
Sang-Hyup Lee, Prof. 
Gastroenterology 
822-2072-4892 
Co-Investigator 
Jin-Young Jang, Prof. 
Surgery 
822-2072-2194 
Co-Investigator 
Hong Beom Kim, Assistant Prof.  
Surgery 
822-2072-1272 
Co-Investigator 
Dong Ho, Lee, Associate Prof. 
Radiology 
822-2072-0348 
Co-Investigator 
In Rae Cho, Assistant Prof.  
Gastroenterology 
822-2072-2199 
Co-Investigator  
Hang Rae Kim, Prof.  
Cell Immunology 
8210-8920-3607 
CRC 
Soo Yeon Kang, Nurse 
Radiology 
822-2072-3073 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 20 / 65 
 
Technician  
Dong Hyuk Park, Radiation Tech. 
Radiology 
822-2072-3073 
CRC 
Seong Ho Choi, Nurse 
Surgery 
822-2072-2194 
CRC 
Hyun Ji Lee, Nurse 
Gastroenterology 
822-2072-4892 
4. Name and Title of Clinical Trial Medical Device Manager. 
◼ Seoul National University Hospital 
Role  
Name and Title 
Affiliation  
Tel.  
Medical device 
manager 
Dong Hyuk Park, 
Radiation tech.  
Radiology 
822-2072-7354 
5. Name and Title of Clinical Trial Monitor 
Role  
Name and Title 
Affiliation  
Tel.  
Clinical trial monitoring 
Hyun-ji Kim, CRA 
Synex Consulting 
Ltd. 
822-2284-9400 
 
6. Goal and Background of Clinical Trial 
6.1. Goal 
This clinical trial is a prospective, single-institute, single-arm, investigator-initiated, open-labelled, 
exploratory one for evaluating the efficacy and safety of drug-delivery-enhancing effects of the 
combined treatment of HIFU (ALPIUS 900) and anti-cancer drugs (FOLFIRINOX) in patients with 
locally advanced pancreatic cancer/borderline resectable pancreatic cancer. 
In addition, we would like to compare the therapeutic effect of HIFU/anti-cancer drug combined 
treatment with the current standard treatment method through the matching method in the 
histological cohort that underwent the current standard treatment, FOLFIRINOX chemotherapy.  
 
6.2 Background  

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 21 / 65 
 
Malignant pancreatic exocrine tumors refer to ductal adenocarcinoma, mucinous cystic 
adenocarcinoma, 
intraductal 
papillary 
mucinous 
carcinoma, 
acinar 
cell 
carcinoma, 
pancreatoblastoma, and solid pseudo-papillary carcinoma, among which ductal adenocarcinoma 
accounts for 80 to 90 percent of pancreatic cancer [1]. Pancreatic cancer is the eighth of all cancers 
in terms of incidence, at 2.3 percent, but the fifth cause of death from cancer. More than 5,000 
people in the country die from pancreatic cancer and more than 200,000 people worldwide are 
dying from pancreatic cancer each year.  
Pancreatic cancer is a pathological feature that does not have clear boundaries with surrounding 
pancreas, and because of its abundance of fibrous tissue and low vascular distribution, it is firm by 
touching and its color is light yellow or gray [1; 2]. Pancreatic cancer tissues characteristically form 
extensive stroma around cancer cells, showing characteristics such as desmoplasia. It is prone to 
invade peripancreatic tissue or organs, and lymph node invasion occurs before vascular invasion 
usually by invading fat tissue, nerve tissue, and lymphatic system around the pancreas first. 55 to 
65% occur in pancreatic head or uncinated process; 15 to 35% in body and tail; and 10 to 20% in 
entire pancreas as a diffuse tumor.  
The diagnostic method can be largely divided into imaging, histopathology and laparoscopic 
examination [3]. The most frequently used imaging modality for the diagnosis and staging is multi-
detector CT, which can be reconstructed with three-dimensional images. Magnetic resonance 
imaging is also used frequently, and it is helpful if the diagnosis or margin of pancreatic cancer is 
unclear in CT, but it is not superior to abdominal CT when evaluating surgical resection. Recently, 
endoscopic ultrasound has been used more and more, and they have the advantage of being able 
to obtain tissues through a fine needle aspiration. PET CT may be required. In the case of pancreatic 
cancer which can be surgically resected, preoperative biopsy is not necessary. Histologic examination 
is needed for chemotherapy, and even when they are not typical for pancreatic cancer, it is also 
needed. The tissue can be obtained through percutaneous and endoscopic approaches. 
Laparoscopic examination is conducted when it is necessary to detect liver or peritoneal metastases 
to avoid unnecessary surgery.  
The prognosis of pancreatic cancer is still very poor, with a five-year survival rate of less than 10 
percent in total patients, despite considerable advances in surgery and medical technology and 
radiation treatment. The 5-year survival rate is 8.7 percent in our country and 5 percent worldwide. 
The reason for the low survival rate is that when pancreatic cancer was discovered, the proportion 
of patients who are surgically treated is only 10 to 20 percent worldwide. Pancreatic cancer has a 
worse prognosis than any other cancer, with a five-year survival rate of only about 10-20 percent 
even after a radical resection. 
For pancreatic cancer patients, the only curable method is surgical resection. However, surgical 
resection can be performed in only 20% of patients with pancreatic cancer at the time of discovery 
due to the absence of screening tests for early detection. There are chemotherapy and radiation 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 22 / 65 
 
treatments for patients with advanced pancreatic cancer that can be operated and borderline 
resectable pancreatic cancer that are not sure whether it can be operated. In a study comparing 
chemo-radiotherapy with chemotherapy alone, conflicting results are published according to the 
research institute, requiring further study.  
What is practically necessary to determine the treatment policy is the evaluation of resectability. 
Pancreatic cancer is divided into metastatic pancreatic cancer and localized pancreatic cancer, and 
localized advanced pancreatic cancer is divided into resectable pancreatic cancer, borderline 
resectable pancreatic cancer and locally advanced pancreatic cancer. In addition to distant metastasis, 
the most important cause to make surgical resection of pancreatic cancer impossible is vital vessel 
invasion, such as superior mesenteric artery or celiac artery invasion by tumors. In the case of locally 
advanced pancreatic cancer (LAPC), FOLFIRINOX regimen (combination of 5-FU, Oxaliplatin, 
Irinotecan, Folinic acid) is regarded as a standard treatment based on its excellent results over 
convention chemotherapy [4-6].  
In addition, the concept of borderline resectable pancreatic cancer (BRPC), a disease in which the 
determination of surgical resectability is ambiguous, has recently been widely accepted. Vascular 
invasion criteria defining borderline resectable pancreatic cancer most commonly use NCCN 2018 
version. Recent studies have shown that neoadjuvant chemotherapy using FOLFIRINOX regimen 
before surgery has a better prognosis than direct surgical resection in BRPC, and gradually, it is 
recommended to implement neosdjuvant chemotherapy for BRPC patients. [7-9] There is still 
controversy over the addition of radiotherapy to neoadjuvant chemotherapy.  
In a recent clinical study of 117 borderline resectable pancreatic or local advanced pancreatic cancers 
published in Korea, the overall survival time of patients treated with prior FOLFIRINOX was 19 
months, and surgery was possible in about a quarter, and the average survival period of patients 
who underwent surgery was 28.6 months, which led to the conclusion that neoadjuvant 
chemotherapy of FOLFIRINOX was helpful in the outcome[10]. 
High Intensity Focused Ultrasound (HIFU) is an extracorporeal non-invasive medical device that uses 
high-intensity focused ultrasound to ablate local tissues or nerves in the body without damaging 
surrounding organs and tissues, and is mainly applied to the treatment of benign and malignant 
tumors such as uterine fibroid, benign prostate hypertrophy, and prostate cancer. The HIFU can be 
divided into a continuous HIFU that continuously gives ultrasonic waves and a pulsed HIFU that 
gives pulsed wave with a frequency. Early studies on the treatment of pancreatic cancer mostly used 
continuous HIFU to generate heat in tumors or used pulsed HIFU using long duty cycle pulse. 
However, such HIFU treatment using high heat can cause heat damage to the surrounding organs 
or tissues. There are many physicians who feel at risk of applying it to the pancreas with complex 
surrounding vital organs. Actually, severe complications caused by this type of HIFU have been 
reported.  

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 23 / 65 
 
The HIFU study on the treatment of pancreatic cancer was published in Spain, Germany, and other 
countries as well as in China, and used heat-producing continuous HIFU.[11-14]. Pancreatic cancer 
treatment by pulsed HIFU has recently begun to be reported [15-17]. The operating principle of the 
pulsed HIFU is almost identical to that of the continuous HIFU, but the difference is that ultrasonic 
waves are given in pulse form. In the case of pulsed HIFU, not only intensity but also pulse repetition 
frequency (PRF) and duty cycle can be adjusted to create various phenomena.  
Recently, research on anti-cancer drugs using a special condition of pulsed HIFU using relatively low 
duty cycle, which only transforms cell barriers without heat generation of tumor tissue, has been 
actively reported.[7; 18; 19]. HIFU and anti-cancer drug combined therapy can minimize side effects 
of anti-cancer drugs and increase the efficacy of anti-cancer drugs against cancer cell apoptosis by 
making anti-cancer drugs act in a more specific and targeted way to the pancreatic cancer cells. 
Relevant reports have shown that HIFU disrupts the cell membrane of targeted cancer cells by 
sonoporation to help drugs get into cancer cells. Figure 1 below shows the main mechanism of 
action in which HIFU transiently disrupts the cell membrane and consequently induces apoptosis of 
cancer cells. 
. 
 
