Conditions: Renal Cell Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
This investigator driven study will examine the safety, efficacy and biological effects of combining pembrolizumab (MK-3475) an antibody targeted against anti-programmed cell death 1 (PD-1), with stereotactic ablative body radiotherapy (SABR) for oligometastatic renal cell carcinoma (RCC). The investigators hypothesise that the safety profile of this combination will be clinically acceptable.

Detailed description:
Dual institutional, single arm, unblinded, phase I/II study.

Arms:
arm 1: SABR treatment (18Gy-20Gy/1#) followed by 200mg pembrolizumab IV once every 3 weeks for a total of 8 cycles

Interventions: intervention 1: Stereotactic Ablative Body Radiosurgery (SABR) intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: 18-20Gy in 1 fraction intervention 2: Pembrolizumab at a dose of 200mg IV, 3-weekly will be delivered for a duration of 6 months, commencing 5 days (+/- 3 days) from the last dose of SABR.

Protocol document:
Prot_SAP_000.pdf: 
RAPPORT Study Protocol: Version 2.2, 16 January 2020 
 
Page 1 of 74 
 
 
 
TITLE: 
Stereotactic Radiotherapy and Anti-PD1 antibody (Pembrolizumab) for 
Oligometastatic Renal Tumours 
 
 
 
 
 
 
IIS Study Number:     53346 
Short Title:  
           RAPPORT 
Protocol Version:  
2.2 
Protocol Date:  
16 January 2020 
SPONSOR:  
 
Peter MacCallum Cancer Centre 
Peter Mac HREC Project Number: HREC/15/PMCC/94 
 
 
 
Coordinating Principal Investigator: 
 
Name:    A/Prof Shankar Siva 
Position: Radiation Oncologist, Peter MacCallum Cancer Centre 
Email:      shankar.siva@petermac.org  
Phone:    (03) 8559 7988 
Mobile:   0404 323 489 
 
 
 
 
 


RAPPORT Study Protocol: Version 2.2, 16 January 2020 
 
Page 2 of 74 
Table of Contents 
1 
SIGNATURE PAGE ........................................................................................................... 4 
2 
SCHEDULE OF EVENTS .................................................................................................... 5 
3 
TRIAL SUMMARY ............................................................................................................ 8 
4 
TRIAL DESIGN ................................................................................................................. 8 
5 
SCHEMA .......................................................................................................................... 9 
6 
OBJECTIVES & HYPOTHESIS .......................................................................................... 10 
 
Hypothesis............................................................................................................................ 10 
 
Primary Objective ................................................................................................................ 10 
 
Secondary Objectives ........................................................................................................... 10 
 
Exploratory Objectives ......................................................................................................... 10 
7 
BACKGROUND & RATIONALE ....................................................................................... 10 
 
Metastatic Renal Cell Carcinoma ......................................................................................... 10 
 
The Concept of Oligometastatic Disease ............................................................................. 11 
 
The Role of Metastasectomy in Oligometastatic Renal Cell Carcinoma .............................. 11 
 
The Role of Conventional Radiation in Renal Cell Carcinoma ............................................. 11 
 
Hypofractionated Radiotherapy in Renal Cell Carcinoma ................................................... 12 
 
SABR for Oligometastatic Malignancies ............................................................................... 12 
 
SABR for Oligometastatic Renal Cell Carcinoma .................................................................. 13 
 
Summary Tables for Outcomes in Extracranial Renal Cell Carcinoma ................................. 14 
 
Current Standard of Care ..................................................................................................... 15 
 
Summary of Risks and Benefits ............................................................................................ 16 
 
Rationale for the Trial and Selected Participant Population ............................................... 20 
 
Rationale for Selection of Immunotherapy to Combine with SABR in the Oligometastatic 
RCC Cohort ........................................................................................................................................ 20 
 
Rationale for Dose Selection/Regimen/Modification of pembrolizumab ........................... 21 
 
Rationale of Endpoints Definition ........................................................................................ 23 
8 
STUDY POPULATION ..................................................................................................... 25 
 
Patient Registration ............................................................................................................. 25 
 
Replacement of Non-Evaluable Patients ............................................................................. 25 
 
Participant Inclusion Criteria ................................................................................................ 25 
 
Participant Exclusion Criteria ............................................................................................... 27 
9 
TRIAL TREATMENTS ...................................................................................................... 29 
 
Megavoltage Radiotherapy .................................................................................................. 29 
 
Concomitant Medications/Vaccinations (allowed & prohibited) ........................................ 41 
 
Rescue Medications & Supportive Care ............................................................................... 42 
 
Diet/Activity/Other Considerations ..................................................................................... 45 
 
Participant Withdrawal/Discontinuation Criteria ................................................................ 46 
 
Withdrawal From The Trial .................................................................................................. 47 
10 
TRIAL PROCEDURES ...................................................................................................... 47 
 
Trial Procedures ................................................................................................................... 48 


RAPPORT Study Protocol: Version 2.2, 16 January 2020 
 
Page 3 of 74 
 
Visit Requirements ............................................................................................................... 50 
 
Safety Follow-Up Visit .......................................................................................................... 51 
 
Follow-up Visits .................................................................................................................... 51 
 
Survival Follow-up ................................................................................................................ 51 
 
Second Course Phase (Pembrolizumab Retreatment Period) ............................................. 51 
 
Assessing and Recording Adverse Events ............................................................................ 52 
 
Attribution of cause of an Adverse Event ............................................................................ 53 
11 
STATISTICAL ANALYSIS PLAN ........................................................................................ 58 
 
Statistical Analysis Plan Summary ........................................................................................ 58 
 
Statistical Analysis Plan ........................................................................................................ 58 
12 
Labelling, Packaging, Storage And Return Of Clinical Supplies .................................... 62 
 
Investigational Product ........................................................................................................ 62 
 
Packaging and Labelling Information ................................................................................... 62 
 
Clinical Supplies Disclosure .................................................................................................. 62 
 
Storage and Handling Requirements ................................................................................... 63 
 
Returns and Reconciliation .................................................................................................. 63 
13 
ADMINISTRATIVE AND REGULATORY DETAILS ............................................................ 63 
 
Confidentiality ...................................................................................................................... 63 
 
Ethical Principles and Regulatory Compliance ..................................................................... 63 
 
Adherence to Protocol ......................................................................................................... 63 
 
Informed Consent ................................................................................................................ 64 
 
Data Management ............................................................................................................... 64 
 
Source Documentation ........................................................................................................ 64 
 
Quality Assurance Reviews .................................................................................................. 64 
 
Trial Management Committee (TMC) .................................................................................. 64 
 
Safety Monitoring Committee (SMC) .................................................................................. 65 
14 
Publication and Presentation Policy............................................................................. 65 
15 
Reference List ............................................................................................................... 66 
16 
APPENDICES.................................................................................................................. 71 
Appendix 1: ECOG Performance Status ................................................................................... 71 
Appendix 2: Numerical Pain Rating Scale ................................................................................ 71 
Appendix 3: Spinal Stability ...................................................................................................... 72 
Appendix 4: Radiotherapy ........................................................................................................ 73 
 
 
 
 
 
 
 
 


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1 
SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that 
the Principal Investigator agrees to conduct the trial in compliance with the approved protocol 
and will adhere to the principles outlined in the NHMRC’s National Statement on Ethical 
Conduct of Research in Humans, the TGA’s Clinical Trial Handbook, Good Clinical Practice, the 
Sponsor’s SOPs, and other regulatory requirements as amended. 
 
I agree to ensure that the confidential information contained in this document will not be used 
for any other purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the Sponsor. 
 
I also confirm that I will make the findings of the study publicly available through publication 
or other dissemination tools without any unnecessary delay and that an honest accurate and 
transparent account of the study will be given; and that any discrepancies from the study as 
planned in this protocol will be explained. 
 
 
For and on behalf of the Study Sponsor: 
 
Signature 
 
Date 
 
Name (please print) 
 
 
 
Position 
 
 
Principal Investigator: 
 
Signature 
 
Date 
 
Name (please print) 
 
 
 
 
 


RAPPORT Study Protocol: Version 2.2, 16 January 2020 
 
Page 5 of 74 
2 
SCHEDULE OF EVENTS 
Table 1: Schedule of Events 
 
Trial Period: 
Screening 
Phase 
Radiotherapy 
Treatment Cycles 
Safety Follow-up 
Follow-up17 
Progression 
(Upon first 
progression) 
Treatment Cycle/Title: 
Screening 
SABR±CRT3 
Day 1 
Cycle 1 
Day 1 
Cycle 2-8 
Scheduling Window (Days): 
-35 to -1 
Commence within  
4 weeks of 
registration3 
5 days post 
SABR ± 3 days 
21 days post 
previous cycle 
Day 1 ± 3 days 
30 days from date of 
last dose of 
pembrolizumab 
± 3 days 
3 months from SABR  
± 14 days 
Clinical/Administrative Assessments 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
Disease Specific Medical History 
X 
 
 
 
 
 
 
SINS score for Spinal Targets 
X 
 
 
 
 
 
 
Full Physical Examination 
X 
 
X 
X 
 
 
 
Directed physical Examination 
 
 
 
 
 
X 
 
Vital Signs1 and Body Measurements 
X 
 
X 
X 
 
X 
 
ECOG Performance Status 
X 
 
X 
X 
 
X 
 
Review Adverse Events2 
X 
 
X 
X 
X 
X 
X 
Radiotherapy planning 
X 
 
 
 
 
 
 
Trial Treatment Administration – 
SABR 3 
 
X 
 
 
 
 
 
Trial Treatment Administration – 
Pembrolizumab4 
 
 
X 
X 
 
 
See section 
10.6 
Review Prior/Concomitant 
Medications 
X 
 
X 
X 
 
 
 
Numerical Pain Rating Score 
 
X 
X 
X 
 
X 
 
New Anti-Cancer Therapy Status / 
Second phase pembrolizumab 
 
 
 
 
X 
X 
X 
Survival Status18 
 
 
 
 
 
X 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 


RAPPORT Study Protocol: Version 2.2, 16 January 2020 
 
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Trial Period: 
Screening 
Phase 
Radiotherapy 
Treatment Cycles 
Safety Follow-up 
Follow-up17 
Progression 
(Upon first 
progression) 
Treatment Cycle/Title: 
Screening 
SABR±CRT3 
Day 1 
Cycle 1 
Day 1 
Cycle 2-8 
Scheduling Window (Days): 
-35 to -1 
Commence within  
4 weeks of 
registration3 
5 days post 
SABR ± 3 days 
21 days post 
previous cycle 
Day 1 ± 3 days 
30 days from date of 
last dose of 
pembrolizumab 
± 3 days 
3 months from SABR  
± 14 days 
Pregnancy Test5 – Urine or Serum 
β-HCG 
X 
 
X 
X 
 
 
 
Haematology6 
X 
 
X 
X 
 
As clinically 
indicated 
 
Chemistry7,8 
X 
 
X 
X 
 
 
T3, FT4 and TSH9 
X 
 
X 
X 
 
 
PT/INR and aPTT10 
X 
 
 
 
 
 
HIV, Hepatitis B and C11 
X 
 
 
 
 
 
 
Tumour Evaluation 
 
Tumour assessment by CT scan or 
MRI12 (Chest, Abdo, Pelvis) reported 
as per RECIST 1.1 
X 
 
X  
(Every 3 months from SABR) 
 
CT scan (Brain) (if clinically 
indicated)12 
X 
 
 
X (Cycle 4 & 8 
only) 
 
As clinically 
indicated 
 
Whole body bone scan (if clinically 
indicated)12 
X 
 
 
X (Cycle 4 & 8 
only) 
 
As clinically 
indicated 
 
Metastatic FFPE Biopsy13 
X 
 
 
 
 
X (month 9 only) 
X 
Primary Surgery FFPE sample14 
X 
 
 
 
 
 
 
Blood Serum Sample 
 
X 
X 
X 
 
X (9, 12 and 24 
months) 
X 
Whole Blood Sample15,16 
 
X 
X 
X 
 
X (9, 12 and 24 
months) 
X 
 
 
Clinical/Administrative Assessments 
1. Vital signs include blood pressure, heart rate, respiratory rate and temperature. Height will be measured at screening only. 
2. Baseline abnormalities (using CTCAE v4.03) must be recorded from signature of informed consent to prior to start of treatment. Adverse events (using CTCAE v4.03) are then required to be 
assessed on day 1 of every pembrolizumab cycle and at 30 days following last pembrolizumab treatment. SABR related adverse events will be collected at every subsequent follow-up visit until 
2 years after completion of SABR.   


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3. Conventional hypofractionated radiotherapy of 30-36Gy may be delivered to individual lesion(s) if SABR is determined to be not technically or safely possible to deliver.  If CRT is required it 
must be completed prior to SABR administration. At least one lesion must receive SABR. 
4. Pembrolizumab should be administered at 5 days (+/- 3 days) of the last SABR treatment for a total of 8 cycles. 
Laboratory Procedures/Assessments – All diagnostic laboratory tests should be performed within 10 days of study registration (to determine eligibility), and also within 3 days prior to every cycle 
of pembrolizumab (unless indicated otherwise below) 
5. Urine or serum pregnancy test for patient of childbearing potential should be performed within 7 days of study registration and also 72 hours within first dose of pembrolizumab. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
6. Haematology:  Haematocrit, haemoglobin, platelet count, white blood cell count (total and differential), red blood cell count, absolute neutrophil count and absolute lymphocyte count.  
7. Chemistry:  Carbon dioxide (if considered standard of care only), uric acid, calcium chloride, glucose, phosphorus, potassium, sodium, magnesium, total protein. 
8. Liver Function Tests:  Albumin, Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Lactate Dehydrogenase (LDH), Gamma-Glutamyl Transferase 
(GGT, total bilirubin and direct bilirubin if total bilirubin is elevated above the ULN), Kidney Function Tests:  Urea, creatinine. 
9. Thyroid Function:  T3, T4 and TSH. 
10. Coagulation Profile:  PT (INR), aPTT. These need only be done if there is clinical concern regarding patient anticoagulation. 
11. HIV, Hepatitis B and C tests only need to for those patients at risk of prior or current active infection as determined by the investigating clinician. These tests only need to be performed within 
7 days of study registration only. 
Tumour evaluation - Screening CT and WBBS should be completed within 35 days prior to study registration.  
12. Clinical and radiological tumour assessments will be performed by CT scan (or MRI as required if tumour is in extremity) at screening and every 3 monthly post-SABR treatment until the last 
evaluable patient completes 12 months of follow-up.  
Brain CT will be performed if clinically indicated at the same time points. Whole body bone scans will be performed at 3 and 6 months post SABR treatment only in patients with bone disease 
at baseline and as clinically indicated at the 3 monthly post SABR treatment follow-up visits. 
Disease progression should be confirmed with repeat imaging 4 to 6 weeks later by the same imaging modality or by biopsy. If PET-CT scan has been done clinically this can be used for 
confirmation of disease progression provided the CT component of the PET-CT scan is of adequate resolution.  
Biological Evaluations 
13. If an archival biopsy specimen from a metastases exists then this should be submitted (block or unstained slides). An optional biopsy of metastatic site will be performed at 9 months post 
completion of SABR, if feasible. This will ideally be the same site as biopsied before trial related treatments (also optional). In event of disease progression - A sample from the metastatic site, 
if feasible, is requested. If taken, one-two formalin-fixed, paraffin-embedded (FFPE) tumour blocks should be requested. 
14. If the patient had surgery for the primary tumour, one tumour block from resection should be submitted. 
15. Prior to radiotherapy, first dose of pembrolizumab (all cycles), at disease progression (if this occurs) and at 9, 12 and 24 months post SABR treatment, whole blood samples will be collected for 
immune endpoints (refer to the RAPPORT Laboratory Manual for details on collection and processing). 
16. EDTA whole blood sample (refer to the RAPPORT Laboratory Manual for details for collection and processing). 
Follow-Up Visits 
17. Study Follow-Up Visits - follow-up assessments (e.g visits @ 1, 3, 6, 9, 12, 15, 18, 21 and 24 months post end of SABR Treatment) should be undertaken within ± 14 days of the scheduled time 
point. In the event of overlapping visits (i.e. between day 1 of each pembrolizumab cycle and post-SABR follow-up visits), only one visit is required but all protocol mandated investigations (for 
both timepoints) must be undertaken. 
18. All patients will be followed for survival until the last evaluable patient completes 12 months of follow-up. Participants who start a new systemic therapy, are retreated with pembrolizumab or 
who have distant progression will be followed for survival only. 


   
RAPPORT Study Protocol: Version 2.1, 25 Jan 2019  
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3 
TRIAL SUMMARY 
 
Title 
Stereotactic Radiotherapy and Anti-PD1 antibody 
(Pembrolizumab) for Oligometastatic Renal Tumours 
Abbreviated Title 
RAPPORT 
Trial Phase 
Phase 1b/II 
Clinical Indication 
Patients with oligometastatic renal cancer (1-5 metastases) 
considered safe for stereotactic ablative body radiosurgery 
(SABR) 
Trial Type 
Prospective, single arm study 
Route of administration 
SABR treatment (18Gy-20Gy/1#) followed by 200mg 
pembrolizumab (MK-3475) IV once every 3 weeks for a total 
of 8 cycles (~6 months).  
Trial Blinding 
Open label 
Number of trial subjects 
30 evaluable* patients in total. 
Estimated enrolment 
period 
24 months 
Estimated duration of 
trial 
36 months 
Duration of Participation ~20 months 
 
* Evaluable patients are defined as participants who complete at least one SABR treatment and receive at least one dose of 
study drug (18-20Gy/1# to at least one lesion with at least one dose of pembrolizumab). 
 
