A Prospective Phase Ⅱ Clinical Study of Stereotactic Radiotherapy Combined With Chemotherapy With Different Biological Effective Doses (<70gy vs. >70Gy) in Locally Advanced Pancreatic Cancer
Phase: NA
Conditions: Treatment
Sponsor: Changhai Hospital

Synopsis 
Clinical Trial NCT04603586 
Last approval data: The study protocol was approved on August 18, 2020. 
Study title: Dose escalation of stereotactic body radiation therapy for locally 
advanced pancreatic cancer: an open-label, phase 2, randomized controlled trial 
Regimen:  
Arm A: Stereotactic body radiation therapy (SBRT) with a biologically effective dose 
(BED10, α/β=10) <70Gy. Gemcitabine (1000 mg/m2) and nab-paclitaxel (125mg/m2) 
administered intravenously on day 1 and 8 of each 21-day cycle for six cycles before 
SBRT. 
Arm B: Stereotactic body radiation therapy (SBRT) with a biologically effective dose 
(BED10, α/β=10) >70Gy. Gemcitabine (1000 mg/m2) and nab-paclitaxel (125mg/m2) 
administered intravenously on day 1 and 8 of each 21-day cycle for six cycles before 
SBRT. 
Study phase: phase 2 
Research hypothesis: SBRT with a BED10 >70Gy will provide improved survival for 
patients with locally advanced pancreatic cancer compared with SBRT with a BED10 
<70Gy. 
Objectives: 
Primary objective:  
⚫ 
To assess progression free survival of patients with locally advanced pancreatic 
cancer receiving SBRT with a BED10 >70Gy or BED10 <70Gy after gemcitabine 

and nab-paclitaxel. 
Secondary objective: 
⚫ 
To investigate overall survival. 
⚫ 
To evaluate and compare overall safety and adverse effects of SBRT with a 
BED10 >70Gy or BED10 <70Gy after gemcitabine and nab-paclitaxel, determined 
by National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. 
Pre-specified exploratory analysis 
⚫ To evaluate the overall survival and progression free survival of subgroups. 
Study design: This is an open-label, phase 2, randomized controlled trial, which 
attempts to compare outcomes of patients with locally advanced pancreatic cancer 
receiving SBRT with a BED10 >70Gy or BED10 <70Gy after gemcitabine and nab-
paclitaxel. Patients with cytologically or histologically verified pancreatic 
adenocarcinoma are eligible for this study. Patients were randomly allocated into 
SBRT with a BED10 >70Gy or BED10 <70Gy after gemcitabine (1000 mg/m2) and 
nab-paclitaxel (125mg/m2) administered intravenously on day 1 and 8 of each 21-day 
cycle for six cycles. Prior treatment, assessment of eligibility and safety evaluations 
during the study are conducted by a committee composed of a group of study 
investigators who are experts in treating patients with pancreatic cancer. Any patient 
who meets criteria for discontinuation following treatment will proceed to follow-up. 
All patients who are discontinued from treatment will continue to be followed for 
safety, progression, and overall survival after discontinuation of study medication 

based on the assessment schedules. This study will continue for about five years. 
Study durations: 
Enrollment is planned to take about three years. 
Treatment continues until disease progression or unacceptable toxicities. 
Follow-up is completed within approximately 3 years after the initiation of treatment. 
Anticipated duration of the study is about 5 years. 
Study center: single center 
Patient eligibility criteria: 
Key inclusion criteria: 
⚫ 
Cytologically or histologically verified pancreatic adenocarcinoma  
⚫ 
Imaging examinations confirmed locally advanced pancreatic cancer 
⚫ 
No previous radiotherapy, chemotherapy, immunotherapy or targeted therapy 
⚫ ECOG of 0 to1 
⚫ Age of 18 years or older 
⚫ Adequate bone marrow function, defined as: Absolute neutrophil count (ANC) ≥ 
1.5×109 cells/L, leukocyte count≥ 3.5×109 cells/L, platelets ≥ 70×109 cells/L, 
hemoglobin ≥ 8.0 g/dl 
⚫ Adequate liver and renal, defined as: Albumin > 2.5 g/dL, total bilirubin < 3 mg/dL, 
creatinine < 2.0 mg/dL, AST<2.5 × ULN (Upper Limit of Normal) (0-64U/L), 
ALT<2.5 × ULN (0-64U/L) 
⚫ Adequate blood clotting function, defined as: international normalized ratio (INR) 
< 2 (0.9-1.1) 

⚫ Ability of the research subject or authorized legal representative to understand and 
the willingness to sign a written informed consent document 
Key exclusion criteria: 
⚫ Previously receiving radiotherapy, immunotherapy or targeted therapy 
⚫ Evidences of metastatic disease confirmed by chest CT or PET-CT 
⚫ ECOG ≥2 
⚫ Age <18 years 
⚫ Secondary malignancy 
⚫ Abnormal results of blood routine examinations and liver and kidney and 
coagulation tests 
⚫ Patients with active inflammatory bowel diseases or peptic ulcer 
⚫ Gastrointestinal bleeding or perforation within 6 months 
⚫ Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals 
⚫ Medical history of symptomatic congestive heart failure: New York Heart 
Association Class III to IV 
⚫ Medical history of respiratory insufficiency 
⚫ Women who are pregnant or breastfeeding 
⚫ Participation in another clinical treatment trial 
⚫ Inability of the research subject or authorized legal representative to understand 
and the willingness to sign a written informed consent document 
Statistical considerations: 
Sample size: It is estimated that the progression free survival of SBRT with a 

BED10 >70Gy and BED10 <70Gy is 12 months and 7 months, respectively. Therefore, 
we calculated that 120 patients were needed to be enrolled (60 per group) to give 80% 
power to detect a statistically significant difference between treatment groups with a 
type I error of 5% (two-sided). 
Analyses: 
Demographics and baseline characteristics: Demographic, disease and treatment 
characteristics were summarized with frequency and percentage for categorical 
variables, and median and interquartile range (IQR) for continuous variables. 
Categorical binary variables were compared with Fischer’s exact test or χ² test 
(depending on number of observations).  Student t-test or Mann-Whitney U test was 
used for analysis in the case of normally or non-normally distributed continuous 
covariates. 
Efficacy analyses: The primary endpoint is progression free survival (PFS), defined 
as the time from the random assignment to treatment until documentation of any 
clinical or radiological disease progression or death, whichever occurred first. The 
corresponding 95% CI will be estimated using the Kaplan-Meier product-limit 
method. OS curves will be plotted using the Kaplan-Meier method. Log-rank method 
will be used to compare PFS of two groups. 
The secondary endpoint is overall survival (OS), defined as the time from the random 
assignment to treatment until death irrespective of cause.  
Safety analyses: Safety analyses will be summarized in all treated patients. 
Descriptive statistics of safety will be presented using National Cancer Institute (NCI) 

Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All 
treatment-emergent adverse effects and severe adverse effects will be tabulated using 
worst grade per NCI CTCAE by system organ class and preferred term. On-study lab 
parameters including hematology, chemistry, liver function and renal function will be 
summarized using worst grade per NCI CTCAE criteria. 
Exploratory analyses: Post-hoc subgroup analyses of OS and PFS will be 
performed. Patients will be categorized into different subgroups according to 
specified factors.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1. Introduction 
1.1 Background 
Pancreatic cancer is one of the most lethal malignancies and fourth leading cause of 
cancer death in both genders in US, where the mortality and incidence increase over 
the past decade with a lowest 5-year survival rate of 13% among all cancers.1 
Although surgical resection is deemed to provide long-term disease control, only 20% 
patients were candidates for upfront surgery. Therefore, SBRT as local therapy with 
chemotherapy is preferred. However, proper doses of SBRT for pancreatic cancer 
remain ambiguous. Though ablative radiotherapy is deemed to achieve a good local 
control that may contribute to survival benefits, high radiation doses prescribed for 
lung cancer may not be appropriate for pancreatic cancer in the case of lesions 
adjacent to the gastrointestinal tracts. Additionally, the precise radiation dose that was 
used for SBRT as a radical local therapy for pancreatic cancer was unknown. 
Previously, it was demonstrated in our study that favorable outcomes could be 
achieved with BED10 >70Gy compared with BED10 of 60Gy-70Gy.2 A similar result 
was found in another study.3 Furthermore, A recent study also reported that ablative 
radiation in patients with technically resectable pancreatic cancer led to effective local 
tumor control and favorable overall survival despite advanced age, poor Karnofsky 
Performance Status score, and conservative use of chemotherapy in the cohort 
studied.4 However, no prospective studies have confirmed the survival benefits 
ascribed to high radiation doses of SBRT. As a result, the aim of our study was to 
evaluate outcomes of SBRT with BED10 >70Gy or BED10 <70Gy following 

chemotherapy for locally advanced pancreatic cancer. 
 
1.2 Research hypothesis 
SBRT with BED10 >70Gy would provide improved survival for locally advanced 
pancreatic cancer compared with SBRT with BED10 <70Gy. 
 
1.3 Objectives 
1.3.1 Primary objective 
⚫ 
To assess progression free survival of patients with locally advanced pancreatic 
cancer receiving SBRT with a BED10 >70Gy or BED10 <70Gy after gemcitabine 
and nab-paclitaxel. 
1.3.2 Secondary objective: 
⚫ 
To investigate overall survival. 
⚫ 
To evaluate and compare overall safety and adverse effects of SBRT with a 
BED10 >70Gy or BED10 <70Gy after gemcitabine and nab-paclitaxel, determined 
by National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. 
1.3.3 Exploratory analysis 
⚫ To evaluate the overall survival and progression free survival of subgroups. 
 
2. Ethical considerations 
2.1 Good clinical practice 

This study will be conducted in accordance with Good Clinical Practice, as defined by 
the International Conference on Harmonization and in accordance with the ethical 
principles underlying European Union Directive 2001/20/EC and the United States 
Code of Federal Regulations, Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee approval/favorable opinion prior to initiation of 
the study. 
Personnel involved in conducting this study will be qualified by education, training, 
and experience to perform their respective tasks. 
 
2.2 Institutional Review Board/Independent Ethics Committee 
Before the study, investigators must have written and dated approval/favorable 
opinion 
from the Institutional Review Board/Independent Ethics Committee for the protocol, 
consent form, and any other written information to be provided to participants. 
Investigators should also provide the Institutional Review Board/Independent Ethics 
Committee with a copy of the Investigator Brochure or product labeling information 
to be provided to participants and any updates. 
Investigators should also provide the Institutional Review Board/Independent Ethics 
Committee with reports, updates and other information (eg, expedited safety reports, 
amendments, and administrative letters) according to regulatory requirements or 

institution procedures. 
All potential serious breaches must be reported to Institutional Review 
Board/Independent Ethics Committee immediately. A serious breach is a breach of the 
conditions and principles of Good Clinical Practice in connection with the study or 
the protocol, which is likely to affect, to a significant degree, the safety or physical or 
mental integrity of the subjects of the study or the scientific value of the study. 
 
2.3 Informed consent 
Participants must be clearly and fully informed of the purpose of procedures of the 
study, their potential benefits and risks, and other critical issues about the clinical trial 
by investigators. However, in situations where participants could not receive consent, 
their legally acceptable representatives should be informed of procedures of the study, 
their potential benefits and risks, and other critical issues about the clinical trial.  
Investigators should prepare an appropriate informed consent, which include all 
elements required by International Conference on Harmonization, Good Clinical 
Practice and applicable regulatory requirements. The sample informed consent form 
will adhere to the ethical principles that have their origin in the Declaration of 
Helsinki. 
Investigators must: 
(1) Provide the informed consent form and written information in the language where 
participants are most proficient. The purposes and procedures, potential benefits and 
risks and other issues of the study should be clarified clearly, and the language must 

be non-technical and easily understood. 
(2) Provide enough time for participants or their leally acceptable representatives to 
have a comprehensive understanding about the details of the study. 
(3) Obtain and keep an informed consent signed and personally dated by the 
paticipant or the participant's legally acceptable representative and by the person who 
conducted the informed consent discussion. 
(4) Obtain the Institutional Review Board/Independent Ethics Committee’s written 
approval/favorable opinion of the written informed consent form and any other 
information to be provided to the participants before study initiation, and after any 
revisions are completed for new information. 
(5) If informed consent is initially given by a participant’s legally acceptable 
representative, and the participant later becomes capable of making and 
communicating his or her informed consent during the study, consent must 
additionally be obtained from the participant. Meanwhile, the participant must also be 
informed about the details of the study to the extent compatible with his or her 
understanding 
(6) Revise the informed consent whenever important new information becomes 
available that is relevant to the participant's consent. The investigator or a person 
designated by the investigator should fully inform the participant or the participant's 
legally acceptable representative of all pertinent aspects of the study and of any new 
information relevant to the participant's willingness to continue participation in the 
study. This communication should be documented. 

The confidentiality of records that could identify participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements. 
The consent form must also include a statement that regulatory authorities have direct 
access to subject records.  
The explicit wish of a participant who is unable to provide his or her written consent, 
but who is capable of giving an opinion and assessing information to refuse 
participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator. 
 
3. Investigational plan 
3.1 Study design 
This is an open-label, single center, phase 2, randomized controlled trial to compare 
outcomes of patients with locally advanced pancreatic cancer receiving SBRT of 
BED10 >70Gy following chemotherapy with those of patients receiving SBRT with 
BED10 <70Gy after chemotherapy. Patients with cytologically or histologically 
verified pancreatic adenocarcinoma are eligible for the study. Patients enrolled in the 
study will be randomly allocated into two groups: SBRT of BED10 >70Gy and BED10 
<70Gy following chemotherapy. Treatment continued until disease progression or 
unacceptable toxicity. 
For patients with SBRT of BED10 >70Gy following chemotherapy: gemcitabine 
(1000 mg/m2) and nab-paclitaxel (125mg/m2) administered intravenously on day 1 
and 8 of each 21-day cycle for six cycles. SBRT would be performed two to three 

weeks after completion of chemotherapy. It would be delivered in five to six fractions, 
and BED10 of the total prescription dose should be more than 70Gy. 
For patients with SBRT of BED10 <70Gy following chemotherapy: The same 
chemotherapy regimen would be given. The BED10 of the total prescription dose 
would be less than 70Gy, delivered in five to six fractions. 
 