Fig. 1. Mode of Action of HIFU in combination with anticancer drugs. Ultrasound causes changes 
in pressure in the propagation medium. Microbubbles are generated in extracellular fluid and cells 
by negative pressure of ultrasound. The microbubble expansion and contraction occur due to 
pressure changes, and eventually the microbubbles collapse due to liquid microstreaming or Jetting. 
The force generated by the high pressure jet and shear stress by liquid streaming are sufficient to 
damage or increase permeability of the surface of surrounding cell membrane. It results in 
anticancer drug to easily penetrate cells.  
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 24 / 65 
 
We have conducted various preclinical study treatment to prove the combined effect of HIFU and 
anti-cancer drugs on pancreatic cancer for 10 years and reported the results in SCI papers [16; 19-
21], and recently conducted a preclinical study to evaluate the combined treatment effect of HIFU 
and anti-cancer drugs under HIFU conditions where its mechanical effect is exaggerated [19]. The 
effect of tumor suppression was higher when the mechanical effect was increased by adjusting the 
duty cycle and intensity, proving that the effect of anti-cancer drugs on tumor cells could increase 
when tumors are irradiated with stronger intensity at a shorter duration rather than with lower 
intensity at a longer duration under the same energy conditions, and reported that significant tumor 
growth suppression and complete remission of 30% were found when the above conditions were 
repeated at intervals of one week like clinical regimen (Fig. 2).  
 
Fig. 2. Change in tumor size during the four-cycle treatment (one cycle = three-week treatment + 
one-week monitoring) in two groups (gemcitabine only group vs. combined treatment group of 
gemcitabine and HIFU (using mechanical effect-dominant condition). The combined treatment 
group (red color) shows significant inhibition of tumor growth, compared to gemcitabine only group 
(blue color).  
Therefore, our preclinical studies can be summarized as follows: all our studies continued to show 
the following facts: the concurrent use of HIFU and anti-cancer drugs increases apoptosis rates of 
pancreatic cancer cells and decreases the growth of pancreatic cancer tissues. In addition, using 
mechanical effect-dominant HIFU condition is more beneficial to enhance tumor growth suppression.  
Last year, we performed a pilot clinical trial to investigate the safety and initial efficacy of combined 
treatment of HIFU (parameter: 1.5 kW/cm2 to 2.5 kW/cm2, duty cycle of 2%) and chemotherapy in 
nine patients with unresectable pancreatic cancer, using ALPIUS 900 unit (US-guided HIFU system, 
Alpinion Medical System), which is clinically being used in our institute to treat uterine myoma and 
uterine adenomyosis. A total of nine patients was treated safely without aggravating the side effects 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 25 / 65 
 
of chemotherapy. In particular, the intermediate intensity group (2.0kW/cm2) showed statistically 
significant extension of the survival period (median survival > 28 months, p<0.01). All patients in 
intermediate intensity group are still survived. This results were presented at the RSNA 2019. Given 
the safety and potential effectiveness identified in the pilot clinical studies and the theoretical 
advantages that HIFU/anti-cancer combined therapy has, we can believe that HIFU and anti-cancer 
drug combined treatment could lead to improvement of tumor response in LAPC/BRPC patients, 
and furthermore, would help improve the prognosis of pancreatic cancer patients. Therefore, this 
clinical trial was planned to evaluate the therapeutic effect of combined treatment of HIFU and 
anti-cancer drug in LAPC/BRPC patients with a study design having a higher power of proof.    
 
7. Overview of Clinical Trial Medical Device 
7.1 Name of Medical Device, Item Classification, and Prior Permission 
-Name of Medical Device: 'ALPIUS 900' (Subject 14-3227, Manufacturer: Alpine Medical System 
Co., Ltd.) 
- Item Classification: U.S.-guided High Intensity Focused Ultrasonic Surgical Unit Degree 3, 
A35100.02, a device for treating cancer or others using ultrasound integrated with high intensity. 
- - Pre-authorization: Non-invasive treatment of uterine myoma and adenomyosis not less than 
3cm but less than 12cm non-invasively using ultrasound-guided high intensity focused ultrasound 
 
7.2 Composition  
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 26 / 65 
 
 
 
7.3 Specification   
1) Treatment Transducer   
(1) Number of Transducer elements: 256 
(2) Diameter: 135mm 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 27 / 65 
 
(3) Frequency: 1 MHz  
(4) Power: < 600W 
(5) Adjustable insonation range for treatment: Lateral ± 13 mm, Axial ± 25 mm 
(6) Focal distance: Variable with beam steering  
(7) Diameter of focus: -6 dB length: according to beam steering 1.6 mm ± 20%  
(8) Length of focus: -6 dB length: according to beam steering 11 mm ± 20% 
(9) Sonication Energy: 800J/point  
(10) Reflection/cavitation monitoring: Passive Cavitation Monitoring  
2) Pre-scan Transducer  
(1) Acoustic Power: 173.2 mW/cm2 
(2) Applied frequency: 1~6 MHz 
(3) Application Plane Size: 66*16mm 
(4) Scanning depth: 300 mm 
(5) Vertical Resolution: 1.7 mm (@65mm), 1.1 mm(@ 105mm) 
(6) Horizontal resolution: 3.4 mm (@65mm), 4.2mm(@105mm) 
(7) FOV: 60 도 
※ A previous approved product (Approval No. 10-1247) is used for ultrasonic imaging devices.  
3) Supply power 
(1) Input power: 200-230 VAC, 50/60Hz 
(2) Power consumption: 3.5 KVA  
4) OCM workstation minimum specification 
(1) CPU: Intel Core i7 > 3.40G 
(2) Standard Desktop PC 
(3) 3xPCI 
(4) Memory: > 1MB Cash   
(5) Hard disk capacity: > 100GB   

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 28 / 65 
 
(6) HP CD-RW (IDE) 8x or higher 
(7) Audio (Built in PCI) 
(8) 2xFast Ethernet adaptor 
(9) 1Xapg GE Graphics Adaptor  
(10)  21.5 inch Color LCD monitor 
5)  Imaging module Control Computer Minimum Specification (CPC) 
(1) Intel core 2 duo > 2.26G  
(2) Power Supply System: 350W  
(3) HDD capacity: > 40GB  
(4) 1x Fast Ethernet PCI adaptor  
(5) 18.5 inch color LCD monitor 
(6) OS: Microsoft Windows XP 
(7) Input power: 220 VAC, 50/60Hz  
6) Water Circulation Module  
(1) Degassing method: Gas separation membrane type. standard flow rate: 1L/min 
(2) Vacuum meter: > Max 60 (-700mmHG)  
(3) Power: single phase 220 VAC, 60Hz  
(4) Power Consumption: 300W 
7) Software  
 
 
 
7.4 How to use 
The procedures for the use of clinical trial device are as follows, and the detailed instructions of the 
manufacturer (attached Form) shall be followed. 
◼ 
Prerequisites for medical device use 
 
Checking the power supply and turning it on/off 
 
Connecting and disconnecting imaging transducers 
Number Name 
version 
1 
ALPIUS 900 
1.0 
2 
Armstrong ALPIUS 900 
3.5 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 29 / 65 
 
 
Confirm activating and deactivating imaging transducers 
◼ 
How to use and operate 
1. Pre-treatment Patient Preparation Procedure 
 
Fasting from 4 hours before the procedure 
 
Keep skin clean 
 
Shaving (mechanical chemical shaving) depending on skin condition 
 
Anesthetic or sedative administered according to the patient's prescription 
 
Posture : Supine position 
 
Measurement of vital signs (blood pressure, pulse rate, respiration rate, oxygen saturation) 
2. HIFU Procedure 
 
After checking patient's readiness for treatment, scan the treatment area. Clinicians treat 
patient in accordance with a pre-established treatment plan. 
 
The clinicians check tumor response in real-time during treatment through ultrasound and, 
if necessary, immobilizes the subject. 
3. Post-treatment procedure 
Subjects who have completed the procedure can return to the inpatient ward and observe 1 to 2 
hours after the end of the chemotherapy, and may return home or stay in the hospital for 1 to 2 
days, depending on the opinion of the medical faculties. 
 
4. Precautions for Use 
<Refer to Annex> ALPIUS 900 User Manual 
.  
7.5 Technical Features and Performance 
The clinical trial medical device has a transducer that produces high-intensity focused ultrasound, 
its supporting structures and hardware and software to monitor treatment. Its electrical 
characteristics are 220VAC, 60Hz, and 3.5kVA, and its protection type and degree is Class 1 and BF 
type. The medical device for this clinical trial consists of imaging display monitor, operational display 
monitor, positioning arm, treatment head, handle, treatment head membrane, body and mobile 
wheel (see 9.5.1 Overview of clinical trial medical device). Various ultrasound examinations are 
possible and even deep-seated tumors can be visualized using imaging control panels, and the 
treatment head has imaging probes for real-time imaging, membrane in contact with the human 
body, and temperature sensor that measures the temperature of cooling water. The operational 
display monitor shows all the information and real-time treatment scenes as well as the images 
acquired (see attached item license). 
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 30 / 65 
 
7.6 Purpose of Use 
In this clinical trial, ALPIUS 900 (U.S.-guided HIFU System) will be used to enhance drug delivery 
of anticancer drug by applying focused ultrasound beam with relatively low Duty cycle pulse that 
can induce deformation of the cell barrier of tumor tissue without heat generation to pancreatic 
cancer.  
 
7.7 Target Diseases and Indications 
Locally advanced/ borderline resectable pancreatic cancer is targeted in patients who have not 
received any other treatment with histological diagnosis of pancreatic adenocarcinoma.  
 
8. Inclusion Criteria, Exclusion criteria, and Target Population 
Number and its Reasoning 
8.1 Inclusion and Exclusion Criteria 
8.1.1 Inclusion Criteria 
All of the following selection criteria must be met before they can be registered for this clinical 
trial. 
1. 
Adults over 19–85  
2. 
Persons with a Karnofsky Performance Scale (KPS) of 70 percent or more; 
3. 
A person diagnosed as a tubular adenocarcinoma through biopsy.  
4. 
A person diagnosed with LAPC/BRPC by computed tomography (CT) or magnetic 
resonance imaging (MRI) 
- Diagnosis results based on CT or MRI taken at the hospital where pancreatic cancer was 
first diagnosed or being treated are recognized as valid. However, only the results obtained 
within 4 weeks from the screening date are accepted.  
- LAPC/BRPC is determined by investigators based on the American Point Committee on 
Cancer (AJCC) guidelines (see table below).  
T staging  
 
T1  
Tumor diameter < 2cm 
T2 
2cm ≤ tumor diameter ≤ 4cm  
T3 
Tumor diameter > 4cm 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 31 / 65 
 
T4 
Invasion of the celiac trunk, the superior mesenteric artery, 
and proper hepatic artery, regardless of tumor size. 
 