4 
TRIAL DESIGN 
This is a prospective, single arm study that will evaluate the safety profile, and the clinical and 
biological efficacy of combining SABR with pembrolizumab.  
 
Pembrolizumab at a dose of 200 mg IV, 3-weekly will be delivered for a total duration of 6 
months, commencing 5 days (+/- 3 days) from the last dose of SABR. 
 
Tumour response will be evaluated by Response Evaluation Criteria in Solid Tumours version 
1.1 (RECIST 1.1). 
 
Tumour tissue and peripheral blood samples will be collected pre, during and post-treatment 
to assess longitudinal changes in immune subsets within tumour tissue and peripheral blood. 
 
 
 
 
 
 


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5 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Metastatic renal cancer (1-5 Metastases) 
Informed Consent 

Medical History & Physical Examination (Vital Signs, Weight, ECOG) 

CT and Whole Body Bone Scan (if applicable) 

Baseline Symptoms/Adverse Events & Concomitant Medications 

Blood Tests 
Screening Investigations 
SABR (18 Gy-20 Gy/1#; +/- conventional RT*) 
+ 
Pembrolizumab  (MK-3475) 
(200mg, 8 cycles, 3 weekly, commencing 5 days 
[± 3 days] after SABR) 
RAPPORT Study Registration 
Study Follow-Up 
Figure 1: Study Schema 
* Conventional hypofractionated radiotherapy may be delivered to individual lesion(s) if SABR is determined
to be not technically or safely possible to deliver. 


RAPPORT Study Protocol: Version 2.2, 16 January 2020 
 
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6 
OBJECTIVES & HYPOTHESIS 
 
Hypothesis 
This investigator driven study will examine the safety, efficacy and biological effects of 
combining pembrolizumab (MK-3475) an antibody targeted against anti-programmed cell 
death 1 (PD-1), with stereotactic ablative body radiotherapy (SABR) for oligometastatic renal 
cell carcinoma (RCC). We hypothesise that the safety profile of this combination will be 
clinically acceptable. 
 
 
Primary Objective 
The primary objective for this study is to determine the safety profile of SABR in combination 
with pembrolizumab. 
 
 
Secondary Objectives 
Secondary objectives are to examine evidence of clinical efficacy of the combination:   
1. 
To describe overall survival (OS). 
2. 
To describe time to local progression (TTLP). 
3. 
To describe distant progression free survival (DPFS). 
4. 
To describe overall response rate (ORR). 
5. 
To describe disease control rate (DCR) 
6. 
To describe changes in pain ratings over time. 
 
 
Exploratory Objectives 
The exploratory objectives are to investigate the biological effects of the combination. These 
will include, but are not limited to: 
1. 
Evaluate PD-L1 expression in primary tumour and metastatic lesions using 
immunohistochemistry. 
2. 
Evaluate longitudinal cellular and molecular changes in archival tumour tissue, 
and/or fresh tumour biopsies. This will include tumour infiltrating lymphocytes (TILs) 
and other markers. 
3. 
Evaluate longitudinal changes in immunological subsets within peripheral blood.  
 
7 
BACKGROUND & RATIONALE 
 
Metastatic Renal Cell Carcinoma  
Renal cell carcinoma (RCC) is the ninth most common cancer in Australia and the fourteenth 
most common cancer worldwide [1, 2]. The incidence of RCC is rising, particularly in patients 
aged 70 to 90 years [3]. Overall, 17% of patients present with metastatic disease and another 
50% of patients initially treated with curative intent will develop metastatic disease [4, 5]. 
Historically patients with metastatic renal cell carcinoma (mRCC) have a poor prognosis, with 
5-year survival rates of ≤10% [6]. In patients with metastatic disease, the median survival time 
ranges from 6 to 12 months, and in patients with brain metastases, the mean survival time is 
3 months [7, 8]. In the first line setting, the use of both sunitinib [9] and pazopanib [10] is 
associated with progression free survival rates of approximately 11 months, whilst sorafenib 
in the second line setting is associated with progression free survival rates of approximately 5 
months [11].  
 


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The Concept of Oligometastatic Disease 
The concept of oligometastases, introduced by Hellman and Weichselbaum in 1995, describes 
an intermediate state of metastases in which the number and site of metastatic tumours are 
limited [12]. This clinical entity can be broadly divided into two groups of patients: those with 
occult widespread and incurable but mostly subclinical metastatic disease and those with truly 
limited metastatic disease who might be potentially curable. The clinical implication of this 
hypothesis for the latter group is that locally extirpative or ablative treatments may achieve 
prolonged remission in these patients with small numbers of metastases. The absolute 
number of metastatic lesions that is considered defines the oligometastatic state remains 
controversial and highly dependent on the clinical scenario. Typically, this is defined as either 
less than 3 or less than 5 deposits [13].  
 
Notably, prolonged survival has been observed in patients with solitary or oligometastatic 
renal cell carcinoma whose disease is amenable to resection [14]. With more sensitive imaging 
methods, the incidence of diagnosing oligometastatic is increasingly observed thereby 
highlighting the need to revisit optimal management strategies for this subgroup of patients. 
Although surgery has long been considered the main modality to offer patients with truly 
oligometastatic disease long term remission, this is not always feasible due to the location of 
the disease, the morbidity of the surgery and the patient’s other medical comorbidities. The 
advent of stereotactic ablative body radiation therapy (SABR), allows for delivery of high 
biological doses of radiation using highly conformal image guided techniques. SABR is being 
increasingly investigated as a local ablative therapy in this setting. 
 
 
The Role of Metastasectomy in Oligometastatic Renal Cell Carcinoma 
Surgery is a long established modality in the treatment of selected patients with metastatic 
disease. The first case of metastasectomy for RCC was reported by Barney et al., in which the 
patient remained disease free for 23 years [15]. Despite this there are no randomized studies 
examining the role of metastasectomy in patients with stage IV disease. Nevertheless, several 
observational studies have examined outcomes from metastectomy in patients with limited 
metastatic disease. In a bi-institutional retrospective study of 109 patients, the five-year 
cancer specific survival (CSS) was 46.9% and median CSS was 54.7 months (range: 0.4–211) in 
patients undergoing resection for oligometastatic disease [14]. Of these patients, 99 (90.8%) 
had solitary metastasis. Similarly, in a study of 92 patients undergoing pulmonary 
metastasectomy at the Cleveland Clinic, the 5-year CSS was 45% [16]. These findings are 
similar to a series of 65 patients from Paris undergoing pulmonary metastasectomy which 
found a 5-year overall survival of 37% [17]. The NCCN guidelines recommend that for patients 
with presentation of primary disease and potentially resectable solitary metastases, that a 
nephrectomy and metastasectomy be performed. The European Urology Association (EUA) 
guidelines recommend consideration of metastasectomy for patients with oligometastatic 
disease based on systematic review of level 3 evidence [18].  
 
 
The Role of Conventional Radiation in Renal Cell Carcinoma 
Definitive external beam radiotherapy (EBRT) is often used to treat medically inoperable 
patients with cancers in many different organs. However, RCC is conventionally considered 
“radioresistant” to fully fractionated EBRT. Clinical trials of EBRT delivered in the neoadjuvant 
or adjuvant setting for primary RCC throughout the 1970’s and 1980’s failed to demonstrate 
a survival benefit [19-22]. A recently published meta-analysis of 7 randomized controlled trials 
involving 735 patients treated with post-operative radiotherapy (PORT) showed a significant 
reduction of locoregional failure in patients treated with PORT (p = 0.0001), but no difference 


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in overall survival (p= 0.29) (29). The majority of patients were treated with traditional large 
2-field techniques, and the authors called for newer trials with more modern techniques. 
Currently the role of conventional EBRT for primary RCC is limited, possibly to patients with 
poor pathological features who are high risk of local tumour recurrence [23]. Consequently, 
conventional external beam radiotherapy is largely limited to palliative treatments. In an 
effort to overcome the perceived “radioresistance” of RCC, hypofractionated EBRT in the form 
of SABR has renewed interest in the management of primary RCC with radiotherapy. 
 
 
Hypofractionated Radiotherapy in Renal Cell Carcinoma 
In contrast, ablative stereotactic radiotherapy has been used effectively for treatment of 
intracranial RCC for decades. With the advent of SABR techniques, renewed interest in high-
dose-per-fraction radiotherapy has led to impressive results in the context of primary RCC 
with local control rates in excess of 90% at 2-years [24]. The advantage of hypofractionated 
radiotherapy in RCC is suggested by the relatively low α/β values of RCC cell lines compared 
to other malignancies. Generally, cell lines with a high α/β ratio of >10 are considered 
radiosensitive. Ning et al. [25] at Stanford University performed a study in which two common 
human RCC cell lines Caki-1 and A498 were used to perform clonogenic survival assays. The 
cells were irradiated to doses of 0 – 15Gy and surviving fractions calculated. When cells were 
irradiated using conventional fractionation of 2Gy per fraction, only a small proportion of cell 
kill was noted, compared to an exponential rate of cell kill noted at doses above 6Gy per 
fraction. In this study, the α/β ratio of Caki-1 and A498 were 6.9 and 2.6 respectively. It has 
been hypothesized that severe hypofractionation has a different mechanism of cell kill than 
conventional radiation which relies largely on mitotic cell arrest. Stereotactic radiotherapy is 
more likely to induce ceramide-pathway cell kill and apoptosis as well as vascular endothelial 
cell damage [26-28].  
 
 
SABR for Oligometastatic Malignancies 
There is a large body of literature on SABR for oligometastatic malignancies.  For practical 
reasons only the landmark SABR oligometastatic studies will be summarized to highlight 
tolerability and efficacy.  
 
Salama and colleagues [29] reported on patients with 1 to 5 metastatic cancer sites based on 
18F-flourodeoxyglucose positron emission tomography (FDG-PET) imaging and a life 
expectancy of at least 3 months who were treated with SABR. Patients received escalating 
doses of RT, starting at a dose 24Gy (three 8Gy fractions) 2Gy per fraction dose-escalations 
and a dose ceiling of 60Gy (three 20Gy fractions). The commonest metastatic sites treated 
were lung (36.3%), lymph nodes (19.4%), liver (19.4%), bone (13.3%) and adrenal glands 
(8.0%).  At a median follow up of 20.9 months no dose limiting toxicity was seen.  One patient 
with a centrally located right upper lobe metastases who received 36Gy (three 12Gy) fractions 
developed haemoptysis 10 months after SABR.  CT and bronchoscopy revealed disease 
recurrence and this patient died shortly afterwards.  More recent studies due to toxicity 
recommend excluding central lung lesions outside the contexts of clinical trials [30].  
 
A number of phase I and II studies of SABR to spinal metastasis have demonstrated favourable 
local disease control rates (86-90%) for patients without spinal cord compression [31-34].  
Similar to intracranial stereotactic radiosurgery, SABR has been shown to be effective in the 
retreatment of metastases that progress following standard EBRT [35]. Additionally, SABR has 
been shown to be very effective in palliating pain associated with spinal metastases [36, 37]. 
 


RAPPORT Study Protocol: Version 2.2, 16 January 2020 
 
Page 13 of 74 
Several Phase I and II studies have investigated SABR for hepatic metastases using fixed RT 
doses [38], escalation RT doses [39, 40] and normal tissue complication probabilities [41]. 
These studies have consistently demonstrated high rates of disease control in the treated 
metastatic deposits (71-92%). However in general liver metastases control rates have been 
lower than observed in pulmonary or spinal metastases which may reflect challenges in 
defining the true extent of the metastatic target as well as organ motion with respiration. 
 
Several studies examining SABR for oligometastases in the lung with both single dose [42] and 
dose-escalation [43] have demonstrated high rates of treated-metastasis control (89-96%) 
with promising 2-year survival rates (38-39%).  Similar to SABR for early-stage non-small cell 
lung cancer, the use of three or less fractions for centrally located tumours, defined as within 
2cm of the proximal bronchial tree, can result in high rates of treatment related toxicity and 
should be avoided[44].  
 
 
SABR for Oligometastatic Renal Cell Carcinoma 
Our group has recently performed a systematic review of SABR in oligometastatic RCC 
following the PRISMA guidelines [45]. The definition of ‘oligometastatic disease’ in these 
studies was typically 1-5 metastases. A total of 10 studies were found suitable for inclusion, 
of which 2 were prospective studies.  There were 389 patients with 730 targets identified in 
the extracranial SABR literature. The patient population was heterogeneous in terms of 
baseline characteristics, burden of metastatic disease, and prior treatment. Median or mean 
age in seven studies ranged from 58 to 63 years. Five studies included patients treated with 
SABR to bony metastases only, predominantly to the spine, while the remaining five studies 
included a variety of locations, most commonly to the lung.  
 
 
Radiotherapy Characteristics 
Within the extracranial studies, a wide range of total doses and dose fractionation schedules 
were used. The biological effective dose (BED) calculated using the α/β ratio of Caki-1 and 
A498 renal cell lines (discussed above) were BED6.9 ranging 48 -143 Gy and a BED2.6 ranging 
from 98 – 305 Gy. Five studies incorporated the use of single fraction regimens, with the total 
SRS dose ranging from 8Gy to 24Gy.  
 
 
Local Control and Survival 
Nine out of 10 studies had crude local control (LC) data available. The crude LC was 89%. 
Median overall survival for all patients with metastatic RCC only was reported in three studies 
and ranged from 11.7 to 22 months. Two studies reported estimated 1 year OS of 48.9% and 
72%, while another study by Ranck et al. [46] reported 2 year OS of 85%. In the latter study, 
67% (12/18) of patients had oligometastatic disease (five or less metastatic lesions) and 
underwent SABR to all known sites of disease. Wersall et al. provided median survival 
outcomes for patients with limited disease (one to three lesions), and found this to be higher 
compared to those with greater than three lesions (37 months and 19 months respectively). 
Overall, the 1-year weighted LC for intracranial SRS and SABR was 88% and 86% respectively. 
These data are comparable to studies that have included patients with non-RCC histology [47-
50], challenging the long-held view that RCC is a radio-resistant disease. 
 
 
Treatment Related Toxicity 
Toxicity data was available for all ten studies. Grade 3 to 4 toxicities ranged from 0% to 4%. 
There were a total of two treatment related deaths. One patient who had a large metastatic 


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lesion (516cc) in the lung close to the pleura, died 10 weeks after receiving SABR (48Gy in 4 
fractions). This patient was admitted to hospital with electromechanical dissociation (EMD). 
The second mortality was due to a fatal gastric haemorrhage 4 months after treatment for a 
metastasis in the pancreas adjacent to the stomach and duodenum. No details regarding 
radiotherapy dose was available in this patient.  
 
 
Summary Tables for Outcomes in Extracranial Renal Cell Carcinoma 
A summary table for outcomes in extracranial renal cell carcinoma is presented in Table 2. 
 
Table 2: Outcomes in Extracranial Renal Cell Carcinoma 
Author / 
Date 
Patients 
(Targets) 
Locations 
Median 
Follow Up 
(months) 
Crude LC 
(%) 
1 year 
LC (%) 
Median 
OS 
(months) 
Toxicity 
(toxicity grading 
system) 
Balagamwala 
2012 
57 (88) 
Spine 
5 
77 
50 
12 
33% (19/57) any 
toxicity 
10.5% (6/57) Grade 1  
2% (1/57) Grade 3 
nausea/ vomiting 
No Grade 4+ toxicity 
Gerszten 
2005 
 
48 (60) 
Spine  
37 
88# 
96 
NR 
0% radiation toxicity^ 
Jhaveri 
2012 
18 (24) 
14 spine,  
4 ribs/clavicle,  
6 pelvis 
10 
NR 
NR 
NR 
6% (1/ 18) Grade I 
toxicity  
(NCI CTCAE version 
not stated) 
Nguyen 
2010 
48 (55) 
Spine  
13 
78 
80 
22 
23% (9/48) Grade I 
fatigue.  
13% Grade II fatigue  
18% Grade II nausea  
and vomiting 
2% (1/48) Grade III 
pain 
2% (1/48) Grade III 
anaemia (NCI CTCAE 
v.2) 
Staehler 
2010 
55 (105) Spine 
33 
98 
94 
17 
2% (1/55) Grade I 
abdominal pain (NCI 
CTC v.3) 
Zelefsky 
2012 
55* (105) 59 spine, 22 pelvic 
bones, 14 other, 9 
femur, 1 lymph 
node 
12 
72* 
72 
NR 
4% (2/55) Grade 2 
dermatitis 
7% (4/55) fractures 
2% (1/55) Grade 4 
erythema 
Svedman 
2006 
(Prospective 
Phase II trial) 
26 (77) 
63 lung,  
5 kidney, 5 
adrenal,  
4 thoracic, 3 abdo 
lymph nodes  
3 liver, 1 pelvis,  
1 spleen 
52+ 
99 
100 
32+ 
58% (15/26) Grade I - 
II toxicity 
4% (1/26) Grade V 
toxicity 
(NCI CTCAE version 
not stated) 


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Author / 
Date 
Patients 
(Targets) 
Locations 
Median 
Follow Up 
(months) 
Crude LC 
(%) 
1 year 
LC (%) 
Median 
OS 
(months) 
Toxicity 
(toxicity grading 
system) 
Teh 
2007 
14 (23) 
head and neck, 
lung, 
mediastinum, 
spine, non-spine 
bone, abdominal 
wall 
9+ 
86# 
81 
NR 
No grade 2 or higher 
toxicity  
RTOG/ EORTC toxicity 
criteria 
Wersall 
2005 
50 (154) 117 lung,  
7 kidney, 
6 adrenal gland,  
5 kidney 
metastases,  
5 thoracic wall,  
4 bone,  
6 lymph nodes,  
2 liver, 1 spleen,  
1 pancreas 
37+ 
98 
99 
NR 
40% (23/58) any 
toxicity 
2% (1/58) mortality+ 
Ranck 
2012 
18 (39) 
11 bone,  
10 abdominal 
lymph node,  
7 mediastinum,  
4 lung, 2 kidney 
metastases, 2 
adrenal, 2 liver, 1 
soft tissue 
16 
95 
96 
NR 
61% (11/18) Grade I 
fatigue.  
No Grade 3 or higher 
acute toxicity 
(CTCAE v3.0) 
11% (2/18) Grade 1 rib 
fracture 
6% (1/18) Grade 2 
radiculitis 
6% (1/18) Grade 2 
bone pain 
*Information obtained via personal correspondence; #according to number of patients rather than targets; 
+includes patients with metastatic and primary RCC; ^no toxicity grading system used; NR, not reported; SABR, 
stereotactic ablative body radiotherapy; CRT conventional radiotherapy; EBRT, external beam radiotherapy  
 
