Clinical trial NCT03287050
Conditions: Urothelial Carcinoma
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2018-01-24; Completion date: 2020-11-10
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a feasibility trial of anti-PDL1/PD1 (pembrolizumab) and stereotactic body radiation therapy (SBRT) in patients with advanced, platinum-refractory urothelial carcinoma.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Pembrolizumab intervention 2: SBRT
Intervention descriptions: intervention 1: 200 mg IV q 21 days intervention 2: Stereotactic body radiation therapy (SBRT) that will commence not later than the initiation of the second cycle of pembrolizumab. SBRT dose and fractionation will be at the discretion of the treating radiation oncologist, and will be selected to respect the normal tissue tolerance of adjacent organs at risk.

Protocol documents:
Prot_SAP_000.pdf: 
UMCC 2017.069 
FAST: Feasibility trial of Anti-PD(L)1 and SBRT in the Treatment of Advanced, Platinum-Refractory 
Urothelial Carcinoma 
Principal Investigator: 
Zachery Reichert, MD, PhD 
University of Michigan 
Internal Medicine/Hematology-Oncology 
Phone 
Email: 
Sub-Investigator(s): 
David Smith, MD 
University of Michigan 
Internal Medicine/Hematology-Oncology 
Email: 
Phillip Palmbos, MD, PhD 
University of Michigan 
Internal Medicine/Hematology-Oncology 
Email: 
Megan Caram, MD 
University of Michigan 
Internal Medicine/Hematology-Oncology 
Email: 
Sarah Yentz, MD 
University of Michigan 
Internal Medicine/Hematology-Oncology 
Email: 
Ajjai Alva, MD       
University of Michigan 
Internal Medicine/Hematology-Oncology 
Email: 
Ulka Vaishampayan, MD 
University of Michigan 
Internal Medicine/Hematology-Oncology 
Email: 
Daniel Spratt, MD 
University of Michigan 
Radiation-Oncology 
Email: 
Jason Hearn MD 
University of Michigan 
Radiation-Oncology 
Email: 
NCT03287050


 
Arul Chinnaiyan MD, PhD 
University of Michigan 
Director, Michigan Center for Translational Pathology 
Professor of Pathology and Urology 
 
 
Phone 
 
 
 
Biostatistician: 
Ryan Ross, MS              
University of Michigan 
Biostatistics Department 
 
Phone 
 
Email: 
 
 
 
Study Drug: 
Pembrolizumab (Keytruda ®) 
 
 
 
Initial version: 
August 18, 2017 
Amendment: 
December 19, 2017 
February 14, 2018 
 
 
 
 
    October 5, 2020 
 
 


1 
 
TABLE OF CONTENTS 
ABBREVIATIONS 
4 
STUDY SCHEMA 
5 
STUDY SYNOPSIS 
5 
1.0 
BACKGROUND AND RATIONALE 
8 
1.1 
Disease Background 
8 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
8 
1.3 
Rationale 
9 
1.4 
Correlative Studies 
10 
2.0 
STUDY OBJECTIVES 
11 
2.1 
Primary Objectives 
11 
2.2 
Secondary Objectives 
11 
2.3 
Correlative Objectives 
11 
2.4 
Endpoints 
11 
3.0 
PATIENT ELIGIBILITY 
12 
3.1 
Inclusion Criteria 
12 
3.2 
Exclusion Criteria 
12 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
13 
5.0 
TREATMENT PLAN 
13 
5.1 
Treatment Dosage and Administration 
13 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
13 
5.3 
SBRT 
20 
5.4 
Concomitant Medications/Treatments 
23 
5.5 
Other Modalities or Procedures 
24 
5.6 
Duration of Therapy 
24 
5.7 
Off Treatment Criteria 
24 
5.8 
Duration of Follow-Up 
24 


2 
 
5.9 
Off Study Criteria 
24 
5.10 
Patient Replacement 
25 
6.0 
STUDY PROCEDURES 
25 
6.1 
Follow-Up Procedures 
25 
6.2 
Time and Events Table 
25 
7.0 
MEASUREMENT OF EFFECT 
27 
7.1 
Antitumor Effect- Solid Tumors 
27 
7.2 
Immune Related Response Criteria 
31 
7.3 
Safety/Tolerability 
34 
8.0 
ADVERSE EVENTS 
34 
8.1 
Adverse Event Reporting Requirements 
34 
8.2 
Definitions 
35 
8.3 
Adverse Event Characteristics 
36 
8.4 
Serious Adverse Event Reporting Guidelines 
37 
8.5 
Routine Reporting 
37 
8.6 
Reporting of Unanticipated Problems 
37 
9.0 
DRUG INFORMATION 
38 
9.1 
Pembrolizumab 
38 
10.0 CORRELATIVES/SPECIAL STUDIES 
39 
10.1 
Sample Collection Guidelines 
39 
10.2 
Specimen Banking 
40 
11.0 
STATISTICAL CONSIDERATIONS 
40 
11.1 
Study Design/Study Endpoints/ Sample Size & Accrual 
40 
11.2 
Data Analyses Plans 
41 
12.0   DATA AND SAFETY MONITORING 
41 
13.0 
REFERENCES 
42 


3 
 
ABBREVIATIONS 
 
 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
Anti-PD(L)1 
Anti-Programmed Death (Ligand) 1 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSU 
Clinical Trials Support Unit 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
PRC 
Protocol Review Committee 
SAE 
Serious Adverse Event 
SBRT 
Stereotactic Body Radiation Therapy 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
UaP 
Unanticipated Problem 
UMCCC 
University of Michigan Comprehensive Cancer Center 
WBC 
White Blood Cells 


4 
 
STUDY SCHEMA 
 
 
 
 
Figure 1: Study Schema. Abbreviations: Anti-PD(L)1=Pembrolizumab in this trial, Anti-PD(L1) Cycle Length= 
3 weeks *Imaging will occur at week 12 +/- 7 days 
 
 
 