N staging   
N0 
No LN metastasis  
N1 
Regional LN metastasis 1~3  
N2 
Regional LN metastasis 4 or more  
 
 
 
- Cases with distant metastasis are excluded; LAPC indicates T4NxM0; and BRPC indicates 
when T4 is not clear with NxM0.  
5. 
A person willing to voluntarily agree to a clinical trial and comply with the test plan 
8.1.2 Exclusion Criteria 
The following exclusion criteria may not be registered in clinical trials. 
1. The presence of a cystic lesion within pancreatic cancer to be treated with HIFU or at the 
pancreas adjacent to the pancreatic cancer.  
2. The presence of a wide range of scar or surgical clips observed in the passage through the 
ultrasonic beam.  
3. In case proper ultrasound images for HIFU procedures are not shown 
4. A person who cannot lie down in a comfortable position.  
5. A person who has difficulty communicating 
6. A person who has experience in toxic or hypersensitive reactions to FOLFIRINOX anticancer 
drugs. 
7. A person pregnant or breastfeeding 
8. Pancreatic cancer patients who have previously been anti-cancer treatment 
9. If severe side effects such as aortic rupture, duodenum perforation, gastrointestinal damage or 
intestinal necrosis are expected due to HIFU procedures.  
10. Other cases where participation in this clinical trial is judged inappropriate by the investigator 
(specific reasons should be recorded in the case report form) 
M staging  
 
M0  
No distant metastasis   
M1  
Distant metastasis   

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 32 / 65 
 
 
8.2 Estimation of Target Population Number and its Reasoning 
Number of subjects: 60 total 
To date, there has been no prior study on how effective the combined treatment of HIFU and 
chemotherapy is in pancreatic cancer patients, so there is no evidence study on the number of 
subjects needed for this study. Studies using FOLFIRINOX, which have been published so far, have 
mostly recruited 30-40 patients, and a recently published randomized clinical trial of FOLFIRINOX 
study included 50 patients with BRPC. A total of 60 patients, including LAPC and BRPC, are 
expected to be needed in consideration of these previous prior studies and considering a 15% 
dropout rate in this study. 
 
9. Clinical Trial Period 
After obtaining approval of the clinical trial plan from the FDA in our country and IRB, it is expected 
that it will take at least 24 months, including 12 months of subject registration (from the date of 
first subject registration to the date of last subject registration) 6 months of treatment and follow-
up observation, and about 6 months for data processing, statistical analysis, and report preparation 
after clinical trial is completed. 
 
10. Clinical Trial Method 
10.1 Research Design 
Prospective, single-center, single-arm, investigator-initiated, open-labeled, exploratory clinical trial 
10.2 Clinical Trial Procedure 
Patients diagnosed with pancreatic cancer through biopsy and diagnosed with LAPC/BRPC through 
computed tomography (CT) or magnetic resonance imaging (MRI) are referred to this clinical trial. 
Patients who voluntarily sign a written consent form after hearing sufficient explanations related to 
this study will be registered for this clinical trial if all criteria for selection/exception are met.  
10.2.1 Subject Numbering 
A management log will be prepared for all subjects who have signed a clinical trial agreement and 
are registered in the study. These management logs are used to assign sequential subject numbers 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 33 / 65 
 
to subjects registered in clinical trials, and subject numbers are assigned 'screening numbers' and 
'registration numbers'.  
The screening number is assigned according to the following methods, including the "S" of the 
screening and two digits in the order of the subjects.  
- Screening : S 
- Two digits according to the screened order 
Example > Identification code of the first screened subject: S – 01 
 
The registration number is assigned according to the following methods, including the "R" of the 
registration and two digits in the order of the subjects.  
- Registration: R 
- Two digits according to the registered order 
Example > Identification code of the first registered subject: R – 01 
 
10.2.2 Screening 
Patients diagnosed with pancreatic cancer through biopsy and diagnosed with LAPC/BRPC through 
computed tomography (CT) or magnetic resonance imaging (MRI) are referred to this clinical trial 
by surgeon or internal physician. Patients who voluntarily sign a written consent form after hearing 
sufficient explanations related to this study are registered for this clinical trial and undergo following 
evaluation if all criteria for selection/exception are met.  
 
Demographic Survey 
 
Pregnancy test 
 
Vital signs  
 
Physical examination  
 
Past medical history  
 
Ultrasound exam 
 
KPS Evaluation 
 
CT scan 
 
Blood test 
 
CA19-9  
 
NRS Pain Assessment 
 
Following items are observed and recorded on ultrasound and CT exams.  
<Ultrasound examination> 
 
The presence of abdominal wall scarring 
 
The presence of surgical clip 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 34 / 65 
 
 
The presence of proper acoustic window for HIFU treatment 
 
< CT examination>  
 
Nature of tumor: Cystic or Solid  
 
Location of tumor in the pancreas: Head, Body, Tail 
 
Number of tumor 
 
TNM stage 
 
The presence and location of distant metastasis.  
 
Whether or not metastasized and the organization that metastasized 
 
10.2.3 Visit 1~ Visit 4 
The subjects will receive combined four-cycle treatments of anticancer drugs (FOLFIRINOX) and HIFU 
(ALPIUS 900) at intervals of two weeks over eight weeks. The CT for tumor response evaluation is 
then taken immediately after the fourth cycle (i.e., 2 months after start of combined treatment). 
Regardless of whether the FOLFIRINOX treatment persists or not, CT is taken at intervals of two 
months up to 6 months after start of combined treatment.    
At the end of each combined treatment, an adverse reaction or skin change is observed. After blood 
collection for blood tests, the subjects may return home or be hospitalized for one to two days 
according to medical faculties opinion. 
1. 
At each visit for combined treatment (Cycles 1, 2, 3, 4), the following items are recorded and 
evaluated: 
 
Vital signs 
 
Blood test 
 
Adverse events / serious adverse events 
 
Confirmation of concurrent medication and treatment 
 
2. 
Detailed combined treatment schedules and procedures and combined treatment protocols are 
as follows. 
A. 
Schedule and procedures for combined treatment  
 
Perform a total of four repeated treatments every two weeks for eight weeks.  
 
Subjects are hospitalized and given anti-cancer drugs for about 50 hours in accordance 
with the standard protocol for FOLFIRINOX. 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 35 / 65 
 
☞ If the medication is canceled or postponed due to the condition of the subject, the 
HIFU procedure will also be canceled or postponed.  
 
After the start of chemotherapy, receive HIFU treatment within 48 hours (30 minutes 
to 1 hour) and go up to the inpatient ward after completion of HIFU treatment for 
post-treatment monitoring for 1 to 2 hours. 
☞ If adverse events caused by anticancer drugs have not been recovered within 24 
hours of administration or adverse events by HIFU treatment have not been fully 
recovered, the HIFU procedure may be canceled or postponed under the judgment of 
investigators.  
 
When anticancer drug administration of combined treatment is completed, the 
subjects shall be hospitalized for one to two days or returned home depending on the 
physical condition of the subject. 
B. 
Combined Treatment Protocol  
 
 
Anti-cancer drug administration (one cycle dose) : The administration of anticancer 
drugs (FOLFIRINOX regimen) is applied equally to each enrolled patient according to 
the institution's standard protocol. 
<Table 1> Dose and schedule of FOLFIRINOX therapy 
No. 
FOLFIRINOX regimen 
Daily 
administration 
dose 
(route) 
Administration schedule 
1 
Oxaliplatin 
 85 mg/m2 (Intravenous, IV) 
It is administered at the 
following schedule every 
two weeks. 
2 
Irinotecan 
 180 mg/m2 
(Intravenous, IV) 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 36 / 65 
 
3 
Leucovorin(Folic 
acid) 
400 mg/m2 
(Intravenous, IV) 
 
Day 1 : Oxaliplatin, 
Irinotecan, 
Leocovorin, 
5-FU 
(IV-push), 5-FU (IV 
infusion) 
 
Day 2-3 : 5-FU (IV 
infusion) 
 
4 
5-FU 
 400 mg/m2 
(IV push) 
5 
5-FU 
2400 mg/m2 
(Intravenous, IV) 
* The FOLFIRINOX dose and administration cycle (interval) can be adjusted by the 
researcher's judgment depending on the condition and progress of the subject. 
e.g. 20% reduction by drug, Oxaliplatin 85mg/m2 -> 60mg/m2, Irinotecan 180mg/m2-
>150mg/m2->120mg/m2 
 
* Anti-cancer drugs used in clinical trials are licensed medicines and are used within the 
scope of permission. 
 