 
Current Standard of Care 
Current standard of care for patients with metastatic renal cell carcinoma depends on the 
biological subtype, extent of disease and patient fitness. The mainstay is surgical resection 
where possible, particularly for single sites of disease. Single metastatic sites present the most 
feasible and best prognosis with the aim to reduce symptoms and/or prolong survival. In 
patients who are not suitable for surgical resection, or where surgery would be considered 
morbid, other local therapy (such as radiotherapy) can be considered. This is particularly true 
for patients with several sites of oligometastases in which multiple surgical resections can be 
morbid. Patients with more than one oligometastases are often considered carefully for local 
therapies taking into account both tumour and patient related factors. This group often 
undergoes a period of surveillance or receives local therapy before receiving any systemic 
therapies. Indeed Rini et al. presented a prospective observational study that demonstrated 
that patients with metastatic RCC who fit similar criteria do not require standard TKI therapy 
for mRCC therapy for a median of 14.1 months ((ASCO 2014, ASCO Annual Meeting 
Proceedings (Vol. 32, No. 15_suppl, p. 4520)). In total 52 patients were enrolled, with the 
estimated 12 month and 24 month rates of continued surveillance without systemic therapy 
of 58% and 33%, respectively when local therapies only were used. Neither location nor 
number of metastatic sites impacted the length of observation. Patient anxiety/depression 
were not prevalent at baseline, and scores did not worsen over time. Importantly patients 
could have local treatments (such as SABR) during this observation period. Similar local 


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experience a retrospective publication of outcomes in patients with metastatic renal cell 
carcinoma across four academic institutions in Melbourne and Canberra identified 125 
patients with metastatic RCC who received systemic therapy with sunitinib. In all, 43% of 
patients who received sunitinib underwent a watchful-waiting period of >90 days before 
initiating treatment, with local therapies allowable; these patients had a median overall 
survival of 56.3 months [51]. Consensus guidelines for Canada and others also identify 
observation as a valid management strategy in the first instance for certain patients with 
metastatic RCC [52]. Conclusions from a review of data from five retrospective studies, one 
prospective cohort and a subgroup of a randomized phase III trial lend support to the strategy 
of deferral of systemic therapy and the use of local therapies where appropriate instead for 
carefully selected patients with metastatic RCC and does not induce patient anxiety or impair 
quality of life [53]. 
 
So in selected fit patients with limited oligometastatic disease, the standard of care can 
include aggressive local management such as extirpative metastasectomy or local high-dose 
radiotherapy with deferral of systemic therapy until progression. Other options could also 
include upfront systemic targeted therapy such as tyrosine kinase inhibitors (TKIs). While 
these systemic treatments may prolong survival they are not curative in the oligometastatic 
setting. Alternatively, patients with symptomatic bone metastases or soft tissue disease may 
be treated with palliative external beam radiotherapy, and bisphosphonates/denosumab.  
Such treatment is aimed at symptom control and not prolonging survival.  
 
 Summary of Risks and Benefits  
SABR involves highly hypofractionated radiotherapy given as an ablative treatment.  While 
there is extensive literature suggesting that it is safe and has low rates of major toxicities, such 
studies have tended to have small numbers and relatively short follow up given most patients 
succumb to their metastatic disease. Thus, by combining a short course of immunotherapy 
after SABR, we postulate that this will result in a lower likelihood of patients succumbing to 
further disease recurrence.  
 
The risk of SABR treatment depends on the exact anatomical site of the oligometastatic 
disease irradiated. There is a low but not negligible risk of radiation pneumonitis, bone 
fractures, radiation enteritis, skin fibrosis, renal impairment and proctitis. There is an 
exceedingly low risk of transverse myelitis. 
 
SABR is thought to provide long-term local control of known oligometastatic sites of cancer.  
It also provides good and durable pain relief for painful metastases.  It is postulated that SABR 
to sites of oligometastatic or oligoprogressive renal cell carcinoma, in selected patients, may 
prolong survival.  Clearly studies that determine whether a survival benefit occurs with such 
treatment remain to be conducted and reported. 
 
It is acknowledged that patients may have received previous radiotherapy to an area where 
SABR is to be delivered in this protocol (equivalent dose of 30 Gy in 10 fractions). Due to the 
increased dose that is received in this instance, there is an increased risk of radiation toxicity 
in these patients. This potential increased level of risk has been highlighted in the patient 
information and consent form and must be discussed in each instance prior to informed 
consent. Patients who have received more than this RT equivalent dose schedule to an area 
planned for further SABR treatment are not eligible for this study. 


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 Immunity and Control of Renal Cancer Metastases 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation 
between tumour-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumours.  
 
 Ablative Radiotherapy as a Means to Enhance Immune Responses 
Radiotherapy has long been used a cancer therapy and is known for its direct cytotoxic effects 
on tumour cells through generation of DNA damage. However, interest has grown around the 
idea that radiotherapy can have immunological effects. This includes the generation of 
antigenic peptides through cell death which enhance MHC Class I and adhesion molecules, as 
well as the subsequent production of cytokines and peptides that can augment immune 
responses. Therefore, evidence suggests that radiation therapy can trigger a tumour-directed 
immune response. 
 
Radiation also seems to be able to prime the immune system for an adaptive response. Direct 
ionizing radiation elicits innate immune recognition of tumour following tumour cell release 
of “danger signals” [54, 55]. Three molecular signals are required for the ‘danger’ response: 
dendritic cell (DC) phagocytosis of dying tumour cells, cross-presentation of tumour-derived 
antigens to T cells and the activation of tumour-specific T cells. Translocation of calreticulin 
[(CRT)/ERp57] to the surface of dying irradiated cancer cells provides an “eat-me” signal 
important for DC recognition and engulfment of dying tumour cells [56]. The release of 
inflammatory molecules from radiation-exposed tumour cells such as high-motility group 
protein B1 (HMGB1) and ATP, which bind to toll-like receptor 4 (TLR4) or the purinergic 
receptor P2X7, respectively, also promote antigen processing and cross-presentation by DC 
and T cell priming through the release of IL-1β [57, 58]. All of these molecules provide the 
tools for an improved recognition and killing by tumour-specific T cells [59]. The intense 
localized radiotherapy provided by SABR drives release of tumour antigen, which is taken up 
by resident dendritic cells (DCs) the DCs mature and migrate to the draining lymph node, 
where they induce a tumour-specific T cell response (both CD4+ and CD8+). Effector T cells 
then traffic to the tumour microenvironment where they release effector molecules and 
induce tumour cell apoptosis. 
 
We hypothesize that SABR is more immunogenic than conventional radiation therapy. The full 
immunological potential of radiotherapy may be influenced by the dose and fractionation of 
radiation employed, for both single fraction and fractionated approaches [60]. The ablative 
dose/fractionation spectrum employed by SABR heralds a potential for even greater 
augmentation of the tumouricidal immune response than conventional radiotherapy [28]. 
Immogenic responses at sites distant to the SABR therapy have already been reported by our 
group [61] and others [62]. Ablative doses result in a greater degree of stromal / vascular 
damage, ceramide-induced endothelial cell damage and increased apoptosis of tumour cells 
[63, 64]. This results in a tumour microenvironment enriched with tumour-derived antigens, 
with co-existing DC activation, antigen cross-presentation and tumour-specific T cell 
responses. Thus, in the B16 mouse melanoma model, tumour inhibition was more pronounced 
with ablative doses of radiation as compared to conventional radiation [65]. Significant cross-
priming of T-cells against tumour antigens have been demonstrated to be induced by a single 
dose of 15Gy in the draining lymph nodes [66]. Our group at the Peter MacCallum Cancer 


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Centre (Peter Mac) identified that single dose (12Gy) radiotherapy did not deplete established 
tumours of effector cells (CD8+ T, CD4+ T and NK cells) critical to the antitumour activity of 
radiotherapy when used in combination with immunotherapy. Indeed irradiated mammary 
tumours were enriched for functionally active, tumour-specific T cells and Ly-6C+ memory 
CD8+ T cells [67]. It is unclear whether single fraction or hypofractionated RT is optimal in 
combination with immunotherapy, with reports from New York University suggesting 3 x 8Gy 
fraction therapy resulting in enhanced immunogenicity in comparison to single fraction 
ablation [68, 69]. However, more recently, single fraction 20Gy ablative RT has been shown to 
synergize with the T-cell checkpoint inhibitor anti-PD-1 in murine models [70], allowing for 
induction of an anti-tumour immune response by relief of tumour-mediated 
immunosuppression. Similarly a report by demonstrated that single fraction 30 Gy to tumour 
nodules in murine model resulted in an intense CD8+ T cell tumor infiltrate, and a loss of 
myeloid derived suppressor cells (MDSCs) [71]. In murine models of melanoma and renal cell 
carcinoma, single fraction 15Gy SABR combination with PD-1 blockade has been 
demonstrated to synergize for additive tumour response in both the irradiated and distant 
tumour sites [72]. A further study in a melanoma model also found single fraction SABR 
synergised with anti-PD-1, with a possible dose response as 18 Gy of radiotherapy resulted in 
increased activation and proliferation of antigen-specific T-cells when compared to 12Gy [73]. 
 
 Combination Radiotherapy and T Cell Checkpoint Blockade can Augment Immune 
Responses and Reduce T Regulatory Cells 
There is increasing data to suggest that radiotherapy effects may be enhanced from coincident 
or subsequent immunotherapy. In established triple negative mouse breast cancer models, 
the anti-tumour effect of radiotherapy could be enhanced by combinations of 
immunostimulatory antibodies including anti-PD-1 antibody. In one study from the Peter Mac 
(Verbrugge et al; [67]), PD-1 signaling was found to be critical and was synergistic when 
inhibited in order to promote rejection of triple negative mouse tumours. Of note, 
radiotherapy was found not to deplete tumours of functionally active tumour specific effector 
cells. These data support concomitant targeting of immunostimulatory and/or inhibitory 
checkpoints with radiotherapy.  Hence, this research presents an opportunity to test this drug 
in the first line setting along with SABR, which is typically used in patients with treatment naïve 
oligometastatic disease and may help change the natural history of the disease. 
 
The abscopal effect is a phenomenon when local radiotherapy is associated with regression of 
metastatic cancer distant from the irradiated site. This effect is thought to be mediated by 
activation of the immune system though its biological basis is not well understood. This effect 
was recently observed in a patient with melanoma treated with radiotherapy and ipilimumab 
(Postow et al. [74]. Tumour shrinkage over time was observed in the irradiated site as well as 
in distant sites. These correlated with changes in peripheral-blood immune cells (decrease in 
CD4+ ICOS high cells, increases in HLA-DR expression and decreases in myeloid derived 
suppressor cells (MDSCs CD14+ HLA-DRlow) as well as increases in humoral antibody response 
to a range of antigens after radiotherapy. We will investigate for potential immunological 
changes induced in the peripheral blood by the combination therapy as possible evidence of 
mechanisms that may support abscopal effects in future studies. 
 
Refer to the Investigator’s Brochure (IB)/approved labelling for detailed background 
information on pembrolizumab. 


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 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumour-infiltrating lymphocytes (TILs) in cancer tissue and favourable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumours. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumours to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively regulate 
antigen receptor signalling upon engagement of its ligands (PD-L1 and/or PD-L2).  The 
structure of murine PD-1 has been resolved.  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for 
ligand binding and a cytoplasmic tail which is responsible for the binding of signalling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signalling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in 
the CD3 T-cell signalling cascade.  The mechanism by which PD-1 down modulates T-cell 
responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an 
overlapping set of signalling proteins.  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  
Expression has also been shown during thymic development on CD4-CD8- (double negative) 
T-cells as well as subsets of macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and 
PD-L2) are constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumours. Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signalling motifs. Binding of either PD-1 ligand to PD-
1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low 
levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas 
PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid 
tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function 
in peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers 
were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been 
suggested to regulate tumour-specific T-cell expansion in participants with melanoma (MEL). 
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumour immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 


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 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
 Rationale for the Trial and Selected Participant Population 
This study will evaluate the safety profile, efficacy and biological effects of the combination of 
pembrolizumab, a T cell checkpoint inhibitor and SABR for oligometastatic renal cancer (1-5 
sites of disease). Our hypothesis is that this treatment combination will have a safety profile 
that is clinically acceptable and demonstrate anti-tumour efficacy.  
 
The sample size of 30 is pragmatic. It is recognized that the findings of this study will serve as 
the basis for larger randomized studies in the future. Whilst previously, patients with 
oligometastatic renal cancer have been thought to be incurable, long term survival has been 
reported with judicious use of surgery or SABR treatment. We hypothesize that augmentation 
of immunity in this subgroup of patients may enhance long-term control of the disease. 
 
Whist the overlapping toxicities of SABR and pembrolizumab are not yet fully understood, 
none are expected as the toxicity profiles are due to non-overlapping mechanisms. Safety will 
be monitored carefully throughout the trial in all patients. 
 
 Rationale for Selection of Immunotherapy to Combine with SABR in the 
Oligometastatic RCC Cohort 
In the context of local therapies for patients with oligometastatic disease, the major site of 
disease recurrence after local therapies such as surgery or surgery is distant. In large 
prospective database studies, patients with a single site of metastasis have significantly longer 
survival and lower probability of disease recurrence than those with two or more, however, 
the majority of patients with a solitary metastases still recurred with distant disease. In a 
prospective study published in the Lancet Oncology of 1194 patients by Yamamoto et al. [75] 
of patients with brain metastases treated with stereotactic radiotherapy, patients with a 
solitary metastasis had a significantly longer survival (p < 0.001) than patients with 2 or more 
metastases. In patients with RCC the median survival for patients with a solitary metastasis 
was 16.3 months versus 13.7 months in those patients with 2-4 metastases. Similarly, the large 
multinational registry study of 5206 patients with pulmonary metastases by Pastorino et al. 
[76] also addressed the number of metastases as a prognostic factor for survival. Patients with 
a single metastasis had significantly better survival than those with two or more metastases 
(Figure 1). The 5-year survival was 43% for single lesions and 27% for four or more lesions (p 
< 0.001), however there was no statistically significant difference between patients with 2-3 
metastases versus 4 or more. 
 
Overall, this suggests that in patients with oligometastases, some form of systemic therapy 
may be useful in order to limit the risk of progression of occult micrometastatic disease. 
However there is no proven benefit of adjuvant systemic TKI therapy in the setting of renal 
cell carcinoma. Systemic targeted agents (TKI) have not been proven to prolong survival in 
patients in the primary setting after nephrectomy, indicating that it is incapable of totally 
eradicating any micrometastatic disease. This evidence could be extrapolated to those 
patients treated with local therapy SABR for oligometastatic disease, as there is no synergistic 
effect with radiation and TKIs at distant micrometastatic sites. Pembrolizumab not only can 
potentiate the effectiveness of radiation at the irradiated tumours, it has the potential to 


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evoke a sustained anti-tumour immune response at distant sites, which has resulted in a 
proportion of patients observed to have long-term disease control and perhaps even cure.  
 
 Rationale for Dose Selection/Regimen/Modification of pembrolizumab 
As of the data cut-off dates for this IB (18-Apr-2014 for P001 melanoma subjects, 29-Aug-2014 
for P001 NSCLC subjects, 12-May-2014 for P002, and 30-Nov-2014 for other protocols), the 
safety and efficacy of pembrolizumab treatment in subjects with hematologic malignancies 
and solid tumors have been evaluated in 18 ongoing, Merck-sponsored clinical trials: P001, 
P002, P006, P010, P011, P012, P013, P021, P022, P023, P024, P025, P028, P029, P030, P041, 
P045, and P055. An outline of selected studies and design are described below. 
 
P001 was an open-label, Phase I, first-in-human (FIH) study of IV pembrolizumab in subjects 
with progressive locally advanced or metastatic carcinomas, especially melanoma or NSCLC. 
Part A of the study involved dose escalation that used a traditional 3+3 design. Cohorts of 3 to 
6 subjects were enrolled sequentially at escalating doses of 1, 3, or 10 mg/kg administered 
Q2W. Once the dose escalation was completed, additional subjects were enrolled into Parts 
A1 and A2 to further characterize the PK and pharmacodynamics of pembrolizumab. In Parts 
B and D, subjects with metastatic melanoma were enrolled to assess the safety and antitumor 
activity of pembrolizumab. Additionally, Part B explored 3 different dose regimens in subjects 
with metastatic melanoma: 10 mg/kg Q2W, 10 mg/kg Q3W, and 2 mg/kg Q3W. In Part C, 
subjects with NSCLC (with prior systemic therapy) were enrolled at 10 mg/kg Q3W to assess 
the tolerability, safety, and antitumor activity of pembrolizumab in NSCLC. In Part F, subjects 
with NSCLC in Cohort F-1 (without prior systemic therapy) and Cohort F-2 (with prior systemic 
therapy), whose tumors expressed PD-L1, were enrolled at 10 mg/kg Q2W and 10 mg/kg Q3W 
to characterize the tolerability, safety, and antitumor activity of pembrolizumab. A small 
cohort of previously treated subjects with NSCLC and at least 2 lines of systemic therapy, 
whose tumors did not express PD-L1, were enrolled and treated at a dose of 10 mg/kg Q2W 
in Cohort F-2. In Cohort F-3, previously treated subjects with NSCLC whose tumors express PD-
L1 were enrolled at 2 mg/kg Q3W to better characterize the efficacy, safety, and antitumor 
activity of pembrolizumab. Each of the 2 disease specific cohorts (melanoma and NSCLC) were 
enrolled to confirm tolerability and evaluate tumor response to pembrolizumab. 
 