STUDY SYNOPSIS 
 
Title 
FAST: Feasibility trial of Anti-PD(L)1 and SBRT in the Treatment of 
Advanced, Platinum-Refractory Urothelial Carcinoma 
Phase 
Feasibility 
Methodology 
Single Arm 
Study Duration 
12 months treatment, up to 24 months follow-up 
Study Center(s) 
University of Michigan 
Objectives 
Primary Objective 
To assess the feasibility of treating patients with sequential 
pembrolizumab and SBRT in patients with metastatic urothelial 
carcinoma who have progressed on platinum based chemotherapy 
Secondary Objectives 
1) 
To determine the safety of the combination of SBRT and 
pembrolizumab in patients with platinum-refractory metastatic 
urothelial carcinoma 
2) 
To determine the anti-tumor efficacy of the combination of SBRT and 
pembrolizumab in patients with platinum-refractory metastatic 
urothelial carcinoma 
Exploratory Correlative Objectives 
1. 
To determine PD-L1 expression on tumor cells and tumor immune 
infiltrating cells in archival tumor specimens and correlate these 
findings with clinical outcomes 
2. 
To evaluate the tumor mutational profile and burden by tissue 
based next generation sequencing (MI-Oncoseq) of fresh and/or 
archival tissue and correlate with clinical outcomes 
3. 
To evaluate the tumor immune infiltrate of tumor tissue by gene 
expression profiling using CIBERSORT/TIMER and correlate 
these findings with clinical outcome 
Number of Subjects 
20 
SBRT and Anti-PD(L)1 Schedule 
 
 
 
 
 
 
 
 
 
 
 
 


5 
 
Inclusion Criteria 
1. Subjects must have a histologic diagnosis of urothelial 
carcinoma. 
2. Subjects must have radiologic evidence of metastatic disease 
with measurable disease by RECIST 1.1 criteria other than the 
target lesion(s) for SBRT. 
3. Subjects must have at least 1 metastatic lesion previously not 
radiated that is amenable to SBRT per treating radiation 
oncologist. 
4. Subjects must have had progression of disease within 12 months 
of platinum-containing chemotherapy (chemotherapy could have 
been given in the neoadjuvant, adjuvant or metastatic setting) for 
urothelial cancer 
5. ECOG performance status of 0 to 2. 
6. Absolute neutrophil count of ≥ 1000/mm3, platelet count ≥ 
100,000/mm3, hemoglobin ≥ 8.0 g/dl; total bilirubin/ALT/AST < 
2.5 x upper limit of normal (patients with known gilbert disease 
who have serum bilirubin ≤3x ULN may be enrolled); serum 
creatinine <3.0mg/dl or if elevated, a calculated estimated 
glomerular filtration rate (eGFR) of ≥30 mL/min/1.73 m2 
7. Subjects must have recovered to baseline or ≤ grade 1 CTCAE v 
4.03 from toxicities related to any prior treatments unless AE(s) 
are clinically non-significant and/or stable on supportive therapy 
8. Patients must be ≥ 2 weeks from most recent systemic therapy or 
most recent radiation therapy. 
9. Women of childbearing potential must have a negative serum or 
urine pregnancy test within 28 days prior to registration. Women 
of non-childbearing potential are defined as those who have no 
uterus, ligation of the fallopian tubes, are naturally 
postmenopausal for at least 12 consecutive months or have 
undergone surgical removal of the ovaries 
10. Age ≥ 18 years 
Key Exclusion Criteria 
1. Prior treatment with anti-PD-1/PD-L1 and anti-CTLA-4 is NOT 
allowed. Prior intravesical BCG therapy is allowed. 
2. Treatment with any investigational agent or on an 
interventional clinical trial within 30 days prior to treatment on 
protocol 
3. No prior or concurrent malignancy is allowed except for: 
adequately treated basal cell or squamous cell skin cancer, in 
situ cervical cancer, localized or locally advanced prostate 
cancer definitively treated without recurrence or with 
biochemical recurrence only, or any other cancer fully treated 
or from which the subject has been disease-free for at least 2 
years. 
4. Autoimmune diseases such as rheumatoid arthritis are NOT 
allowed. Vitiligo, mild psoriasis (topical therapy only) or 
hypothyroidism are allowed. 
5. Need for systemic corticosteroids > 10mg prednisone daily or 
equivalent alternative steroid (except physiologic dose for 
adrenal replacement therapy) or other immunosuppressive 
agents (such as cyclosporine or methotrexate). Use of topical 
and inhaled corticosteroids is permitted. 
6. Any history of organ allografts 
7. Any history of HIV or hepatitis B infection 
8. Known brain metastases 
Study Product(s), Dose, 
Route, Regimen 
• 
Pembrolizumab 200 mg IV q 21 days 
• 
Stereotactic body radiation therapy (SBRT) that will commence 
not later than the initiation of the second cycle of pembrolizumab. 
SBRT dose and fractionation will be at the discretion of the 
treating radiation oncologist, and will be selected to respect the 


6 
 
normal tissue tolerance of adjacent organs at risk. The minimum 
dose will be 8 Gy for a 3-fraction course, or 6 Gy for a 5-fraction 
course. 
Duration of Administration 
• 
Patients will continue pembrolizumab until progression, toxicity, 
or a total of 17 cycles, whichever comes first 
• 
Patients will receive one course of SBRT on protocol. Further 
courses if clinically indicated are at discretion of treating physician 
Reference Therapy 
Pembrolizumab Monotherapy 
Statistical Methodology 
The primary aim of this study is to determine the feasibility of treating 
patients with metastatic urothelial carcinoma who have progressed after 
platinum based chemotherapy with sequential pembrolizumab and 
SBRT. Treatment success will be defined as completion of 4 cycles of 
pembrolizumab and at least one course of treatment of SBRT within 15 
weeks from first dose of pembrolizumab. The trial will define the 
combination treatment as feasible if 70% of the patients receive the 
treatment as defined. With 20 evaluable patients, if 14 out of 20 (70% 
[95% Confidence Interval: 50% - 90%]) achieve successful treatment 
then the trial will conclude that further evaluation of sequential 
pembrolizumab and SBRT should be explored. A patient is evaluable 
for feasibility if they receive at least one dose of pembrolizumab. 
Patients who achieve a complete response prior to SBRT are not 
evaluable for feasibility. Non-evaluable patients will be replaced. 