HIFU procedure 
The details of the pre-procedure, procedure, and post-procedure care of the subjects are 
in accordance with the manufacturer's ALPIUS 900 User Manual (see Supplemental 
material). 
< Pre-treatment Preparation>  
1) Preparation of subjects 
Depending on the condition of the skin, the subject will be shaving (using shaving cream) 
on the skin to which HIFU will be applied within three days prior to the treatment, and 
no cream should be used after shaving. To reduce side effects by gases or food in the 
gastrointestinal tract, fasting is required from midnight the day before the procedure 
(NPO 4 hours prior to HIFU treatment). 
2) Pancreatic cancer treatment area plan 
The volume ratio of pancreatic cancer to be treated will be determined by the investigator 
(typically, the treatment area is planned with a safety margin of 0.5 cm from the margin 
of pancreatic cancer). Based on the ultrasound image findings of pancreatic cancer, only 
pancreatic cancer tissues that can be identified in the ultrasound images will be 
considered for treatment. 
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 37 / 65 
 
<HIFU procedure> 
The operator shall perform the HIFU procedure according to the pre-established 
procedure plan. HIFU parameter that is used in this trial is seen in Table 2 based on the 
result of our pilot clinical trial. After the entire planned procedure is completed, keep the 
entire treatment record in the patient record. 
<Table 2> HIFU parameter 
Acoustic Intensity 
Duty cycle 
Exposure time 
PRF 
2.0 kW/cm2 
1% 
3 sec/point 
10 Hz 
 
During the procedure, observe and record the following items: 
- vital signs such as body temperature, blood pressure (a retractor/a relaxation device), 
pulse rate, respiration rate, and oxygen saturation. 
- Treatment time 
- HIFU insonation time  
- HIFU insonation energy 
 
<Post-HIFU Treatment Process> 
After the HIFU procedure is completed, the subjects will observe one to two hours of 
abnormal cases, including skin changes, in the inpatient ward and will be given residual 
anticancer drugs. 
 
10.2.4 Visit 5~ Visit 7 
After completion of 4th cycle combined treatment (2M), 2 months after completion of the 
combined treatment, 4 months after completion of the combined treatment (4M), the subjects 
visit to our hospital and the following items are recorded and evaluated. The clinical trial will be 
ended for a subject after all assessment are completed if there are no adverse event to need to 
be followed for the subject. The following items are recorded and evaluated during follow-up 
period.  
- Vital signs 
- KPS evaluation (only conducted at Visit 5) 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 38 / 65 
 
- CT scan. 
- Blood test 
- CA19-9 values  
- NRS Pain Assessment 
- Evaluation of survival rate 
- Adverse event cases / Serious adverse event cases  
- Checking concurrent medication and treatment 
 
10.3 Prohibition and Permission in Concomitant Medication or Therapy 
Drugs or alternative treatments that may affect the results of the clinical trial are prohibited. All 
medications already taken due to underlying diseases are recorded in the screening.  Only 
medications added after the start of clinical trial are recorded in case report form. If they receive 
prohibited drugs or alternative treatments during the clinical trial period, they will be eliminated 
from the study and the reasons for the elimination are recorded. 
 
However, if a prohibited drug is required in a one-time manner, it can be used within the extent 
that it does not affect the outcome of the clinical trial according to the investigator's judgment, 
and the details are recorded in the column of the concomitant medications in the case report 
form. 
 
Based on the investigator's judgment, painkillers and local anesthetics can be administered in 
accordance with the institution's standard procedures, taking into account the subjects' condition. 
 
- Prohibited medication/therapy 
Anti-cancer drugs and radiotherapy other than FOLFIRINOX are prohibited during the combined 
treatment period. 
 
- Allowed medication/treatment 
Analgesics to be commonly used for conservative symptom management of cancer patients 
(Codeine, Diamorphine, Fentanyl, Hydrocodone, Meperidine, Methadone, Morphine, Oxycodone, 
Propoxyphene, Supethanil, Tramadol), G-CSF, Dexamethasone, antiemetics (Ondansetron, 
Aprepitant etc), Gabapentin, tricyclic antidepressant, etc. are not prohibited. Anti-cancer drugs are 
administered until the tumor's progression is confirmed in accordance with the standard 
treatment procedure of FOLFIRINOX, or until it is no longer possible to administer to the patient 
due to drug side effects. 
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 39 / 65 
 
10.4 Therapy after ending combined HIFU/chemotherapy treatment 
Subsequent treatment of patients who have completed the first 4 cycle HIFU/FOLFIRINOX combined 
treatment is determined and performed in accordance with the CT findings, the overall condition 
of the patient, and the standard care guidelines. The implementation of surgery, continuation of 
FOLFIRINOX chemotherapy, conversion to other anticancer drugs, and further radiation therapy can 
be considered as possible treatments. This assessment is conducted after 8 or 12 cycles of treatment 
if the treatment continues for FOLFIRINOX chemotherapy, and will be determined later in accordance 
with the standard care guidelines. If surgery is performed after 8 or 12 cycles, additional (Adjuvant) 
chemotherapy may be performed according to surgical and pathological findings and should be 
determined in accordance with the standard care guidelines. 
 
11. 
Observation 
Items, 
Clinical 
Examination 
Items, 
and 
Observational Inspection Methods 
Screening 
Period of combined treatment and follow-up observation 
Visits  
V1  
(Cycle1**) 
V2 
(Cycle2) 
V3 
(Cycle3) 
V4 
(Cycle4) 
V5 
 V6 
V7 
Days elapsed 
≤ -4W 
Day1 
Day15 
Day29 
Day43 
After four-
cycle 
treatment 
(Month 2) 
Two 
months 
after four-
cycle 
treatment 
(Month 4) 
Four 
months 
after four-
cycle 
treatment 
(Month 6) 
Visit window 
 
-* 
± 14 days ± 14 days ± 14 days ± 14 days ±28 days ±28 days 
Observation Form 
Visiting 
hospitaliza
tion 
hospitaliza
tion 
hospitaliza
tion 
hospitaliza
tion 
outpatient/
hospitaliza
tion 
outpatient
/hospitaliz
ation 
outpatient
/hospitaliz
ation 
Consent 
acquisition 
√ 
 
 
 
 
 
 
 
Inclusion/Exclusio
n Criteria 
√ 
 
 
 
 
 
 
 
Demographic 
Survey1) 
√ 
 
 
 
 
 
 
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 40 / 65 
 
Pregnancy Test2) 
√ 
 
 
 
 
 
 
 
Vital Signs3) 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Physical 
Examination4) 
√ 
 
 
 
 
 
 
 
Medical History5) 
√ 
 
 
 
 
 
 
 
Ultrasound6) 
√ 
 
 
 
 
 
 
 
KPS evaluation7) 
√ 
 
 
 
 
√ 
 
 
CT Imaging8) 
√ 
 
 
 
 
√† 
√† 
√† 
Blood Test9) 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
CA-19-910) 
√ 
 
 
 
 
√ 
√ 
√ 
NRS Pain 
Assessment(11) 
√ 
 
 
 
 
√ 
√ 
√ 
Survival rate12) 
 
 
 
 
 
√ 
√ 
√ 
Co
mbi
ned 
trea
tme
nt 
Anticancer 
drug 
medication13) 
 
√ 
√ 
√ 
√ 
 
 
 
 
HIFU 
treatment14) 
 
√ 
√ 
√ 
√ 
 
 
 
Adverse 
events/Serious 
adverse event15) 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Concurrent 
medication and 
treatment16) 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Immune analysis 17) 
 
√ 
√ 
√ 
 
√ 
 
 
 
* Based on the first date of chemotherapy 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 41 / 65 
 
** Cycle: Anti-cancer drug administration interval according to FOLFIRINOX standard treatment 
protocol, FOLFIRINOX is administered every two weeks, so it becomes a cycle of two weeks. The 
first anti-cancer drug administration cycle will be one cycle and the next two weeks later. 
Visit 5: Visit for CT scanning and other examinations immediately after completion of 4 cycles of 
cancer. 
Visit 6: Visit for CT scanning and other examinations 2 months after Visit 5. Subject's visit is 
terminated with Visit 5 if surgery is performed based on the findings of CT performed on Visit 5. 
Visit 7: Visit for CT scanning and other examinations 4 months after Visit 5. Subject's visit is 
terminated with Visit 6 if surgery is performed based on the findings of CT performed on Visit 6. 
† CT scan: CT for response assessment is usually performed during an outpatient visit before the 
next chemotherapy treatment, but if he/she is a local resident or there are any special 
circumstances, CT is performed during hospitalization for the next chemotherapy treatment. 
 
1. Demographic Survey  
date of birth, gender, height, weight record 
2. Pregnancy test 
In the case of fertile women, urine hCG test is performed prior to the procedure to confirm 
pregnancy, and those who have been confirmed pregnant are excluded from this clinical trial. 
3. Vital signs 
Body temperature, blood pressure, pulse rate, respiration rate, and oxygen saturation 
4. Physical examination 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 42 / 65 
 
examination of appearance, skin, head and neck, thoracic cage/lung, heart, abdomen, 
genitourinary system, extremities, musculoskeletal system, nervous system, lymph nodes, and 
other organs 
5 Past medical history  
Medical history within the past one year 
6 Ultrasound examination  
For subject screening, the presence or absence of abdominal scarring and surgical clips in the 
passage through which the ultrasonic beam passes are checked. It is also checked if adequate 
acoustic window for HIFU procedure is secured.  
7 KPS Evaluation  
 
The Karnofsky Performance Status (KPS) is evaluated, and those with a KPS index of less than 70% 
during screening are excluded from the subjects subject to this clinical trial. 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 43 / 65 
 
8. CT exam  
To evaluate the size change and tumor response of pancreatic cancer by the combined 
treatment, the size of pancreatic cancer tissue is measured by computed tomography (CT) 
before and after treatment. It is measured with the longest length in the axial image of CT with 
the largest pancreatic tumor visible. It is also determined whether or not metastasis is present. 
9. Blood test  
Specific test items for blood test are as follows. 
Purpose 
items 
Complete Blood Count 
Hemoglobin, Hematocrit, Red blood cell count, White blood cell 
count with differential, Platelet count 
Renal function 
Blood urea nitrogen(BUN), Creatinine 
Liver function 
serum 
Aspartate 
aminotransferase(AST), 
Alanine 
aminotransferase(ALT),  
Albumin, Bilirubin 
Pancreatic function 
Amylase, Lipase 
 
10. CA19-9 
Measure serum CA19-9 levels to observe significant changes after HIFU treatment. 
11 NRS pain assessment  
For the evaluation of pancreatic cancer-related pain, a survey using a numerical rating scale 
(NRS, 0-10 points) is performed. 
12. Survival rate  