3.2 Durations of the study 
Enrolment is planned to occur approximately 2 to 3 years. Follow-up is projected to 
be continued for approximately 3 years after the initiation of treatment. Therefore, the 
anticipated duration of the study is about 5 years. 
The screening period is about 2 to 3 weeks. Patients are required to receive 6 cycles of 
chemotherapy. Upon commencing study treatment, patients may continue receiving 
study drug until the occurrence of any of unacceptable toxicity. Regardless of reason 
for discontinuation from study treatment, all participants may be contacted every 
month until death or until follow-up data collection is no longer of scientific value or 
otherwise needed (at the investigator’s discretion), to obtain information about 
subsequent treatment(s) and survival status.  
 
3.3 Study population 
For entry into the study, the following criteria MUST be met. 
3.3.1 Inclusion criteria 
1. Signed written informed consent 

1) Participants must have signed and dated an Institutional Review Board/Independent 
Ethics Committee approved written informed consent form in accordance with 
regulatory and institutional guidelines. This must be obtained before the performance 
of any protocol related procedures that are not part of normal care. 
2) Participants must be willing and able to comply with scheduled visits, treatment 
schedule, laboratory testing, and other requirements of the study. 
2. Target population 
1) Cytologically or histologically verified pancreatic adenocarcinoma. 
2) No history of radiotherapy, chemotherapy, immunotherapy or targeted therapy. 
3) Contrast enhanced CT/MR and PET-CT are required to determine stage by 
multidisciplinary approach. These imaging examinations provided should be obtained 
one to two weeks before study initiation, when available, so that the imaging is 
representative of the baseline state prior to entry into the present study. 
4) ECOG of 0 to1 
5) Age of 18 years or older 
6) Adequate bone marrow function, defined as:  
⚫ Absolute neutrophil count (ANC) ≥ 1.5×109 cells/L 
⚫ Leukocyte count≥ 3.5×109 cells/L 
⚫ Platelets ≥ 75×109 /L 
⚫ Hemoglobin ≥ 8.0 g/dl 
7) Adequate liver and renal function, defined as:  
⚫ Albumin > 2.5 g/dL 

⚫ Total bilirubin < 3 mg/Dl 
⚫ Creatinine <2.0 mg/Dl 
⚫ AST<2.5 × ULN (Upper Limit of Normal) (0-64U/L) 
⚫ ALT<2.5 × ULN (0-64U/L) 
8) Adequate blood clotting function, defined as: 
⚫ International normalized ratio (INR) < 2 
9) Women must not be breastfeeding nor pregnant. 
10) Investigators shall counsel women of childbearing potential and male subjects 
who are sexually active with women of childbearing potential on the importance of 
pregnancy prevention and the implications of an unexpected pregnancy. Investigators 
shall advise women of childbearing potential and male subjects who are sexually 
active with women of childbearing potential on the use of highly effective methods of 
contraception. And they must agree to use a highly effective form of contraception or 
avoid intercourse during and upon completion of the study and for at least 4 months 
after the last dose of study drug. For the purpose of this protocol, methods considered 
as highly effective methods of contraception including: 
⚫ Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
——Oral 
——Intravaginal 
——Transdermal 
⚫ Progestogen-only hormonal contraception associated with inhibition of ovulation: 

——Oral 
——Intravaginal 
——Implantable 
⚫ Intrauterine device (IUD) 
⚫ Intrauterine hormone-releasing system 
⚫ Bilateral tubal occlusion 
⚫ Vasectomized partner 
⚫ Complete sexual abstinence 
 
3.3.2 Exclusion criteria 
1) Treatment prior to enrolment into the study including radiotherapy, chemotherapy, 
immunotherapy and targeted therapy. 
2) Lack of sufficient imaging examinations to evaluate objective response during 
chemotherapy. 
3) Age of 18 years or younger. 
4) ECOG of 2 points or more. 
5) Medical history of myocardial infarction within 6 months before registration, 
symptomatic congestive heart failure (New York Heart Association Class III to IV), 
troponin levels consistent with myocardial infarction as defined according to 
American College of Cardiologists (ACC) guidelines, unstable angina, or serious 
cardiac arrhythmia requiring treatment 
6) Medical history of respiratory insufficiency 

7) Significant gastrointestinal bleeding or perforation within the last 6 months of 
randomization/registration 
8) History of active inflammatory bowel diseases or peptic ulcer 
9) History of other malignancy(ies) 
10) Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals 
11) Inadequate bone marrow function, defined as:  
⚫ Absolute neutrophil count (ANC) < 1.5×109 cells/L 
⚫ Leukocyte count < 3.5×109 cells/L 
⚫ Platelets < 75×109 /L 
⚫ Hemoglobin < 8.0 g/dl 
12) Inadequate liver and renal function, defined as:  
⚫ Albumin ≤ 2.5 g/dL 
⚫ Total bilirubin ≥ 3 mg/ dL 
⚫ Creatinine ≥ 2.0 mg/dL 
⚫ AST ≥ 2.5 × ULN (Upper Limit of Normal) (0-64U/L) 
⚫ ALT ≥ 2.5 × ULN (0-64U/L) 
13) Inadequate blood clotting function, defined as: 
⚫ International normalized ratio (INR) ≥ 2 
14) Social, familial, or geographical factors that would interfere with study 
participation or follow-up 
15) Current participation in a therapeutic clinical study 
16) Pregnant or breastfeeding, or planning to become pregnant 

17) Inability of the research subject or authorized legal representative to understand 
and the willingness to sign a written informed consent document 
 
3.4 Concomitant treatments or examinations 
3.4.1 Prohibited and/or restricted treatments 
Any immunosuppressive agents or systemic corticosteroids should be consulted via 
multidisciplinary approaches. 
 
3.4.2 Restrictions and precautions of contrast enhanced CT or MRI 
Participants with renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate. 
Specific to CT and MRI, participants with severe renal insufficiency (ie, estimated 
glomerular filtration rate (eGFR) < 30 mL/min/1.73m2) are at increased risk of 
nephrogenic systemic fibrosis. Contrast should not be given to this subject population. 
In addition, participants with surgically implanted devices (pacemaker, deep brain 
stimulator, metallic implants, etc.) incompatible with MRI should not undergo such 
imaging techniques. The local imaging facility and principal investigator should 
determine the appropriate precautions or guidelines that should be instituted for 
subjects with tattoos, body piercings or other body art. The ultimate decision to 
perform CT and MRI in an individual patient in this study rests with the site 
radiologist, the investigator and the standard set by the Institutional Review 
Board/Independent Ethics Committee. 

 
3.5 Discontinuation of participation following any treatment with study drugs or 
SBRT 
Participants MUST discontinue chemotherapy drug or SBRT at the discretion of the 
investigator for any of the following reasons: 
⚫ 
Participant’s request to stop study treatment 
⚫ 
Any clinical adverse event, laboratory abnormality or intercurrent illness which, 
in the opinion of the investigator, indicates that continued participation in the 
study is not in the best interest of the participant 
⚫ 
Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (eg, infectious 
disease) illness 
⚫ 
Additional protocol specified reasons for discontinuation including the 
development of treatment-emergent, treatment-related unacceptable toxicity 
In the case of pregnancy, the investigator must immediately notify the Institutional 
Review Board/Independent Ethics Committee of this event. In most cases, the study 
drug will be permanently discontinued in an appropriate manner. If the investigator 
determines a possible favorable benefit/risk ratio that warrants continuation of study 
drug, a discussion between the investigator and the Institutional Review 
Board/Independent Ethics Committee must occur. 
All participants who discontinue treatment should comply with protocol specified 
follow-up procedures. The only exception to this requirement is when a participant 

withdraws consent for all study procedures including post-treatment study follow-up 
or loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for 
the treatment of either a psychiatric or physical illness). 
If chemotherapy or SBRT is discontinued prior to the participant’s completion of the 
study, the reason for the discontinuation must be documented in the participant’s 
medical records and entered on the appropriate case report form page. 
The primary reason for the permanent discontinuation of study treatment must be 
documented in the subject’s medical records and electronic case report form. Once a 
subject has permanently discontinued from study treatment, the subject will not be 
allowed to be retreated with study regimens. 
If the subject voluntarily discontinues from treatment due to toxicity, adverse events 
will be recorded as the primary reason for permanent discontinuation in the electronic 
case report form. 
All subjects who permanently discontinue all study treatment will have safety 
assessments at the time of discontinuation and during post-study treatment follow-up. 
All subjects who permanently discontinue all study treatment without disease 
progression will be followed for progression. In addition, all subjects who 
permanently discontinue all study treatment will be followed for survival and new 
anti-cancer therapy. Follow-up contact to assess survival and new anti-cancer therapy 
may be made via clinic visit, phone, or email. 
 
3.6 Withdraw of consent 

Participants who request to discontinue treatment will remain in the study and must 
continue to be followed for protocol specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further 
contact with him/her or persons previously authorized by participant to provide this 
information. Participants should notify the investigator of the decision to withdraw 
consent from future follow-up in writing, whenever possible. The withdrawal of 
consent should be explained in detail in the medical records by the investigator, as to 
whether the withdrawal is from further treatment with study drug only or also from 
study procedures and/or post treatment study follow-up, and entered on the 
appropriate case report form page. In the event that vital status (whether the subject is 
alive or dead) is being measured, publicly available information should be used to 
determine vital status only as appropriately directed in accordance with local law. 
All reasonable efforts must be made to locate participants to determine and report 
their ongoing status. This includes follow-up with persons authorized by the 
participant as noted above. Lost to follow-up is defined by the inability to reach the 
participant after a minimum of three documented phone calls, faxes, or emails as well 
as lack of response by participant to one registered mail letter. All attempts should be 
documented in the participant’s medical records. If it is determined that the participant 
has died, the site will use permissible local methods to obtain the date and cause of 
death. If after all attempts, the participant remains lost to follow-up, then the last 
known alive date as determined by the investigator should be reported and 
documented in the participant’s medical records. 

 
4. Rationale 
4.1 Rationale for the trial and selected population 
Pancreatic cancer is one of the most lethal malignancies and fourth leading cause of 
cancer death in both genders in US, where the mortality and incidence increase over 
the past decade with a lowest 5-year survival rate of 13% among all cancers.1 
Although surgical resection is deemed to provide long-term disease control, only 20% 
patients were candidates for upfront surgery. Therefore, regarding locally advanced 
pancreatic cancer, SBRT is given the first priority as the radical local therapy, which 
was recommended in NCCN guideline. Additionally, gemcitabine and nab-paclitaxel 
was also considered as the first-line chemotherapy regimen. Therefore, SBRT plus 
gemcitabine and nab-paclitaxel was a preferred in the case of locally advanced 
pancreatic cancer. Nevertheless, an ablative dose that may contribute to improved 
survival without increased risk of gastrointestinal toxicity have not been determined. 
Therefore, the aim of the study was to compare outcomes of patients with locally 
advanced pancreatic cancer receiving SBRT of BED10 >70Gy with those of patients 
receiving SBRT of BED10 <70Gy following chemotherapy. 
 
4.2 Rationale for dose selection/regimen/modification 
4.2.1 Gemcitabine and nab-paclitaxel 
Gemcitabine (1000 mg/m2) and nab-paclitaxel (125mg/m2) is administered 
intravenously on day 1 and 8 of each 21-day cycle for six cycles, which has been 

recommended in NCCN guideline. Doses calculated from body surface area are 
truncated in 10 mg/body and nab-paclitaxel is truncated in 10 mg/body. However, the 
acceptable range drug dose is ±10%. Calculation of body surface area and drug 
dosage is the responsibility of the institution, and the body surface area and drug 
dosage at the time of enrollment are for double-checking with the physician's 
calculation. Weight change after initiation of treatment should not be corrected for 
dosage if the weight is less than 5kg to that at enrollment. However, if weight loss 
exceeding 5kg is observed, the body surface area should be recalculated to determine 
the dosage again. After recalculation, if weight loss exceeds 5kg relative to body 
weight at recalculation, the body surface area should be recalculated to determine the 
dose. Details of dose modifications would be shown in following sections. 
 
4.3 Rationale for endpoints 
4.3.1 Efficacy endpoints 
Primary endpoints:  
The primary efficacy endpoint of the study is progression free survival (PFS). Given 
that it was a phase 2 trial, PFS could be considered as the primary outcome. PFS is an 
acceptable measure of clinical benefit for a randomized phase III trial that 
demonstrates superiority of a new antineoplastic therapy, especially if the magnitude 
of effect is large and the therapy has an acceptable risk-benefit profile. Furthermore, it 
is an endorsed regulatory endpoint for many clinical trials on outcomes evaluations of 
immunotherapy or targeted therapy in different types of cancer. PFS will be assessed 

per RECIST 1.1 by a blinded independent central imaging vendor that will be blinded 
to the treatment assignment to minimize any bias in the response assessments. In 
addition, final determination of radiologic progressive disease will be based on the 
blinded independent central imaging vendor assessment of progression, rather than 
local site investigator/radiology assessment. Expedited assessment by the blinded 
independent central imaging vendor in instances of suspected radiological progression 
will be communicated to the study team.  
Secondary endpoint: 
The secondary endpoint of the study is overall survival (OS). Although the study 
allows participants to select other subsequent anti-cancer treatment recommended by 
NCCN guideline upon progression, which may affect the assessment of OS, OS is still 
a standard endpoint to demonstrate superiority of anticancer therapy. 
 
4.3.2 Safety endpoints 
The safety objective is to characterize the safety and tolerability of SBRT with 
BED10 >70Gy and BED10 <70Gy following chemotherapy in patients with locally 
advanced pancreatic cancer. The following safety parameters will be analyzed: 
adverse effects and severe adverse effects graded per NCI CTCAE, Version 4.0 
criteria with time to onset/recovery, causality and outcome; changes in laboratory 
values, vital signs since baseline, treatment discontinuations and reason for 
discontinuation, death and cause of death, etc. Concomitant medications will be 
collected with time and reasons for use. These are routine safety parameters collected 

and analyzed in Phase II/III oncology trials.  
 