7 
 
1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background Disease Background 
 
Bladder cancer is the 4th most common malignancy in men [1]. While the majority of 
patients present with disease confined to the bladder, those who develop metastatic 
disease have a poor prognosis with an average overall survival of 15 months [2]. 
Regrettably, this statistic has not significantly changed over the past 15 years and the 5 
year overall survival of patients with metastatic disease remains only 15% [3]. The 
current standard of care for metastatic urothelial carcinoma is a platinum containing 
chemotherapy regimen. Inevitably, most patients progress despite adequate 
chemotherapy. 
 
Since 2016, several new drugs including pembrolizumab have been approved for the 
treatment of metastatic platinum refractory urothelial carcinoma (PRUC). Pembrolizumab 
works by inhibiting the interaction of programmed death ligand-1 (PD-L1) with its 
receptor, programmed death protein 1 (PD-1). By inhibiting this interaction, 
pembrolizumab may allow T cells to attack the tumor. Unfortunately, pembrolizumab only 
benefits a subset of patients as evidenced by the overall response rate of only 21% [4]. 
Given the potential for prolonged responses with immunotherapy, there is an urgent 
unmet clinical need for combination therapies that increase the response rate to 
immunotherapy. 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
Pembrolizumab 
Pembrolizumab is a monoclonal antibody designed to bind to PD-1. Pembrolizumab 
received accelerated approval for the treatment of platinum refractory urothelial 
carcinoma as a result of findings from KEYNOTE-045, a multicenter, randomized trial in 
patients with locally advanced or metastatic urothelial carcinoma with disease 
progression on or after platinum-containing chemotherapy. Patients were randomly 
assigned (1:1) to receive either pembrolizumab 200 mg every 3 weeks (n=270) or 
investigator’s choice of a chemotherapy regimen (paclitaxel [n=84], docetaxel [n=84], or 
vinflunine [n=87]) every 3 weeks (n=272). The trial demonstrated statistically significant 
improvements in overall survival (OS) and objective response rate (ORR) for patients 
assigned to pembrolizumab as compared to chemotherapy. Median OS was 10.3 and 7.4 
months in the pembrolizumab and chemotherapy arms, respectively (HR 0.73; 95% CI: 
0.59, 0.91, p=0.004). ORR was 21% for pembrolizumab and 11% for chemotherapy 
(p=0.002). No statistically significant difference in progression-free survival between the 
two arms was observed [4]. 
 
 
Stereotactic Body Radiation Therapy (SBRT) 
 
The addition of radiation to immunotherapy has shown promise in the pre-clinical setting. 
Radiation has long been known to be tumoricidal by inducing local DNA breaks. Recent 
research has shown that radiation affects the tumor immune microenvironment as well. In 
the pre-clinical setting, radiation has been shown to decrease the frequency of 
immunosuppressive myeloid derived suppressor cells (MDSCs) [5] and lead to an 
increased frequency of CD8 positive T cells in both the tumor and tumor draining lymph 
nodes [6]. 
 
Additionally, the way in which radiation is delivered has differential effects on the immune 
system. For example, some studies have shown that low dose conventional fractionated 
therapy (as compared to ablative, hypofractionated therapy) is in part 
immunosuppressive by continuously killing off effector T cells alongside tumor cells [7]. 
Despite these beneficial immuno-modulating effects, radiation has some 
immunosuppressive effects as well. Radiation has been shown to increase the number of 


8 
 
immunosuppressive T-regulatory (Treg) cells in the tumor immune infiltrate [8] as well 
activate the immunosuppressive cytokine TGFβ [9]. While the overall effect of radiation is 
felt to be immune-stimulatory, radiation alone typically does not induce a potent enough 
immune response to incite systemic tumor responses. However, if combined with a 
systemic therapy such as anti-PD1 checkpoint immunotherapy, the radiation-induced 
immune effects have the potential to be synergistic and robust. 
 
1.3 
Rationale 
 
Several pre-clinical studies have analyzed the impact of combining radiation and 
checkpoint inhibitors. In a study by Deng et al, the addition of an anti-PDL1 antibody led 
to a 15 fold reduction in intra-tumoral MDSCs as compared to radiation alone [5]. This 
local reduction in MDSCs was associated with enhanced tumor growth delay and tumor 
regression. In another study, radiation was combined with an anti-CTLA4 
immunotherapeutic agent and given at various time intervals. Mice who received the anti- 
CTLA4 drug prior to radiation had significantly more tumor regression than those who 
received the anti-CTLA4 drug after radiation [10], suggesting an ongoing immune- 
facilitatory milieu enhances radiation’s impact. 
 
In addition to focal immune effects at the site of the irradiated tumor lesion, radiation can 
lead to a decrease in size of distant tumor lesions as well, presumably via an immune 
mediated mechanism, sometimes known as the abscopal effect. The abscopal effect is a 
phenomenon wherein local therapy is associated with the regression of metastatic cancer 
at a distance from the site treated with local therapy (See Figure 2). One hypothesis is 
that the local therapeutic effect is amplified by a body-wide immune response. This effect 
was demonstrated in work by Demaria et al in which mice treated with local radiation and 
a CTLA-4 antibody had a reduction in distant lung metastases and an improved overall 
survival as compared with mice treated with the CTLA-4 antibody or radiation alone. [11]. 
The abscopal effect has also been well documented in humans [12]. 
 