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 44 / 65 
 
The duration of the subject's life from the diagnosis date of pancreatic cancer or from the 
combined treatment date to the date of death is tracked and observed for the evaluation of 
survival rate. 
13-14 Anti-cancer Drug Administration & HIFU Treatment 
The subjects registered in this clinical trial are treated with anticancer drugs on the scheduled 
date of treatment and receive HIFU procedures in accordance with ALPILUS 900 User Manual 
within 24 hours of administration. A total of four combined treatments are performed for eight 
weeks. 
15. Adverse events/Serious Adverse Events   
Evaluate in accordance with the criteria defined in chapter 14 of the clinical trial proposal and 
record them in the case report form. 
16 Concomitant medication and treatment  
Drugs and treatment activities that may affect the results of this clinical trial are prohibited, and 
all medications already taken due to underlying diseases are recorded during screening, and 
only additional medications and treatment activities are recorded in the case report form 
17 Immune analysis  
Perform phenotypic analysis of leukocytes with flow cytometry analysis of blood samples just 
before HIFU-chemo treatment at each visit to prove if any immune reaction occurs during the 
treatment by the help of an immunology professor in our college (Kim HR, 20 years’ experience 
in cell immunology). All remaining blood samples for immune analysis will be stored in deep 
freezer.  
* Phenotypic analysis of leukocytes 
  
Set1 
Set2 
Set3 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 45 / 65 
 
 viable dye 
viable dye 
viable dye 
 CD45 
CD45 
CD45 
1 CD19 
CD4 
CD4 
2 CD27 
CD8 
CD8 
3 IgD 
CCR7 
CD25 
4 CD38 
CD45RA 
PD-1 
5 CD24 
IL-7R 
FoxP3 
6 CD14 
PD-1 
Ki-67 
7 CD16 
Tim3 
GzmB 
8 CD56 
Lag3 
T-bet 
9 TCRδ 
CD38 
Tcf1 
10 TCR 
CTLA-4 
Tox 
 
Set1: B-cell subsets (naive, memory, regulatory B cells, and plasma/plasambalst), 
monocyte-subset (classical, intermediate, and inflammatory monocytes), CD56bright NK 
(regulatory), CD56dim NK cells,  T cells, δ T cells 
Set2: Effector/memory T-cell subsets (CD4 and CD8 T-cell subsets), exhausted/activated 
phenotype of T cells (immune checkpoint molecules: PD-1, Tim-3, Lag3, CD38, CTLA-
4). 
Set3: regulatory T cells (FoxP3), proliferating T cells (PD-1, Ki-67+), effector molecule 
expression (granzyme B), and effector/memory/exhausted subsets by transcriptional 
factors (T-bet, Tcf1, and Tox) 
 
12. Expected Adverse Events  
12.1 Expected Adverse Events by HIFU  
① Skin burns, bleeding, or infections in the treatment area; 
② Subcutaneous fat sclerosis  
③ Abdominal pain 
④ Pancreatitis 
⑤ Tumor hemorrhage 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 46 / 65 
 
⑥ Peritonitis  
⑦ Jaundice 
⑧ Vascular injury (aortic rupture) 
⑨ Pancreatoduodenal injury and perforation. 
⑩ Gastric injury and perforation 
⑪ Bowel necrosis 
12.2 Expected Adverse Events by Anticancer Drugs  
① Thrombocytopenia 
② Neutropenia 
③ leukopenia 
④ Anemia 
⑤ Lymphopenia 
⑥ Febrile neutropenia 
⑦ Hair loss 
⑧ Peripheral sensory neuropathy 
⑨ Lacking appetite 
⑩ Rash 
⑪ Nausea  
⑫ Dullness 
⑬ Fatigue 
⑭ Diarrhea 
⑮ Alanine aminotransferase (ALT) increase 
16 Hyponatremia 
 
13. Clinical Trial Suspension and Termination Criteria  

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 47 / 65 
 
13.1 Suspension Criteria 
①  If it is deemed that the conditions observed during the clinical trial are unreasonable to 
continue the clinical trial, the clinical trial PI may suspend the clinical trial, and shall 
immediately notify the IRB of this fact and submit a detailed statement of reasons for early 
termination and suspension.  
② Clinical trials may also be suspended in the event of a life-threatening adverse event/ 
adverse device effects or for the treatment of an adverse event occurring. 
13.2 Termination Criteria 
① When the subject or legal representative requests discontinuance of participation in clinical trials; 
② When surgery, medication, or medical devices that may affect safety and validity are used in 
combination 
③ When it is impossible to continue participating in a clinical trial due to a serious adverse event. 
④ When the measurement method is not performed properly 
⑤ When the subject fails to comply with the instructions of investigator or fails to comply with the 
conditions given in the consent form, which affects the evaluation of the validity of the study 
⑥ When clinical trial personnel determine that there is a problem with the progression of clinical 
trial 
13.3 Suspension Process 
① In case that the clinical trial is suspended, record and store the reason for the suspension and 
data related to the clinical trial conducted before the suspension, and submit a statement of reasons 
to the IRB.  
② If the clinical trial is suspended, appropriate measures and follow-up monitoring shall be taken.  
③ Suspended subjects are excluded from the validity assessment. 
13.4 Termination Process 
① 
1 In the case of termination from a clinical trial, the reason for the termination and data 
related to the clinical trial conducted before termination shall be recorded and stored, and a 
statement of reasons shall be submitted to the IRB.  
② 
Date collected until the subjects are dropped out are included in safety analysis and 
excluded from the validity assessment. 
 
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 48 / 65 
 
14. Efficacy and Safety: Evaluation Criteria, Evaluation Methods and 
Reporting Methods  
14.1 Efficacy Evaluation.. 
14.1.1 Efficacy Variables 
<Primary endpoints> 
1) Tumor response on CT after 2 months, 4 months and 6 months after the start of combined 
treatment 
2) Percentage of subjects who were subject to surgical resection 4 months and 6 months after the 
start of combined treatment 
<Secondary endpoints>  
1) Time-to-Progression 
2) Survival time 
14.1.2 Evaluation Criteria and Methods 
Efficacy variables were based on clinical studies to investigate the effectiveness of the FOLFIRINOX 
neoadjuvant chemotherapy. [23-27]. These efficacy variables are commonly used in clinical trials for 
conventional anticancer drugs, and the same variables are used in this study because HIFU is an 
auxiliary equipment used to enhance the efficacy of chemotherapy. Tumor response is to evaluate 
tumor reaction by anticancer drugs by size and is the primary and most widely used evaluation 
method for evaluating tumor reactions. The percentage of subjects that were subject to surgical 
resection is a measure that must be addressed in view of the curative effects of pancreatic cancer 
patients by FOLFIRINOX. Both LAPC and BRPC are tumors that are either impossible or seemingly 
impossible to surgical resection, and when the invasions of vital vessel become smaller or eliminated 
by the effects of anticancer drugs, they can be treated by surgical resection, which can produce a 
better outcome. Although many patients are reported to be able to be operated on after the 
completion of the eight-cycle FOLFIRINOX chemotherapy, or four months after the start of 
chemotherapy [23], the percentage of subjects who are subject to surgical resection after the 12-
cycle treatment (or 6 months after start of the combined treatment) was also evaluated in this study, 
as surgery is often performed between one and two months after the last anti-cancer treatment, or 
six months after the start of chemotherapy. Both tumor progression and overall survival rate are 
essential measures used to see prognosis in chemotherapy. [24-27]. The success criteria of clinical 
efficacy are statistically significantly higher than the historical cohort. 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 49 / 65 
 
1) Tumor response on CT taken 2 months, 4 months and 6 months after the start of combined 
treatment 
Based on CT findings taken 2 months, 4 months, and 6 months after the start of combined treatment 
(each cycle is 14 days), 2-month, 4-month, and 6-month tumor responses are evaluated with 
complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) 
according to the Response Evaluation Criteria In Solid Tumors (RECIST, Ver 1.1) 
Table> Response Evaluation Criteria In Solid Tumors (RECIST, Ver. 1.1) 
Classification 
Criteria 
CR 
Complete Response 
Disappearance of all lesions and pathologic lymph 
nodes 
PR 
Partial Response 
≥ 30% decrease in the sum of longest diameters of 
targeted lesions 
SD 
Stable Disease 
Neither PR nor PD  
PD 
Progressive Disease 
≥ 20% increase in the sum of longest diameters and ≥ 5 
mm absolute increase in the sum of longest diameters  
or new lesions  
Reference) Watanabe H, Okada M, Kaji Y, Satouchi M, Sato Y, Yamabe Y, Onaya H, Endo M, Sone M, Arai 
Y.New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1)Gan To Kagaku 
Ryoho. 2009 Dec; 36(13):2495-501. 
 
2) Percentage of subjects who were subject to surgical resection 4 months or 6 months after 
the start of combined treatment 
When surgery is determined according to AJCC(American Joint Committee on Cancer, 8 edition) 
guidelines based on computed tomography (CT) images taken at 8th and 12th cycles (4M, 6M) after 
the onset of the combined treatment, the percentage of subjects who were able to be operated on 
compared to the total number of registered subjects is calculated.  
3) Time-to-Progression  
The time taken from the date of diagnosis of pancreatic cancer or from the start date of combined 
treatment of pancreatic cancer until the date of first documented progression, assessed up to 24 
months. Judging by RECIST ver. 1.1 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 50 / 65 
 
4) Survival time 
The time taken from the date of diagnosis of pancreatic cancer or the start date of combined 
treatment of pancreatic cancer until the date of death from any cause, assessed up to 24 months 
14.2. Safety Evaluation  
14.2.1 Safety Variables 
All adverse events that occurred to the subject during the clinical trial period. 
14.2.2 Evaluation Criteria and Methods 
The safety assessment is observed for all adverse events that occurred from the start of the first 
cycle of chemotherapy and HIFU combined therapy to the end of the clinical trial as follows: 
All undesirable medical findings that are newly observed during clinical trial are classified as an 
adverse event. Side effects predicted according to the definitions and criteria described in the 
section "14. Evaluation Criteria, Evaluation Methods, and Reporting Methods for Safety including 
Side Effects" are also classified as adverse events. The degree of adverse events caused by medical 
devices is graded according to the NCI-CTCAE (Version 4.03) criteria, and the use of terms in medical 
coding is based on MedDRA's "Preferred Term" and "System organ class". However, in case of an 
adverse events that do not have any applicable items, write 'Other' of the appropriate 'Categories' 
and record the details and select the appropriate grade from grade 1-5 (see 14.3.1 Severity Degree 
Assessment Section). 
 