5. Study treatments 
5.1 Treatment assignment 
5.1.1 Treatment group 
Patients will be randomly assigned to two different treatment groups: SBRT of 
BED10 >70Gy and BED10 <70Gy following gemcitabine and nab-paclitaxel. Once 
assigned, participants will remain on study in their treatment group and will not 
change groups. 
 
5.1.2 Method of treatment allocation 
Patients are enrolled by the investigators and randomly assigned (1:1) to receive 
SBRT of BED10 >70Gy or BED10 <70Gy following gemcitabine and nab-paclitaxel 
with an interactive voice or web response system. A randomization list is produced by 
the response technology provider, which ensure random assignment of patients’ ID to 
randomization numbers after they are eligible. Each number is linked to a treatment 
group. 
 
5.1.3 Blinding 
This study is an open-label study and no blinding will be performed. 
 
5.2 Study drugs 

Study drug includes both Investigational [Medicinal] Product and Non-investigational 
[Medicinal] Product and can consist of the following: 
⚫ 
All products, active or placebo, being tested or used as a comparator in a clinical 
trial. 
⚫ 
Study required premedication 
⚫ 
Other drugs administered as part of the study that are critical to claims of efficacy 
⚫ 
Diagnostic agents: (such as glucose for glucose challenge) given as part of the 
protocol requirements must also be included in the dosing data collection. 
 
5.2.1 Investigational agents 
There are no investigational products in this study. 
 
5.2.2 Non-investigational agents 
Other medications used as support or escape medication for preventative, diagnostic, 
or therapeutic reasons, as components of the standard of care for a given diagnosis, 
may be considered as non-investigational products. 
In this protocol, non-investigational product is: gemcitabine and nab-paclitaxel. 
 
5.3 Administration 
Trial Treatment should begin within 3 days of randomization. The treatments to be 
used in this trial are outlined below in Table 1. 
The investigator shall take responsibility for and shall take all steps to maintain 

appropriate records and ensure appropriate supply, storage, handling, distribution and 
usage of trial treatments in accordance with the protocol and any applicable laws and 
regulations. 
 
 
 
 
 
 
 
 
 
 
 

Table 1. Trial treatment 
Drug 
Dose/Potency 
Dose frequency 
Route of Administration 
Regimen/ Treatment Period 
Use in Study 
SBRT of BED10 >70Gy following gemcitabine and nab-paclitaxel 
Gemcitabine 
1000 mg/m2 
Q3W 
IV infusion 
d1, 8, each 21-day cycle for 6 cycles 
Experimental 
Nab-paclitaxel 
125 mg/m2 
Q3W 
IV infusion 
d1, 8, each 21-day cycle for 6 cycles 
Experimental 
SBRT of BED10 <70Gy following gemcitabine and nab-paclitaxel 
Gemcitabine 
1000 mg/m2 
Q3W 
IV infusion 
d1, 8, each 21-day cycle for 6 cycles 
Comparator 
Nab-paclitaxel 
125 mg/m2 
Q3W 
IV infusion 
d1, 8, each 21-day cycle for 6 cycles 
Comparator 
Abbreviations: Q3W=every 3 weeks, PD=progressive disease 
 

5.4 Handling and storage of study drugs 
Gemcitabine and nab-paclitaxel must be stored in a secure area under the appropriate 
physical conditions for the products. Study treatments are to be stored at the 
temperature specified on the label. Maintenance of a temperature log (manual or 
automated) is required. Access to and administration of the study treatment will be 
limited to the investigator and authorized site staff. Gemcitabine and nab-paclitaxel 
must be dispensed or administered only to participants enrolled in the study and in 
accordance with the protocol. Procedures for final disposition of unused study 
treatments will be provided in the Study Procedures Manual. 
 
5.5 Treatment compliance 
Compliance with study treatment will be assessed through querying the participant 
during the site visits and documented in the source documents and electronic case 
report form. 
A record of the number of study drugs dispensed to and taken by each participant 
must be maintained and reconciled with study treatment and compliance records. 
Treatment start and stop dates, including dates of dose modifications and/or 
interruptions or dose reductions will also be recorded in the electronic case report 
form. The investigator will make every effort to bring non-compliant subjects in to 
compliance. 
 
5.6 Procedures of SBRT 

SBRT was performed via Cyberknife, an image-guided frameless stereotactic robotic 
radiosurgery system (Accuray Corporation, Sunnyvale CA). The protocol was similar 
to that in our previous studies.5, 6 Gold fiducials within or adjacent to the pancreatic 
tumor were preferable. Gross tumor volume (GTV) was defined as a radiographically 
evident gross disease, while clinical target volume (CTV) included areas of the 
potential subclinical disease. In most cases, the CTV was equal to GTV. A 2-5mm 
margin expansion on GTV formed planning target volume (PTV). Dose constraints of 
organs at risk were referred to the American Association of Physicists in Medicine 
guidelines in TG-101.7 The initial contours were reviewed together by a radiation 
oncologist and a radiologist for accuracy. Ninety percent of PTV should be covered 
by the prescription dose. The prescription isodose line is limited to 70-75%, which 
would restrict the tumor Dmax. The prescribed dose of PTV varies from 35-40Gy/5f 
with a single dose of 7-8Gy.  
 
Table 2. Dose constraints 
Serial tissues 
Max critical volume 
above threshold 
Five fractions 
 
 
 
Threshold dose (Gy) 
Max point dose (Gy) 
Spinal cord 
<0.35cc 
23 (4.6Gy/f) 
30 (6Gy/f) 
Esophagus 
<5cc 
19.5 (3.9Gy/f) 
35 (7Gy/f) 
Stomach 
<10cc 
18 (3.6Gy/f) 
32 (6.4Gy/f) 
Duodenum 
<5cc 
18 (3.6Gy/f) 
32 (6.4Gy/f) 
 
<10cc 
12.5 (2.5Gy/f) 
 
Jejunum/ileum 
<5cc 
19.5 (3.9Gy/f) 
35 (7Gy/f) 
Colon 
<20cc 
25 (5Gy/f) 
38 (7.6Gy/f) 
Parallel tissues 
Minimum critical 
volume below threshold 
Threshold dose (Gy) 
Max point dose (Gy) 
Liver 
700cc 
21 (4.2Gy/f) 
NA-Parallel tissue 
Renal cortex 
200cc 
17.5 (3.5Gy/f) 
NA-Parallel tissue 

(right and left) 
 
5.7 Dose selection 
Gemcitabine and nab-paclitaxel: the dose amount required to prepare the gemcitabine 
and nab-paclitaxel infusion solution will be based on 1000 mg/m2 and 125 mg/m2, on 
day 1 and 8, each 21-day for a cycle. Details on the dose calculation, preparation and 
administration are provided in the Pharmacy Manual. 
 
5.8 Protocol treatment termination/completion criteria 
5.8.1 Definition of protocol treatment completion 
There is no definition of protocol treatment completion because both groups continue 
protocol treatment until they meet protocol discontinuation criteria. 
 
5.8.2 Criteria for termination of protocol treatment 
Protocol treatment is terminated in any of the following cases: 
1) Judged as protocol treatment is ineffective (when progression of the underlying 
disease was observed after initiation of treatment). 
*Even if it is judged to be PD in the response evaluation by the image, it is not 
considered to be the progression of the pathogenesis, when it is judged that the 
protocol treatment continuation is clinically appropriate, and the protocol 
treatment is continued. 
2) Protocol treatment cannot be continued due to adverse events. 
(a) Grade 4 non-hematologic toxic (except for the following adverse events) 

'hypernatremia', 'hyponatremia', 'hyperkalemia', 'hypokalemia', 'hyperglycemia', 
'hypoglycemia', 'increased alkaline phosphatase', 'alanine aminotransferase', 'increased 
aspartate aminotransferase', 'increased blood bilirubin', 'increased serum amylase', 
'increased lipase', 'increased GGT'. (Non-hematological toxicity: Adverse events other 
than anemia, bone marrow hypocellular, lymphocyte count decreased, neutrophil 
count decreased, white blood cell decreased, platelet count decreased, and CD4 
lymphocyte decreased in CTCAE v4.0) 
(b) In the presence of Grade 1-3 pneumonitis (interstitial pneumonitis) 
(c) When an allergic response to Grade 3 is observed 
(d) When macular edema is confirmed 
(e) If the next course cannot be initiated beyond 21 days due to adverse events related 
to the protocol treatment, determine as possible, probable, definite. 
f) When the criteria for terminating protocol treatment in the treatment modification 
criteria (5.9) are met. 
g) Adverse events other than the treatment modification criteria that the 
investigator/sub-investigator judges to require termination of protocol treatment 
(3) If the patient offers termination of protocol treatment for reasons not denied to be 
associated with the adverse event 
⚫ 
This category should be used if an association with an adverse event cannot be 
ruled out. 
(4) When the patient offers termination of protocol treatment because of reasons for 
denial of association with adverse events 

⚫ 
In case of patient refusal after enrollment and before initiation of protocol 
treatment 
⚫ 
If an adverse event is initially ruled out, such as a relocation of the person or 
family during protocol treatment 
(5) Death during protocol treatment 
⚫ 
Death before deciding to terminate protocol treatment for other reasons 
(6) Other 
⚫ 
Progression before initiation of post-enrollment treatment (protocol treatment 
could not be initiated due to rapid progression) 
⚫ 
When protocol violation is found 
⚫ 
When the treatment is changed due to ineligibility due to changes in the 
pathological diagnosis after enrollment, etc 
⚫ 
When it is judged difficult to continue protocol treatment due to social reasons or 
safety management problems 
The protocol treatment discontinuation date is the date of death in case of 6.2.2.5, the 
date of ineligibility by the treating physician in case of ineligibility after enrollment, 
and the date of discontinuation of protocol treatment in other cases. 
 
5.9 Treatment modification criteria 
The following terms shall be used for the treatment modification. 
⚫ 
Termination: Discontinuation of a part of or all of the treatment without 
restarting. 

⚫ 
Deferral: Prolonged dosing interval, delayed dosing beyond regulation 
⚫ 
Suspending: temporary interruptions or withdrawals that may be resumed if 
conditions are met 
⚫ 
Skip: Do not administer one or more drugs and proceed to the next schedule. 
"Infection" and "rash" in this chapter refer to the following. 
Infection: Bronchial infection; Lung infection; Upper respiratory tract infection; 
Catheter-related infection; Biliary tract infection; Urinary tract infection; Peritoneal 
infection; Infectious small bowel colitis 
Rash: Maculopapular rash, palmar-plantar erythrodysesthesia syndrome, urticaria 
 
5.9.1 Treatment modification criteria for gemcitabine and nab-paclitaxel 
(1) Dose level 
Dose level 
 
Gemcitabine 
Nab-paclitaxel 
Level 0 (starting dose) 
1000mg/m2 
125mg/m2 
Level-1 
800mg/m2 
100mg/m2 
Level-2 
600mg/m2 
75mg/m2 
 
(2) Course initiation criteria after the second course 
⚫ 
After the second course, the course should be started on the day of or prior to the 
course, after confirming that all the criteria for administration of the gemcitabine 
and nab-paclitaxel administration criteria are met (Table 3). 

⚫ 
Both gemcitabine and nab-paclitaxel will be administered if all of the 
gemcitabine and nab-paclitaxel administration criteria (Table 3) are met and if the 
nab-paclitaxel administration criteria are met (Table 4). 
⚫ 
If all the 6.3.1.a gemcitabine and nab-paclitaxel administration criteria (Table 3) 
are met but the nab-paclitaxel administration criteria are not met, only 
gemcitabine will be administered and nab-paclitaxel will be stopped (if the nab-
paclitaxel Dosing Criteria (Table 4) are met after the next dose, nab-paclitaxel 
will be restarted). 
⚫ 
If any one of 6.3.1.a gemcitabine and nab-paclitaxel administration criteria (Table 
3) are not met, postpone the initiation of the course. If the initiation of the course 
is deferred, day 1 is the date gemcitabine and nab-paclitaxel administration is 
started. 
⚫ 
If the next course cannot be initiated beyond 21 days of the expected course due 
to adverse events related to the protocol treatment (if the course cannot be 
initiated by day 1 of the expected course start date and by day 22), the protocol 
treatment should be discontinued. 
⚫ 
If the next course cannot be initiated beyond 14 days of the expected course due 
to adverse events related to the protocol treatment, the protocol treatment should 
be discontinued. 
⚫ 
If nab-paclitaxel cannot be restarted beyond 21 days after nab-paclitaxel pause 
day due to peripheral sensory neuropathy/peripheral motor neuropathy, the 
protocol treatment is discontinued. 

⚫ 
Gemcitabine and nab-paclitaxel is temporarily paused and gemcitabine 
monotherapy is administered if all of the gemcitabine and nab-paclitaxel 
administration criteria (Table 3) are met and the nab-paclitaxel administration 
criteria (Table 4) are met but nab-paclitaxel cannot be administered due to 
discontinuation of nab-paclitaxel. Even if the dose is reduced or rescheduled 
during gemcitabine and nab-paclitaxel, gemcitabine monotherapy is initiated as 
one course at gemcitabine 1,000 mg/m2, day 1 and 8. If the treatment is changed 
to other than GEM monotherapy, the protocol treatment should be discontinued. 
⚫ 
Though gemcitabine and nab-paclitaxel is resumed in principle after nab-
paclitaxel supply is resumed, gemcitabine monotherapy can be continued or 
gemcitabine and nab-paclitaxel can be used. 
⚫ 
After resuming nab-paclitaxel supply, when resuming gemcitabine and nab-
paclitaxel, resume administration at the same dose level and on the same 
schedule as prior to gemcitabine and nab-paclitaxel cessation. 
⚫ 
If nab-paclitaxel can be resumed when gemcitabine monotherapy is considered 
ineffective, gemcitabine and nab-paclitaxel should not be discontinued as a 
protocol treatment. 
 