 
Figure 2: Representation of presumed mechanism of the abscopal effect [13]. 
Abbreviations: DC, dendritic cell; HLA: human leukocyte antigen; MHC: major 
histocompatibility complex; RT: radiation therapy; TCR: T cell receptor; Th: T helper 
 
Pre-clinical studies have clearly demonstrated a benefit to the combination of radiation 
and immunotherapy. However, the mechanism by which this combination is immune- 
stimulatory has not been fully elucidated. The prevalent basic hypothesis is that radiation 
leads to increased tumor antigen release translating to a stronger immune reaction when 
subsequently treated with immunotherapeutic drugs. While this is a plausible hypothesis, 


9 
 
it has not been extensively evaluated in patients treated with new immunotherapies and 
new forms of radiation such as stereotactic body radiation therapy (SBRT). In a small 
phase one study, the combination of Interleukin-2 (IL-2) and SBRT led to a substantially 
improved response rate compared to historical controls in patients with melanoma and 
kidney cancer [14]. Case reports have shown similar responses with newer 
immunotherapy drugs such as ipilimumab, an anti-CTLA4 drug [12]. Given these 
encouraging results, the concept of combining SBRT with immunotherapy warrants 
further evaluation with newer immunotherapeutics such as pembrolizumab that are more 
widely applicable than IL-2. 
 
We propose a single-center feasibility trial to study the combination of SBRT with 
pembrolizumab in patients with metastatic urothelial carcinoma who have progressed on 
or within 12 months of platinum based chemotherapy. One dose of pembrolizumab will 
be given followed by SBRT to at least 1 amenable lesion chosen at the discretion of the 
radiation oncologist. This will be followed by three further cycles of pembrolizumab before 
the patient is assessed radiographically. Subjects must have RECIST 1.1 measurable 
disease in addition to the lesion proposed to be treated with SBRT. 
 
1.4 
Correlative Studies 
 
Correlative studies comprehensively evaluating the tumor immune profile and mutational 
profile will be performed as described below. We plan to evaluate the following: 
 
1) Evaluation of PD-L1 expression on the tumor cells and tumor infiltrating 
lymphocytes and correlation of these levels with clinical response to treatment 
 
In the IMvigor 210 trial, PD-L1 expression on immune cells infiltrating tumor tissue did 
correlate with response. Twenty-six percent of patients whose tumor immune cells 
were highly positive by IHC responded whereas only 8% of patients whose tumor 
immune cells were PDL1 negative had a response. While displaying an important 
trend, PD-L1 expression is not a perfect biomarker, as evidenced by the fact that 2% 
of patients in the PD-L1 negative group had a complete response to atezolizumab 
[15]. 
 
2) Evaluate tumor mutational profile and burden by tissue based next generation 
sequencing (MI-Oncoseq) and correlate with clinical outcomes 
 
Recent studies have shown that tumor mutational burden may predict for response to 
checkpoint inhibitors with a higher mutational load corresponding to improved efficacy. 
[16], [17]. In addition, specific mutations may predict for improved responses to 
immunotherapy as evidenced by the improved survival seen in patients with mismatch 
repair deficient colon cancer treated with pembrolizumab [18]. We will co-consent 
subjects to the University of Michigan tumor sequencing protocol MI-Oncoseq. Fresh 
and/or archival tumor tissue and germline tissue will undergo genomic profiling. We 
will also offer patients an optional biopsy at progression to look for changes in the tumor 
genome. 
 
3) Evaluation of the tumor immune infiltrate by gene expression profiling 
(CIBERSORT)/TIMER) using RNASeq data 
 
While the tumor immune environment is often characterized by IHC analysis, it is also 
possible to evaluate the tumor immune environment with gene expression profiling. In 
a recent publication by Newman et al, they describe a technique called CIBERSORT 
(Cell-type Identification by Estimating Relative Subsets of RNA Transcripts) [19]. This 
is a technique that combines gene expression profiling with a complex computational 
method that can identify the relative fractions of immune cell subsets in tumor tissue. 
This technique correlated well with flow cytometry but has not been extensively 
evaluated clinically. It is possible this technique could be superior to standard 
evaluation by immunohistochemistry (IHC) due to the limited repertoire of phenotypic 


10 
 
markers used for classification of the immune infiltrate by IHC. As a subproject of 
OncoSeq analysis, we will analyze gene expression profiles using next generation 
sequencing based computational methods that accurately resolves relative fractions of 
various cell subsets using CIBERSORT/TIMER. We will obtain tumor tissue and 
explore an analysis of the tumor immune infiltrate by CIBERSORT. We will explore 
correlation between the CIBERSORT/TIMER data and clinical outcomes. 
 
 
 
2.0 STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Primary Objective 
1. To assess the feasibility of treating patients with sequential pembrolizumab and 
SBRT in patients with metastatic urothelial carcinoma who have progressed on 
platinum based chemotherapy 
 
2.2 
Secondary Objectives 
1. To determine the safety of the combination of SBRT and pembrolizumab in patients 
with platinum-refractory metastatic urothelial carcinoma. 
2. To determine the anti-tumor efficacy of the combination of SBRT and pembrolizumab 
in patients with platinum-refractory metastatic urothelial carcinoma. 
 
2.3 
Correlative Objectives 
1. To determine PD-L1 expression on tumor cells and tumor immune infiltrating cells in 
archival tumor specimens and correlate these findings with clinical outcomes 
2. To evaluate the tumor mutational profile and burden by tissue based next generation 
sequencing (MI-Oncoseq) of fresh and/or archival tissue and correlate with clinical 
outcomes. 
3. To evaluate the tumor immune infiltrate of tumor tissue by gene expression profiling 
using CIBERSORT/TIMER and correlate these findings with clinical outcome. 
2.4 
Endpoints 
Primary Endpoint 
1. Proportion of subjects who receive 4 doses of pembrolizumab and at least one session 
of treatment of SBRT within 15 weeks from the first dose of pembrolizumab. 
 
Secondary Endpoints 
1. Frequency and severity of Grade 3-5 drug-related adverse events graded by CTCAE 
v4.30. 
2. Overall response proportion (Best Overall Response) and Progression Free Survival 
by RECIST, and Immune Related Response Criteria. 