14.3. Data Collection and Statistical Analysis 
All data measured and recorded in this study will be summarized according to the definition of the 
appropriate analysis group as defined in 14.3. Summary statistics are based on average ± standard 
deviation for continuous data and frequency (percentage) for categorical data. 
14.3.1. Definition of Analysis Group 
[Efficacy Analysis Group] 
The demographic information is analyzed for the FAS analysis group, and the efficacy analysis is 
conducted for the FAS and PP analysis groups respectively. 
- Full Analysis Set (FAS): It is the main analysis group of the efficacy assessment of this study and  
is defined as all subjects who, after agreeing to participate in the study, are treated with the device 
for clinical trials and have more than one effective assessment data. 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 51 / 65 
 
- Per Protocol Analysis Set (PP): It is defined as all subjects who after agreeing to participate in the 
study, are treated with the device for clinical trial and have finished the clinical trial in accordance 
with the study plan without significant research plan violations until the end of the study. Any 
concomitant medication or alternative treatment that affects efficacy during the clinical trial period 
is excluded from the PP analysis group. 
☞ Significant research contract violations:  
① 
In case of violation of inclusion and exclusion criteria 
② 
In case of taking a prohibited medication or a prohibited medical treatment that 
affects the efficacy evaluation during the clinical trial period. 
[Safety Analysis Group]  
The safety assessment is performed in the SAS analysis group.   
- Safety Analysis Set (SAS): After agreeing to participate in the study, SAS is defined as all subjects 
who have received at least one combined treatment.  
[Processing of missing data (missing value)]  
If missing values occur in the efficacy variables, they are excluded from the analysis.  
  
14.3.2 Statistical analysis methods 
[General analysis]  
For demographic information, continuous data are summarized in descriptive statistics (numbers, 
means, standard deviations, median, minimum and maximum), while categorical data are presented 
with frequency and fraction. This study is an exploratory study and therefore does not necessarily 
require a statistical hypothesis validation. However, if a statistical validation is possible or necessary, 
but both tests are carried out at a significant level of 5% unless they are specifically stated where 
statistical tests are possible or necessary. unless specifically stated, a two-sided test shall be carried 
out at a significant level of 5%. All statistical analyses are conducted using the MedCalc (ver 19.4.1) 
statistical program. Regarding covariate variables related to chemotherapy, since patients with past-
medical history of previous anticancer treatment for pancreatic cancer are excluded by exclusion 
criteria, and FOLFIRINOX regimen are fixed variables, previous anticancer medication, drug type, 
medication interval, and medication method are all controlled. Therefore, the covariates related to 
chemotherapy will proceed in a controlled state, but if there are other uncontrolled variables, they 
will be corrected by using 1) multivariate regression, 2) propensity score matching, or 3) inverse 
probability of treatment weighting. 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 52 / 65 
 
 
[Analysis of Efficacy Variables] 
Primary endpoints  
1) Tumor response after 4th, 8th, and 12th cycles (2M, 4M, 6M)  
- The tumor response measured at each time point is presented with the number and percentage 
of subjects for each tumor response category (CR, PR, SD, PD).  
2) The percentage of operated subjects to total subjects after 8 or 12 cycles (4M, 6M) 
- The number and percentage of subjects who are subject to operation at each time point shall be 
presented.  
 
Secondary endpoints  
3) Time for tumor progression and overall survival rate are estimated using the Kaplan-Meier 
method.  
4) After the initial analysis, for comparison with a standard FOLFIRINOX treatment, the control group 
is established by performing matching with clinical trial group, using the following variables in the 
histological cohort treated with LAPC/BRPC in our institute  
 - Location of pancreatic cancer tumors (head-uncinate/neck-body/tail), size of tumors, presence 
and degree of vascular invasions (SMA, Celiac Axis, common hepatic artery, SMV, MPV), age, sex, 
CA19-9 at the time of diagnosis 
5) In the control group, tumor response after 4th, 8th, and 12th cycles (2M, 4M, 6M) ia evaluated 
and compared with test group using the chi-square test. 
6) the percentage of patients who were able to be operated on after 8 or 12 cycles (4M, 6M) is 
calculated from the control group and compared with test group using the chi-square test. 
7) Time for tumor progression and survival rate are estimated in the control group and compared 
with the test group using log-rank test.  
 - Consideration of potential covariates: For major covariates related to chemotherapy, a 
stratification analysis is conducted for each evaluation variable to evaluate its effects. 
 
[Analysis of Safety Variables]  

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 53 / 65 
 
All adverse events that occurred during the clinical trial period are classified into 'System Organ 
Class' of MedDRA (ver 18.0) and 'Preferred Term' and presented as the number of subjects, 
proportion (%) and number of cases for each degree.  
 
15. Evaluation Criteria, Methods and Reporting of Adverse 
Events 
15.1 Definition of Adverse Events 
① "Adverse Event (AE)”: Any untoward medical occurrence, unintended disease or injury or ant 
untoward clinical signs (including an abnormal laboratory finding) in subjects, users or other persons 
whether or not related to the investigational medical device   
② “Adverse Device Effect (ADE)”: All harmful and unintended reactions caused by medical devices 
for clinical trials, which cannot exclude causality with medical devices for clinical trials.  
③ “Unexpected Adverse Device Effect” refers to an event or reaction that is not listed in the 
investigator’s brochure or is not listed at the specificity or severity that has been observed; or if an 
investigator’s brochure is not required or available, is not consistent with the risk information.. 
15.2 Serious Adverse Events/Adverse Device Effect: Definition 
Serious adverse event/adverse device effect refers to any of the following adverse events caused by 
medical devices used in clinical trials: 
① Resulted in death or a life threatening illness or injury 
② Required in-patient hospitalization or prolongation of existing hospitalization . 
③ Resulted in a permanent impairment of a body structure or a body function  
④ Resulted required in medical or surgical intervention to prevent life threatening illness or 
injury or permanent impairment of a body structure or a body function  
15.3 Evaluation of Adverse Events 
15.3.1 Severity Evaluation 
The severity of adverse events is assessed according to the NCI-CTCAE (Version 4.03) criteria. 
However, in case of an adverse event with no applicable item, 'Other' of appropriate 'Categories' 
shall be written and the details shall be recorded, and the appropriate grade shall be selected 
according to the definitions below. 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 54 / 65 
 
Grade 
Explanation  
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living  
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to adverse events. 
 
15.3.2 Evaluation of Causal Relationships with Medical Device  
Causality  
Evaluation criteria  
Definitely related 
 The relationship between the occurrence of adverse events and the 
use of the medical device is reasonable, and is most likely explained 
by the use of the medical device than for any other reason. 
 Symptoms of adverse events disappear by discontinuance of the 
medical device, and hazardous cases appear when reused (performed 
only if reusable).  
 The occurrence of an adverse event is consistent with the 
information already known about the medical device or its affiliated 
medical device.  
Probably related 
 There is evidence that the medical device has been used, the time 
order of the use of the medical device and the occurrence of adverse 
events is reasonable, and is more likely to be explained by the use of 
the medical device than by other causes. 
 Symptoms of adverse events disappear by the discontinuation of 
the medical device  

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 55 / 65 
 
Possibly related 
 There is evidence that the medical device has been used, and the 
time order of the use of the medical device and the occurrence of 
adverse events is reasonable, and it is deemed to be due to the use 
of the medical device at the same level as other possible causes.  
 Symptoms of adverse events disappear by the discontinuation of 
the medical device  
Possibly not related 
 There is evidence that the medical device has been used, there is a 
more likely other cause for adverse events, and disappearance of the 
symptoms of adverse events by discontinuation of the medical device 
is present or ambiguous  
 Symptoms of adverse events are not shown or ambiguous at reuse 
of the medical device (performed only if reusable)  
Definitely 
not 
related 
 The medical device is not used or the time order of use of the 
medical device and adverse event development is not appropriate; 
 There are other obvious causes for adverse events. 
Unknown 
 Cannot be determined because of insufficient or conflicting 
information and cannot be supplemented or verified; 
The investigator shall evaluate the relevance of the medical device in the event of adverse events 
and describe the investigator’s opinion according to the criteria above.  
 