Table 3. Gemcitabine and nab-paclitaxel administration criteria 
Item 
gemcitabine and nab-paclitaxel 
administration criteria 
Neutrophil count 
≥ 1.0×109 cells/L 

Platelet count 
≥ 75×109 /L 
Total bilirubin 
≤ 3.0 mg/dL 
AST, ALT 
≤ 150U/L 
Anorexia, nausea/vomiting and diarrhea 
Grade 0-1 
Oral mucositis, rash 
Grade 0-2 
Infection 
Grade 0-1 
Symptomatic of suspected macular edema 
None 
Rash: Maculopapular rash, palmar-plantar erythrodysesthesia syndrome, urticaria 
Infection: Bronchial infection; lung infection; upper respiratory tract infection; 
catheter-related infection; biliary tract infection; urinary tract infection; peritoneal 
infection, enterocolitis infectious 
Symptomatic of suspected macular edema: Decreased visual acuity, blurred vision, 
metamorphopsia (distorted vision), etc. 
 
Table 4. Nab-paclitaxel administration criteria 
Item 
Nab-paclitaxel administration criteria 
Peripheral sensory neuropathy 
Peripheral motor neuropathy 
Grade 0-2 
(3) Day 8 criteria for gemcitabine and nab-paclitaxel administration and 
schedule modification 
⚫ 
The day of administration of gemcitabine, nab-paclitaxel may be changed as long 
as 1 day before or after, depending on the patient's convenience, etc. However, 

when the change is made, the day of administration of both gemcitabine, nab-
paclitaxel should be changed (gemcitabine, nab-paclitaxel should be administered 
on the same day). 
⚫ 
On or before the expected date of day 8 administration, the administration should 
be performed after confirming that all items of gemcitabine and nab-paclitaxel 
administration criteria (Table 3). 
⚫ 
Both gemcitabine and nab-paclitaxel will be administered if all of the 
gemcitabine and nab-paclitaxel administration criteria are met and if the nab-
paclitaxel administration criteria are met. 
⚫ 
If all gemcitabine and nab-paclitaxel administration criteria are met but the nab-
paclitaxel administration criteria are not met, only gemcitabine will be 
administered and nab-paclitaxel will be stopped (resume nab-paclitaxel if the 
nab-paclitaxel administration criteria will be met after the next dose). 
⚫ 
If any one of the gemcitabine and nab-paclitaxel administration criteria are not 
met, both drugs are skipped. If day 8 is skipped, day 15 will be the expected date 
of starting the next course. 
⚫ 
If two consecutive courses do not meet the gemcitabine and nab-paclitaxel 
administration criteria and day 8 administration is skipped, and during that time 
does not fall under the dose reduction criteria for gemcitabine and nab-paclitaxel, 
the subsequent administration will be 1 week on and 1 week off. 
⚫ 
After the schedule is changed, the original schedule is not restored. 
 

(4) Dose reduction for gemcitabine and nab-paclitaxel 
⚫ 
If an event that is judged to be related to a drug corresponding to the following 
dose reduction criteria for gemcitabine and nab-paclitaxel are confirmed between 
the start of the previous drug administration and the day of the next drug 
administration, the dose of each drug will be reduced from the next drug 
administration according to the criteria. 
⚫ 
Re-escalation (increase level) of the drug once the dose has been reduced is not 
performed. 
⚫ 
If more than one “dose reduction criterion” is met, the lowest drug dose level 
should be used. 
⚫ 
Dose reduction only with gemcitabine during a pause of nab-paclitaxel due to 
peripheral sensory neuropathy/peripheral motor neuropathy. 
⚫ 
If further dose reductions from level-2 occur with either gemcitabine or nab-
paclitaxel, the protocol treatment should be discontinued. 
 
Table 5. Dose reduction for gemcitabine and nab-paclitaxel 
Item 
Dose reduction 
criteria 
Nab-paclitaxel 
Gemcitabine 
Neutrophil count 
<0.5×109 cells/L 
1-level reduction 
1-level reduction 
Platelet count 
<50×109 /L 
1-level reduction 
1-level reduction 
Febrile neutropenia 
Grade 3 
1-level reduction 
1-level reduction 
Infection 
Grade 3 
1-level reduction 
1-level reduction 

Anorexia, nausea/vomiting and 
diarrhea 
Grade 3 
1-level reduction 
1-level reduction 
Oral mucositis, rash 
Grade 3 
1-level reduction 
1-level reduction 
Peripheral sensory neuropathy 
Peripheral motor neuropathy 
Grade 3 
Level 0, 1: 1-level 
reduction 
1-level reduction 
Level 2: No dose 
reduction 
No dose reduction 
Infection: Bronchial infection; lung infection; upper respiratory tract infection; 
catheter-related infection; biliary tract infection; urinary tract infection; peritoneal 
infection, enterocolitis infectious 
Rash: Maculopapular rash, palmar-plantar erythrodysesthesia syndrome, urticaria 
 
(5) Criteria for initiating gemcitabine monotherapy 
Gemcitabine and nab-paclitaxel is temporarily paused and gemcitabine monotherapy 
is administered if all of the gemcitabine and nab-paclitaxel administration criteria are 
met and nab-paclitaxel administration criteria are met but nab-paclitaxel cannot be 
administered due to discontinuation of nab-paclitaxel supply. Gemcitabine 
monotherapy is initiated as one course of gemcitabine 1,000 mg/m2, day1 and 8, even 
if the dose is reduced or rescheduled during gemcitabine and nab-paclitaxel. 
On or before the start of the course, the course should be started after confirming that 
all of the gemcitabine administration criteria are met (Table 6). 
If any one of the gemcitabine administration criteria are not met, the course start is 

postponed. If course initiation is deferred, the date of gemcitabine initiation is day 1. 
If the next course cannot be initiated beyond 14 days of the expected course due to 
adverse events related to the protocol treatment, the protocol treatment should be 
discontinued. 
In principle, gemcitabine and nab-paclitaxel is resumed after nab-paclitaxel supply is 
resumed. However, gemcitabine monotherapy can be continued, or gemcitabine and 
nab-paclitaxel could be used. 
If nab-paclitaxel can be resumed when gemcitabine monotherapy is considered 
ineffective, gemcitabine and nab-paclitaxel should not be discontinued as a protocol 
treatment. 
 
Table 6. Gemcitabine administration criteria 
Item 
Gemcitabine administration criteria 
Neutrophil count 
≥ 1.0×109 cells/L 
Platelet count 
≥ 75×109 /L 
Total bilirubin 
≤ 3.0 mg/dL 
AST, ALT 
≤ 150U/L 
Anorexia, nausea/vomiting and diarrhea 
Grade 0-1 
Oral mucositis, rash 
Grade 0-2 
Infection 
Grade 0-1 
Rash: Maculopapular rash, palmar-plantar erythrodysesthesia syndrome, urticaria 
Infection: Bronchial infection; lung infection; upper respiratory tract infection; 

catheter-related infection; biliary tract infection; urinary tract infection; peritoneal 
infection, enterocolitis infectious 
 
(6) Day 8 criteria for gemcitabine administration and schedule modification 
⚫ 
The day of administration of gemcitabine may be changed as long as 1 day before 
or after, depending on the patient's convenience, etc. 
⚫ 
On or before the expected date of day 8 administration, the administration should 
be performed after confirming that all items of gemcitabine administration 
criteria are met. 
⚫ 
If any one of gemcitabine administration criteria are not met, the administration 
should be skipped. If day 8 is skipped, day 15 will be the expected date of 
starting the next course. 
⚫ 
If two consecutive courses do not meet the gemcitabine administration criteria 
and day 8 administration is skipped, and the patient does not meet the dose 
reduction criteria for gemcitabine during that time (Table 7), the subsequent 
administration will be 1 week on and 1 week off. 
⚫ 
It does not return to the original schedule after the schedule change during 
gemcitabine therapy (if gemcitabine and nab-paclitaxel is resumed, the same 
dose-level as prior to gemcitabine and nab-paclitaxel cessation and resume 
gemcitabine and nab-paclitaxel on the schedule). 
⚫ 
For gemcitabine and nab-paclitaxel, day1 received gemcitabine and nab-
paclitaxel, but nab-paclitaxel was discontinued due to nab-paclitaxel supply, 

resulting in day 8 receiving gemcitabine, then gemcitabine of the course will be 
scheduled at the same dose-level as before gemcitabine and nab-paclitaxel was 
discontinued. 
 
(7) Dose reduction criteria for GEM monotherapy 
⚫ 
If an adverse event is confirmed to be related to a drug that meets the following 
dose reduction criteria for gemcitabine during the period from the start of the 
previous administration to the day of the next administration of the drug, 
gemcitabine will be reduced from the next administration of the drug according 
to the criteria. 
⚫ 
Re-escalation (increase) of gemcitabine once it has been reduced is avoided. 
⚫ 
If further dose reduction from level-2 occurs, discontinue protocol treatment. 
 
Table 7. Dose reduction criteria for gemcitabine 
Item 
Dose reduction criteria 
Gemcitabine 
Neutrophil count 
<0.5×109 cells/L 
1-level reduction 
Platelet count 
<50×109 /L 
1-level reduction 
Febrile neutropenia 
Grade 3 
1-level reduction 
Infection 
Grade 3 
1-level reduction 
Anorexia, nausea/vomiting and diarrhea 
Grade 3 
1-level reduction 
Oral mucositis, rash 
Grade 3 
1-level reduction 
Infection: Bronchial infection; lung infection; upper respiratory tract infection; 

catheter-related infection; biliary tract infection; urinary tract infection; peritoneal 
infection, enterocolitis infectious 
Rash: Maculopapular rash, palmar-plantar erythrodysesthesia syndrome, urticaria 
 
5.10 Concomitant treatment and supportive care 
5.10.1 Recommended/not recommended concomitant treatment/supportive care 
The following concomitant treatment and supportive care are recommended. Even if it 
is not carried out, it is not regarded as protocol deviation. 
(1) Addressing Fever During Neutropenia 
(i) Assessment at onset of febrile neutropenia 
(a) If the neutrophil count is less than 0.5×109 /L, or less than 1×109 /L and is 
predicted to decrease to less than 0.5×109 /L in less than 48 hours, and if the 
axillary temperature is 37.5°C (oral 38°C) or higher, then immediately assess 
the severity risks and start the supportive treatment as appropriate. 
(b) Severity risk assessment is performed with reference to Multinational 
Association for Supportive Care in Cancer (MASCC) scoring system 
(c) For initial evaluation, complete blood cell count including differential and 
platelet count, renal function, (BUN, creatinine), electrolytes, liver function 
(transaminases, total bilirubin, and alkaline phosphatase) tests, two or more 
sets of venous blood cultures before initiation of antimicrobials, one set of 
cultures from the catheter lumen and one set from a peripheral vein if a central 
venous catheter is in place, culture of suspected infected areas, and plain chest 

x-ray if respiratory symptoms or signs are present. 
(d) When febrile neutropenia develops in a patient with a central venous 
catheter, blood cultures from the catheter and peripheral blood are performed, 
and catheter-related infections are considered if there is a time difference of 
more than 120 minutes in the positivity of both. If appropriate antimicrobial 
therapy does not improve after more than 72 hours, catheter should be 
removed. For infections caused by Staphylococcus aureus, Pseudomonas 
aeruginosa, Bacillus, fungi, and acid-fast bacilli, the catheter should be 
removed and appropriate antimicrobial therapy based on culture results should 
be performed. 
(ii) Antibiotic use 
(a) In high-risk patients, β-lactams with anti-Pseudomonas aeruginosa activity 
are administered intravenously as a single agent. However, other antimicrobials 
(aminoglycosides, fluoroquinolones, and/or vancomycin) may be added to a 
single agent in the initial regimen in patients with unstable or complicated 
conditions or when drug-resistant organisms are strongly suspected. Low-risk 
patients may be treated with antibiotics orally or intravenously, hospitalized, or 
with adequate evaluation, if appropriate, as outpatients. 
(b) The antimicrobial agent should be reassessed 3-4 days after initiation, and 
antimicrobial agents should be continued or changed. As a rule, antimicrobials 
should be continued until the neutrophil count is at least 0.5×109 /L. 
(c) Empiric antifungal therapy is recommended in high-risk patients who do 

not respond to 4-7 days of broad-spectrum antibiotics. 
(d) Fluoroquinolone prophylaxis is recommended in high-risk patients with an 
expected neutrophil count ≤0.1×109 /L lasting >7 days. 
(iii) Therapeutic administration of G-CSF 
Therapeutic administration of G-CSF during the development of FNs is referred 
to the following section. 
Multinational Association for Supportive Care in Cancer (MASCC) scoring 
system. 
Item 
Score 
Clinical manifestations (select one of the followings) 
 
  No symptoms 
5 
  Mild symptoms 
5 
  Moderate symptoms 
3 
No decrease in blood pressure 
5 
No chronic obstructive pulmonary disease 
4 
Solid tumors, or hematopoietic tumors without a history of fungal 
infection 
4 
No dehydration symptoms 
3 
Patients with fever during outpatient management 
3 
Age < 60 
2 
The total score is up to 26 points. Twenty-one points or more are considered low 
risk and 20 points or less are considered high risk. 

 
(2) Influenza and pneumococcal vaccination 
Evidence on the usefulness of immunization and timing of vaccination before or 
during chemotherapy is unclear. However, when the benefit of vaccination is expected 
and the safety is judged to be ensured, consideration should be given to the time of 
protocol treatment and vaccination. 
 
(3) Nausea and vomiting 
Aggressively administer the antiemetic including the prophylactic administration, 
referring to the antiemetic proper use guideline. 
Gemcitabine and nab-paclitaxel is moderately emetogenic risky. Therefore, dual use 
of 5-HT3 receptor antagonists and steroids is recommended. However, the 
administration of steroids may lead to a hyperglycemic state, and the dose adjustment 
should be considered because special attention should be paid to patients with 
pancreatic cancer. Nevertheless, for those with no response to 5-HT3 receptor 
antagonists and steroids, triple combinations of NK1 receptor antagonists, 5-HT3 
receptor antagonists, and steroids are recommended. 
 