11 
 
3.0 PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled to the study. Study 
treatment may not begin until a subject is enrolled. 
 
3.1 
Inclusion Criteria 
 
3.1.1 
Subjects must have a histologic diagnosis of urothelial carcinoma 
3.1.2 
Subjects must have radiologic evidence of metastatic disease with measurable 
disease by RECIST 1.1 criteria other than the target lesion(s) for SBRT 
3.1.3 
Subjects must have at least 1 metastatic lesion previously not radiated that is 
amenable to SBRT per treating radiation oncologist. 
3.1.4 
Subjects must have had progression of disease within 12 months of platinum- 
containing chemotherapy (chemotherapy could have been given in the 
neoadjuvant, adjuvant or metastatic setting) for urothelial cancer 
3.1.5 
ECOG performance status of 0 to 2 
3.1.6 
Absolute neutrophil count of ≥ 1000/mm3, platelet count ≥ 100,000/mm3, 
hemoglobin ≥ 8.0 g/dl; total bilirubin/ALT/AST < 2.5 x upper limit of normal 
(patients with known gilbert disease who have serum bilirubin ≤3x ULN may be 
enrolled); serum creatinine <3.0mg/dl or if elevated, a calculated estimated 
glomerular filtration rate (eGFR) of ≥30 mL/min/1.73 m2 
3.1.7 
Subjects must have recovered to baseline or ≤ grade 1 CTCAE v 4.03 from 
toxicities related to any prior treatments unless AE(s) are clinically non-significant 
and/or stable on supportive therapy 
3.1.8 
Subjects must be ≥ 2 weeks from most recent systemic therapy or most recent 
radiation therapy 
3.1.9 
Women of childbearing potential must have a negative serum or urine pregnancy 
test within 28 days prior to registration. Women of non-childbearing potential are 
defined as those who have no uterus, ligation of the fallopian tubes, are naturally 
postmenopausal for at least 12 consecutive months or have undergone surgical 
removal of the ovaries. Women of childbearing potential should use highly 
effective contraception during treatment and for 6 months after the last dose of 
pembrolizumab 
3.1.10 Age ≥ 18 years 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Prior treatment with anti-PD-1/PD-L1 and anti-CTLA-4 is NOT allowed. Prior 
intravesical BCG therapy is allowed 
3.2.2 
Treatment with any investigational agent or on an interventional clinical trial 
within 30 days prior to registration. 
3.2.3 
No prior or concurrent malignancy is allowed except for: adequately treated basal 
cell or squamous cell skin cancer, in situ cervical cancer, localized or locally 
advanced prostate cancer definitively treated without recurrence or with 
biochemical recurrence only, or any other cancer fully treated or from which the 
subject has been disease-free for at least 2 years. 
3.2.4 
Autoimmune diseases such as rheumatoid arthritis are NOT allowed. Vitiligo, 
mild psoriasis (topical therapy only) or hypothyroidism are allowed 
3.2.5 
Need for systemic corticosteroids >10mg prednisone daily or equivalent 
alternative steroid (except physiologic dose for adrenal replacement therapy) or 
other immunosuppressive agents (such as cyclosporine or methotrexate) Topical 
and inhaled corticosteroids are allowed if medically needed 
3.2.6 
Any history of organ allografts 
3.2.7 
Any history of HIV or hepatitis B infection 
3.2.8 
Known brain metastases 
3.2.9 
Patients who are pregnant or breast feeding 
3.2.10 Patients with a history of thoracic radiation of dose > 30 Gy within the prior 26 
weeks 


12 
 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
After informed consent is obtained and PRIOR to the initiation of protocol therapy all patients 
satisfying the inclusion/exclusion criteria must have eligibility confirmed by the Oncology Clinical 
Trials Support Unit (OCTSU). The patient will not be considered registered and enrolled in the 
study until all information is confirmed by the OCTSU Data Manager. 
 
5.0 
TREATMENT PLAN 
 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within 14 business days of enrollment to the study. 
 
5.1.1 
Therapy will include pembrolizumab 200 mg IV starting on day 1 in 21 day 
cycles. Patients will receive 1 dose (cycle 1) of pembrolizumab and commence 
SBRT no later than initiation of cycle 2. 
 
5.1.2 
SBRT will be given to ≥ 1 metastatic lesion(s) deemed most appropriate for such 
therapy by the treating radiation oncologist. SBRT will be delivered in 3 or 5 
fractions with dose and fractionation selected to respect standard normal tissue 
dose constraints for adjacent organs at risk. See section 5.3 for further details. 
 
5.1.3 
The lesion to which SBRT is given will be identified after the patient receives 1 
dose of pembrolizumab 
 
5.1.3 
Patients will be treated with supportive care pre-medications as clinically 
indicated including anti-emetics. 
 
 
REGIMEN DESCRIPTION 
Agent 
Premedications 
Dose 
Route 
Schedule 
Cycle 
Length 
Pembrolizumab 
None mandated 
200 mg 
IV 
Once every 
21 days (+/- 3 
business 
days) 
SBRT 
None mandated 
3-5 fractions with 
dose and 
fractionation 
selected to respect 
standard normal 
tissue dose 
constraints for the 
relevant organs in 
the vicinity of the 
target lesion(s). 
n/a 
In cycle 1 any 
time after D1 
and will 
commence 
no later than 
initiation of 
cycle 2 
 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives one dose of pembrolizumab will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.4). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity. 
Dose modifications in strength are not permitted for pembrolizumab 
Dosing delays for Pembrolizumab: 
• 
No dose delays for pembrolizumab are needed for hematologic changes. 


13 
 
• 
With any grade 2 or higher non-hematologic toxicity deemed to be related to 
pembrolizumab, hold pembrolizumab and refer to section 5.2.1. If adverse event 
is not an event of interest and improves to grade 1 or better, pembrolizumab may 
be resumed. 
• 
If non-hematologic toxicity does not improve to grade 1 or better in 12 weeks 
from prior dose, discontinue pembrolizumab. 
 