15.3.3 Evaluation Criteria .  
In this clinical trial, an adverse event is defined as all undesirable medical findings that symptoms 
occur that are not observed before the start of the clinical trial. The predicted side effects are also 
classified as adverse events, and the degree of adverse events is classified into 5 grades according 
to the NCI-CTCAE (Version 4.03) criteria, and the use of terms is reported using the 'System Organ 
Class' and 'Preferred Term' of MedDRA (ver 17.0). 
15.3.5 Serious Adverse Events/Adverse Device Effect Reporting  
Subinvestigator shall immediately report all serious adverse device effects to the PI during the 
clinical trial period. The PI shall record the reported adverse events/adverse device effects in the 
Serious Adverse Event CRF and report them to the KFDA and the IRB within 24 hours, regardless of 
whether they are related to the use of medical devices for clinical trials. In such cases, the PI shall 
use the identification code on behalf of the subject's personal information, such as the subject's 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 56 / 65 
 
name, social security number, and address, in order to protect the subject's confidential information, 
and shall comply with the instructions for reporting adverse events. 
In addition, significant risks, taboos, side effects, or events requiring cautions that the PI considers 
critical or related to the use of the medical device shall be recorded as Serious adverse 
events/Adverse Device Effect CRFs and reported immediately to the KFDA and the IRB.  
When reporting the case of death, the PI shall submit additional information, such as an autopsy 
report (applicable only to cases of autopsy) and a death certificate, to the KFDA and the IRB. 
The PI shall report serious and unexpected adverse events (including adverse device effects, serious 
AE/ADE) to the KFDA as soon as possible within the period specified in the following: 
1) In the event of death or life-threatening, additional information shall be reported within seven 
days from the date the PI receives or becomes aware of this fact, and the detailed information 
within eight days from the date of initial report.  
2) In the event of all other serious or unexpected AEs, the PI shall report them within 15 days from 
the date the PI receives or becomes aware of them. 
3) The PI shall regularly report additional safety information regarding serious AE/ADE until the 
relevant AEs are terminated (e.g., the loss of such AE or the inability to conduct follow-up 
investigations). 
4) If the PI intends to report ADEs to the Minister of KFDA according to the 1) and 2) above, PI shall 
submit a ADE CRF in accordance with the Medical Device Clinical Trial Management Standards (No. 
7 Camok 1 of KGCP's attached Form 56 ADE report), along with a prompt report on the ADE in 
accordance with attached Form 55.  
16. Informed Consent 
A written consent form must be received from each subject (or the subject's legal representative) 
before a screening assessment for clinical trials is conducted. Before starting the trial, clinical trial 
investigators should give patients who have met both inclusion and exclusion criteria and their 
guardians in-detail explanations of all aspects of the trial and sufficient time to enable to understand 
all foreseeable outcomes. A copy of the signed consent form shall be kept by the subject and the 
original by the researcher. 
Clinical trial researchers shall prepare and keep a list of all patients who have agreed to participate 
in clinical trials.   
Subjects should be informed of the fact that the subject's trial-related data will be used by the 
researchers and the level of disclosure in accordance with the relevant regulations for clinical trials. 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 57 / 65 
 
It should also inform the subject that the subject's medical records may be reviewed by the clinical 
trial monitor personnel or auditors, IRB or health authorities on-site inspection personnel.  
If the clinical trial plan is amended, the subject's consent form and the subject's consent manual 
may be amended to reflect the change in the plan. Where the subject's consent form and the 
consent documentation are amended, they shall be reviewed and approved by the IRB and the 
newly registered and currently participating subjects shall be explained according to revised content 
and sign on the revised consent form.  
17. Protocol for Compensation for Victims 
In the event of damage caused by the use of medical devices or clinical procedures that the subject 
would not have received if he did not participate in this clinical trial, all treatments will be taken in 
accordance with the hospital's standard procedures, and in the case of damage associated with the 
clinical trial, compensation for damage will be made in accordance with the victim's compensation 
protocol and the terms of the clinical trial insurance policy. 
18. Matters Concerning Treatment of Subjects after Clinical Trial. 
If the subjects are dropped out of the clinical trial due to AEs, or if there are any residual symptoms 
from side effects and AEs after completion of the clinical trial, sufficient treatment will be provided 
in accordance with the hospital's standard medical guidelines until recovery by performing 
appropriate medical measures for the AEs that have occurred, and those whose clinical trials have 
been completed without any AEs will be subject to general clinical observation following the 
hospital's standard procedures after the clinical trials. 
19. Measures for Safety Protection of Subjects 
19.1 Good Clinical Practice for Medical Devices (KGCP) and Helsinki Declaration  
The procedures set out in this proposal are designed to ensure that the PI and investigators comply 
with the basic spirit of the ICH-GCP and the Helsinki Declaration in conducting, evaluating, and 
recording the results. This clinical trial will also be carried out in accordance with domestic laws 
(medical device clinical trial management standards, KGCP). 
19.2 Institutional Review Board (IRB) 
Prior to commencement of clinical trials, the researcher shall submit the clinical trial proposal, subject 
consent form, and materials and documents related to the recruitment of subjects (e.g., advertising) 
to the IRB for review and approval.  
Any changes to the proposal that require approval from the IRB and the KFDA will not be applied 
to the clinical trial until the IRB reviews and approves the revised clinical trial proposal and, if 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 58 / 65 
 
applicable, the revised subject consent from. Any changes of clinical trial proposal to eliminate 
immediate risk factors for subjects may be applied immediately on the condition that they are 
notified to the KFDA and the IRB and requested approval as soon as possible. Changes to the 
proposal related to administrative procedures, such as changes in monitor personnel, changes in 
subinvestigator, changes in emergency contact numbers, etc., may be applied immediately even 
before approval by the IRB. 
The PI shall provide the clinical trial result report, latest information, and other information (e.g., 
safety update) to the IRB in accordance with the relevant regulations or procedures in the hospital. 
19.3 Measures for Safety Protection of Subjects 
Once new information is obtained that may affect the continuation of this clinical trial, it will be 
provided to subject or subject’s representative in a timely manner, and the researchers will discuss 
with the subjects whether or not to continue participating in the clinical trial. 
19.4 Clinical Trial Institution  
The head of the institution shall ensure that clinical laboratories, equipment, and professional 
personnel necessary for carrying out the clinical trial are equipped and shall ensure that the clinical 
trials are carried out properly, such as allowing necessary measures to be taken in case of emergency. 
19.5 Investigator  
The term "investigator" means PI, co-investigator, and subinvestigator. The investigators shall 
conduct the clinical trials in compliance with the clinical trial plan approved by IRB and the Minister 
of KFDA.  
① During or after a clinical trial, the investigator shall take measures to ensure that the subjects 
receive appropriate medical treatment for all AEs in the clinical trial, including clinically 
meaningful laboratory tests, and inform the subjects in case that medical treatment is required 
for the subjects' concurrent diseases that the investigators has become aware of.  
② In accordance with paragraph 14.6.3. Serious AE/ADE, the PI shall be obliged to report AEs 
reported by the subinvestigator to the KFDA and the IRB.  
③ The investigators shall accurately analyze and understand the clinical trial plan and actively 
respond to the subject's problems. 
 
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 59 / 65 
 
20. Others: Matters Necessary for Conducting Clinical Trial Safely 
and Scientifically  
20.1 Confidentiality 
20.1.1 Data 
The investigators shall observe confidentiality of all information relating to the trial plan provided 
by the clinical trial monitor personnel. Exceptions are made to IRB, subjects, or health authorities 
that require disclosure in accordance with laws or related regulations. 
20.1.2 Anonymity of Subjects  
The anonymity of subjects involved in clinical trials must be ensured. The identification of the subject 
shall consist of the subject's initials and the subject number specified in the CRFs and other data 
submitted to the clinical trial monitor. Inform the subjects that all trial materials are stored on the 
computer and are strictly confidential. The signed consent forms shall be kept by the PI. The PI 
keeps a list of subjects' numbers and names so that they can find the records later. Subject consent 
forms and list of subjects shall be kept for three years. 
Materials for identifying subjects should be strictly confidential by researchers. Exceptions shall be 
made if necessary for audit by health authorities, clinical trial monitors, or designated agents. 
20.1.3 Privacy Protection Methods 
The personal information of the subjects who participated in the clinical trial is used up to six 
months after the end of the study, and the collected information is properly managed in accordance 
with the Personal Information Protection Act. The personal information is not provided to other 
people except researchers but is kept confidential. Records that can be identified shall be 
anonymized by assigning a management number. Research-related data shall be kept in a place 
where there is a locking device, and access is prohibited other than those involved in the research. 
In addition, personal information will be kept for three years after the completion of the research 
and will be discarded afterwards.  
Personal information, including research participation records and medical records, is provided only 
to those in charge. Exceptions shall be made if necessary for audit by health authorities, clinical trial 
monitors, or designated agents. 
20.2 Compliance and Change in Clinical Trial Protocol 
If it is necessary to change the contents of this proposal during clinical trials, the revised proposal 
shall be prepared by the PI. The investigators shall not apply any changes to the clinical trial until 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 60 / 65 
 
obtaining approval from the IRB, except to immediately prevent harm to the subject. Significant 
proposal violations shall be recorded in the CRF. 
If a modification or change of the clinical trial proposal is applied before obtaining approval from 
the IRB to prevent any immediate harm to the subject, such modification or change shall be 
submitted to the IRB (for future approval) and the KFDA (if required by relevant regulations) as soon 
as possible. 
Significant changes in the clinical trial proposal include changes affecting the safety of the subject, 
changes in the scope of the study, changes in the scientific query of the clinical trial, changes in the 
experimental design, changes in evaluation variables, changes in the number of subjects, and 
changes in the inclusion criteria of subjects. These changes must be recorded and will be provided 
as data to demonstrate their validity. 
The PI must prepare these changes with the revised clinical trial proposal, and the revised clinical 
trial proposal must be approved by the IRB or the relevant authorities before implementation. 
Regarding the procedure for changing the clinical trial proposal, revised version of the original 
approved one will be submitted to the grant authority in parallel with the progress of IRB approvals. 
If the modified clinical trial proposal requires a change in the consent form, it must be approved 
by the IRB. 
Urgent deviance from the clinical trial proposal to exclude obvious and urgent risks of a particular 
subject involved in a clinical trial is considered critical for the safety and well-being of the subject 
and can only be implemented for that particular subject. 
If the changes in the clinical trial proposal are minor, it is sufficient for the PI to notify the IRB. 
However, if there is an inherent change in the clinical trial design or an increased risk to the subject, 
1) the subject's consent form must be modified and submitted to the IRB for review and approval, 
2) If such a change affects the subjects, new consent must be obtained from the subjects already 
recruited for the clinical trial with the newly modified consent form, and 3) new consent form should 
be used to obtain their consent from newly enrolled subjects. 
20.3 
 Clinical Trial Monitoring  
Monitoring Responsibility : PI Jae Young Lee, Prof.  
Clinical Trial Monitor : Hyun-Ji Kim, CRA / Synex Consulting Ltd. 
Prior to the start of the clinical trial, the PI, co-investigators and sub-investigators will hold a meeting 
of researchers or a meeting of clinical trial initiation for this clinical trial. The meeting will discuss in 
detail the clinical trial plan, the performance of clinical trial procedures, the preparation of CRFs, the 
methods of examination, etc. Researchers who are unable to attend such meetings or meetings or 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 61 / 65 
 
who will later participate in clinical trials should be properly trained by the PI or by the person  
authorized by the PI. 
The PI shall provide guidance and data to the co-investigators in a proper way and have the 
monitoring personnel responsible for this clinical trial monitor the progress and data before and 
during the clinical trial period. In order to ensure that the study is conducted in accordance with 
KGCP and that trial data can be recognized at home and abroad, the PI may conduct monitoring 
and auditing. The monitoring personnel explain the monitoring plan to the researchers before 
starting the clinical trial, and monitor the data and safety information at least three times during 
the clinical trial period to verify if the researchers perform the clinical trial in accordance with the 
clinical trial plan and the relevant regulations. Clinical trial monitors routinely visit and contact 
researchers, and are authorized to monitor various records of clinical trials. 
It is the responsibility of the clinical trial monitor to monitor the CRFs regularly throughout the 
clinical trial period to demonstrate the completeness, consistency and accuracy of the recorded data 
and to demonstrate that the recorded data was faithful to the clinical trial plan. The findings should 
be properly discussed with the investigators. The investigators shall appropriately inform the clinical 
trial monitor personnel of any findings during the clinical trial and cooperate with the monitoring 
activities.  
 