P006 was a multicenter, worldwide, randomized, controlled, open-label, 3-arm pivotal Phase 
III study of 2 dosing regimens of IV pembrolizumab versus IV IPI in subjects with unresectable 
or metastatic melanoma who had not received prior IPI treatment. Subjects were randomized 
in a 1:1:1 ratio to receive pembrolizumab at 10 mg/kg Q2W, 10 mg/kg Q3W, or IPI at 3 mg/kg 
Q3W for a total of 4 doses. 
 
P010 is a multicenter, worldwide, randomized, adaptively designed Phase II/III trial of IV 
pembrolizumab at 2 dosing schedules versus docetaxel in subjects with NSCLC with PD-L1 
positive tumors, who have experienced disease progression after platinum-containing 
systemic therapy. Subjects were randomized in a 1:1:1 ratio to receive pembrolizumab 10 
mg/kg Q3W, 2 mg/kg Q3W, or docetaxel 75 mg/m2 Q3W. 
 
P011 was an open-label, nonrandomized, multicenter Phase I study of pembrolizumab 
monotherapy in Japanese subjects with advanced solid tumors and in combination with 
cisplatin/pemetrexed and carboplatin/paclitaxel in subjects with advanced NSCLC in Japan. In 
Part A (monotherapy, 3+3 design), subjects with advanced solid tumors received escalating 
doses of pembrolizumab 2 mg/kg Q2W (dose level 1) or 10 mg/kg Q2W (dose level 2). In Part 


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B (combination, 3+6 design), subjects with advanced NSCLC receive pembrolizumab 10 mg/kg 
Q3W in combination with either cisplatin/pemetrexed (Cohort 1) or carboplatin/paclitaxel 
(Cohort 2) are to be enrolled. 
 
P012 was a multicenter, nonrandomized, multi-cohort Phase Ib trial of pembrolizumab in 
subjects with PD-L1 positive advanced solid tumors. All subjects receive pembrolizumab 10 
mg/kg Q2W. Cohort A enrolled subjects with triple negative breast cancer; Cohorts B and B2 
enrolled subjects with squamous cell carcinoma of the head and neck; Cohort C enrolled 
subjects with urothelial tract cancer of the renal pelvis, ureter, bladder, or urethra; and Cohort 
D enrolled subjects with adenocarcinoma of the stomach or gastroesophageal junction. 
 
P021 was a multicenter, open-label Phase I/II study of IV pembrolizumab at 2 dosing schedules 
in combination with chemotherapy or immunotherapy in subjects with locally advanced or 
metastatic NSCLC.  
 
P022 is a multicenter, worldwide, Phase I/II 3-part trial of IV pembrolizumab in combination 
with oral dabrafenib and/or trametinib in subjects with advanced or metastatic melanoma. 
Part 1 is a non-randomized, multi-site, open-label portion of the study using a traditional 3+3 
design to evaluate safety, tolerability, and dosing of pembrolizumab (MK) in combination with 
dabrafenib (D) and trametinib (T) in BRAF mutation-positive (V600 E or K) melanoma subjects. 
Additionally in Part 1, dosing of pembrolizumab in combination with trametinib only (MK+T) 
will be explored in BRAF mutation-negative (without V600 E or K) melanoma subjects, to 
evaluate safety, tolerability, and efficacy of MK+T in Part 2 in this population. Part 2 is a non-
randomized, multisite, open-label portion of the study using an expansion cohort to further 
evaluate safety and confirm dose of MK+D+T. Also in Part 2, an expansion cohort will be used 
to further evaluate safety and preliminary efficacy in the MK+T combination. Part 3 is a 
randomized (1:1), active-controlled, multi-site, 2-arm study of the confirmed dose of the 
triplet combination (MK+D+T) versus placebo (PBO) in combination with D+T (PBO+D+T). 
 
P029 is a multicenter, open-label, 3-part Phase I/II trial of IV pembrolizumab in combination 
with subcutaneous Pegylated Interferon Alfa-2b (PEG-IFN) or IV IPI in subjects with advanced 
or metastatic melanoma or renal cell carcinoma. Part 1A, the Phase I portion of the trial, will 
define the preliminary MTD or MAD of pembrolizumab + PEG-IFN (Group A) and 
pembrolizumab + IPI (Group B), and confirm the tolerability of these treatment doublets.  
 
P030 is a multisite, worldwide, expanded access program for subjects with metastatic 
melanoma who have limited or no treatment options. Subjects must have progressed after 
prior systemic therapy, including standard-of-care agents which include IPI and a BRAF/MEK 
inhibitor when indicated. Subjects cannot be eligible for an available pembrolizumab clinical 
trial or have participated in a pembrolizumab clinical trial. Subjects are evaluated for safety at 
baseline and before each cycle of treatment with pembrolizumab 2 mg/kg/Q3W. Subjects are 
treated until progression of disease or until the subject has received up to 2 years of 
treatment. 
 
P045 is a randomized, active-controlled, multisite, open-label, Phase III trial to evaluate the 
efficacy of treatment with pembrolizumab versus paclitaxel, docetaxel, or vinflunine in 
subjects with metastatic or locally advanced/unresectable urothelial cancer that has recurred 
or progressed following platinum-containing chemotherapy. Subjects are randomized in a 1:1 
ratio to receive pembrolizumab 200 mg Q3W or the Investigators’ choice of paclitaxel 175 


RAPPORT Study Protocol: Version 2.2, 16 January 2020 
 
Page 23 of 74 
mg/m2 Q3W, docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W. The study also 
evaluates the safety and tolerability profile of pembrolizumab in subjects with 
recurrent/progressive metastatic urothelial cancer. 
 
P055 is a multicenter, unblinded, open-label, single-cohort, Phase II trial to determine the 
safety, tolerability, and antitumor activity of a 200 mg Q3W dose of pembrolizumab in subjects 
with recurrent and/or metastatic head and neck squamous cell carcinoma who have 
progressed on platinum and cetuximab therapy. Antitumor activity is also assessed in the 
subset of subjects for whom a biopsy sample is determined to be PD-L1 positive. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage.  
 
A favourable safety profile and preliminary evidence of clinical activity led to the design of a 
multi-dose trial of nivolumab (anti-PD-1) in 296 patients, confirming antitumor efficacy in 
melanoma, RCC and NSCLC [77]. In this study, cumulative response rates were 18% for 
patients with non-small-cell lung cancer (NSCLC), 28% for patients with melanoma, and 27% 
(9 of 33 patients) for patients with RCC. Recently, in 2015, the results of a randomized, dose-
ranging phase II trial of nivolumab in 168 pretreated metastatic RCC patients were published. 
The median progression-free survival was 2.7 months in the 0.3 mg/kg group, 4.0 months in 
the 2 mg/kg group, and 4.2 months in the 10 mg/kg group. The median overall survival was 
18.2 months in the 0.3 mg/kg group, 25.5 months in the 2 mg/kg group, and 24.7 months in 
the 10 mg/kg group. More than 50% of responders with all doses had objective responses 
lasting more than 12–20 month [78]. 
 
The CheckMate 025 study is a phase III randomized trial of nivolumab versus everolimus in 
patients with advanced RCC [ClinicalTrials.gov identifier: NCT01668784]. Patients who 
received one or two prior anti-angiogenic therapies for advanced RCC (but not more than 
three total previous therapies) were randomized to receive nivolumab at 3 mg/kg every 2 
weeks versus everolimus until disease progression or unacceptable side effects. The primary 
endpoint of this study was overall survival. In July 2015, the independent Data Monitoring 
Committee concluded that the study had met its primary endpoint. While full results remain 
forthcoming, this study will likely establish anti-PD-1 as a new standard of care for previously 
treated patients with metastatic kidney cancer.  
 
 Rationale of Endpoints Definition 
Primary Endpoint: 
Safety (acute and long term) will be evaluated using CTCAE version 4.03 in all patients who 
have received at least one SABR treatment and one dose of pembrolizumab. Acute adverse 
events (AE) are defined as AEs occurring from the time of first SABR treatment to 30 days post 


RAPPORT Study Protocol: Version 2.2, 16 January 2020 
 
Page 24 of 74 
end of pembrolizumab treatment and long term AE are defined as AEs occurring after 30 days 
post end of pembrolizumab treatment. 
 
Secondary Endpoints:  
To evaluate effectiveness of the treatment combination, using the following measures:  
a) Overall survival (OS), time to local progression (TTLP), distant progression free survival 
(DPFS) and overall response rates 
i. OS will be measured from the date of commencement of SABR treatment to the date 
of death from any cause. 
ii. TTLP will be measured from date of commencement of SABR treatment to the date 
of first local progression. Death and commencement of a further course of systemic 
therapy will be considered as censoring events. 
iii. DPFS will be measured from the date of commencement of SABR treatment to the 
date of first distant progression at site not documented at registration, or date of 
death from any cause for patients without distant progression. Commencement of 
second course of a further course of systemic therapy will be considered as censoring 
event. 
b) Overall response is defined as complete response or partial response, measured using 
RECIST 1.1 criteria. The RECIST definition of complete response has been modified to 
include disappearance of the target tumor radiographically or complete metabolic 
response. The primary is excluded from the evaluation of the overall response. 
c) Disease control is defined as complete response or partial response at any time after 
treatment commencement or stable disease for at least 6 months, measured using RECIST 
1.1 criteria. The RECIST definition of complete response has been modified to include 
disappearance of the target tumor radiographically or complete metabolic response. The 
primary is excluded from the evaluation of the disease control. 
d) Pain will be evaluated using the Numerical Pain Rating Scale at the following time points: 
pre-conventional radiotherapy treatment (if CRT performed), pre-SABR treatment, prior 
to each cycle of pembrolizumab, then 3 monthly until 24 months after the end of SABR 
treatment. 
 
Exploratory Endpoints 
A number of translational endpoints will be evaluated including: 
1. PD-L1 
expression 
in 
primary 
tumour 
and 
metastatic 
lesions 
using 
immunohistochemistry. 
 
2. Tumour infiltrating lymphocytes (TILs) using a previously defined method at primary 
tumour and metastatic lesions. 
 
3. Blood samples will be collected at multiple timepoints (prior to radiotherapy, prior to 
each pembrolizumab administration, at disease progression (if this occurs) and at 9, 12 
and 24 months post SABR treatment). These will be analysed for the following (this is a 
non-exhaustive list): 
i. 
Absolute lymphocyte counts using a blood analyser. 
ii. 
The presence of CD8+ T cells by flow cytometric analysis. 
iii. 
Presence of tumour reactive T cells. These may include markers for HLA-DR, CD4+, 
CD8+ T cells, PD-1, TIM-3 signifying antigen presentation and experience. 
 


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8 
STUDY POPULATION 
Male and female patients ≥ 18 years of age with a histological or cytological diagnosis of renal 
cell carcinoma, with the presence of oligometastases (1-5 metastases). One or more lesions 
must be deemed suitable for treatment with SABR. For patients with metastases involving the 
spine, lesions will be highly selected so they do not pose a significant risk for spinal canal 
impingement or spinal cord compression. 
 
 
Patient Registration 
Recruitment will cover a 2-year period. Screening for individual participants will take place 
within 35 days prior to registration onto the study.  
 
The Investigator should ensure that all requirements are met prior to registering eligible 
patients on the trial: 
● Patient meets all inclusion and exclusion criteria requirements 
● Patient has signed and dated all consent forms 
● All screening assessments have been completed and recorded in the patient’s medical 
records complete with all relevant source documents 
 
Sites will register eligible patients electronically using the online RAPPORT electronic data 
capture (EDC) system. Confirmation of registration will also be provided electronically (via 
email) as well as, a unique 6-digit patient identification number for the patient.   
 
Full training on the RAPPORT EDC system will be provided to sites prior to site activation. 
 
 
Replacement of Non-Evaluable Patients  
Evaluable patients are defined as participants who complete at least one SABR treatment and 
receive at least one dose of study drug (18-20Gy/1# to at least one lesion with at least one 
dose of pembrolizumab). 
 
If a patient receives no treatment (SABR or pembrolizumab) or completes 1 x SABR treatment 
but does not receive any pembrolizumab treatment (i.e. withdraws or is withdrawn from the 
study before receiving any study drug), that patient is deemed as ‘non-evaluable. Accrual will 
continue until 30 evaluable patients are obtained. 
 
 
Participant Inclusion Criteria 
In order to be eligible for participation in this trial, the participant must: 
 
1. Has provided written informed consent for the trial. 
 
2. Be  18 years of age on day of signing informed consent. 
 
3. Have oligometastases (1-5 metastases), and measurable disease based on RECIST 1.1.   
 
4. Participants must have a histologically or cytologically confirmed metastatic renal cell 
carcinoma. Oligometastatic lesions do not need to be biopsied but they must be 
clinically consistent to represent metastatic disease. 
 


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5. Patient can either be treatment naïve or have previously received up to 2 lines of 
systemic treatment (eg. Pazopanib or Sunitinib).  If patient has received prior systemic 
therapy, the total number of metastases that have not been treated with definitive 
local therapies should not number more than 5. 
 
6. Must have had surgical consideration for metastasectomy and thought appropriate for 
SABR due to medical inoperability, technical factors or patient declining surgery. 
 
7. Must have at least one metastasis for which SABR is technically deliverable. 
 
8. Be willing to provide archival tissue from a previously biopsied or excised primary or 
metastatic RCC lesion (if available). If safe to do so, a request for newly obtained 
specimen (obtained up to 5 weeks prior to trial registration) will be made, however 
participation for this biopsy is entirely optional. 
 
9. Have a performance status of 0-2 on the ECOG Performance Scale (Appendix 1)  
 
10. Demonstrate adequate organ function as defined in Table 3, all screening labs should 
be performed within 10 days of registration.   
 
Table 3: Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Haematological 
 
Absolute neutrophil count (ANC) 
 ≥1.5 X 10^9/L 
Platelets 
 ≥100 X 10^9/L 
Haemoglobin 
≥90 g/L or ≥5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance (GFR can also be used in 
place of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥30 mL/min for participant with creatinine levels > 
1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for participants with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for participants with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) 
or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of 
anticoagulants ≤1.5 X ULN unless participant is 
receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 


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11. Life expectancy > 12 months. 
 
12. Be willing and able to comply with all study requirements, including treatment, 
attending assessments and follow-up. 
 
13. Female participant of childbearing potential should have a negative urine or serum 
pregnancy within 7 days prior trial registration.  If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required.   
 
14. Female participants of childbearing potential should be willing to use 2 methods of 
birth control or be surgically sterile, or abstain from heterosexual activity for the 
course of the study through 120 days after the last dose of study medication (see 
Section 9.4.2: Contraception).  Participants of childbearing potential are those who 
have not been surgically sterilized or have not been free from menses for > 1 year.  
 
15. Male participants should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 120 days after the last dose of study 
therapy. 
 
 
Participant Exclusion Criteria 
The participant must be excluded from participating in the trial if the participant: 
 
1. Based on clinician assessment of disease volume and rate of progression of patient's 
tumour deposits, the patient requires immediate TKI therapy. 
 
2. Has had previous high dose radiotherapy (biological equivalent of >30Gy in 10#) to an 
area to be treated which includes vertebral bodies (see below). 
Note:  Previous high dose radiotherapy is defined as a biological equivalent dose to above that of 30 Gy 
in 10 fractions using an / ratio [82] of 3. Where a patient has received radiotherapy to an equivalent 
or lower dose than defined above, stereotactic radiotherapy of the area may be considered.  In doing 
so, assessment of the volume and total dose received by any overlap region must be made, and 
documented by generating a cumulative plan incorporating both the previous and current treatment 
fields.  It is the treating radiation oncologist’s responsibility to review both the current plan and the 
cumulative plan inclusive of previous radiotherapy. 
3. Has evidence of untreated or active intracranial metastases. Patients who have had 
fully resected brain metastasis or those controlled by stereotactic radiotherapy are 
eligible as long as they are not requiring corticosteroids for symptomatic control. 
 
4. Has evidence of Spinal Cord Compression. 
 
5. Has a Spinal Instability Neoplastic Score ≥ 7 unless lesion reviewed by a neurosurgical 
service and considered stable (see Appendix 3). 
 
6. Requires surgical fixation of bone lesion for stability. This must be performed before 
enrolment into the trial. 
 
7. Has a known history of active TB (Bacillus Tuberculosis). 
 
8. Hypersensitivity to pembrolizumab or any of its excipients. 


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9. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks of registration 
or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks earlier. 
 
10. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks of registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to a previously administered agent. 
Note:  Participants with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the 
study. 
Note:  If participant received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy.   
 
11. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
 
12. Has active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.  
 
13. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
 
14. Has an active infection requiring systemic therapy. 
 
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant’s 
participation for the full duration of the trial, or is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.   
 
16. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
17. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment. 
 
18. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
 
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
  
21. Has received a live vaccine within 30 days of registration. 
 


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9 
TRIAL TREATMENTS 
The treatment regimen involves the delivery of a single fraction of highly conformal SABR 
delivered with either photons, electrons or mixed modalities.  No cytotoxic chemotherapy is 
allowed within 3 weeks either side of, or concurrently with respect to the investigational 
treatment. Consultation with both the treating radiation oncologist and medical oncologist is 
strongly recommended if chemotherapy is to be considered after the investigational 
treatment and before documented disease progression, to prevent unforeseen combined 
toxicities. The first dose of pembrolizumab will be delivered at 5 days (+/- 3 days) after the last 
SABR treatment for a total of 8 cycles. 
 
 
Megavoltage Radiotherapy 
The investigational treatment will be prescribed to the covering isodose, ensuring that 99% of 
the PTV is covered by 100% of the dose (D99=100%). However, a target coverage of D95=100% 
is acceptable if required to respect an organ-at-risk dose tolerance. Intensity Modulated 
Radiation Therapy (IMRT) is not compulsory but will be considered if very steep dose gradients 
have to be achieved or targets ‘wrap around” a critical structure.  This is the near minimum 
dose to the target as considered by the International Commission of Radiation Units and 
Measurements (ICRU) in their report 83 [83]. Multi-field photon treatment, intensity 
modulated radiation therapy (IMRT), dynamic conformal arcs, electrons and volumetric 
modulated arc therapies (VMAT) can all be considered.   
 
A single fraction of SABR approach will be utilized, which is the most commonly used 
dose/fractionation schedule utilized at the Peter MacCallum Cancer Centre. The dose will be 
prescribed using a 'stereotactic' paradigm to an isodose line no less than 70% of the maximum 
dose, aiming for a prescription isodose of 80%. This allows for larger target dose 
inhomogeneities but results in a steeper dose fall off outside of the target volume.  
 
If more than one lesion is to be treated in a single patient, treatment of all lesions ideally 
would be given in one setting for patient convenience.  However for practical or logistic 
reasons this may not always be possible and in such cases all lesions should be treated within 
a time window spanning not more than 21 calendar days. Dose for each lesion will be 
independently verified before treatment and image guidance will be used to ensure accurate 
patient positioning. 
 
Statement of Treatment Aim and Rationale 
Treatment rationale is to provide long-term local and distant disease control by treating 
limited oligometastatic renal cancer (1-5 isolated metastases) with a single fraction of 
stereotactic ablative radiotherapy in conjunction with pembrolizumab.  
 
 
Treatment Schedule 
Radiation therapy should commence within 4 weeks of patient registration on the study. A 
single dose of 20 Gy should be prescribed, although a single 18Gy fraction can be used as an 
alternative for a centrally located lung lesion or a spinal lesion with a SINS score of > 7 after 
review at SABR chart round. Typically a single fraction of 20Gy should be prescribed for spinal 
vertebral lesions, however, for those with a SINS score of > 7 after review at SABR chart round, 
a single 18Gy fraction is preferred.  
 


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Procedures if SABR is not Technically Deliverable  
If after evaluation of a tumour location and treatment plan dosimetry, SABR is not technically 
or safely possible to deliver, a conventional hypofractionated course of radiotherapy of 30Gy 
in 10 fractions or 36Gy in 12 fractions should be delivered (total dose selected at clinician 
discretion). In this scenario, delivery of SABR to other sites of disease should be scheduled 
towards the end of, or immediately after, the course of conventional radiotherapy.  
 
 
Planning Simulation  
Simulation procedures will vary according to treatment site. These procedures are in 
accordance with the Royal Australian and New Zealand College of Radiologists (RANZCR) SABR 
guidelines (Foote, M. et al., J Med Imaging Radiat Oncol, 2015. 59(5): p. 646-53).  
 
 
Patient Positioning 
Patients will be positioned supine in a manner which isolates the region for treatment from 
surrounding anatomy where possible e.g. arms above the head for thoracic targets.  The final 
treatment position used will be determined based on the clinical judgement of the treating 
Radiation Therapy team.  The underlying principle that should always be observed is that the 
patient position must ensure an appropriately stable position that is both reproducible and 
able to be tolerated by the patient for the anticipated length of planning and treatment 
delivery procedures. 
 
 
Reference Points/Tattoos 
In room lasers will be used to setup and align the patient into the correct position.   
In order to facilitate the pre-treatment setup, skin tattoos will be placed at the following 
locations: 
1. Anteriorly at the anticipated isocentre location on an appropriately stable anatomical 
point. 
2. Laterally at the level of the anticipated isocentre position to facilitate reproduction of 
patient rotation. 
3. At an appropriate distance (typically 15-20cm) superior or inferior to the isocentre 
position to facilitate midline alignment. 
 
Variation to the above described tattoo locations is permitted at the judgement of the 
planning radiation therapy team to optimise reproduction of patient position, provided there 
is clear documentation of the change.  The position of skin tattoos will be documented in the 
radiation oncology management system, and photographs taken to facilitate identification of 
relevant tattoos by the treating radiation therapists. 
 
 
Immobilisation 
Effective immobilisation customised to the treatment site is essential to ensure reproducibility 
of patient position. A high quality customised vaclock style device capable of indexation to the 
treatment couch is required. The vaclock bag device must adequately encompass the 
treatment volume and an appropriate area beyond to permit reproducibility of the target and 
surrounding anatomy. 
 
The actual design of the immobilisation will depend on the treatment site. When deciding on 
immobilisation consideration must be given to: 


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 Patient comfort as the treatment time can exceed 45 minutes in particular if more than 
one lesion is to be treated in a single session. 
 The possible need to immobilise more than one lesion at the same time. 
 Motion management (see section 9.1.9). 
 Reproducibility between planning, mock-up and treatment. 
 Image guidance as the field of view of CBCT is limited and patient shifts between imaging 
and treatment should be avoided. 
 
 
Planning Imaging 
A planning CT scan with patient in the treatment position will be used for treatment planning.  
The CT must be of 3mm slice spacing and width or less. In order to allow placement of 
non-coplanar beams through valid body contours, the CT scan length should extend as a 
minimum ten centimetres superior and inferior to the intended treatment volume.  CT scan 
length should also include the entire volume of any organ at risk for which a volumetric dose 
constraint is set.  
 
 
Consideration of Motion 
Motion must be considered in the planning stage for lesions that may be affected by breathing 
motion. For target volumes in the abdomino-thoracic region, consideration of organ motion 
should be made as part of the radiotherapy plan when necessary. In such cases, a 
4-dimensional CT scan will be acquired for planning. The internal target volume (ITV) concept 
developed by the International Commission on Radiation Units and measurements will be 
used for target delineation. An ITV is developed by combining all positions of the target across 
the respiratory cycle.   
 
For target volumes outside of the abdomino-thoracic region not participant to respiratory 
excursion, a three-dimensional planning CT scan is adequate. 
 
Gated delivery would only be considered in extreme cases where the lesion moves more than 
1 cm. 
 
 Pre-Treatment Mock-up (only if required) 
When deemed as required, a patient will be asked to attend a mock-up session on the Linear 
accelerator prior to the treatment delivery appointment. The purpose of the mock-up is 
two-fold: 
 To test adequate visualisation of the target and surrounding anatomy with use of the 
proposed verification imaging. 
 To test physical clearance of beam angles. 
 
When a pre-treatment mock-up is required, the patient will be positioned in the treatment 
position and the beam isocentre set. Verification imaging will be acquired, and assessed online 
to ensure adequate target visualisation. All beam angles will be set to ensure deliverability on 
the Linear accelerator.   
 
 Target Volume Definitions/Field Borders 
Target Volumes 
Target Volumes must be defined as per ICRU 50, 62, and 83 with clear definitions, individual 
contouring and standardised labelling [83-85]. These include:  


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 Gross Tumour Volume (GTV)  
 Internal Target Volume – The Internal Target Volume (ITV) is a concept developed by the 
International Commission on Radiation Units and Measurements (ICRU1999)[86] and 
will be used for lesions that move or are likely to change their shape during treatment. 
The ITV takes into account the total tumour excursion through respiration. It is a Boolean 
combination of all locations that would be occupied by the target at any phase of the 
breathing cycle.  
 Planning Target Volume (PTV) – ITV to PTV margins must take into consideration setup 
uncertainties. A PTV expansion of 5mm global expansion in the axial and craniocaudal 
directions is required as a minimum.  For locations that do not require a 4D CT for motion 
management – PTV = GTV + 5mm 
 
For contouring of bone metastases all available imaging will be taken into account.  
 
For contouring of spinal bone metastases international consensus guidelines (Appendix 4) will 
be followed. 
 
Field Borders 
Conformal field shaping must be performed using a multileaf collimator device with central 
leaf width of 5mm or less projected to isocentre. The margin between the target volume and 
the field edge is typically expected to be 0- 2mm in the axial direction, however individual 
beams eye views may be optimized based on the resultant dose distribution to maximise 
conformity of the prescription isodose to the PTV. Negative margins from field edge to target 
volume may also be employed to achieve greater conformity. In order to achieve coverage of 
the planning target volume with the prescription isodose, it may be necessary to accept a 
larger than 0-2mm margin from the target volume to the MLC defined field edge, particularly 
in the craniocaudal axis.  
 
 Dose Prescription and Fractionation 
Dose is prescribed to the covering isodose of the PTV. For plan optimisation, a minimum of 
D99=100% of the prescription isodose will be accepted except for treatment of the spine. 
However, a target coverage of D95=100% is acceptable if required to respect an organ-at-risk 
dose tolerance. Within the spine, in the case of no previous radiotherapy a D90 of > 90% 
(prescription dose) is ideal, however a D90 of > 80% (prescription dose) is acceptable. In 
particular for small lesions treated using 3D conformal beam arrangements a large dose 
inhomogeneity can be expected with the maximum dose far exceeding the prescription dose. 
During the optimisation process, the PTV max dose should typically aim to achieve a DMax of 
125%. This is common in stereotactic treatments and effectively aims for a prescription to the 
80% isodose (covering isodose) when normalised to the PTV max. Prescription to lower 
isodose ranges (between 70 to 80%) is acceptable, particularly for smaller targets. 
 
Maximum dose and dose to the ICRU reference point (centred on the CTV/ITV) should be 
reported. 
 
The use of IMRT/VMAT in general will make target dose more homogeneous. Care must be 
taken to not allow any cold spots in the ITV/GTV when using IMRT/VMAT.  Phantom volumes 
with the PTV can be used as planning objectives during plan optimisation to enable desired 
dose inhomogeneity. 
 


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 Treatment Duration 
Wherever possible, all target metastases to be treated with SABR should be treated on the 
same day for patient convenience. If this is not possible for practical or logistical reasons all 
lesions will be treated within 21 calendar days.  
 
 Normal Tissue Contouring and Dose Constraints 
Targets in the head and neck region, or in the mediastinum should not be treated with SABR. 
Targets should generally be located > 1cm from any hollow gastrointestinal luminal structure 
or major nervous plexus. 
 
Table 4: Normal Tissue Contouring and Dose Constraints 
Organ 
Contouring 
Parameter 
Dose-Volume 
Constraints 
Kidney 
Entire kidney 
V10 
33% 
Spinal 
planning risk 
volume 
(PRV) 
Spinal Cord + 3mm 
expansion or Thecal 
Sac (1cm above and 
below target)* 
Maximum dose 
0.03cc ≤ 12Gy 
Brain Stem 
Including midbrain, 
pons and medulla 
Maximum Dose 
0.03cc<12.5Gy 
Skin (5mm 
subcutis) 
Body surface – 5mm 
Maximum Dose 
0.03cc ≤ 24Gy 
Small Bowel 
All small bowel 
contoured 5cm above 
and below PTV 
Maximum Dose/ 
Volume 
 
Maximum Dose 
30cc ≤ 12.5Gy 
 
       0.03cc ≤ 20 Gy 
Stomach 
Entire Stomach 
Maximum Dose 
0.03cc < 20Gy 
Liver 
Entire liver 
Maximum Dose/ 
Volume 
700cc ≤ 15Gy 
Lung 
Combined Left and 
right Lung - GTV 
Maximum 
Dose/Volume 
1000cc ≤ 7.4Gy 
Oesophagus 
Cricoid to gastro-
oesophageal junction 
Maximum Dose 
0.03cc ≤ 15.4Gy 
Rectum 
Recto-sigmoid to anal 
canal (solid structure) 
Maximum Dose/ 
Volume 
20 cc ≤ 14.3Gy 
Bladder wall 
Entire structure 
Maximum Dose/ 
Volume 
15 cc ≤ 11.4Gy 
Heart / 
Pericardium 
Entire Structure 
Maximum Dose/ 
Volume 
15 cc  ≤ 16Gy 
Brachial 
Plexus 
Including nerve roots 
Maximum Dose 
0.03 cc   ≤ 15.4Gy 
 
Dose constraints have been informed by QUANTEC recommendation guidelines (Table 4), 
completed RTOG protocols, and the AAPM TG101 [87] working party consensus guidelines. 
* Where an MRI is not feasible or thecal sac/spinal cord cannot be clearly delineated, spinal 
canal may be used to define spinal PRV. 
 


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Note: Maximum dose is defined to a point.  The minimum meaningful volume for a point is 
0.035 cc. 
 
When planning more than one lesion a summary plan must be created. The dose constraints 
apply to the summary plan. 
 
SPINAL CANAL:  QUANTEC summary [88] recommendations for maximum dose for a single 
fraction is a Dmax of 13Gy, and in 3 fractions is 20Gy. Limits for our technique are more 
conservative at 12Gy for a single fraction SBRT. This is also lower than the AAPM consensus 
recommendation of a max point dose of 14Gy [87]. In instances where the spinal cord has 
received previous radiotherapy, the spine should be re-imaged using an MRI or other 
appropriate investigations to check for radiation myelopathy/spinal necrosis if neurological 
symptoms are present. 
 
BRAINSTEM: QUANTEC summary [89] recommends that for single fraction stereotactic 
radiosurgery a maximum brainstem dose of 12.5Gy is associated with a low risk of toxicity.  
They also note that higher doses (15-20Gy) have been used with low reported incidence of 
complications in patient groups with poor prognosis for long term survival (e.g brainstem 
metastases [90, 91]).  We have used the lower recommended limit of 12.5Gy. 
 
SKIN: 
National 
Comprehensive 
Cancer 
Network 
(NCCN) 
consensus 
guideline 
recommendations are that dose to skin should be limited to 26Gy for a single fraction and 
30Gy in 3 fractions. Limits for our technique are more conservative than this at 24Gy for a 
single fraction 
 
SMALL BOWEL: QUANTEC summary [92] recommendations are that dose circumferentially 
covering any volume of small bowel should not be > 12.5Gy in a single fraction. The maximum 
point dose recommendation for a 3-fraction approach is <30Gy.  This 30Gy recommendation 
concurs with the seminal phase I/II study reported by Rusthoven et al.[39]. As an alternative, 
The University of Wurzberg constrains the dose to half the circumference of small bowel, 
which should not receive more than the prescription dose during SBRT [personal 
correspondence]. 
 
STOMACH: QUANTEC summary [92] recommendations are that a maximum point dose should 
be <30Gy in 3 fraction SBRT. The volume receiving >22.5Gy should be < 5cc.  
 
LIVER: QUANTEC summary [93] recommendations are that ≤ 700mL of normal liver receives 
≤15Gy in SBRT. University of Wurzberg do not use a dose constraint for single fraction 
radiosurgery of 30Gy in liver targets [M Guckenberger, personal communication]. As the 
proportion of irradiated liver will be considerably smaller during SABR for bone or lymph node 
metastases than in radiosurgery of the liver, it is reasonable not to apply a liver dose constraint 
to the single fraction cohort receiving 20Gy. 
 
LARGE VESSELS: Conventional radiotherapy is known to cause late fibrosis and injury to small 
and large vessels, usually many years after the initial irradiation. In the context of SABR 
treatment, it is important to note that despite the pancreas’ proximity to major vessels such 
as the superior mesenteric vessels and abdominal aorta, no toxicities secondary to large vessel 
injury have been reported secondary to SBRT. Similarly in the liver, no clinically relevant large 
vessel effects have been reported secondary to irradiation of the inferior vena cava. This may 


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be in part due to the patient population, who typically are medically inoperable and have life-
spans limited by other medical comorbidities. To the study team’s knowledge, clinically 
significant large vessel injuries have been reported only in the context of combined surgery 
and radiation, or re-irradiation using SBRT of significantly higher doses than in is allowable in 
the context of this study. Doses should be limited to the large vessels following ALARA 
principles. 
 
OESOPHAGUS: Based on recommendations from AAPM Task Group 101 consensus 
recommendations [87], circumferential irradiation of oesophagus is not allowed. 
 
 Treatment Planning and Dosimetry 
9.1.15.1 
Planning System Requirements 
A 3D computerised planning system capable of incorporating datasets derived from 4DCT and 
utilising a 3D dose calculation algorithm with pixel based inhomogeneity correction (eg 
convolution/superposition) will be used. Systems that can account for variation in lateral 
scatter in the presence of 3D-CT defined heterogeneities are required. Widely available 
systems that have this capability currently include Philips Pinnacle, CMS XiO, and Varian 
Eclipse.  
 
Other features of the planning system must include: 
a) 
The planning system must be capable of handling the large CT datasets required for 
multiple lesions and non-coplanar beam arrangements.  
 
b) 
Dimensions of the dose calculation grid must be equal or smaller than 2.5mm.  
 
c) 
The system must be able to display summary plans. 
 
d) 
Can provide hardcopy of superimposed isodose distributions on axial CT images 
(sagittal and coronal planes desirable). 
 
e) 
Can provide digitally reconstructed radiographs (DRRs) with superimposed target 
volume, critical structure contours and treatment aperture. 
 
f) 
Provides planning data in DICOM RT or RTOG format that can be downloaded onto a 
CD or via a network. 
For the inclusion of IMRT, the planning system must have a suitable inverse planning module 
with dose optimisation including non-coplanar beams. The maximum photon energy in this 
case will be restricted to 6MV. The planning system must have the capability to export a 
patient plan to a QA phantom for physical QA. All IMRT plans for patients in the study must 
be verified prior to treatment using physical phantom measurements.  
 
