Stereotactic Body Radiation Therapy Plus Pembrolizumab and Trametinib vs. Stereotactic Body Radiation Therapy Plus Gemcitabine for Locally Recurrent Pancreatic Cancer After Surgical Resection: an Open-label, Randomized, Controlled, Phase 2 Trial
Phase: PHASE2
Conditions: Pancreatic Cancer
Sponsor: Changhai Hospital

Official title: Stereotactic body radiation therapy plus pembrolizumab and trametinib 
versus stereotactic body radiation therapy plus gemcitabine for locally recurrent 
pancreatic cancer after surgical resection: an open-label, randomized phase 2 trial 
NCT number: NCT02704156 
Document state: 5th January 2021 
 
1. Participants and eligibility 
The following inclusion and exclusion criteria would be employed to preserve high 
internal validity and reduce risks of SBRT, gemcitabine, immunotherapy or targeted 
therapy-related adverse effects. 
Inclusion criteria: 
1. Histologically confirmed pancreatic ductal adenocarcinoma with unequivocal first 
progression after surgery followed by chemotherapy 
2. Without any immunotherapy or targeted therapy 
3. A life expectancy of >3 months 
4. ECOG of 0 to1 
5. Age of 18 years or older 
6. Analysis of surgical specimens showed KRAS mutations and positive 
immunohistochemical staining of PD-L1, including IC1 or TC1, IC2 or TC2, IC3 or 
TC3. 
7. Blood routine examination: 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 

8. Liver and kidney function tests: 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) 
9. INR < 2 (0.9-1.1) 
10. Ability of the research subject or authorized legal representative to understand and 
the willingness to sign a written informed consent document. 
Exclusion criteria: 
1. Prior immunotherapy or targeted therapy 
2. Evidences of metastatic disease confirmed by chest CT or FDG PET-CT 
3. Contraindication to receiving immunotherapy, targeted therapy or SBRT 
4. ECOG ≥2 
5. Age <18 years 
6. Analysis of surgical specimens showed KRAS wild type or negative 
immunohistochemical staining of PD-L1, including IC0 or TC0. 
7. Secondary malignancy 
8. Abnormal results of blood routine examinations and liver and kidney and coagulation 
tests 
9. Patients with active inflammatory bowel diseases or peptic ulcer 
10. Gastrointestinal bleeding or perforation within 6 months 
11. Heart failure: NYHA III-IV 
12. Respiratory insufficiency 
13. Women who are pregnant 

14. Participation in another clinical treatment trial while on study 
15. Patients in whom fiducial implantation was not possible 
16. Inability of the research subject or authorized legal representative to understand and 
the willingness to sign a written informed consent document. 
 
2. Analysis of KRAS mutations and immunohistochemical staining of PD-L1 
All patients’ surgical specimens underwent immunohistochemical staining of PD-L1, 
evaluated by the SP142 immunohistochemistry assay (Ventana Medical Systems, 
Tucson, AZ). PD-L1 TC expression was scored as the percentage of PD-L1 TC, which 
was stratified as TC3 ≥ 50% or TC2 ≥ 5% but < 50% or TC1 ≥ 1% but <5%. PD-L1 IC 
expression was scored as the percentage of tumor area stained positive, which was 
classified as IC3 ≥ 10% or IC2 ≥ 5% but < 10% or IC1 ≥ 1% but <5%. KRAS mutations 
were analyzed by PCR amplification and direct sequencing of exon 2. K-RAS Mutation 
Kit (DxS, Manchester, UK) was used in the case of failure of direct sequencing. 
Additionally, Restriction Length Fragment Polymorphism method was used for further 
confirmation. All immunochemistry assays and variants were reviewed by a molecular 
pathologist. 
 