20.4 Record and Use of Trial Results  
20.4.1 Case Report Form and Source Document  
All information required for clinical trials should be recorded on the corresponding case report form 
(CRF) page. In addition, the investigators must sign the investigator's signature column in each CRF 
to ensure the accuracy of the data. 
The investigators should allow direct access to source data and source documents during monitoring, 
inspection, IRB review and on-site inspection related to clinical trials. The original CRFs of each 
subject will be verified by the clinical trial monitor personnel against source documents in the clinical 
trial institution. 
The PI shall maintain and provide clinical trial essential documents. Essential documents for clinical 
trials refer to documents that enable individual or overall evaluation of the performance of clinical 
trials and the quality of data obtained from them. Essential documents for clinical trials include 
source documents, which include hospital records, medical records, clinical laboratory test results, 
subjects logs, various examination papers and records kept by pharmacies, pathology laboratories, 
and medical and technical departments involved in clinical trials.  

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 62 / 65 
 
Source documents, CRFs, and other clinical trial-related documents shall be kept in the testing 
institution, and the PI shall retrieve the original copy and keep a copy in the testing institution. 
Investigators shall keep all records related to clinical trials until the KFDA completes inspection, and 
keep them until the deadline set by the PI after the inspection is completed. 
20.4.2 Storage of Clinical Research Data  
All CRFs and data and management logs provided shall be stored for three years from the end of 
the clinical trial. No clinical research material shall be destroyed or transferred to another location 
without prior written consent of the PI. If an investigator is excluded from the clinical trial due to 
relocation or retirement or other reasons, he/she shall notify the PI and agree to appropriate 
solutions.  
Investigators shall retain the clinical medical device use records, copies of the CRFs and source data 
related to clinical trials for a period of three years as prescribed by local regulations.  
In addition, all clinical research materials listed above shall be disposed of by requesting a disposal 
company after a list of disposal documents and reasons for disposal are written in the document 
disposal records in accordance with the agency's SOP after three years of preservation. 
 
 
 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 63 / 65 
 
References   
1 
류지곤 (2016) 췌장암의 원인 및 병인 In: 윤정환, 김주성, 류지곤, (eds) 김정룡 소화기계 
질환 일조각 서울, pp 1380-1388 
2 
김용태 (2019) 췌장암의 원인과 진단 In: 김선회, 서경석, 이광웅, 장진영, (eds) 
간담췌외과학 도서출판 의학문화사 pp 943-955 
3 
황진혁 (2016) 췌장암의 임상상 및 진단 In: 윤정환, 김주성, 류지곤, (eds) 김정룡 소화기계 
질환 일조각 서울 pp 13891395 
4 
Conroy T, Desseigne F, Ychou M, et al. (2011) FOLFIRINOX versus gemcitabine for metastatic 
pancreatic cancer. N Engl J Med 364:1817-1825 
5 
Conroy T, Hammel P, Hebbar M, et al. (2018) FOLFIRINOX or Gemcitabine as Adjuvant 
Therapy for Pancreatic Cancer. N Engl J Med 379:2395-2406 
6 
우상명 (2016) 췌장암의 항암화학요법. In: 윤정환, 김주성, 류지곤, (eds) 김정룡 소화기계 
질환 일조각, 서울 pp 1401-1416 
7 
Murphy JE, Wo JY, Ryan DP, et al. (2018) Total Neoadjuvant Therapy With FOLFIRINOX 
Followed by Individualized Chemoradiotherapy for Borderline Resectable Pancreatic 
Adenocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol 4:963-969 
8 
Choi YH, Lee SH, You MS, et al. (2020) Prognostic Factors for Patients with Borderline 
Resectable or Locally Advanced Pancreatic Cancer Receiving Neoadjuvant FOLFIRINOX. Gut 
Liver 
9 
Hackert T, Sachsenmaier M, Hinz U, et al. (2016) Locally Advanced Pancreatic Cancer: 
Neoadjuvant Therapy With Folfirinox Results in Resectability in 60% of the Patients. Ann 
Surg 264:457-463 
10 
김선회 (2019) 췌장암의 외과적 치료 In: 김선회, 서경석, 이광웅, 장진영, (eds) 
간담췌외과학 도서출판 의학문화사 pp 956-967 
11 
Wu F, Wang ZB, Zhu H, et al. (2005) Feasibility of US-guided high-intensity focused 
ultrasound treatment in patients with advanced pancreatic cancer: initial experience. 
Radiology 236:1034-1040 
12 
Jung SE, Cho SH, Jang JH, Han JY (2011) High-intensity focused ultrasound ablation in 
hepatic and pancreatic cancer: complications. Abdom Imaging 36:185-195 
13 
Vidal-Jove J, Perich E, Del Castillo MA (2015) Ultrasound Guided High Intensity Focused 
Ultrasound for malignant tumors: The Spanish experience of survival advantage in stage III 
and IV pancreatic cancer. Ultrason Sonochem 27:703-706 
14 
Marinova M, Huxold HC, Henseler J, et al. (2019) Clinical Effectiveness and Potential Survival 
Benefit of US-Guided High-Intensity Focused Ultrasound Therapy in Patients with Advanced-
Stage Pancreatic Cancer. Ultraschall Med 40:625-637 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 64 / 65 
 
15 
Li T, Wang YN, Khokhlova TD, et al. (2015) Pulsed High-Intensity Focused Ultrasound 
Enhances Delivery of Doxorubicin in a Preclinical Model of Pancreatic Cancer. Cancer Res 
75:3738-3746 
16 
Lee ES, Lee JY, Kim H, et al. (2013) Pulsed high-intensity focused ultrasound enhances 
apoptosis of pancreatic cancer xenograft with gemcitabine. Ultrasound Med Biol 39:1991-
2000 
17 
Lee JY, Choi BI, Ryu JK, et al. (2011) Concurrent chemotherapy and pulsed high-intensity 
focused ultrasound therapy for the treatment of unresectable pancreatic cancer: initial 
experiences. Korean J Radiol 12:176-186 
18 
Rapoport N, Payne A, Dillon C, Shea J, Scaife C, Gupta R (2013) Focused ultrasound-
mediated drug delivery to pancreatic cancer in a mouse model. J Ther Ultrasound 1:11 
19 
Park EJ, Ahn YD, Lee JY (2018) In vivo study of enhanced chemotherapy combined with 
ultrasound image-guided focused ultrasound (USgFUS) treatment for pancreatic cancer in 
a xenograft mouse model. Eur Radiol 28:3710-3718 
20 
Kim JH, Kim H, Kim YJ, Lee JY, Han JK, Choi BI (2014) Dynamic contrast-enhanced 
ultrasonographic (DCE-US) assessment of the early response after combined gemcitabine 
and HIFU with low-power treatment for the mouse xenograft model of human pancreatic 
cancer. Eur Radiol 24:2059-2068 
21 
Yu MH, Lee JY, Kim HR, et al. (2016) Therapeutic Effects of Microbubbles Added to Combined 
High-Intensity Focused Ultrasound and Chemotherapy in a Pancreatic Cancer Xenograft 
Model. Korean J Radiol 17:779-788 
22 
Lee JY, Oh D, Lee K, et al. (2019) Combined treatment of chemotherapy (Gem/nPac) and 
focused ultrasound for unresectable pancreatic cancer: Prospective study for safety and 
initial efficacy. RSNA Oral presentation:  
23 
Yoo C, Lee SS, Song KB, et al. (2020) Neoadjuvant modified FOLFIRINOX followed by 
postoperative gemcitabine in borderline resectable pancreatic adenocarcinoma: a Phase 2 
study for clinical and biomarker analysis. Br J Cancer 
24 
Janssen QP, Buettner S, Suker M, et al. (2019) Neoadjuvant FOLFIRINOX in Patients With 
Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-
Analysis. J Natl Cancer Inst 111:782-794 
25 
Suker M, Beumer BR, Sadot E, et al. (2016) FOLFIRINOX for locally advanced pancreatic 
cancer: a systematic review and patient-level meta-analysis. Lancet Oncol 17:801-810 
26 
Rombouts SJ, Walma MS, Vogel JA, et al. (2016) Systematic Review of Resection Rates and 
Clinical Outcomes After FOLFIRINOX-Based Treatment in Patients with Locally Advanced 
Pancreatic Cancer. Ann Surg Oncol 23:4352-4360 
27 
Petrelli F, Coinu A, Borgonovo K, et al. (2015) FOLFIRINOX-based neoadjuvant therapy in 
borderline resectable or unresectable pancreatic cancer: a meta-analytical review of 
published studies. Pancreas 44:515-521 

Protocol No. CureHIFUpanc_01                                    Version 5.4 / Date 20210813 
 
Page 65 / 65