For the use of electron radiation, the planning system must have an adequate dose calculation 
algorithm that can take homogeneities from CT scans into account. This will typically be a 
Monte Carlo based algorithm. 
 
If Monte Carlo calculations or Boltzman radiation transport equation solvers (ACUROS™) are 
used the dose calculations must be dose to water to be equivalent with other dose 
calculations. 
 


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Please consult with the trial physicist if in doubt. 
 
9.1.15.2 
Photon Planning 
Treatment plans are typically expected to be using 3D conformal radiotherapy approach. 
These must be delivered with at least six (6) non‐opposing conformal megavoltage photon 
beams from linear accelerators. It is anticipated that a typical range of beam numbers would 
be 8 to 12, comprising of at least 6 co‐planar beams and 1‐2 non‐coplanar beams.  The 
treatment couch shall be included in the dosimetry of all plans. Arc therapy (including VMAT) 
and IMRT is allowed. 
 
The maximum and minimum doses in the PTV shall be calculated and reported as per ICRU 
report 83.  
 
A DVH must be generated for the PTV and all contoured organs at risk. DVH format and 
labelling of all structures must be clear. 
 
9.1.15.3 
Beam Arrangements 
Radiation beams are expected to be of megavoltage quality and of 6MV, 10MV or 18MV 
energy. Flattening-Filter-Free modes are permitted. At least six (6) non-opposing radiation 
beams must be used to fulfil dosimetric criteria.  Conformal arcs are allowed with a variable 
cumulative arc length, expected to be 200 degrees or more. The minimum field size for energy 
of 6mv is 3cm and for 18mv is 4cm. Smaller field sizes may be permissible when using Monte 
Carlo planning calculations or otherwise in consultation with trial physicist. 
 
9.1.15.4 
Shielding & Customised Blocks 
Treatment must be delivered conformally using a multi-leaf collimator.  Customised blocks are 
prohibited. The use of fields with a jaw setting of less than 3.0 cm x 3.0cm is discouraged to 
maintain accuracy of dose modelling, unless small field size geometry has been specifically 
commissioned. Shielding using multi-leaf collimation within field sizes smaller than this should 
be verified wherever possible, using phantom dosimetric measurements.  
 
9.1.15.5 
IMRT and Arc Therapy 
The use of IMRT is generally not required for small lesions and may unnecessarily prolong 
treatment delivery. However, IMRT can be used (and may be required) if steep dose gradient 
have to be achieved. The use of arc therapies (VMAT and Dynamic Conformal Arc) are allowed 
to expedite treatment delivery.  
 
9.1.15.6 
Electron Planning 
Electron techniques will only be used after approval from the Technical Implementation Group 
(TIG) of the Division of Radiation Oncology and Cancer Imaging. 
 
Superficial lesions may be better treated using electron irradiation. In this case a single 
electron beam shall be used.  
 
The electron energy and field size should be selected so that the 90% isodose line 
encompasses the PTV. Electrons should be prescribed and reported at the depth of maximum 
dose (R100). The limits for dose variation within the PTV are -10% and +10% of the dose at the 
reference point. 


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Electron energies should not exceed 12MeV.  Skin dose may be a limiting factor and use of 
bolus will not be allowed. 
 
The following dose values should be reported for treatment conditions: 
 depth of maximum dose and nominal energy of the electron beam. 
 location of and dose value at the prescription point, or ICRU Reference Point, if not 
located at the level of the maximum dose. 
 
A planning CT is required to determine the tumour depth, and for mandatory outlining of the 
tumour bed and PTV. If planned on CT images using Monte Carlo algorithm, the maximum and 
minimum doses in the PTV shall be calculated and reported as per ICRU71.  Junctions between 
electron beams and any other beam are not allowed. 
 
The method of monitor unit calculation is at the discretion of the treating clinician, and will be 
determined by standard clinical practice at the Trial Site. MU calculation method will be:  
 
 Manual calculation using data issued by the Trial Site, and including depth dose tables 
and factors to correct for non-standard applicator, beam shaping, and treatment 
distance  
 Preference will be for calculation using a treatment planning system which has been 
commissioned for electron beams with heterogeneous tissue. MU calculations using 
pencil beam algorithms are generally not considered sufficiently accurate for clinical 
use, and an alternative (manual) method is recommended. Note that the calculated 
dose distribution is similarly not reliable. MU calculations using Monte Carlo algorithms 
may be used if that is the normal practice at the trial centre. 
 
Therefore, if an electron field is used, the method of monitor unit calculation is at the treating 
clinician’s discretion which is determined by the standard clinical practice at the Trial Site. 
 
9.1.15.7 
Dose Distribution/Reporting 
External Beam Radiation Therapy 
Dose reporting requirements follow ICRU reports 50 and 62 for photons [84, 86] .  Dose and 
volume reporting shall follow the ICRU level 2, including the dose to ICRU reference point as 
well as 3D dose distributions with inhomogeneity corrections, all supported by a quality 
assurance program covering the entire process.  The following will be reported: 
 The absorbed dose at the ICRU reference point. 
 The mean and maximum dose in the PTV will be calculated and reported. 
 The dose to the target shall be reported as the minimum dose received by the PTV, i.e. 
the isodose line covering the PTV. 
 A dose to 99% of the PTV (D99) and 95% of the PTV (D95) should also be reported. There 
will be no restriction on the upper limit of maximum dose within the PTV, however this 
should be ideally between 125%-143% of the prescribed dose.  
 The conformity index will be reported.  This is defined as the ratio between the volume 
encompassed by the prescription isodose and the target volume (ICRU 62). 
 
A conformity index of 1.2 should be the ideal benchmark for radiotherapy plans when IMRT 
or VMAT techniques are used. A conformity index of 1.2-1.3 should be the ideal with 3D 
conformal treatments. A CI100 (volume encompassed by the 100% isodose and the target 


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volume) should usually be 1.6 or less if possible, and a CI50 (volume encompassed by the 50% 
isodose and the target volume) should ideally aim to be 5 or less if possible (acknowledging 
that this may not possible in all cases, and will be more difficult to achieve with smaller target 
volumes). 
 
9.1.15.8 
Treatment Verification and Delivery 
All patients will be treated on a linear accelerator with megavoltage photon beams of a 
nominal energy between 6MV and 18MV. 
 
The linear accelerator must be equipped with multi-leaf collimator of central leaf widths of 
5mm or smaller projected to the isocentre. Due to the non-coplanar delivery required 
isocentre tolerance for quality assurance must be within a 3mm spherical volume in the planes 
of gantry, couch and collimator rotations. 
 
The linear accelerator must be also equipped with verification imaging that allows 
visualisation of the target volume. This must be on board kV imaging, which is expected to be 
cone beam CT (CBCT) or superior technology. If 4D CBCT becomes available and is validated, 
this may be employed. 
 
Verification imaging will be required pre-treatment, mid treatment and post treatment in all 
cases. Verification imaging must be capable of visualising the target with soft tissue matching 
for thoracic, abdominal and pelvic targets. For limb or peripheral targets, kV imaging for bony 
alignment is sufficient. 
 
 Systemic Therapy such as Chemotherapy and Systemic Targeted Agents  
No systemic chemotherapy or systemic targeted agents will be allowed during the six months 
of treatment. Systemic chemotherapy will necessitate ceasing the study drug pembrolizumab.  
 
 Surgical Therapy  
There are no specific surgical techniques included in this study.  If a patient requires surgical 
fixation or procedure for spinal or long bone instability they will be ineligible for the study. 
 
 Dose Selection/Modification of Pembrolizumab (MK-3475) 
The treatment to be used in this trial is outlined below in Table 5 below.  
 
Table 5: Trial Treatment 
Drug 
Dose / 
Potency 
Dose 
Frequency 
Route 
of 
Administration 
Regimen / 
Treatment Period 
Use 
Pembrolizumab 
200 mg  
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
 
Pembrolizumab treatment should begin 5 days (+/- 3 days) post the last SABR treatment. 8 
cycles of pembrolizumab will be delivered. 
 
9.1.18.1 
Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 7: Background 
and Rationale.   
 


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9.1.18.2 
Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per Table 6 below.  
 
See Section 9.3.1 for supportive care guidelines, including use of corticosteroids. 
 
Table 6: Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea / 
Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 
diabetes 
mellitus (if 
new onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus or 
Grade 3-4 hyperglycemia 
associated with evidence of beta 
cell failure 
Resume pembrolizumab when patients are 
clinically and metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab 
can be continued while 
endocrine replacement therapy 
is instituted 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
Hyperthyroidis
m  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidis
m 
 
Therapy with pembrolizumab 
can be continued while thyroid 
replacement therapy is 
instituted 
Therapy with pembrolizumab can be continued 
while thyroid replacement therapy is instituted 
 
Infusion 
Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops 
despite adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal 
Failure 
or Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related 
Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Stevens-
Johnson 
Syndrome 
(SJS) 
signs or 
symptoms 
Refer to the PI and specialist 
Withhold and refer the patient for specialized care 
for assessment and treatment. 
Stevens-
Johnson 
Syndrome 
(SJS) 
confirmed 
Permanently discontinue 
Permanently discontinue  
Toxic 
Epidermal 
Necrolysis 
(TEN) 
signs or 
symptoms 
Refer to the PI and specialist 
Withhold and refer the patient for specialized care 
for assessment and treatment. 
Toxic 
Epidermal 
Necrolysis 
(TEN) 
confirmed 
Permanently discontinue 
Permanently discontinue  
Immune-
mediated 
myocarditis  
 
signs or 
symptoms 
Refer to the PI and specialist 
Withhold and refer the patient for specialized care 
for assessment and treatment. 
  
Immune-
mediated 
myocarditis  
 
confirmed 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or 
equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion 
rate   (e.g., from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be 
premedicated  for the next scheduled dose; Refer to  
 – Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  
Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been 
held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Participants can resume dosing for toxicity if toxicity has resolved according 
to Table 6 requirements, steroid dosing is 10mg or less of prednisolone, and no more than 
12 weeks have passed since last dose. Patients will (or will not) receive additional 
pembrolizumab doses to ensure that each patient has 8 doses pembrolizumab total. 
 
The reason for interruption should be documented in the patient's study record. 
 
 Timing of Dose Administration 
Pembrolizumab treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed in the schedule of events (Table 1).  
 
All trial treatments will be administered on an outpatient basis. 
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks for 8 
cycles. Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window of -
5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 


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 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and participant will know the 
treatment administered. 
 
 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with 
the study Principal Investigator. The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the participant's primary physician.  
 
 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 10.7: Assessing and Reporting Adverse Events.  
 
 
Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. The 
regular use of steroid prophylaxis > 10 mg daily for flare reaction on the day of SABR 
delivery is permitted. 
  
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Participants may receive other medications that the investigator deems to be medically 
necessary. 
 


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The Exclusion Criteria describes other medications which are prohibited in this trial. 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
 
Rescue Medications & Supportive Care 
 
Supportive Care Guidelines 
Participants should receive appropriate supportive care measures as deemed necessary by 
the treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). Refer to Section 9.1.18 for 
dose modification.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
 
Pneumonitis:  
 For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
 For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
 Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
Diarrhoea/Colitis:  
Participants should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhoea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
 All participants who experience diarrhoea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhoea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
 For Grade 2 diarrhoea/colitis, administer oral corticosteroids.  
 For Grade 3 or 4 diarrhoea/colitis, treat with intravenous steroids followed by high dose 
oral steroids.   
 When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
Type 1 diabetes mellitus  


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If new onset, including diabetic ketoacidosis [DKA] OR ≥ Grade 3 Hyperglycemia, if associated 
with ketosis (ketonuria) OR metabolic acidosis (DKA) 
 For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 
3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
haemoglobin, and C-peptide.  
 
Hypophysitis: 
 For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
 For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment.  Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
 Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 
 
Hepatic: 
 For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
 For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
 When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
Renal Failure or Nephritis: 
 For Grade 2 events, treat with corticosteroids. 
 For Grade 3-4 events, treat with systemic corticosteroids. 
 When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
Immune-mediated myocarditis: 


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For suspected immune-mediated myocarditis, ensure adequate evaluation to exclude other 
etiologies, and administer corticosteroids as appropriate. 
 
 
Management of Infusion Reactions:  
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.  
 
Table 7 below shows treatment guidelines for participants who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 7: Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
 
None 
Grade 2 
 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
 
Stop Infusion and monitor 
symptoms. 
 
Additional appropriate medical 
therapy may include but is not 
limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDS 
 
Acetaminophen 
 
Narcotics 
 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
 
If symptoms resolve within one 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be 
held until symptoms resolve and 
the subject should be 
premedicated for the next 
scheduled dose. 
 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
 
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab 
(MK-3475) with: 
 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 


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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grades 3 or 4 
Grade 3: 
 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
 
Life-threatening; pressor 
or ventilatory support 
indicated 
 
Stop Infusion. 
 
Additional appropriate medical 
therapy may include but is not 
limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDS 
 
Acetaminophen 
 
Narcotics 
 
Oxygen 
 
Pressors 
 
Corticosteroids 
 
Epinephrine 
 
 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
 
Hospitalization may be indicated. 
 
Subject is permanently 
discontinued from further trial 
treatment administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. 
 
Diet/Activity/Other Considerations 
 
Diet 
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhoea, nausea or vomiting. 
 
 
Contraception 
Pembrolizumab may have adverse effects on a foetus in utero.  Furthermore, it is not known 
if pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, 
non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 
1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not 
had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.  The two birth control methods can be two 
barrier methods or a barrier method plus a hormonal method to prevent pregnancy. 
Participants should start using birth control from study Visit 1 throughout the study period up 
to 120 days after the last dose of study therapy.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
oestrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
 
Participants should be informed that taking the study medication may involve unknown risks 
to the foetus (unborn baby) if pregnancy were to occur during the study.  In order to 
participate in the study they must adhere to the contraception requirement (described above) 


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for the duration of the study and during the follow-up period defined in Section 10.8.4: 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck.  If there is any question 
that a participant will not reliably comply with the requirements for contraception, that 
participant should not be entered into the study. 
 
 
Use in Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will immediately be removed from the study.  The site will contact the participant 
at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor and 
to Merck without delay and within 24 hours to the Sponsor and within 2 working days to 
Merck if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).   
 
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the foetus or newborn to the Sponsor.   If a male 
participant impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 10.8.4 Reporting of Pregnancy and Lactation to the Sponsor 
and to Merck. 
 
 
Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breast-feeding are not eligible for enrolment. 
 
 
Participant Withdrawal/Discontinuation Criteria 
 
Protocol Treatment Discontinuation  
A participant must be discontinued from the trial treatment for any of the following reasons: 
 The participant or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 Unacceptable adverse experiences as described in Section 9.1.18: Dose Modifications 
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the participant 
 The participant has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 
When a participant discontinues/withdraws treatment prior to trial completion, all applicable 
activities scheduled for the End of Treatment visit should be performed at the time of 
discontinuation. Any AEs which are present at the time of discontinuation/withdrawal should 
be followed in accordance with the safety requirements. After discontinuing treatment (for 
any reason), participants should attend the site for a 30 day (post end of trial treatment) safety 
follow-up visit (see Section 10.3) for assessment of AEs and Efficacy. 
 
The End of Treatment and Follow-up visit procedures are listed in The Schedule of Events 
(Section 2) and Section 10.2: Visit Requirements. After the end of treatment, each participant 
will be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment as described in Section 10.8.5 Serious Adverse 


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Events.  Participants who discontinue treatment will have post-treatment follow-up for 
disease status until initiating a non-study systemic cancer treatment, withdrawing consent or 
becoming lost to follow-up.  
 
 
Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for participants who have attained a 
confirmed CR and had at least two cycles of pembrolizumab beyond the date when the initial 
CR was declared with the option of restarting treatment if they meet the criteria specified in 
Section 10.6: Second Course Phase.   
 
After discontinuing treatment following assessment of CR, these participants should return to 
the site for a Safety Follow-up Visit (described in Section 10.3) and then proceed to the Follow-
Up Period of the study (described in Section 10.5). 
 
Pembrolizumab may also be discontinued or put on hold for specified AEs, see Table 7. 
 
Additional details about follow-up after treatment completion or discontinuation are provided 
in Section 10.2:  Visit Requirements. 
 
 
Withdrawal From The Trial  
Participants may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the investigator should any untoward effect occur.  
 
Total withdrawal would occur in the circumstance that the participant decides to completely 
withdraw from all treatment aspects of the trial, and does not agree to any further scheduled 
follow up assessments. The participants’ total withdrawal must be documented in the medical 
records and transcribed onto the relevant CRF. No further information will be collected from 
this patient for the purpose of this trial. 
 
 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to participants 
4. Plans to modify or discontinue the development of the study drug 
 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to participant treatment can be made. 
 
10 TRIAL PROCEDURES 
The Schedule of Events (Section 2) summarizes the trial procedures to be performed at each 
visit. Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to participant safety. In some cases, such evaluation/testing may 


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be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the participant.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations. 
 
 Trial Procedures 
 Informed Consent 
The Investigator must obtain documented consent from each potential participant prior to 
participating in a clinical trial. 
 
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.  
 
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the participant must receive the IRB/ERC’s 
approval/favourable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s dated signature 
or by the participant’s legally acceptable representative’s dated signature. 
 
The informed consent will adhere to HREC requirements, applicable laws and regulations and 
Sponsor requirements. 
 
 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.  
 
 Demographics 
Demographic will be collected including gender and date of birth. 
 