5.2.1 
Events of interest for Pembrolizumab: 
 
Certain adverse events that are possibly immune mediated warrant special 
monitoring and management, and are outline below to guide investigators. 
 
 
5.2.1.1 Pulmonary: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat 
accordingly and continue protocol therapy. Evaluate with imaging and 
pulmonary consultation. 
 
 
Grade of pneumonitis 
(NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Radiographic Changes Only 
• 
Consider delay of 
pembrolizumab 
• 
Monitor for symptoms every 2- 
3 days 
• 
Consider pulmonary and 
infectious disease 
consultations 
• 
Re-image at least every 3 
weeks 
• 
If worsening, treat as 
grade 2, 3 or 4 
Grade 2 
Mild to moderate new symptoms 
• 
Delay pembrolizumab 
• 
Consult pulmonary and 
infectious disease 
• 
Monitor symptoms daily, 
consider hospitalization 
• 
1.0mg/kg/day 
methylprednisolone IV or oral 
equivalent 
• 
Consider bronchoscopy and/or 
lung biopsy 
• 
Re-image every 1-3 days 
• 
Consider prophylactic 
antibiotics while on 
steroids 
• 
If improves: 
• When symptoms return 
to near baseline, taper 
steroids over at least 
one month 
• When steroids are at 
10mg oral prednisone 
(or equivalent) or 
below, resume 
pembrolizumab 
• 
If not improving after 2 
weeks or worsening, treat 
as grade 3 or 4 
Grade 3 or 4 
Severe new symptoms and/or 
new or worsening hypoxia 
• 
Discontinue pembrolizumab 
• 
Hospitalize 
• 
Consult pulmonary and 
infectious disease 
• 
1-2mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• 
Add prophylactic antibiotics for 
opportunistic infections like 
PCP 
• 
Consider bronchoscopy and/or 
lung biopsy 
• 
If improves to baseline: 
• Taper steroids for at 
least 6 weeks 
• 
If not improving after 48 
hours or worsening 
• Add additional 
immunosuppressive 
agent(s) (e.g. 
infliximab, 
cyclophosphamide, 
intravenous 
immunoglobulin or 


14 
 
mycophenolate mofetil) 
 
5.2.1.2 Gastrointestinal: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat 
accordingly and continue protocol therapy. Opiates or narcotics may mask 
symptoms of perforation. Infliximab should not be used in case of 
perforation or sepsis. 
 
 
Grade of diarrhea/colitis 
(NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
• 
Diarrhea of less than 
4 stools per day over 
baseline 
or 
asymptomatic colitis 
• 
Continue pembrolizumab 
• 
Symptomatic treatment 
such as loperamide 
• 
Close monitoring for worsening 
symptoms 
• 
Educate patient to report 
worsening immediately 
• 
If worsening, treat as grade 2,3 or 
4 
Grade 2 
• 
Diarrhea of 4-6 
stools per day over 
baseline 
OR 
• 
IV fluids needed < 
24 hours due to 
diarrhea 
OR 
• 
Colitis with 
abdominal pain or 
blood in stool 
• 
Delay pembrolizumab 
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg/day prednisone or 
equivalent followed by a 
taper) 
• 
Consider prophylactic 
antibiotics for opportunistic 
infections like PCP if 
steroid treatment 
prolonged 
• 
• 
If improves to grade 1, resume 
pembrolizumab 
• 
Resume pembrolizumab if the 
event improves to grade 0 or 1 
within 12 weeks and 
corticosteroids have been 
reduced to the equivalent of ≤ 
10mg oral prednisone per day 
• 
When symptoms improve to 
grade 1, taper steroids over at 
least one month 
• 
If worsening, treat as grade 3 or 4 
Grade 3 
• 
Diarrhea ≥ 7 stools 
per day over 
baseline 
OR 
• 
IV fluids needed for 
≥ 24 hours due to 
diarrhea 
OR 
• 
Colitis with severe 
abdominal pain or 
medical intervention 
indicated 
• 
Delay pembrolizumab 
• 
1-2mg/kg/day 
methylprednisolone IV or 
IV equivalent 
• 
Start prophylactic 
antibiotics for opportunistic 
infections such as PCP 
• 
Consider lower endoscopy 
• 
If improves 
• 
Continue steroids until 
symptoms are grade 1, then 
taper over at least one month 
• 
Resume pembrolizumab if the 
event improves to grade 0 or 1 
within 12 weeks and 
corticosteroids have been 
reduced to the equivalent of ≤ 
10mg oral prednisone per day 
• 
If persists for >3-5 days or recurs 
after improvement, add infliximab 
5mg/kg if no contraindication 
(Note: infliximab should not be 
used in cases of perforation or 
sepsis) 
Grade 4 
Life threatening or 
perforation 
• 
Discontinue 
pembrolizumab 
• 
1-2mg/kg/day 
methylprednisolone IV or 
IV equivalent 
• 
Start prophylactic 
antibiotics for opportunistic 
infections such as PCP 
• 
Consider lower endoscopy 
• 
If improves 
• 
Continue steroids until 
symptoms are grade 1, then 
taper over at least one month 
• 
If persists for >3-5 days or recurs 
after improvement, add infliximab 
5mg/kg if no contraindication 
(Note: infliximab should not be 
used in cases of perforation or 
sepsis) 


15 
 
5.2.1.3 Endocrinopathy: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat 
accordingly and continue protocol therapy. Consider visual field testing, 
endocrinology consultation and imaging. 
 