(4) Skin rash 
For the rash, the use of external use moisturizer and steroid external use medicine is 
carried out. Systemic therapy may include antihistamines (H1-blocker and H2-
blocker) and corticosteroids. 

 
(5) Palmar-plantar erythrodysesthesia syndrome 
The use of external use moisturizer and steroid external use medicine for Palmar-
plantar erythrodysesthesia syndrome is carried out. Oral administration of pyridoxine 
hydrochloride (vitamin B6) is also recommended. 
 
(6) Mucositis-stomatitis 
Mucosa protective agents such as analgesics, or surface anesthetics should be used as 
appropriate according to symptoms. Narcotics may be used when pain is severe. 
 
(7) Allergic reaction 
Severe symptoms such as dyspnea and hypotension accompanied by oxygen 
desaturation. 
Intramuscular epinephrine, oxygenation, and fluid therapy are performed to ensure the 
stability of the general condition. If cardiac arrest or respiratory arrest occurs, CPR 
such as cardiac massage or mechanical ventilation should be performed. 
Antihistamines (H1- blocker and H2-blocker) and corticosteroids are given to prevent 
further deterioration. 
Symptoms such as hot flushes, rash, hives, pruritus, itching of the pharyngolarynx 
tightness, cold sweat, dyspnea without oxygen desaturation, and fever. If 
chemotherapy is delivered, administration should be once stopped. Management is 
shown in the following Table.  

 
 
 
 
 
 
 
 
 
 
 
 

Table 8. Management of allergic reactions 
Allergic reaction 
Response to the next course 
Grade 1 
If premedication for allergic reaction was not used in the previous course 
⚫ 
Premedication with antihistamines (H1-blocker and H2-blocker) or adequate corticosteroids 
⚫ 
Gemcitabine and nab-paclitaxel are not reduced, but the infusion time may be extended to 4 to 6 h. 
Premedication for allergic reactions in the previous course 
⚫ 
Gemcitabine and nab-paclitaxel are not reduced, but the infusion time may be extended to 4 to 6 h. 
Grade 2 
If premedication for allergic reaction was not used in the previous course 
⚫ 
Premedication with antihistamines (H1-blocker and H2-blocker) or adequate corticosteroids 
⚫ 
Gemcitabine and nab-paclitaxel are not reduced, but the infusion time may be extended to 4 to 6 h. 
Premedication for allergic reactions in the previous course: Discontinue protocol treatment 
Grade 3 
With or without premedication for allergic reactions in the previous course: Discontinue protocol treatment 
Grade 4 
With or without premedication for allergic reactions in the previous course: Discontinue protocol treatment 

(8) Pneumonitis (interstitial pneumonitis) 
If pneumonitis is suspected because of cough or fever, chest X-ray and blood gas 
analysis are performed immediately. When pneumonitis is diagnosed as a result, 
appropriate measures such as discontinuing treatment and starting the administration 
of steroids are taken. 
 
(9) Macular edema 
If symptoms such as decreased visual acuity, blurred vision, and metamorphopsia 
(distorted vision) appear, the possibility of macular edema is suspected and the 
ophthalmologist is consulted early. If needed, corrected visual acuity, fundus 
examination, optical coherence tomography, and fluorescein angiography are 
performed, and if macular edema is confirmed, chemotherapy is discontinued. 
 
(10) Jaundice reduction treatment 
If jaundice or hyperbilirubinemia is observed, appropriate jaundice reduction 
treatment should be taken. 
 
5.10.2 Permitted medications and non-drug therapies 
The investigator must be informed as soon as possible about any medication taken 
from the time of screening until 30 days after the last dose of study treatment with the 
exception of new anti-cancer therapy, if taken after study treatment discontinuation; 
these will be documented until study completion/withdrawal or death. Any 

concomitant medication(s), including dietary supplements, taken during the study will 
be recorded in the electronic case report form. The minimum requirement is that drug 
name, dose, and the dates of administration are to be recorded. Additionally, a 
complete list of all prior anti-cancer therapies will be recorded in the electronic case 
report form. 
Participants should receive full supportive care during the study, including 
transfusions of blood and blood products, and treatment with antibiotics, anti-emetics, 
anti-diarrheals, and analgesics, and other care as deemed appropriate, and in 
accordance with their institutional guidelines. Use of anticoagulants such as warfarin 
is permitted provided that INR is monitored in accordance with local institutional 
practice. Therapeutic administration of G-CSF should be performed according to the 
approved dosage and administration shown in the table below. 
 
Table 9. Therapeutic administration of G-CSF 
Time of initiation 
When neutrophil count are below 1×109 /L and fever (38°C or 
higher as a general rule) occurs 
When neutrophil count < 0.5×109 /L were observed 
Dosage 
Dosing regimen 
⚫ 
Filgrastim: 50 μg/m2 subcutaneously once daily or 100 μ
g/m2 intravenously once daily 
⚫ 
Naltograstim: 1 μg/kg subcutaneously once daily or 2μg/kg 
IV once daily 
⚫ 
Renograstim: 2 μg/kg subcutaneously once daily or 5μg/kg 

IV once daily 
Timing of discontinuation 
⚫ 
If neutrophil count reaches a nadir level of at least 0.5×109 
/L after the elapse, discontinue administration 
⚫ 
If the neutrophil count recover to ≥2×109 /L, if there are no 
symptoms suspicious of infection, and if the patient's safety 
is determined to be ensured, discontinue or reduce the dose 
of the drug. 
 
5.10.3 Prohibited medications and non-drug therapies 
(1) Chemotherapy other than that included in the protocol treatment regimen. 
(2) Radiotherapy, surgery, hormonal therapy, immunotherapy, antibody therapy, 
hyperthermia, and other anti-malignancy treatments 
(3) G-CSF administration on the day of anticancer drug administration. 
 
5.11 Treatment after discontinuation of study treatment or withdrawal 
from/completion of study 
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the patient’s medical condition and providing specific post-study 
treatment. 
Post-study treatment will not be provided as part of the protocol. Upon 
discontinuation from assigned study treatment, subjects may receive additional (non-
protocol) anti-cancer therapy at the discretion of the treating physician. New anti-

cancer therapy should be documented in the electronic case report form. Every effort 
should be made to complete the required follow-up evaluations prior to initiating new 
anti-cancer therapy. Subjects will be followed for survival even if other assessments 
are not performed. 
Refer to Section 3.5 for follow-up assessment of subjects who are to be followed for 
survival and/or disease progression after permanently discontinuing both study 
treatments. 
Upon study closure, subjects who are still receiving study treatment will have the 
option to continue to receive study treatment. 
 
6. Study assessment and procedures 
A signed, written informed consent form must be obtained from the subject prior to 
any study-specific procedures or assessments. 
Procedures conducted as part of the subject’s routine clinical management (e.g., 
imaging) and obtained prior to signing of informed consent may be used for screening 
or baseline purposes provided the procedure meets the protocol-defined criteria and 
has been performed within the timeframe specified in the protocol. Central laboratory 
results for coagulation, hematology, clinical chemistry, and serum pregnancy are 
required for eligibility. 
Refer to the Time and Events Table (Table 10) for the timing of all assessments. 
Assessments must be performed on a calendar schedule; delays in treatment 
administration will not delay performance of assessments. Details on efficacy and 

safety assessments are presented in Section 6.1 and Section 6.2, respectively. Details 
on health outcomes are presented in Section 6.3.  
Investigators may be requested to perform additional safety tests during the course of 
the study based on newly available data to ensure appropriate safety monitoring. 
Appropriate local regulatory and ethical approvals should be obtained before any 
additional testing is performed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Table 10. Study assessments and timing for patients with gemcitabine and nab-paclitaxel following SBRT 
 
Treatment cycles (3-week cycle)1 
Study assessments2 
Screening 
1 
1 
1 
2 
2 
2 
3 
3 
3 
4 
4 
4 
5 
5 
5 
6 
6 
6 
SBRT 
Treatment 
Discon 
Day in cycle 
 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
N/A 
 
Visit window 
(Days) 
≤28 days except 
where noted3,5 
±1 days 
±7 days 
Clinical and safety assessments 
 
Informed consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
data5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past and current 
medical condition6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Family history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease 
characteristics7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior anti-cancer 
therapy8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Staging 
assessment9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal and 
pelvic CT/MRI10 
X 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
X 
(Before 
SBRT) 
X 
PET-CT11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Inclusion/exclusion 
criteria12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination13 
X complete 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X 
brief 
X brief 
X brief 
Adverse event14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dermatologic skin 
assessment15 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
ECG16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest CT17 
X 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
X 
(Before 
SBRT) 
X 
Concomitant 
medications18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study treatments 
 
Dispensation of 
medication19 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of 
compliance20 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory assessments 
 
Chemistry and 
hematology21 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation22 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Pregnancy test23 
X serum (≤7 days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CA19-924 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Urinalysis35 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
1. Patients would not discontinue receiving gemcitabine and nab-paclitaxel until disease progression if no unacceptable adverse effects occur.  
2. All assessments mandated throughout the study must be performed on a calendar schedule; delays in treatment administration will not delay performance of 
assessments. A post baseline study visit window of 1 days is allowed for visits during treatment. 
3. Screening procedures may be performed up to 28 days prior to randomization, unless otherwise noted in the table. Screening visits with a different window are noted 

in parentheses. 
4. Informed consent may be given at any time prior to the performance of any study-related procedures. 
5. Record demographic data. 
6. Record past and current medical conditions, surgical procedures and cardiovascular family history. 
7. Record date of diagnosis, primary tumor type, histology, stage, and other disease characteristics as indicated in the electronic case report form. 
8. Details of treatment for pancreatic cancer before local recurrence should be recorded. 
9. Staging before treatment initiation must be done to preclude distant metastases. 
10. Diagnostic quality, contrast enhanced CT scan of the abdomen and pelvis must be performed at all visits indicated in the table. Intravenous contrast should be used, 
for the CT scans, and preferably with oral contrast as well. CT contrast of the chest, with contrast-enhanced MRI of the abdomen and pelvis should be substituted for full 
CT scanning if the CT scanning frequency is not permitted or ethics requirements or if CT contrast is contraindicated. If MRI scanning is not possible, and CT 
intravenous contrast is contraindicated, CT without contrast is allowed, but it is the least preferable option. Method of imaging should be consistent throughout the study 
(i.e. if CT is done at screening, CT must be done at all future time points). Abdominal and pelvic CT/MRI should be performed after the third cycle and before the 
initiation of SBRT. 
11. PET-CT should be performed for eligibility to preclude distant metastases. Additionally, for patients with suspected disease progression during treatment and follow-
up, PET-CT should be performed at the discretion of physicians. 
12. Only subjects who meet all inclusion and exclusion criteria will be eligible to enter into the study. 
13. All physical exams will include the measurement of height (screening only) and weight using the metric scale, collection of vital signs including blood pressure, 
body temperature, pulse rate, and respirations. In addition, a complete physical exam including a thorough genitourinary (pelvic) examination, inspection of the head and 

neck region, and digital rectal examination for both male and female subjects must be performed at Screening, or discontinuation if discontinuation occurs. For female 
subjects the genitourinary exam must include a PAP smear. If the subject has had a genitourinary and rectal exam within 6 months of randomization these do not need to 
be repeated at screening. Brief physical examinations will be performed at all other time points as indicated. 
14. Adverse events will be recorded from the time the first dose of study treatment is administered until discontinuation of study treatment. Serious adverse events will 
be collected over the same time period as adverse events except serious adverse events assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment, concomitant medication which must be recorded from the time a subject consent to participate in the study 
up to and including any follow-up contact. 
15. A thorough dermatologic exam should be performed by the Investigator at Screening, or at discontinuation if discontinuation occurs. This may be referred to a 
dermatologist at the discretion of the investigator. If possible, the same physician should perform each exam for the duration of the study (i.e. if the subject is referred to 
a dermatologist for the screening exam, the dermatologist should do all follow up dermatologic assessments) to ensure consistency between evaluations. 
16. ECG must be performed at Screening. A single 12-lead ECG will be performed by qualified site personnel after the subject has rested in a semi-recumbent or supine 
position for at least 5 minutes. Two copies of the ECG tracing should be obtained at the time of the ECG; the first copy will be kept in the subject’s medical chart and the 
second copy will be kept in the study file for retrospective collection if necessary. ECGs should be done in triplicate when the initial test is abnormal. 
17. Chest CT is required for evaluations of pulmonary toxicity. For those with respiratory symptoms, chest CT must be performed to identify the causes of symptoms. 
Additionally, for patients with suspected disease progression, chest CT may be given if PET-CT is not permitted to confirm lung metastases. Chest CT should be 
performed after the third cycle and before the initiation of SBRT. 
18. All medications taken by the subject during the study from the time of screening until 30 days after the last dose of study treatment will be recorded; any new anti-
cancer therapy, if taken after study treatment discontinuation will be recorded. 

19. Dosing instructions must be provided to the subject. Subjects should start treatment as soon as possible after randomization but no later than 72 hours post-
randomization. Study treatment will be dispensed at randomization and monthly. 
20. Compliance will be assessed at all visits after Day 1 (Randomization). To assess compliance subjects should be instructed to return study drug at each visit; 
compliance will be assessed by querying the subject. Dose reductions, dose interruptions/delays, and/or dose escalations must be recorded in the electronic case report 
form. 
21. Analysis of clinical chemistry and hematology samples including those at screening will be performed by a central laboratory. Screening labs must be performed 
within 28 days prior to randomization. Comprehensive chemistry and hematology assessments should be performed at Day 1, 8 and 15 in each cycle. 
22. Coagulation sample to be obtained at screening and before the initiation of each cycle and analyzed by a central laboratory. 
23. For all women of childbearing potential a serum pregnancy test will be required within 7 days prior to randomization; preferably, as close to the first dose as 
possible. A serum test can be considered if urine is not appropriate. Monthly pregnancy testing should be conducted as per local regulations where applicable. A urine 
test must be performed to confirm the subject is not pregnant prior to restarting study treatment. 
24. Sometimes, patients may present with elevations of CA19-9 but without any progressions in imaging, which may indicate micro-metastases. Therefore, CA19-9 
should be performed every cycle, which is more frequently than imaging examinations.  
25. Urinalysis should be performed at Day 1 in each cycle to identify whether proteinuria occurs. 
 