 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  The medical history will also 
include: 
 Disease status and prior treatments 
 Any new disease symptoms 
 
 Disease Specific Medical History 
The investigator or qualified designee will obtain prior and current details regarding disease 
status, including all prior cancer treatments, e.g. systemic treatments, radiation and surgeries. 
 


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 SINS Score for Spinal Targets 
The investigator or qualified designee will assess the SINS score for spinal targets at Screening. 
 
 Physical Exam 
The investigator or qualified designee will perform a full physical exam during the screening 
period and also during the treatment phase. Clinically significant findings will be recorded as 
adverse events.   
 
The investigator or qualified designee will perform a directed physical exam as clinically 
indicated during the follow up phase.   
 
 Vital Signs and Body Measurements 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of pembrolizumab and at treatment discontinuation and during 
follow up as specified in the Schedule of Events (Section 2).  Vital signs will include 
temperature, pulse, respiratory rate and blood pressure. Body measurements will include 
weight (all visits) and height (screening only). 
 
 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of pembrolizumab and discontinuation of trial treatment as 
specified in the Schedule of Events (Section 2).  
 
 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential 
new or worsening AEs as specified in the Schedule of Events and more frequently if clinically 
indicated. Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.03.  AEs will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
 
Please refer to Section 10.7 for detailed information regarding the assessment and recording 
of AEs.  
 
 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the participant within 
35 days before starting the trial.  Treatment for the disease for which the participant has 
enrolled in this study will be recorded separately and not listed as a prior medication. 
  
 Concomitant Medications 
The investigator or qualified designee will record medication, if any, related to reportable SAEs 
which should be recorded as defined on the SAE CRF. 
 
 Numerical Pain Rating Score 
 Numerical Pain Rating score (refer to Appendix 2) will be completed by the patient at the time 
points specified in the Schedule of Events (Section 2). 
 


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 Tumour Imaging and Assessment of Disease 
Imaging will be performed as per below: 
 
All pre-registration/screening investigations (CT Scan and WBBS) should be completed 
within 35 days prior to study registration. 
 
Clinical and radiological tumour assessments (post study registration) will be performed 
by CT scan or MRI (Chest, Abdo, Pelvis, and Brain if clinically indicated) reported with 
RECIST 1.1 (if possible) unless evidence of progression earlier or clinically inappropriate. 
WBBS will be performed at 3 and 6 months post SABR treatment in patients with bone 
disease detected at baseline, and/or if clinically indicated at any of the 3 monthly 
follow-up visits. Follow-up visits will continue until the last evaluable patient completes 
12 months of follow-up. 
 
Disease progression, as per RECIST 1.1, should be confirmed with repeat imaging 4 to 6 weeks 
later by the same imaging modality or by biopsy. If PET-CT scan has been done this can be 
used for confirmation of disease progression provided the CT component of the PET-CT scan 
is of adequate resolution. Complete response includes disappearance of the target tumor 
radiographically or metabolically (standardized uptake value = 0 when the pre-treatment PET, 
if done, was metabolically active). Efficacy will be evaluated by time to local progression as 
well as failures in other sites. 
 
 Laboratory Procedures/Assessments 
Laboratory assessments will be performed as specified in the Schedule of Events.  
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
 
 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a participant initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before 
the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the 
participant will move into survival follow-up.  
 
 Continuing Pembrolizumab beyond Radiological Progression 
There are patients who experience progression prior to response to pembrolizumab. Hence, 
radiological progression should be confirmed with follow-up imaging 4-6 weeks later. 
Pembrolizumab can be continued if there is evidence of benefit by the investigator, if there 
are no signs or symptoms indicating unequivocal disease progression, no decline in ECOG 
performance status attributed to disease progression and no growth of the tumour in critical 
sites. If radiological progression is still documented pembrolizumab can still be continued until 
there is unequivocal symptomatic deterioration attributed to disease progression that 
requires initiation of new systemic or local therapy. 
 
 Visit Requirements 
Visit requirements are outlined in The Schedule of Events (Section 2). Specific procedure-
related details are provided above in Section 10: Trial Procedures. 


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 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted 30 days + 3 days after the last dose 
of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first. All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Participants 
with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anti-neoplastic therapy, whichever occurs first. SAEs that occur within 90 
days of the end of treatment or before initiation of a new anti-cancer treatment should also 
be followed and recorded.  
 
 Follow-up Visits 
Participants who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 3 months by radiologic imaging 
to monitor disease status until the last evaluable patient completes 12 months of follow-up. 
Every effort should be made to collect information regarding disease status until the start of 
new systemic therapy, death, end of the study or if the participant begins retreatment with 
pembrolizumab as detailed in Section 10.6: Second Course Phase. Information regarding post-
study anti-neoplastic treatment will be collected if new treatment is initiated. Participants 
who start a new systemic therapy, are retreated with pembrolizumab or have distant 
progression will be followed for survival only. 
 
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 10.6 Second Course Phase will move from the follow-up phase to the Second 
Course Phase when they experience disease progression. 
 
 Survival Follow-up 
All patients will be followed for survival until the last evaluable patient completes 12 months 
of follow-up. 
 
 Second Course Phase (Pembrolizumab Retreatment Period) 
Participants who stop pembrolizumab with SD or better response who then experience 
radiographic disease progression may be eligible for up to one year of additional treatment 
with pembrolizumab via the Second Course Phase at the discretion of the investigator if: 
 no cancer treatment was administered since the last dose of pembrolizumab,  
 the participant meets the safety parameters listed in the Inclusion/Exclusion criteria 
below, and  
 the trial is open.   
 
Participants will resume therapy at the same dose and schedule at the time of initial 
discontinuation. This retreatment is termed the Second Course Phase of this study and is only 
available if the study remains open and the participant meets the following conditions: 
 
EITHER  
 Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing therapy 
 Received at least two cycles of pembrolizumab beyond the date when the initial CR was 
declared 


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OR 
 Had SD, PR or CR and stopped pembrolizumab treatment for reasons other than disease 
progression or intolerability 
AND 
 Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
 Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
 
 Has a performance status of 0 or 1 on the ECOG Performance Scale 
 Demonstrates adequate organ function as detailed in Section 8.3. 
 Female participant of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
 Female participant of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Section 9.4.2 
Contraception). Participants of child bearing potential are those who have not been 
surgically sterilized or have been free from menses for > 1 year.  
 Male participant should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.   
 Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the participant’s participation for the full duration 
of the trial or is not in the best interest of the participant to participate, in the opinion 
of the treating investigator. 
 
Participants who restart treatment will be retreated at the same dose and dose interval as 
when they last received pembrolizumab. Treatment will be administered for up to one 
additional year. Management of all immunotherapy related toxicities are outlined in Section 
9.3.1 Supportive Care Guideline. This guideline should be followed in the retreatment period, 
however, any prior events and subsequent interventions or treatment modification during the 
initial treatment period should be continued in the retreatment phase. Any patient having 
sustained immunotherapy induced severe (grade 3) pneumonitis/ colitis / haematologic 
events etc. corticosteroids for > 12 weeks, or life-threatening events should be excluded from 
retreatment.  
 
Once any new systemic anti-cancer therapy or, second course of pembrolizumab has been 
initiated, the participant will have concluded their participation in the treatment phase of the 
study. On completion of the treatment phase of the study the participant enters the follow-
up phase and will be followed up for survival from the date any new treatment starts. 
 
 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product (or any other protocol 
specified intervention including radiation therapy, surgery or use of a device) and which does 
not necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal product 
or protocol-specified procedure (including radiation therapy, surgery or use of a device), 
whether or not considered related to the medicinal product or protocol-specified procedure. 


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Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of 
a pre-existing condition that is temporally associated with the use of the medicinal product, 
(or associated with the use of any other protocol specified intervention including radiation 
therapy, surgery or use of a device), is also an adverse event. 
 
Adverse events may occur during the course of the use of protocol treatment in clinical trials 
or within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
 
Adverse events may also occur in screened participants during any pre-allocation baseline 
period as a result of a protocol-specified intervention, including washout or discontinuation 
of usual therapy, diet, placebo treatment or a procedure. 
 
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
 
 Attribution of cause of an Adverse Event 
The causal relationship to protocol treatment (attribution), as assessed by the Investigator is 
also to be recorded. Attribution of cause requires at least a reasonable possibility of a causal 
relationship between the event and the use of the investigational drug or any other protocol-
specified intervention.  
 
All protocol-specified interventions (including pharmaceutical products, radiation therapy, 
surgery or use of a device) administered prior to the date of the event must be attributed a 
degree of causality from one of the following codes: 
 Definite:  
The AE is clearly related to protocol treatment 
 Probable: 
The AE is likely related to protocol treatment 
 Possible: 
The AE is may be related to protocol treatment 
 Unlikely:  
The AE is doubtfully related to protocol treatment 
 Unrelated: 
The AE is clearly NOT related to protocol treatment 
 
An AE does not include: 
 Medical or surgical procedures (e.g. surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure is an AE 
 Pre-existing diseases or conditions present or detected prior to start of study product 
administration, that do not worsen 
 Situations where an untoward medical occurrence has not occurred (e.g. hospitalisation 
for elective surgery, social and/or convenience admissions) 
 Overdose of either study product or concomitant medication without any signs or 
symptoms unless the subject is hospitalised for observation. 
 Progression of the disease under study 
 
 Adverse Event Reporting 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following completion of pembrolizumab treatment. SABR related adverse events will be 
followed at each follow-up visit until 2 years after completion of SABR.  
 


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All adverse events, which occur whilst the participant is enrolled on the trial (including the 
follow-up phase), must be reported in the patients’ medical records and recorded on the 
Adverse Events CRF. The Common Terminology Criteria for Adverse Events (CTCAE version 
4.03 – see appendices) or other more specific AE tools must be used to grade the severity of 
an event.  Laboratory values need reporting as AEs only if abnormal and deemed clinically 
significant by the investigator 
 
All adverse events must be recorded on the Adverse Events CRF with the following 
information: 
 The severity grade using CTCAE version 4.03 
 Its relationship to the study drug(s)  
 Treatment changes 
 Whether it constitutes a serious adverse event (SAE) 
 
 Late Toxicities 
Late toxicities (AEs) which are deemed by the investigator to be attributed to protocol 
specified SABR treatment are to be reported on the AE CRF.  Late Toxicities are defined as AEs 
directly attributed by the Investigator to SABR treatment on this study, recorded from 30 days 
post last MK-3475 treatment until 24 months following the last SABR treatment.  
 
 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose). No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the participant should be observed 
closely for signs of toxicity. Appropriate supportive treatment should be provided if clinically 
indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of pembrolizumab, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met. 
 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect” on the Adverse Event CRF page. 
 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX +1-215 993-1220). 
 
 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a participant 
(spontaneously reported to them), including the pregnancy of a male participant's female 
partner that occurs during the trial or within 120 days of completing the trial completing the 
trial, or 30 days following cessation of treatment if the participant initiates new anticancer 


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therapy, whichever is earlier. All participants and female partners of male participants who 
become pregnant must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX +1 215 993-1220). 
 
 Serious Adverse Events 
Adverse events and adverse drug reactions are considered ‘serious’ if they threaten life or 
function.  
 
SAEs include ‘Serious Adverse Drug Reactions’. During clinical investigations, adverse events 
may occur, which if suspected to be medicinal product related (‘adverse drug reactions’) might 
be significant enough to lead to important changes in the way the medicinal product is 
developed (e.g. change in dose, population, monitoring, consent). This is particularly true for 
reactions, which in their most severe form threaten life or function.   
 
Due to the significant information they provide, Serious Adverse Events (including Serious 
Adverse Drug Reactions) require expedited reporting. SAEs are defined as any adverse event 
or adverse drug reaction which: 
 Results in death (i.e. fatal/grade 5 CTC AE) 
 Is life-threatening (i.e. grade 4 CTC AE) 
 Requires inpatient hospitalisation or prolongation of existing hospitalisation* 
 Results in persistent or significant disability/incapacity; or 
 Is a congenital anomaly/birth defect 
 Is a new cancer (that is not a condition of the study) 
 Is associated with an overdose 
 Other significant medical event 
 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was immediately at risk of death at the time of event; it does not refer to an event, 
which hypothetically might have caused death if it were more severe.  
 
*An event that results in hospitalisation or prolongs an existing hospitalisation will not be 
considered a serious adverse event if the only reason for the hospitalisation or prolongation 
was: 
 Administration of chemotherapy 
 Administration of trial procedures 
 Placement of a permanent intravenous catheter 
 Hospice placement for terminal care 
 Pre-trial scheduled elective surgery 
 Outpatient hospitalisation for procedures such as: 
o Elective day surgery 
o Convenience purposes (e.g. transportation difficulties) 


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o Planned admission as part of supportive care for insertion of PEG tube or naso-
gastric tube for commencement of enteral feeding (i.e. did not occur following 
urgent admission as a result of weight loss or other patient medical events) 
 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any participant from 
the time the consent is signed through 90 days following cessation of pembrolizumab 
treatment, or the initiation of new anti-cancer therapy, whichever is earlier, whether or not 
related to protocol treatment, must be reported within 24 hours to the Sponsor and within 2 
working days to Merck Global Safety.  
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to protocol treatment that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220. 
 
10.8.5.1 
Serious Adverse Event Reporting 
Trial Sites/Investigators 
All SAEs that occur from the time a participant has signed consent for the Trial to within 90 
days of the final protocol-specified treatment, intervention or procedure or the initiation of 
new anti-cancer therapy, whichever is earlier, are required to be reported to the Sponsor 
whether or not considered related to the treatment under investigation.   
 
The Principal Investigator (PI) or delegate must: 
 Determine whether an AE is ‘Serious’  
 For SAEs, the PI or delegate must then ascertain the suspected cause 
 Ascertain severity 
 Record the SAE in the patients’ medical records and submit an   SAE form.  
 Report the SAE on the Trial SAE form to Sponsor and Merck no later than 24 hours after 
becoming aware of the event. The investigator may be requested by the Sponsor or Merck 
to provide or obtain specific additional follow-up information in an expedited fashion for 
the purpose of safety assessment 
 
 
10.8.5.2 
Sponsor Responsibility  
The Sponsor is responsible for: 
 Implementing and maintaining a suitable recording system to record information from 
all SAEs received from Trial Sites. 
 Ensuring that the Coordinating Principal Investigator (CPI) is notified of each SAE to 
enable the SAE to be assessed by the CPI and any other appropriate reviewers for nature 
(expected/unexpected), causality and whether the TGA needs to be notified of the SAE. 
 Notifying the TGA (Australia) in accordance with the regulatory authority’s detailed 
guidance of any SUSARs that are fatal or life threatening as soon as possible but no later 
than 7 days after the site gained first knowledge of the event. Incomplete reports must 
be completed and forwarded as soon as possible within 8 additional calendar days. All 


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other SUSARs should be reported to the TGA within 15 days after the site gained first 
knowledge of the event. 
 Considering information provided by (non-serious) adverse event data. 
 Informing each trial site of new information arising from serious and non-serious 
adverse events and adverse drug reactions that may affect the conduct of the Trial, or 
the rights, interests, safety or wellbeing of trial patients. 
 Notifying the TGA of any significant issue that has arisen from analysis of overseas 
reports or action that has been taken by another country’s regulatory authority within 
72 hours of first knowledge. 
SAEs must be reported by completing the sponsor Trial SAE form and FAXING or Emailing to 
the following: 
 
Sponsor 
Email: Safety_BaCT@Petermac.org  
Merck Global Safety 
+1-215-993-1220 
 
 
SAE forms are required at the following points: 
 
Initial Report             
Within one working day/24 hours of discovery or notification 
of the event.  If the reporting of an SAE is delayed by more 
than 24 hours, an explanation must be provided.  This report 
may be signed by a clinician who is not the treating doctor. 
Incomplete Reports*   If all details are not available at the time of the initial report a 
completed report must be sent within the next 10 days. 
Updated Report 
If the event is not resolved (or is ‘on-going’) at the time of the 
initial report, the ‘UPDATE: Outcome of Event’ section’ of the 
SAE Form must be completed and the form submitted to BaCT 
and the SAE reviewer as soon as the event is resolved (with or 
without sequelae) or if death has occurred.  
 
*The Investigator is ultimately responsible for reporting the SAE and must sign the final SAE 
report(s). Should this Investigator not be available to sign the initial SAE form within the 24-
hour period, a comment to this effect must be written on the form and the form signed by the 
clinician attending to the patient at the time and faxed to the Sponsor. The investigator must 
sign the SAE form as soon as possible and re-fax to the Sponsor 
 
The Investigator at the Trial Site is responsible for determining the local SAE reporting 
requirements of the responsible HREC and subsequently notifying the HREC of SAEs as 
required.  
 
All participants with serious adverse events must be followed up for outcome. 
 
10.8.5.3 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 


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reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX +1 215 993-1220). 
 
For the time period beginning when the consent form is signed until treatment commences, 
any ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours to 
the Sponsor and within 2 working days to Merck Global Safety if it causes the subject to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
 
For the time period beginning at first treatment through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to protocol 
treatment, must be reported within 24 hours to the Sponsor and within 24 hours to Merck 
Global Safety. 
 
Events of clinical interest for this trial include: 
1. an overdose of pembrolizumab, as defined in Section 10.8.3 Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results.  
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 
 
11  STATISTICAL ANALYSIS PLAN 
 Statistical Analysis Plan Summary 
This is a prospective, single arm Phase 1b/II study to evaluate the safety profile, efficacy and 
biological effects of SABR in combination with pembrolizumab in patients with oligometastatic 
renal cancer.  
 
As the sample size of 30 in this study is a pragmatic one, to demonstrate a safety and efficacy 
signal, results are intended to be descriptive. Evidence that the combination is well tolerated, 
efficacious and generates activation of immune parameters will provide confidence to move 
to a more definitive and larger randomized study.  
 