Endocrinopathy 
Management 
Follow-up 
Asymptomatic thyroid- 
stimulating hormone (TSH) 
elevation 
• 
Continue pembrolizumab 
• 
If TSH <0.5 x LLN or TSH 
>2x ULN, or consistently out 
of range in subsequent 
measurements, include free 
T4 in subsequent 
measurements as clinically 
indicated 
• 
Consider endocrinology 
consult 
Symptomatic Hypothyroidism 
• 
Initiate thyroid replacement 
Symptomatic 
Hyperthyroidism 
• 
Delay pembrolizumab 
• 
Consider endocrinology 
consult 
• 
Initiate anti-thyroid drug 
• Resume pembrolizumab when 
symptoms of hyperthyroidism 
are controlled and thyroid 
function is improving 
Hypophysitis 
• 
Administer corticosteroids 
and hormone replacement 
as clinically indicated 
• 
Delay pembrolizumab for 
grade 2 or 3 hypophysitis 
• 
Permanently discontinue 
pembrolizumab for grade 4 
hypophysitis 
Symptomatic Adrenal 
Insufficiency 
• 
Delay pembrolizumab 
• 
Administer 
methylprednisolone 1-2 
mg/kg/day IV followed by 
oral prednisone 1-2mg/kg 
per day or equivalent once 
symptoms improve 
• 
Add prophylactic antibiotics 
for opportunistic infections 
• 
If improves to ≤ grade 1, taper 
steroids over at least one month 
• 
Resume pembrolizumab if the 
event improves to grade 0 or 1 
within 12 weeks and 
corticosteroids have been 
reduced to the equivalent of ≤10 
mg oral prednisone per day and 
the patient is on stable 
replacement therapy if required 
 
5.2.1.4 Hepatic: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat 
accordingly and continue protocol therapy. Consider imaging for 
obstruction. 
 
Grade of Liver Test 
Elevation 
(NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
AST or ALT >ULN to 3x 
ULN and/or total bilirubin 
>ULN to 1.5x ULN 
• 
Continue 
pembrolizumab 
• Continue liver function test monitoring 
per protocol 
• If worsening, treat as grade 2,3, or 4 
Grade 2 
AST or ALT >ULN to 3-5x 
ULN and/or total bilirubin 
>ULN to 1.5-3x ULN 
• 
Delay pembrolizumab 
• 
Administer 
corticosteroids at a dose 
of 1-2mg/kg/day oral 
prednisone 
• Resume pembrolizumab if returns to 
baseline 
• If persists >5-7 days or worsens, treat 
as grade 3 or 4 


16 
 
Grade 3 or 4 
AST or ALT >5x ULN 
and/or total bilirubin >3x 
ULN 
• 
Discontinue 
pembrolizumab 
• 
Increase frequency of 
monitoring to every 1-2 
days 
• 
1-2mg/kg/day 
methylprednisolone IV 
or IV equivalent for 
grade 3 and 2 
mg/kg/day 
methylprednisolone IV 
for grade 4 
• 
Add prophylactic 
antibiotics for 
opportunistic infections 
like PCP 
• 
Consult 
gastroenterologist 
• If improves to grade 2, taper steroids 
over at least one month 
• If does not improve within 3-5 days or 
worsens after improvement: 
• 
Add mycophenolate mofetil 1g 
twice daily 
• 
If no response within an 
additional 3-5 days, consider 
other immunosuppressive 
agents per local guidelines 
 
5.2.1.5 Pancreatic: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat 
accordingly and continue protocol therapy. Consider imaging for 
obstruction. 
 
Grade of pancreatic 
toxicity 
(NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1-2 
Amylase or Lipase up 
to 2x ULN 
• 
Continue pembrolizumab 
Grade 2 or 3 
Pancreatitis or Grade 3 
serum amylase or 
lipase level (>2x ULN) 
• 
Delay or pembrolizumab 
• 
Treat with 1-2mg/kg IV 
methylprednisolone or 
equivalent per day 
• Once symptoms improve, follow with 1- 
2mg/kg of oral prednisone or equivalent 
per day 
• Resume pembrolizumab if 
amylase/lipase improves to ≤ grade 1 
within 12 weeks, symptoms of 
pancreatitis have resolved, and 
corticosteroids have been reduced to ≤ 
10 mg oral prednisone or equivalent per 
day 
Grade 4 or recurrent 
pancreatitis 
• 
Discontinue pembrolizumab 
• 
Treat with 1-2mg/kg IV 
methylprednisolone or 
equivalent per day 
• Once symptoms improve, follow with 1- 
2mg/kg of oral prednisone or equivalent 
per day and taper for ≥ 1 month 
 
5.2.1.6 Neurological: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat 
accordingly and continue protocol therapy. 
 
Grade of neurological 
toxicity 
(NCI CTCAE v 4.03) 
Management 
Follow-up 
Grade 1 
• 
Asymptomatic or 
mild symptoms 
• 
Intervention not 
indicated 
• 
Continue pembrolizumab 
• Continue to monitor the patient, if 
worsening treat as grade 2, 3, or 
4 


17 
 
Grade 2 
• 
Moderate symptoms 
• 
Limiting instrumental 
ADLs 
• 
Delay pembrolizumab 
• 
Treat symptoms per 
institutional guidelines 
• 
Consider 0.5-1mg/kg per 
day methylprednisolone IV 
or oral equivalent 
• 
If returns to baseline, resume 
pembrolizumab 
• 
If worsens, treat as grade 3 or 4 
Grade 3 or 4 
• 
Severe symptoms 
• 
Limiting self-care 
ADLs 
• 
Discontinue 
pembrolizumab 
• 
Consult Neurology 
• 
Treat symptoms per 
institutional guidelines 
• 
1-2mg/kg per day IV 
methylprednisolone or IV 
equivalent 
• 
Add prophylactic antibiotics 
for opportunistic infections 
• 
If improves to grade 2, taper 
steroids over at least one month 
• 
If worsens, consider IVIG or 
other immunosuppressive 
therapies per institutional 
guidelines 
Meningitis or Encephalitis 
• 
Discontinue 
pembrolizumab 
• 
1-2mg/kg 
per 
day 
IV 
methylprednisolone or IV 
equivalent 
• 
Add prophylactic antibiotics 
for opportunistic infections 
• 
If improves, convert to oral 
steroids (prednisone 60mg/day 
or equivalent) 
• 
When symptoms improve to ≤ 
grade 1, taper steroids over at 
least one month 
 