 
 
 

Table 11.  
 
Follow-up8 
Study 
completion10 
 
Before recurrence 
After recurrence 
Conclusion 
Study assessments1 
Every 2-3 Months 
(M3-M36) 
Every 3 Months 
After Month 36 
Every 2-3 Months 
(M3-M36) 
Every 3 Months 
After Month 36 
Conclusion 
Visit windows (Days) 
±7 days 
±7 days 
±7 days 
±7 days 
N/A 
Hematology and chemistry2 
X 
X 
X 
X 
 
ECOG 
X 
X 
X 
X 
 
Physical examination3 
X (brief) 
X (brief) 
X (brief) 
X (brief) 
 
Chest, abdomen and pelvic 
CT scans4 
X 
X 
X 
X 
 
Concomitant medication5 
X 
X 
X 
X 
 
Adverse events6 
X 
X 
X 
X 
 
Tumor biomarker (CA19-9)7 
X (every month) 
X (every month) 
X (every month) 
X (every month) 
 
Follow-up contact, anti-
cancer therapies and best 
response8 
X 
X 
X 
X 
X 
PET-CT9 
 
X (after recurrences confirmed) 
If clinically indicated 
 
Subject completion 
 
 
 
 
X 
Death 
 
 
 
 
X 
1. All assessments mandated throughout the study must be performed on a calendar schedule. A study visit window of ±7 days is allowed for all follow-up visits. 
2. Analysis of clinical chemistry and hematology samples will be performed by a central laboratory. Labs should be drawn at Month 18 then annually thereafter during 
follow-up prior to disease recurrence and at the time of disease recurrence. 
3. All physical exams will include the measurement of height (screening only) and weight using the metric scale, collection of vital signs including blood pressure, body 
temperature, pulse rate, and respirations. In addition, a complete physical exam including a thorough genitourinary (pelvic) examination, inspection of the head and neck 

region, and digital rectal examination for both male and female subjects must be performed at Month 18. For female subjects the genitourinary exam must include a PAP 
smear. Brief physical examinations will be performed at all other time points as indicated. 
4. Diagnostic quality, contrast enhanced CT scan of the chest, abdomen and pelvis must be performed at all visits indicated in the table. Intravenous contrast should be 
used, for the CT scans, and preferably with oral contrast as well. CT contrast of the chest, with contrast-enhanced MRI of the abdomen and pelvis should be substituted 
for full CT scanning if the CT scanning frequency is not permitted per country or ethics requirements or if CT contrast is contraindicated. If MRI scanning is not 
possible, and CT intravenous contrast is contraindicated, CT without contrast is allowed, but it is the least preferable option. Method of imaging should be consistent 
throughout the study (i.e. if CT is done at screening, CT must be done at all future time points). MRI (preferred) or CT (only if MRI contraindicated or unavailable) of 
the brain should be performed as clinically indicated. 
5. All medications taken by the subject during the study from the time of screening until 30 days after the last dose of study treatment will be recorded; any new anti-
cancer therapy, if taken after study treatment discontinuation will be recorded. 
6. Adverse events will be recorded from the time the first dose of study treatment is administered until 30 days after discontinuation of study treatment. Serious adverse 
events will be collected over the same time period as adverse events except severe adverse events assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy), study treatment, concomitant medication which must be recorded from the time a subject consents to 
participate in the study up to and including any follow-up contact. 
7. Tumor biomarker (CA19-9) is required to assess recurrences and response to the treatment. 
8. Follow-up will start once treatment is complete and continue through the end of the study even if disease recurs. Follow-up contact prior to disease recurrence will 
include clinic visits. Follow-up after disease recurrence should follow the schedule as noted in Table 17. However, the information collected will be limited to: quality of 
life information, any radiotherapy, surgical procedure or new anti-cancer therapy initiated until study completion, withdrawal or death, best response to any follow-up 

treatment, method of assessment of best response, subsequent progression dates, and survival data. 
9. PET-CT will be performed in the case of patients with suspected progression at the discretion of physicians. 
10. To be completed if the subject permanently withdraws from the study (i.e. death, withdrawal of consent, lost to follow-up). 
 

6.1 Efficacy 
6.1.1 Primary endpoint 
The primary endpoint of this study is progression free survival (PFS), which is 
defined as the time from randomization to disease recurrence or death from any cause. 
Recurrence of or death from the same cancer and all deaths from other causes are 
events. And lost to follow-up is censored. 
⚫ 
Types of recurrence to be considered as an event include loco-regional, distant 
metastases. 
⚫ 
Any death occurring without prior documentation of tumor recurrence will be 
considered as an event (and will not be censored in the statistical analysis). 
⚫ 
If no event has occurred by the time of the analysis, then the time to event will be 
censored as the date of the last adequate assessment of the patient in question. 
⚫ 
Any new primary cancer at another site will not be considered as a recurrence 
and should be reported as a severe adverse event. Tumor tissue sample should be 
obtained for histopathological examinations. 
 
6.1.2 Secondary endpoints 
The secondary endpoint of this study is overall survival (OS), which is defined as the 
interval from randomization to the date of death, irrespective of the cause of death; 
patients still alive will be censored at the date of the last contact. And lost to-follow-
up is censored. 
Additionally, one-year PFS and OS will also be included in the secondary endpoints. 

One-year OS is defined as the proportion of patients alive at 1 year. One-year PFS is 
defined as the proportion of patients without disease progression at 1 year. 
 
6.1.3 Efficacy assessments 
See the Time and Events Tables (Table 10-11) for the schedule of efficacy 
assessments. Assessments must be performed on a calendar schedule and should not 
be affected by dose interruptions/delays. For post-baseline efficacy assessments, a 
window of ±3 days is permitted to allow for flexible scheduling.  
The following are required for efficacy assessment: 
⚫ 
Clinical examination 
⚫ 
Diagnostic quality, contrast-enhanced CT scan of the chest, abdomen and pelvis 
should be performed at baseline and subsequent time points as indicated in the 
Time and Events Tables (Table 10-11). Intravenous contrast should be used for 
the CT scans preferably with oral contrast as well. CT contrast of the chest, with 
contrast-enhanced MRI of the abdomen and pelvis should be substituted for full 
CT scanning if the CT frequency prescribed in the Time and Events Table is not 
permitted or ethics requirements or if CT contrast is contraindicated. The method 
of imaging should be consistent throughout the study (i.e. if CT is done at 
screening, CT will be done at all future time points). All CTs/MRIs will be 
collected. 
⚫ 
A baseline abdominal and pelvic CT and MRI of the recurrent lesion is required 
for all subjects. Subsequent abdominal and pelvic CT and MRI should be 

performed according to the Time and Events Tables (Table 10). Additionally, the 
imaging examinations may be performed at any time as clinically indicated. 
Abdominal and pelvic CT and MRI will be collected. 
 
6.1.4 Assessment guidelines 
Please note the following: 
⚫ 
The same diagnostic method, including use of contrast, when applicable, must be 
used throughout the study. Contrast agents must be used in accordance with the 
Image Acquisition Guidelines presented in the Study Procedures Manual, where 
not contraindicated. 
⚫ 
Fluorodeoxyglucose positron emission tomography (FDG)-PET can be useful in 
confirming new sites of disease where a positive FDG-PET scans correlates with 
the new site of disease present on CT/MRI. 
⚫ 
If PET/CT is performed then the CT component can only be used for standard 
disease assessments if performed to diagnostic quality, which includes the 
required anatomical coverage and prescribed use of contrast. The method of 
assessment should be noted as CT on the case report form. 
CT and MRI: Contrast enhanced CT with 5mm contiguous slices is recommended. 
MRI is acceptable (refer to Section 6.1.3), but when used, the technical specification 
of the scanning sequences should be optimized for the evaluation of the type of 
disease. Whenever possible the same scanner should be used. 
Scans of the recurrent lesion of pancreatic cancer: For the baseline scans of the 

recurrent lesion of pancreatic cancer and any post-baseline imaging examinations, 
contrast enhanced MRI and CT are both required. 
 
6.1.5 Follow-up assessments for subjects permanently discontinued from study 
treatment prior to protocol treatment period 
Refer to Section 3.5 Discontinuation of participation following any treatment with 
study drugs and the Time and Events Schedule (Table 18) for follow-up assessment of 
subjects for disease recurrence and survival after permanently discontinuing from 
study treatment. 
 
6.1.6 Assessment of subject completion 
If a subject withdraws from the study during Months 1 through Month 24, the last 
radiographic assessment was more than 3 months prior to withdrawal from study and 
disease recurrence has not been documented, a disease assessment should be obtained 
at the time of withdrawal from study. 
If a subject withdraws from the study after Month 24, the last radiographic assessment 
was more than 6 months prior to withdrawal from study and disease recurrence has 
not been documented, a disease assessment should be obtained at the time of 
withdrawal from study. 
 
6.2 Safety 
6.2.1 Safety endpoints 

The secondary endpoints of the study include characterizing the safety of SBRT of 
BED10 >70Gy and BED10 <70Gy following gemcitabine and nab-paclitaxel. As a 
consequence, clinical assessments including vital signs and physical examinations, 
12-lead ECG, chemistry and hematology laboratory values, and adverse events will be 
monitored and evaluated. 
 
6.2.2 Adverse events 
The investigators will be responsible for detecting, documenting and reporting events 
that meet the definition of an adverse event or severe adverse event as outlined in 
Section 6.2.2.1 and Section 6.2.2.2, respectively. 
 
6.2.2.1 Definition of an adverse event 
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
Note: An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. For marketed medicinal 
products, this also includes failure to produce expected benefits, abuse, or misuse. 
Examples of events meeting the definition of an adverse event include: 
⚫ 
Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or grade of the condition. 

⚫ 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study. 
⚫ 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
⚫ 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
adverse event/severe adverse event) unless this is an intentional overdose taken 
with possible suicidal/self-harming intent. This should be reported regardless of 
sequelae. 
“Lack of efficacy” or “failure of expected pharmacological action” per se is not to be 
reported as an adverse event or severe adverse event. However, any signs and 
symptoms and/or clinical sequelae resulting from “lack of efficacy” will be reported 
as an adverse event or severe adverse event, if they fulfill the definition of an adverse 
event or severe adverse event. 
Events that do not meet the definition of an AE include: 
⚫ 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition 
that leads to the procedure is an adverse event. 
⚫ 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
⚫ 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
⚫ 
The disease/disorder being studied, or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 

subject’s condition. 
 
6.2.2.2 Definition of a severe adverse event 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c. Requires hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or out-
subject setting. Complications that occur during hospitalization are adverse events. If 
a complication prolongs hospitalization or fulfills any other serious criteria, the event 
is serious. When in doubt as to whether “hospitalization” occurred or was necessary, 
the adverse event should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an adverse event. 
d. Results in disability/incapacity, or 
NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 

of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. Is a congenital anomaly/birth defect. 
f. Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
g. Protocol-specific severe adverse events: 
⚫ 
All events of possible drug-induced liver injury with hyperbilirubinaemia defined 
as ALT ≥3xULN and bilirubin ≥2xULN (>35% direct) (or ALT ≥3xULN and 
INR>1.5, if INR measured) or termed ‘Hy’s Law’ events (INR measurement is 
not required and the threshold value stated will not apply to patients receiving 
anticoagulants). 
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 

direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin ≥2xULN, then the event is still reported 
as a severe adverse event. If INR is obtained, include values on the severe adverse 
event form. INR elevations >1.5 suggest severe liver injury. 
⚫ 
Any new primary cancers and treatment emergent malignancies. 
⚫ 
Laboratory abnormalities. 
⚫ 
Central serous retinopathy or retinal vein occlusion. 
⚫ 
Renal insufficiency, and/or severe rigors/chills in the absence of an obvious 
infectious cause. 
 
6.2.2.3 Laboratory and other safety assessment abnormalities reported as 
adverse events and severe adverse events 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, and events felt to be clinically significant 
in the medical and scientific judgment of the investigator are to be recorded as an 
adverse event or severe adverse event, in accordance with the definitions provided. 
In addition, an associated adverse event or severe adverse event is to be recorded for 
any laboratory test result or other safety assessment that led to an intervention, 
including permanent discontinuation of study treatment, dose reduction, and/or dose 
interruption/delay. 
However, any clinically significant safety assessments that are associated with the 

underlying disease, unless judged by the investigator to be more severe than expected 
for the subject's condition, are not to be reported as adverse events or severe adverse 
events. 
 
6.2.2.4 Disease-related outcomes not qualifying as severe adverse events 
An event which is part of the natural course of the disease under study (i.e., disease 
recurrence or hospitalization due to disease recurrence) does not need to be reported 
as a severe adverse event. Death due to disease under study is to be recorded on the 
Death case report form. However, if the underlying disease (i.e., recurrence) is greater 
than that which would normally be expected for the subject, or if the investigator 
considers that there was a causal relationship between treatment with pembrolizumab 
and trametinib or gemcitabine or protocol design/procedures and the disease 
recurrence, then this must be reported as a severe adverse event. Local or distant 
relapse is the primary efficacy endpoint of the study and should not be reported as a 
severe adverse event. 
 
6.2.2.5 Time period and frequency of detecting adverse events and severe adverse 
events 
The investigator is responsible for detecting, documenting and reporting events that 
meet the definition of an adverse event or severe adverse event. 
From the time a subject consent to participate in and completes the study, all severe 
adverse events assessed as related to study participation (e.g., protocol-mandated 

procedures, invasive tests, or change in existing therapy), will be reported promptly to 
Institutional Review Board/Independent Ethics Committee. Severe adverse events 
will be collected over the same time period as stated above for adverse events. In 
addition, any new malignancy (defined in Section 6.2.2.2) or any severe adverse 
events assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment or concomitant 
medication must be recorded from the time a subject consent to participate in the 
study up to and including any follow-up contact. All severe adverse events will be 
reported to Institutional Review Board/Independent Ethics Committee within 24 
hours, as indicated in Section 6.2.2.6.  
After discontinuation of study treatment, the investigator will monitor all adverse 
events/severe adverse events that are ongoing until resolution or stabilization of the 
event or until the subject is lost to follow-up. At any time after 30 days from the last 
dose of study treatment, the investigator may report any adverse event that they 
believe is possibly related to study treatment. Treatment emergent malignancies 
should be reported regardless of the time from treatment discontinuation to 
occurrence of the event. 
 