 Statistical Analysis Plan 
 Populations for Analyses  
 Enrolled participant population includes all participants who provided informed 
consent.  
 Treated participant population (evaluable patients) is defined as the participants who 
completed at least one SABR treatment and received at least one dose of 
pembrolizumab. This is the primary population for the safety and efficacy analyses.  


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 Response-evaluable participants are those treated participants who have CT/MRI scans 
performed at respective follow-up visit. 
 
 Statistical methods 
Demographics and baseline characteristics of patients will be summarized using descriptive 
statistics.  
 
The analyses of the all endpoints will occur at 12 months after the last evaluable patient is 
recruited.  
 
No imputation for missing data is intended. 
 
 Safety analysis 
Safety will be assessed using CTCAE v4.03 and the maximum toxicity grade of each adverse 
event will be derived and presented in table format. The proportion of patients who suffer 
from grade 3 or higher toxicities (each toxicity and overall) will be provided along with its exact 
95% CI for all patients who have received at least one dose of pembrolizumab and completed 
at least one SABR treatment. Events of clinical interest will be also tabulated (see Section 
10.8.5.3 Events of Clinical Interest). 
 
 Time-to-event analysis 
A cut-off date for follow-up will be determined at the time of analysis. The cut-off date will be 
chosen to enable data on follow-up to that date to be collected, where possible, on all living 
patients. All events occurring after this date will be ignored in the analysis in order to minimise 
reporting bias.  
 
The Kaplan-Meier method will be used to describe TTLP, DPFS and OS curves. Estimates at 1 
and 2 years will be provided with 95% confidence interval. TTLP will be assessed at lesion level 
and Kaplan-Meier estimates will be adjusted for patient effect.  
 
 Pain analysis 
Pain will be described as change over time using linear mixed models. The linear mixed model 
will include time (as a factor) as fixed effect and patients as random effect. Mean and 95% 
confidence intervals will be calculated for each time point and the data will be displayed 
graphically. If strong floor effect is observed or if the assumptions of the model do not hold, 
simple descriptive statistics will be provided instead for each time point. 
 
 Response analysis 
All tumour response measurements (pre- and post-treatment) must be recorded using the 
definitions of RECIST 1.1 following SABR treatment. RECIST assessments will take into account 
post-treatment inflammatory processes that occur after SABR treatment in pulmonary and 
liver tissues.  
 
DCR, ORR at 3, 6, 12 and 24 months and best overall response will be described as percentages 
with exact 95% confidence intervals for: a) DCR; b) ORR at 3, 6, 12 and 24 months and c) best 
overall response. If at least one patient has non-target disease only with response classified 
as non-CR/non-PD, then the response rate of CR will be reported instead of CR+PR.  
 


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The change in lesions size over time will be displayed graphically on the subset of lesions with 
measurable disease at baseline, with each lesion represented as a separate line and line colour 
representing the radiotherapy modality (SABR or conventional RT). 
 
 Exploratory Endpoints 
All exploratory endpoints (PD-L1 expression, TILs, peripheral blood markers and other 
markers) will be described over time using linear mixed models. The linear mixed model will 
include time as fixed effect (as factor) and patients as random effect. Mean and 95% 
confidence intervals will be calculated for each time point and the data will be displayed 
graphically. Contrasts from the LMM will be used to test whether there is a change in 
expression levels from baseline to post-treatment sample time points, baseline to cycle 8 and 
baseline to 12 months post SABR. Variable transformation may be required for some of the 
collected variables. If the assumptions of the model do not hold, simple descriptive statistics 
will be provided for each variable at each time point.  
 
A number of further exploratory translational endpoints will be evaluated including 
1. 
Primary and metastatic lesions for PD-L1 expression using immunohistochemistry. 
Protein expression of PD-L1 will be measured using a previous defined 
immunohistochemistry method on H&E stained slides using Merck’s diagnostic PD-L1 
assay. Changes in PD-L1 in primary and metastatic lesions (if accessible) will be 
evaluated. Levels of PD-L1 in Primary sample will be correlated with changes in levels of 
T cell activation and T cell immunosuppression from baseline to cycle 8 of 
pembrolizumab using spearman’s correlation.  
 
2. 
Primary and metastatic lesions for quantity of tumour infiltrating lymphocytes (TILs) 
using a previously defined method. 
TILs will be measured as a continuous variable using a previous defined method on H&E 
stained slides using percentage (%) infiltrating stromal located lymphocytic infiltration. 
Changes in TILs in primary and metastatic lesions (if accessible) will be evaluated. Levels 
of TILs in Primary sample will be correlated with changes in levels of T cell activation and 
T cell immunosuppression from baseline to cycle 8 of pembrolizumab using spearman’s 
correlation.  
 
3. 
Other immune endpoints including antibody titres and peripheral blood markers of 
immune activation and suppression 
 
4. 
Seroconversion to a range of epitopes will be measured in serum samples. An assay to 
detect soluble PD-L1 assay will also be used.  
 
 Immune Endpoints Evaluation 
It is expected that pembrolizumab will promote the anti-tumour immune response initiated 
by the SABR therapy.  The working hypothesis is that the induced anti-tumour immune 
response will be systemic, and this will promote immune surveillance of metastatic lesions. 
The tumour microenvironment is characterized by an inverse relationship between effector T 
cells (Teff) and regulatory CD4+ T cells (Treg), tumour associated macrophages (TAM2) and 
myeloid derived suppressor cells (MDSCs). We expect that SABR+ pembrolizumab (MK-3475) 
will change this inverse Teff:Suppressor cell balance so that the Teff cells predominate over 
Tregs and MDSCs. Peripheral blood will be collected before and at intervals during therapy. 
Alterations in the above immune subsets will be determined by the following (but not limited 


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to); multi-parameter FACS for T cells (CD3, CD4, CD8, CD45RA, CCR7, CD45Ro), B (CD19), NK 
(CD3-CD56+CD16+), Treg (CD3,CD4, CD127, FoxP3) and MDSC subsets (CD14+HLADR- and lin-
HLADR-CD33+CD15+). We will also examine the immune suppression molecules (TIM3) as well 
as activation molecules (OX-40) on PB T cell subsets to determine whether these change 
following treatment with SABR + pembrolizumab.  
 
In the context of renal cancer, therapy-induced tumour-specific T cell responses are difficult 
to assess as tumour antigens are only partially described. Therefore, we will reveal therapy-
induced T cell responses indirectly by examining the TCR repertoire for clonal expansion (next 
generation sequencing on Illumina). 
 
Lastly, we will examine plasma levels of PD-L1 (sPD-L1) before, during and after therapy to 
examine whether there is a correlation between patient baseline PD-L1, and whether clinical 
response correlates with changes in sPD-L1 levels during or after therapy. This will be 
performed using a commercial ELISA kit assay (see laboratory manual). 
 
 Sample Size Calculation  
This is a Phase Ib/II study to evaluate the safety profile and efficacy that would then be 
evaluated in a larger and more appropriately powered future study. The sample size of 30 
patients is pragmatic.  
 
The primary objective of the study is to provide a description of the safety profile of the 
combined SABR and pembrolizumab therapies. Table 8 illustrates different scenarios for grade 
3 or 4 AEs rate ranging from 0% to 40% with the respective 95% exact confidence intervals, 
assuming 30 patients.  
 
Table 8: Confidence Intervals for Adverse Event Rates 
Number of patients 
with grade 3+ AE 
Grade 3+ AE rate 
95% confidence 
interval 
1 
3% 
0% - 17% 
2 
7% 
1% - 22% 
3 
10% 
2% - 27% 
4 
13% 
4% - 31% 
5 
17% 
6% - 35% 
6 
20% 
8% - 39% 
7 
23% 
10% - 42% 
8 
27% 
12% - 46% 
9 
30% 
15% - 49% 
10 
33% 
17% - 53% 
11 
37% 
20% - 56% 
12 
40% 
23% - 59% 
 
Expected toxicities related to the pembrolizumab treatment are listed in the Investigator’s 
Brochure. Therefore, immune related events such as hypothyroidism, pneumonitis, and colitis 
are expected. They should occur in <5%. Pneumonitis and colitis are considered to be the most 
serious but are rare events. Immune events and other events of clinical interest will be 
monitored for closely in this study, with early stopping rules as detailed below. 
 


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Recruitment will occur over a two-year period. An interim analysis after 15 patients completes 
6 months of follow-up will be conducted for presentation purpose. The final analyses will be 
at the completion of 12 months after the last participant has completed SABR treatment.  
 Early Termination Criteria 
A Safety Monitoring Committee (SMC) will be formed prior to trial activation, to review the 
information from the safety analyses performed after the first 12 patients have completed 
SABR and 12 weeks of pembrolizumab treatment. The Trial Management Committee (TMC), 
will have responsibility for any final decisions about protocol stopping or modification.   
 
Consideration of the cessation of participant accrual will occur if an unacceptable rate of 
toxicity is detected. The expected rates of grade 3+ pneumonitis and colitis are expected to 
be less than 5%. Thus, after 12 patients have completed 12 weeks of follow up following 
treatment, consideration by the SMC will be given to stopping the trial if any of the following 
is observed:  
a. The number of ≥ grade 3 pneumonitis toxicity events is ≥ 2 (expected rate of <5%)  
b. The number of ≥ grade 3 bowel toxicity events is ≥ 2 (expected rate of <5%)  
 
If the true grade 3+ pneumonitis and bowel toxicities rates are 5%, the probability of early 
stopping due to unacceptable toxicity rate is 22% assuming the two types of toxicities are 
independent. 
 
  Deviations  
Any deviations from the statistical plan should be described and justified in the protocol (i.e. 
protocol amendment) or in the statistical report. 
 
12 LABELLING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
 Investigational Product  
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
Clinical Supplies will be provided by Merck as summarized in Table 9. 
 
Table 9: Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 Packaging and Labelling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
 Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
 


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 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the participants and the 
amount remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
13 ADMINISTRATIVE AND REGULATORY DETAILS 
 Confidentiality 
The trial will be conducted in accordance with applicable Privacy Acts and Regulations. All 
information regarding trial participants must be treated in strict confidence. Data, which 
identify any trial participant, must not be revealed to anyone not directly involved in the trial 
or the clinical care of that participant. An exception is where the trial participant has provided 
written consent for his/her records to be included in source document verification. In this 
instance, the records may be inspected by a representative of a government regulatory 
authority for the purposes of official inspection. Records must be made available for 
inspection on the understanding that all information relating to trial participants will be 
treated in strict professional confidence. 
 
 Ethical Principles and Regulatory Compliance 
The trial will be conducted according to the following regulations and guidelines: 
● Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) annotated with TGA 
comments (Australia, July 2000) 
● The Australian Code for Responsible Conduct of Research (August 2007) 
● Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects 
(last amended by the World Medical Association, 2008) 
● National Statement on Ethical Conduct in Human Research, (Australia, 2007) 
 
This Protocol, including the Participant Information Sheet and Consent Form (PICF) must be 
approved by the responsible HREC before enrolment of trial participants.  
 
 Adherence to Protocol 
Except for an emergency situation in which proper care for the protection, safety and well-
being of the trial participant requires that an alternative treatment be used, the trial shall be 


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conducted exactly as described in the approved protocol. Any deviation from the protocol 
must be recorded and explained. 
 
  Informed Consent 
The Principal Investigator or delegate is responsible for ensuring that signed written Informed 
Consent is obtained from trial participants before trial entry. 
 
 Data Management 
Trial participants are to be identified by initials and trial registration number. All de-identified 
study data collected on electronic CRFs and source documents will be kept in a separate study 
specific de-identified database at BaCT. All trial data required for the monitoring and analysis 
of the study will be recorded electronically on the Electronic Data Capture e-system provided 
by BaCT. All required data entry fields must be completed. Data corrections will be done 
according to the instructions provided. Site investigators will be asked to confirm the accuracy 
of completed eCRFs by signing key eCRFs as indicated.  
 
Source documents pertaining to the trial must be maintained by investigational sites and 
copies provided to BaCT when requested. Source documents may include a subject's medical 
records, hospital charts, clinic charts, the investigator's subject study files, as well as the 
results of diagnostic tests such as laboratory tests, and electrocardiograms. The investigator's 
copy of the case report forms serves as part of the investigator's record of a subject's study-
related data. BaCT will conduct analysis from data stored in the patient database, kept in a 
secure location, with all de-identified. BaCT shall complete two reports: the first report will be 
after 15 patients completes 6 months of follow-up for presentation purpose only and the final 
report will be at 12 months from the completion of the last participant’s SABR treatment.  
 
 Source Documentation 
Source documents relating to the study must be maintained by the study site.  Source 
documents may include (but are not limited to) a participant’s medical history, site trial 
history, hospital records/charts, radiological investigations, laboratory tests, pembrolizumab 
drug charts and radiotherapy treatment records (including verification films and portal 
images). All study-related source documentation must be retained for 15 years following 
completion of the study and be made available for checking or clarification of queries if 
required, in accordance with ICH-GCP Guidelines. 
 
 Quality Assurance Reviews 
QA processes will be employed in different departments which will conform to recommended 
standards for that department. 
 
 Trial Management Committee (TMC) 
The Trial Management Committee (TMC) will oversee the study planning and progress, and 
assess/implement recommendations from other committees (e.g. PMCC HREC).   
 
The TMC will also consider recommendations from the Safety Monitoring Committee (SMC) 
about whether to continue the study as planned, modify, or stop it, based on the planned 
interim analyses or other information. 
 


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The TMC will meet on a regular basis and will consist of the Study Coordinating Principal 
Investigator, Principal Investigators, Associate Investigators, Medical Physicist, Statistician and 
Trial Manager.  
 
 Safety Monitoring Committee (SMC) 
The Safety Monitoring Committee will consist of one independent Radiation Oncologist, one 
independent Medical Oncologist and the study statistician.  They will meet to review the 
information from the safety analyses in Section 11.2.3 Safety Analysis in addition to the below: 
1. Assessing the conduct and progress of the trial – accrual, treatment toxicity and serious 
adverse events. 
 
14 PUBLICATION AND PRESENTATION POLICY 
The TMC will be responsible for decisions regarding presentations and publications arising 
from this trial according to Sponsor guidelines. 
 


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16 APPENDICES 
Appendix 1: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 
2 
In bed <50% of the time. 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 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* 
As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of 
The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern 
Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
 
 
Appendix 2: Numerical Pain Rating Scale 
 
 
From:  
Mirels, H. Metastatic disease in long bones.  A proposed scoring system for diagnosing 
impending pathological fractures.  Clin Orthop Relat Res 1989;249:256-64. 
 
 


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Appendix 3: Spinal Stability 
Spine Instability Neoplastic Score (SINS) 
From Fourney et al[95] and Fisher et al[96] 
 
 


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Appendix 4: Radiotherapy 
1. Spinal Metastases Volumes 
The international spine radiosurgery consortium anatomic classification (figure 1) will be used. 
 
Figure 1 Anatomical Classification used by International Spine Radiosurgery Consortium (from 
Cox et al[97]) 
Underlying principles from the consensus guidelines[97] is shown in table 1 
 
GTV Involvement 
CTV Description 
Any portion of the vertebral body 
Include the entire vertebral body 
Lateralised within the vertebral body Include the entire vertebral body and the 
ipsilateral pedicle/transverse process 
Diffusely involves the vertebral body 
Include the entire vertebral body and the 
bilateral pedicles/transverse processes 
GTV involves vertebral body and 
unilateral pedicle 
Include entire vertebral body, pedicle, 
ipsilateral transverse process, and ipsilateral 
lamina 
GTV involves vertebral body and 
bilateral 
pedicles/transverse 
processes 
Include entire vertebral body, bilateral 
pedicles/transverse processes, and bilateral 
laminae 
GTV involves unilateral pedicle 
Include pedicle, ipsilateral transverse process, 
and ipsilateral lamina ± vertebral body 
GTV involves unilateral lamina 
Include lamina, ipsilateral pedicle/transverse 
process, and spinous process 
GTV involves spinous process 
Include entire spinous process and bilateral 
laminae 
 
In summary for spinal SABR the international guidelines[97] for contouring GTV, CTV and PTV 
in spinal radiosurgery are: 
GTV: 
- Contour gross tumour using all available imaging 
 
- Including epidural and paraspinal components of tumour 
 
CTV: 
- Include abnormal marrow signal suspicious for microscopic spread 
 
- Include bony CTV expansion to account for subclinical spread 
 
- Should contain GTV 
- Circumferential CTVs encircling the cord should be avoided except in rare  
   instances 
where the vertebral body, bilateral pedicles/lamina, and spinous process are all involved or 


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when there is extensive metastatic disease along the circumference of the epidural space 
without spinal cord compression. 
 
 
PTV:  - Uniform expansion around the CTV 
 
- CTV to PTV margin 2mm 
- Modified at dural margin and adjacent critical structures to allow spacing at  
   discretion 
of the treating physician unless GTV compromised 
 
- Never overlaps with cord 
 
- Should contain entire GTV and CTV 
 
Pictorial Representations of Spinal Target Volumes 
To follow consensus clinical target volume contours for spinal stereotactic radiosurgery [97]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Organ at Risk – Brachial Plexus Contouring 
BRACHIAL PLEXUS (C5-T1)*  (FROM TROG 09.02 CHISEL) 
1. Identify the T1 vertebral body – T1 nerve root (fig 2) is inferior to the neck of first rib, 
at the lower half of T1 vertebral border, and C8 nerve root (fig 1) is cranial to the neck 
of first rib, at C7/T1 level 
2. C7, C6 and C5 nerve roots can be found alongside the upper part of their respective 
vertebral bodies, but can be difficult to identify 
3. Identify Scalenus Anterior and Scalenus Medius 
a. The trunks of brachial plexus run between Scalenus Anterior and Scalenus