3. Doses of pembrolizumab, trametinib and gemcitabine 
In the SBRT plus pembrolizumab and trametinib group, 200mg pembrolizumab was 
administered intravenously every 3 weeks and 2mg trametinib was given orally once 
daily. The pembrolizumab dose could be temporarily interrupted due to toxicity. And 

pembrolizumab could be resumed if the adverse events had been reduced to grade 1 or 
0. The dose of trametinib could be reduce to 1.5mg then 1mg daily to manage toxic 
effects, while a further reduction below 1mg once daily was not allowed. If one of the 
drugs were withheld, the other drug could be continued. Treatment continued until 
disease progression, unacceptable toxicity, or patient or investigator decision to 
discontinue. Delivery of pembrolizumab and trametinib was initiated one week after 
SBRT. 
In the SBRT plus gemcitabine group, patients received intravenous gemcitabine 
(1000mg/m2) on day 1 and 8 of each 21-day cycle for eight cycles in the absence of 
disease progression. Dose modifications depended on the grade of adverse effects. For 
grade 3 or more toxicity, treatment was delayed until adverse effects resolved to grade 
2 or less, and gemcitabine could be reduced to 750mg/m2. Similarly, treatment also 
continued until disease progression, unacceptable toxicity, patient refusal to participate 
in the study, investigator decision to discontinue or intercurrent illness that prevented 
further administration of treatment. Chemotherapy was also initiated one week after 
SBRT. 
 
4. CT simulation for treatment planning of SBRT 
Each patient should fast for at least eight hours before the simulation. Vacuum bags are 
customized with patients in the supine position, according to the patient’s body shape 
for immobilization during Cyberknife. SBRT is delivered via Cyberknife, an image-
guided frameless stereotactic robotic radiosurgery system (Accuray Corporation, 

Sunnyvale CA), that consists of a linear accelerator mounted on a robot arm with six 
degrees of freedom. In this system, the confluence of a large number of non-isocentric 
pencil beams permits the treatment of irregularly shaped target volumes with rapid dose 
falloffs. Cyberknife tracking system automatically compensates for the alignment offset 
and patient motions by adjusting the treatment isocenter. In addition, a CT based 
treatment planning system is used at our institution. Then, plain CT and an enhanced 
pancreatic parenchymal CT are performed for radiation treatment planning and target 
delineations. CT images are acquired under breath hold (preferably end-expiratory). 
Pretreatment diagnostic imaging would be co-registered to the simulation CT in cases 
where the patient is unable to tolerate intravenous contrast. The scan range includes the 
whole pancreas, at least 10 cm above and below the tumor. Spiral CT is performed with 
a slice thickness of 1.5 mm, and images are reconstructed in slices of 1.5 mm at most. 
Intravenous contrast enhancement is performed with an injection of 80-100 ml of 
iodixanol, a flow rate of 2.5 ml/sec, and a delay of 45-55 seconds; as acquired for the 
pancreatic parenchymal phase. 
 
5. Registration and tracking of SBRT 
The co-registrations of biphasic CT images are based on fiducials and anatomical 
(spinal) fusion. Before CT simulation, fiducials should be implanted using endoscopic 
ultrasound or CT guidance. This is pivotal for treatment planning and delivery. CT 
simulation will be performed 7-10 days after fiducial placement. This time interval is 
required to avoid early fiducial marker displacement or migration. In order to improve 

the accuracy of the treatment planning, the recommended number of implanted 
fiducials is preferably close to 3-5. As a result, given that fiducials could simulate the 
spatial location and displacement of the tumor, which is attributable to respiration, 
motion tracking should be performed by means of the correlation with these seeds; and 
fiducial markers render the Synchrony system equipped in Cyberknife feasible. This 
allows for respiratory motion tracking during irradiation. Nevertheless, patients with 
high risk of bleeding, abdominal infection, pancreatitis or pancreatic fistula are 
contradictory to several fiducial implants. Hence, one fiducial plus X-sight spine and 
Synchrony Tracking technique would be alternatively used. Before treatment, direct 
digital radiography images of the spine would be applied to detect 6-D errors; and this 
would be subsequently corrected for X-sight spine tracking on the patient’s positioning. 
This would enable fiducial tracking during treatment. 
 