6.2.2.6 Prompt reporting of severe adverse events and other events to 
Institutional Review Board/Independent Ethics Committee 
Severe adverse events, pregnancies, and liver function abnormalities meeting pre-
defined criteria will be reported promptly by the investigator to Institutional Review 

Board/Independent Ethics Committee as described in the following table once the 
investigator determines the event meets the protocol definition for that event. 
 
Table 12. Time frames for reporting severe adverse events and other events 
 
Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
SAE data 
collection tool 
24 hours 
Updated SAE 
data collection 
tool 
Pregnancy 
24 hours 
Pregnancy 
notification 
form 
2 Weeks 
Pregnancy 
follow up form 
Liver chemistry abnormalities: 
ALT≥3xULN 
PLUS 
Bilirubin≥2xULN 
(>35% direct) (or 
ALT≥3xULN and 
INR>1.5, if INR 
measured)1 
24 hours2 
SAE data 
collection tool. 
Liver Event 
CRF and liver 
imaging and/or 
biopsy CRFs if 
applicable3 
24 hours 
Updated SAE 
data collection 
tool. Updated 
Liver Event 
CRF3 
ALT≥8xULN; 
ALT≥3xULN 
with hepatitis or 
rash or ≥3xULN 
and <5xULN that 
persists≥4 weeks 
24 hours2 
Liver Event 
CRF3 
24 hours 
Updated Liver 
Event CRF3 
ALT≥5xULN 
plus bilirubin 
<2xULN 
24 hours2 
Liver event 
CRF does not 
need 
completing 
unless 
elevations 
persist for 2 
weeks or 
24 hours 
 

subject cannot 
be monitored 
weekly for 2 
weeks3 
ALT≥5xULN and 
bilirubin 
<2xULN that 
persists≥2 weeks 
24 hours2 
Liver event 
CRF3 
24 hours 
Updated liver 
event CRF3 
ALT≥3xULN and 
<5x ULN and 
bilirubin 
<2xULN 
24 hours2 
Liver event 
CRF does not 
need 
completing 
unless 
elevations 
persist for 4 
weeks or 
subject cannot 
be monitored 
weekly for 4 
weeks3 
 
 
1. INR measurement is not required; if measured, the threshold value stated will not 
apply to subjects receiving anticoagulants. 
2. Institutional Review Board/Independent Ethics Committee to be notified at onset of 
liver chemistry elevations to discuss subject safety. 
3. Liver Event Documents (i.e., “Liver Event Case Report Form” and “Liver 
Imaging Case Report Form” and/or “Liver Biopsy Case Report Form”, as applicable) 
should be completed as soon as possible. 
 
6.2.2.7 Regulatory reporting requirements for severe adverse events 
Prompt notification of severe adverse events by the investigator to Institutional 
Review Board/Independent Ethics Committee is essential so that legal obligations and 

ethical responsibilities towards the safety of subjects are met. 
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and are forwarded to 
investigators as necessary. 
An investigator who completes an investigator safety report describing a severe 
adverse event(s) or other specific safety information (e.g., summary or listing of 
severe adverse events) will notify the Institutional Review Board/Independent Ethics 
Committee, if appropriate according to local requirements. 
 
6.2.3 Laboratory assessments 
All protocol required laboratory assessments, as defined in Table 10 should be 
performed by the central laboratory. Laboratory assessments must be conducted in 
accordance with the Central Laboratory Manual and Protocol Time and Events 
Schedule in Table 11. Laboratory requisition forms must be completed and samples 
must be clearly labeled with the subject number, protocol number and visit date. 
Details for the preparation and shipment of samples will be provided by the central 
laboratory. Reference ranges for all safety parameters will be provided by the central 
laboratory. 
If any additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in patient management or are 
considered clinical significant by the investigator (for example severe adverse events 
or adverse events or dose modifications) the results must be recorded in the subject’s 

electronic case report form. 
Clinical chemistry and hematology parameters to be tested are listed in Table 13. 
Female subjects will have a serum pregnancy test at screening. 
 
Table 13. Clinical chemistry and hematology parameters 
Clinical Chemistry Parameters 
Albumin 
Alkaline Phosphatase 
Alanine Transaminase (ALT) or Serum Glutamic Pyruvic Transaminase (SGPT) 
Aspartate Aminotransferase (AST) or Serum Glutamic Oxaloacetic Transaminase (SGOT) 
Bicarbonate 
Blood Urea Nitrogen (BUN) or urea 
Calcium 
Chloride 
Creatinine1 
Glucose (random) 
Lactate Dehydrogenase (LDH) 
Phosphate 
Potassium 
Sodium 
Total Bilirubin2 
Total Protein 
Hematology Parameters 
White Blood Cell (WBC) Count 
Hemoglobin 
International Normalized Ratio (INR; at screening only)3 
Platelet Count 
Prothrombin Time (PT; at screening only) 3 
Partial Thromboplastin Time (PTT; at screening only) 3 
Automated WBC Differential (expressed as %): 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 

Neutrophils 
1. If serum creatinine is > 1.5 mg/dL, creatinine clearance should be calculated using 
the standard Cockcroft-Gault formula. 
2. Bilirubin fractionation is recommended if total bilirubin is > 2 x the upper limit of 
normal. 
3. Coagulation panel to be done at Screening only. 
 
6.2.4 Vital signs 
Vital sign measurements will include systolic and diastolic blood pressure, body 
temperature, pulse rate, body weight, and height (only at screening). Body 
temperature, weight and height measurements should be recorded in the metric scale. 
All blood pressure assessments should be performed under optimal conditions i.e. 
after (i) subject has been seated with back support, ensuring that legs are uncrossed 
and flat on the floor, (ii) subject is relaxed comfortably for at least 5 minutes, (ii) 
preparatory steps including removal of any restrictive clothing over the cuff area and 
selection of the right cuff size have been ensured, (iii) the arm is supported so that the 
middle of the cuff is at the heart level, and (iv) the subject remains quiet during the 
measurement. In subjects with an initial blood pressure reading within the 
hypertensive range, a second reading should be taken at least 1 minute later, with the 
2 readings averaged to obtain a final blood pressure measurement. Only the averaged 
value should be entered in the electronic case report form. 
 
6.2.5 Physical examinations 

All physical exams will include the measurement of height (screening only) and 
weight using the metric scale, collection of vital signs including blood pressure, body 
temperature, pulse rate, and respirations as well as assessments of the head, eyes, ears, 
nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and 
spleen), lymph nodes and extremities. Brief physical examinations will be performed 
at all other time points as indicated in the Time and Events Tables (Table 11). 
 
6.2.6 Dermatologic examination 
Exams may be performed by the investigator or may be referred to a dermatologist, at 
the discretion of the investigator. If possible, the same physician should perform each 
exam for the duration of the study (i.e. if the subject is referred to a dermatologist for 
the screening exam, the dermatologist should do all follow up dermatologic 
assessments) to ensure consistency between evaluations. 
 
6.2.7 Electrocardiograms 
Twelve (12)-lead ECGs will be obtained using an electrocardiograms machine that 
automatically calculates heart rate and measures PR, QRS, QT, RR and QTcB 
intervals. 
At each assessment, a single 12-lead ECG will be performed by qualified site 
personnel after the subject has rested in a semi-recumbent or supine position for at 
least 5 minutes. Two copies of the ECG tracing should be obtained at the time of the 
electrocardiograms; the first copy will be kept in the subject’s medical chart and the 

second copy will be kept in the study file for retrospective collection by the Sponsor if 
necessary. 
 
7. Data management 
For this study subject data will be entered into electronic case report forms, 
transmitted electronically to Institutional Review Board/Independent Ethics 
Committee and combined with data provided from other sources in a validated data 
system. 
Management of clinical data will be performed in accordance with applicable 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data. Adverse events and concomitant 
medications terms will be coded using the Medical Dictionary for Regulatory 
Activities and custom drug dictionary. The electronic case report form (including 
queries and audit trails) will be retained by investigators, and copies will be sent to the 
Institutional Review Board/Independent Ethics Committee to maintain for potential 
future review. 
 
8. Data analysis and statistical considerations 
8.1 Hypotheses 
The primary objective of this two-arm study is to evaluate the efficacy of SBRT with 
BED10>70Gy and BED10<70Gy following gemcitabine plus nab-paclitaxel with 
respect to progression free survival (PFS) for subjects with locally advanced 

pancreatic cancer. 
The study is designed to provide evidence regarding PFS to either support the null 
hypothesis, H0: λ = 1 or reject it in favor of the alternative hypothesis, HA: λ ≠ 1, 
where λ is the hazard ratio (HR) of combination therapy relative to recommended 
therapy. 
 
8.2 Analysis of endpoints 
8.2.1 Efficacy 
The primary endpoint is PFS. PFS is defined as the time from randomization to the 
first documented disease progression per RECIST 1.1 or death due to any cause, 
whichever occurs first. 
The secondary endpoint is OS. OS is defined as the time from randomization to death 
due to any cause. Subjects without documented death at the time of the final analysis 
will be censored at the date of the last follow up. 
 
8.2.2 Safety endpoints 
The secondary objectives of the study include characterizing the safety of SBRT with 
BED10>70Gy and BED10<70Gy following gemcitabine plus nab-paclitaxel. As a 
consequence, clinical assessments including vital signs and physical examinations, 
12-lead ECG, chemistry and hematology laboratory values, and adverse events will be 
monitored and evaluated. 
The investigators will be responsible for detecting, documenting and reporting events 

that meet the definition of an adverse event or severe adverse event as outlined in 
Section 6.2.2.1 and Section 6.2.2.2, respectively. 
 
8.3 Analysis population 
8.3.1 Efficacy analysis population 
The Intention-to-Treat (ITT) population will serve as the population for the primary 
efficacy analyses. All randomized subjects will be included in this population. 
Subjects will be analyzed in the treatment group to which they are randomized. 
Details on the approach to handling missing data are provided in Section 8.4.1 - 
Statistical Methods for Efficacy Analyses. 
 
8.3.2 Safety analysis population 
The All Subjects as Treated population will be used for the analysis of safety data in 
this study. The All Subjects as Treated population consists of all randomized subjects 
who received at least one dose of study treatment. Subjects will be analyzed in the 
treatment group corresponding to the study treatment they actually received for the 
analysis of safety data using the All Subjects as Treated population. For most subjects 
this will be the treatment group to which they are randomized. Subjects who take 
incorrect study treatment for the entire treatment period will be included in the 
treatment group corresponding to the study treatment actually received. Any subject 
who receives the incorrect study medication for one cycle but receives the correct 
treatment for all other cycles will be analyzed according to the correct treatment 

group and a narrative will be provided for any events that occur during the cycle for 
which the subject is incorrectly dosed. At least one laboratory or vital sign 
measurement obtained subsequent to at least one dose of study treatment is required 
for inclusion in the analysis of each specific parameter. To assess change from 
baseline, a baseline measurement is also required. 
 
8.4 Statistical analysis methods 
8.4.1 Statistical methods for efficacy analyses 
This section describes the statistical methods that address the primary and secondary 
objectives. Nominal p-values may be computed for other efficacy analyses, but should 
be interpreted with caution due to potential issues of multiplicity. 
 
8.4.1.1 Overall survival 
The non-parametric Kaplan-Meier method will be used to estimate the survival curves 
in each treatment group including the OS rates at one year (based on data adequacy). 
The treatment difference in survival will be assessed by the stratified log-rank test. A 
stratified Cox proportional hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., the hazard ratio). The 
hazard ratio and its 95% CI from the stratified Cox model with a single treatment 
covariate will be reported. 
 
8.4.1.2 Progression frees survival 

The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in 
each treatment group including the PFS rates at one year (based on data adequacy). 
The treatment difference in PFS will be assessed by the stratified log-rank test. A 
stratified Cox proportional hazard model with Efron's method of tie handling will be 
used to estimate the magnitude of the treatment difference (i.e., hazard ratio) between 
the treatment arms. The hazard ratio and its 95% confidence interval from the 
stratified Cox model with Efron's method of tie handling and with a single treatment 
covariate will be reported. 
Since disease progression is assessed periodically, progressive disease can occur any 
time in the time interval between the last assessment where progressive disease was 
not documented and the assessment when progressive disease is documented. The true 
date of disease progression will be approximated by the date of the first assessment at 
which progressive disease is objectively documented per RECIST 1.1. Death is 
always considered as a confirmed progressive disease event. Subjects who do not 
experience a PFS event will be censored at the last disease assessment. 
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1, one primary 
and two sensitivity analyses with a different set of censoring rules will be performed. 
For the primary analysis, if progressive disease or death events occur immediately 
after more than one missing disease assessment, the PFS data are censored at the last 
disease assessment prior to the missing visits. Also, data after new anti-cancer therapy 
are censored at the last disease assessment prior to the initiation of new anti-cancer 
therapy. 

The first sensitivity analysis follows the intention-to-treat principle. That is, 
progressive diseases/deaths are counted as events regardless of missed study visits or 
initiation of new anti-cancer therapy. The second sensitivity analysis considers 
discontinuation of treatment due to reasons other than complete response or initiation 
of new anti-cancer treatment (whichever occurs later) to be a progressive disease 
event for subjects without documented progressive disease or death. If a subject meets 
multiple criteria for censoring, the censoring criterion that occurs earliest will be 
applied. The censoring rules for primary and sensitivity analyses are summarized in 
Table 14. 
 