6. Treatment planning and target delineation 
After CT simulation, CT images are transferred to the workstation where the target 
volumes are contoured by an attending radiation oncologist. Gross tumor volume (GTV) 
is delineated as a radiographically evident gross disease by contrast CT acquired from 
the portal-venous phase. At the discretion of the physician, clinical target volume (CTV) 
encompassing areas of the potential subclinical disease spread is also designated. In 
most cases, the CTV equals GTV. A 2-5 mm expansion margin is included to determine 
the planning target volume (PTV). When the tumor is adjacent to critical organs, the 
expansion of CTV should be avoided. Therefore, an individualized treatment plan 

would be developed based on tumor geometries and locations. 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. If dose level violates the constraint of 
SBRT, the patient would be considered as ineligible for this trial. The prescribed dose 
of PTV varies from 35-40Gy/5f with a single dose of 7-8Gy. In particular, these doses 
would be reduced if the tumor is approximately one-third or more of the duodenum or 
stomach circumference, or if the tumor abuts the bowel in only one area, as determined 
by the relationship of the tumor to the duodenum in axial, coronal and sagittal planes 
in CT scans, or the space between the tumor and the bowel wall is <3 mm. Normal 
tissue constraints are according to the American Association of Physicists in Medicine 
guidelines in TG-101.  
 
7. Follow-up 
Measureable disease was assessed and documented before treatment. CT or MRI and 
the tumor biomarker (CA19-9) were performed at baseline (2 weeks of beginning 
therapy) and every 2 months thereafter for evaluations of response until disease 
progression or treatment discontinuation, which was based on RECIST version 1.1 by 
blinded independent imaging review. Laboratory evaluations included hematology, 
blood chemistry, and liver and kidney function were performed on days 1 (before drug 
administration), 8 and 15 of each treatment cycle. Treatment-related toxicity toxicity 
was evaluated throughout the whole treatment period and at each one-month follow-up. 
All adverse effects were assessed according to the National Cancer Institute Common 

Toxicity Criteria for Adverse Events (CTCAE) version 4.0. An independent data 
monitoring committee of our center reviewed the safety and efficacy results regularly 
and provided recommendations to the investigators. 
 
8. Outcomes 
The primary endpoint was overall survival (OS), calculated as the time from the start 
of treatment to death. Secondary endpoints included 1-year OS, defined as the 
proportion of patients alive at 1 year; and progression free survival (PFS), calculated as 
the time from the start of treatment until documentation of any clinical or radiological 
disease progression or death, whichever occurred first; 1-year PFS, defined as the 
proportion of patients without disease progressions at 1 year; treatment-related toxicity 
and quality of life assessed by The European Organization for Research and Treatment 
of Cancer (EORTC): Quality of Life Questionnaire-Core 30 (QLQ-C30), which was 
performed at baseline, one, three, six months and twelve months after initiations of 
treatment. Higher scores in function domains and global health status indicate better 
quality of life, while higher scores in symptom domains imply worse quality of life. 
 
9. Statistical analysis 
We calculated that 170 patients were needed to be enrolled (85 per treatment group) to 
give 90% power to detect a statistically significant difference between treatment groups 
with a type I error of 5% (one-sided), assuming a hazard ratio (HR) of 0.77.  
All efficacy endpoints were assessed in the intention-to-treat population. The 

population included all patients enrolled in the trials regardless of receiving treatment. 
Safety was analyzed with data from the patient population who received at least one 
dose of study treatment. 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. OS and PFS associated 95% CIs were 
estimated by Kaplan-Meier methods. The log-rank test was used to compare OS and 
PFS between different treatment groups. Factors with a P-value <0.05 in the univariate 
Cox regression analysis were entered as candidate variables into the multivariate Cox 
proportional hazard regression analysis for identification of predictors correlating with 
OS and PFS. Quality of life was assessed by QLQ-C30. Scores were linearly 
transformed to a 0 to 100 scale. A clinically relevant change was defined as change in 
HRQOL scores of ≥10 points [23, 24]. Patients’ scores at different time points were 
compared with paired samples t-test. All P-values were two-sided. P<0.05 were 
considered as statistically significant. Statistical analyses were performed with IBM 
SPSS version 22.0 (SPSS Inc., Armonk, NY) and SAS version 9.4 (SAS Institute, Inc., 
Cary, NC).