Table 14. Censoring rules for primary and sensitivity analyses of progression free 
survival 
Situation 
Primary Analysis 
Sensitivity Analysis 
1 
Sensitivity Analysis 
2 
PD or death 
documented after ≤ 
1 missed disease 
assessment, and 
before new anti-
cancer therapy, if 
any 
Progressed at date of 
documented PD or 
death 
Progressed at date of 
documented PD or 
death 
Progressed at date of 
documented PD or 
death 
PD or death 
documented 
immediately after ≥ 
2 consecutive 
missed disease 
assessments or after 
new anti-cancer 
therapy, if any 
Censored at last 
disease assessment 
prior to the earlier 
date of ≥ 2 
consecutive missed 
disease assessment 
and new anti-cancer 
therapy, if any 
Progressed at date of 
documented PD or 
death 
Progressed at date of 
documented PD or 
death 

No PD and no death; 
and new anticancer 
treatment is not 
initiated 
Censored at last 
disease assessment 
Censored at last 
disease assessment 
Progressed at 
treatment 
discontinuation due 
to reasons other than 
complete response; 
otherwise censored 
at last disease 
assessment if still on 
study treatment or 
completed study 
treatment. 
No PD and no death; 
new anticancer 
treatment is initiated 
Censored at last 
disease assessment 
before new 
anticancer treatment 
Censored at last 
disease assessment 
Progressed at date of 
new anticancer 
treatment 
The proportional hazards assumption on PFS will be examined using both graphical 
and analytical methods if warranted. The log [-log] of the survival function vs. time 
for PFS will be plotted for the comparison between SBRT of BED10>70Gy and 
BED10<70Gy following gemcitabine and nab-paclitaxel. If the curves are not parallel, 
indicating that hazards are not proportional, supportive analyses may be conducted to 
account for the possible non-proportional hazards effect. 
 
8.4.2 Statistical methods for safety analyses 
Safety and tolerability will be assessed by clinical review of all relevant parameters 
including adverse events, laboratory tests, and vital signs. 
 
8.4.2.1 Adverse events 
Adverse events will be coded using the standard Medical Dictionary for Regulatory 

Activities (MedDRA) and grouped by system organ class. Adverse events will be 
graded by the investigator according to the NCI-CTCAE (version 4.0). 
Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term. Separate summaries will be given for all adverse 
events, drug-related adverse events, serious adverse events and adverse events leading 
to discontinuation of study treatment. If the adverse event is listed in the NCI CTCAE 
(version 4.0) table, the maximum grade will be summarized. The incidence of deaths 
and the primary cause of death will be summarized. 
 
8.4.2.2 Clinical laboratory evaluations 
Hematology and clinical chemistry data will be summarized at each scheduled 
assessment according to NCI CTCAE grade (version 4.0). The proportion of values 
lying outside the reference range will also be presented for laboratory tests that are not 
graded because there are no associated NCI CTCAE criteria. Summaries will include 
data from scheduled assessments only, and all data will be reported according to the 
nominal visit date for which it was recorded (i.e. no visit windows will be applied). 
Unscheduled data will be included in “overall” and “any post-screening” summaries 
which will capture a worst case across all scheduled and unscheduled visits post first 
dose of study treatment. 
 
8.4.2.3 Other safety measures 
The results of scheduled assessments of vital signs, ECOG performance status and 12-

lead ECG will be summarized. Summaries will include data from scheduled 
assessments only. All data will be reported according to the nominal visit date for 
which it was recorded (i.e. no visit windows will be applied). Unscheduled data will 
be included in ‘worse case’ summaries which will capture a worst case across all 
scheduled and unscheduled visits after the first dose of study treatment. 
 
8.4.3 Summaries of demographic and baseline characteristics 
The comparability of the treatment groups for each relevant characteristic will be 
assessed by the use of tables and/or graphs. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of subjects screened 
and randomized, and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (e.g., age), baseline characteristics, and 
prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables. 
 
8.5 Sample size and power calculations 
The study will randomize subjects in a 1:1 ratio into the experimental arm of SBRT 
with BED10>70Gy after gemcitabine and nab-paclitaxel and the control arm of SBRT 
with BED10<70Gy following gemcitabine and nab-paclitaxel. PFS is primary 
endpoint for this study. 
Therefore, for the PFS endpoint, as per the protocol design, the following assumptions 
were made in the estimation of the required sample size: 

⚫ 
Exponential survival distributions. 
⚫ 
We assumed that PFS of the experimental and control group were about 7 months 
and 12 months, respectively. 
⚫ 
A 1:1 randomization scheme. 
⚫ 
An overall 5%, one-sided risk of erroneously claiming superiority of the 
combination therapy in the presence of no true underlying difference (i.e., overall 
Type I error). 
⚫ 
A 90% chance of successfully claiming superiority of the combination therapy in 
the presence of a true underlying difference (i.e., power or Type II error). 
Therefore, an estimated total of 116 subjects (i.e., 58 subjects in each of the arms) 
would need to be enrolled. The final primary PFS analysis will be performed at the 
pre-defined cut-off date, by which time it is expected that approximately 110 PFS 
events will have been accrued. 
 
8.6 Subgroup analysis 
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the dual 
primary endpoints will be estimated and plotted within each category of the following 
classification variables: 
⚫ 
Sex (Female vs. male) 
⚫ 
Age (<65 years vs. ≥65 years) 
⚫ 
ECOG (0 point vs. 1 point) 

⚫ 
CA19-9 level (<200U/ml vs. ≥200U/ml) 
 
9. Study conduct considerations 
9.1 Posting of information on publicly available clinical trial registers 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins. 
 
9.2 Regulatory and ethical considerations, including the informed consent 
process 
Prior to initiation of the study, the investigator will obtain favorable opinion/approval 
from the Institutional Review Board/Independent Ethics Committee to conduct the 
study in accordance with International Conference on Harmonization Good Clinical 
Practice. The study will be conducted in accordance with all applicable regulatory 
requirements. The study will be conducted in accordance with International 
Conference on Harmonization Good Clinical Practice, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of 
Helsinki 2008, including, but not limited to: 
⚫ 
Institutional Review Board/Independent Ethics Committee review and favorable 
opinion/approval of study protocol and any subsequent amendments. 
⚫ 
Subject informed consent. 
⚫ 
Investigator reporting requirements. 
Written informed consent must be obtained from each subject prior to participation in 

the study. 
 
9.3 Quality monitoring 
In accordance with applicable regulations and Good Clinical Practice, Institutional 
Review Board/Independent Ethics Committee will contact our center before the start 
of the study to review with the investigator the protocol, study requirements, and their 
responsibilities to satisfy regulatory and ethical requirements. When reviewing data 
collection procedures, the discussion will include identification, agreement and 
documentation of data items for which the case report form will serve as the source 
document. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the Institutional Review Board/Independent Ethics Committee direct access to 
all relevant documents and to allocate their time and the time to their staff to monitor 
to discuss findings and any issues. 
Monitoring visits will be conducted in a manner to ensure that the: 
Data are authentic, accurate, and complete. 
Safety and rights of subjects are being protected. 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, International Conference on Harmonization Good Clinical Practice, 
and all applicable regulatory requirements. 
 
9.4 Quality assurance 

To ensure compliance with GCP and all applicable regulatory requirements, staff of 
Institutional Review Board/Independent Ethics Committee may conduct a quality 
assurance assessment and regulatory inspection at any time during or after completion 
of the study. In the event of an assessment, the investigator must agree to grant the 
advisor(s), auditor(s) and inspector(s) of Institutional Review Board/Independent 
Ethics Committee direct access to all relevant documents and to allocate their time 
and the time of their staff to discuss the conduct of the study, any findings/relevant 
issues and to implement any corrective and/or preventative actions to address any 
findings/issues identified. 
 
9.5 Source documentation 
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on 
paper or entered electronically. If source data are created (first entered), modified, 
maintained, archived, retrieved, or transmitted electronically via computerized 
systems (and/or any other kind of electronic devices) as part of regulated clinical trial 
activities, such systems must be compliant with all applicable laws and regulations 
governing use of electronic records and/or electronic signatures. Such systems may 
include, but are not limited to, electronic medical/health records, adverse event 
tracking/reporting, protocol required assessments, and/or drug accountability records). 
When paper records from such systems are used in place of electronic format to 
perform regulated activities, such paper records should be certified copies. A certified 

copy consists of a copy of original information that has been verified, as indicated by 
a dated signature, as an exact copy having all of the same attributes and information 
as the original. 
 
9.6 Case report form 
An investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the 
investigation on each individual treated or entered as a control in the investigation. 
Data that are derived from source documents and reported on the case report form 
must be consistent with the source documents or the discrepancies must be explained. 
Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. Case report forms may be requested for adverse 
events and/or laboratory abnormalities that are reported or identified during the course 
of the study. 
The confidentiality of records that could identify subjects must be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable 
regulatory requirement(s). 
The investigator will maintain a signature sheet to document signatures and initials of 
all persons authorized to make entries and/or corrections on case report forms. 
The completed case report form, including any paper or electronic severe adverse 
event/pregnancy case report forms, must be promptly reviewed, signed, and dated by 
the investigator. The investigator must retain a copy of the case report forms including 

records of the changes and corrections. 
 
9.7 Study closure 
Upon completion or termination of the study, staff of Institutional Review 
Board/Independent Ethics Committee will conduct study closure activities with the 
investigator in accordance with applicable regulations and International Conference 
on Harmonization Good Clinical Practice.  
Institutional Review Board/Independent Ethics Committee reserves the right to 
temporarily suspend or terminate the study at any time for reasons including (but not 
limited to) safety issues, ethical issues, or severe noncompliance. If Institutional 
Review Board/Independent Ethics Committee determines that such action is required, 
Institutional Review Board/Independent Ethics Committee will discuss the reasons for 
taking such action with the investigator or head of the medical institution (where 
applicable). When feasible, Institutional Review Board/Independent Ethics 
Committee will provide advance notice to the investigator of the impending action. 
If a study is suspended or terminated for safety reasons, Institutional Review 
Board/Independent Ethics Committee will promptly inform all investigators 
conducting the study and provide the reason(s) for the suspension/termination. 
 
9.8 Record retention 
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe 

and secure location. The records must be easily accessible when needed and must be 
available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff. 
Where permitted by institutional policy, some or all of the records may be maintained 
in a format other than hard copy (e.g., microfiche, scanned, electronic); however, 
caution must be exercised before such action is taken. The investigator must ensure 
that all reproductions are legible and are a true and accurate copy of the original. In 
addition, they must meet accessibility and retrieval standards, including regeneration 
of a hard copy, if required. The investigator must also ensure that an acceptable back-
up of the reproductions exists and that there is an acceptable quality control procedure 
in place for creating the reproductions. 
 
9.9 Independent data monitoring committee 
An Independent Data Monitoring Committee will be utilized in this study to ensure 
external objective medical and/or statistical review of safety and/or efficacy issues in 
order to protect the ethical and safety interests of subjects and to protect the scientific 
validity of the study. 
 
10. Reference 
1. Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics, 2025. CA Cancer J 
Clin. 2025; 75: 10-45. 
2. Zhu X, Cao Y, Su T, et al. Failure patterns and outcomes of dose escalation of 

stereotactic body radiotherapy for locally advanced pancreatic cancer: a multicenter 
cohort study. Ther Adv Med Oncol. 2020: 12: 1758835920977155. 
3. Krishnan S, Chadha AS, Suh Y, et al. Focal radiation therapy dose escalation 
improves overall survival in locally advanced pancreatic cancer patients receiving 
induction chemotherapy and consolidative chemoradiation. Int J Radiat Oncol Biol 
Phys 2016; 94: 755-765.  
4. Reyngold M, Schoenfeld JD, O'Reilly EM, et al. Nonoperative management of 
technically resectable pancreatic cancer with ablative radiation therapy. JAMA Oncol. 
2025; 11: 609-616. 
5. Zhu X, Cao Y, Ju X, et al. Personalized designs of adjuvant radiotherapy for 
pancreatic cancer based on molecular profiles. Cancer Sci 2020; 112: 287-295. 
6. Zhu X, Ju X, Cao Y, et al. Patterns of local failure after stereotactic body radiation 
therapy and sequential chemotherapy as initial treatment for pancreatic cancer: 
implications of target volume design. Int J Radiat Oncol Biol Phys 2019; 104: 101-
110. 
7. Benedict SH, Yenice KM, Followill D, et al. Stereotactic body radiation therapy: 
the report of AAPM Task Group 101. Med Phys 2010; 37: 4078-4101. 
 
 
 
 
 

 
11. Appendices 
11.1 Appendix 1: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Activity Status 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5 
Dead. 
Reference: 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5(6): 649-655. 
 
 
 
 
 
 
 
 
 

 
11.2 National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) 
NCI CTCAE version 4.0 will be utilized for adverse events reporting 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
11.3 New York Heart Association (NYHA) Guidelines 
The New York Heart Association Functional Classification provides a simple way of 
classifying the extent of heart failure [The Criteria Committee of the New York Heart 
Association, 1994]. It places subjects in 1 of 4 categories based on the level of 
limitation experienced during physical activity: 
Functional Capacity 
Objective Assessment 
Class I: Subjects with cardiac disease but 
without resulting limitation of physical 
activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea, or 
angina pain. 
A: No objective evidence of cardiovascular 
disease. 
Class II: Subjects with cardiac disease 
resulting in slight limitation of physical 
activity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
B: Objective evidence of minimal 
cardiovascular disease. 
Class III: Subjects with cardiac disease 
resulting in marked limitation of physical 
activity. They are comfortable at rest. Less 
than ordinary physical activity causes 
fatigue, palpitation, dyspnea, or anginal 
pain. 
C: Objective evidence of moderately severe 
cardiovascular disease. 
Class IV: Subjects with cardiac disease 
resulting in inability to carry on any 
physical activity without discomfort. 
Symptoms of heart failure or the anginal 
syndrome may be present even at rest. If 
any physical activity is undertaken, 
discomfort is increased. 
D: Objective evidence of severe 
cardiovascular disease. 
 
Reference: 

The Criteria Committee of the New York Heart Association. Nomenclature and 
criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, Mass: 
Little, Brown, & Co; 1994:253-256.