5.2.1.6 Skin: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat 
accordingly and continue protocol therapy 
 
Grade of Rash 
(NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1-2 
Covering ≤ 30% body 
surface area (BSA) 
• 
Symptomatic therapy 
(such as antihistamines, 
topical steroids) 
• 
Continue pembrolizumab 
• 
If persists 1-2 weeks or recurs 
• 
Consider skin biopsy 
• 
Delay pembrolizumab 
• 
Consider 0.5-1mg/kg/day 
methylprednisolone IV or oral 
equivalent 
• 
Once improving, taper steroids 
for at least one month 
• 
Consider prophylactic 
antibiotics for opportunistic 
infections like PCP 
• 
Resume pembrolizumab if rash 
improves to ≤ grade 1 within 12 
weeks and corticosteroids have 
been reduced to ≤ 10 mg oral 
prednisone or equivalent per 
day 
• 
If worsens, treat as grade 3 or 4 
Grade 3-4 
Covering >30% BSA or life 
threatening consequences 
• 
Delay or discontinue 
pembrolizumab 
• 
Consider skin biopsy 
• 
If patient is diagnosed 
with Stevens-Johnson 
Syndrome (SJS) or Toxic 
Epidermal Necrolysis 
(TEN), pembrolizumab 
must be discontinued 
• 
Consult dermatology 
• 
If improves to grade 1: 
• 
Taper steroids over at least 
one month 
• 
Resume pembrolizumab if 
rash improves to ≤ grade 1 
within 12 weeks and 
corticosteroids have been 
reduced to ≤ 10 mg oral 
prednisone or equivalent per 
day 


18 
 
• 
1-2mg/kg/day 
methylprednisolone IV or 
IV equivalent 
• 
Add prophylactic 
antibiotics for 
opportunistic infections 
 
5.2.1.7 Renal: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat 
accordingly and continue protocol therapy 
 
Grade of elevation in serum 
creatinine 
(NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Serum creatinine >ULN and 
>baseline but ≤1.5x baseline 
• Continue pembrolizumab 
• Monitor serum creatinine 
weekly 
• 
If returns to baseline, resume 
creatinine monitoring per protocol 
• 
If worsens, treat as grade 2, 3, or 
4 
Grade 2 or 3 
Serum creatinine 1.5x 
baseline to ≤ 6 x ULN 
• Delay or discontinue 
pembrolizumab 
• Monitor serum creatinine 
every 2-3 days 
• 0.5-1 mg/kg/day 
methylprednisolone IV or 
oral equivalent 
• Add prophylactic 
antibiotics for opportunistic 
infections 
• Consider renal biopsy 
• 
If improves to grade 1 
• Taper steroids over at least 
one month 
• Resume pembrolizumab if 
improves to ≤ grade 1 within 
12 weeks and 
corticosteroids have been 
reduced to ≤ 10 mg oral 
prednisone or equivalent per 
day 
• 
If elevation persists >7 days or 
worsens, treat as grade 4 
Grade 4 
Serum creatinine <6x ULN 
• Discontinue 
pembrolizumab 
• Monitor serum creatinine 
daily 
• 1-2mg/kg/day 
methylprednisolone IV or 
IV equivalent 
• Add prophylactic 
antibiotics for opportunistic 
infections 
• Consult nephrology 
• Consider renal biopsy 
• 
If improves to grade 1 
• Taper steroids over at least 
one month 
• Resume pembrolizumab if 
improves to ≤ grade 1 within 
12 weeks and 
corticosteroids have been 
reduced to ≤ 10 mg oral 
prednisone or equivalent per 
day 
 
5.2.1.8 Infusion Related Reactions 
Pembrolizumab can cause severe or life-threatening infusion-related reactions, 
including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) 
of 2799 patients receiving Pembrolizumab. 
 
Monitor patients for signs and symptoms of infusion-related reactions including 
rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and 
fever. 
 
For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, 
stop infusion and permanently discontinue pembrolizumab 


19 
 
5.3 
Stereotactic Body Radiotherapy 
Stereotactic body radiotherapy (SBRT) involves advanced planning and delivery 
techniques to administer ablative doses of radiation to a target in a small number of 
fractions (treatment sessions). This has radiobiologic advantages and has been shown 
to be safe in numerous settings. A high priority is placed on minimizing exposure to 
surrounding normal tissues. Patients on this protocol will receive between three and five 
fractions of treatment. The dose per fraction will be determined per standard clinical 
practice and will be dependent on the location of the treated site and the adjacent organs 
at risk. SBRT will commence no later than initiation of the second cycle of 
pembrolizumab. 
 
Both 3D-conformal radiotherapy and intensity-modulated radiotherapy (including 
volumetric arc radiotherapy [VMAT]) are acceptable planning techniques. Daily image 
guidance is required for this study. 
 
5.3.1 
Dose and Fractionation 
 
The 3-fraction regimen will employ a minimum fraction size of 8 Gy and the 5- 
fraction regimen will employ a minimum fraction size of 6 Gy. Dose and 
fractionation will be determined per standard clinical practice and will be 
dependent on the location of the treatment site and adjacent organs at risk (i.e. to 
respect normal tissue tolerances). 
 
Dose rate: For the purposes of this protocol, dose rate will be that which is 
commissioned by the manufacturer and the medical physics group for external 
beam radiotherapy delivery by the University of Michigan. There will be no 
special dose rate modifications required for this study. 
 
5.3.2 
Localization, Simulation, and Immobilization 
 
Patients will be immobilized in an appropriate position to isolate the target lesion 
and will then undergo CT-based treatment planning. The CT scan must capture 
the region of interest as well as surrounding organs at risk (OAR) with adequate 
margin for treatment planning. The CT scan should be obtained with a uniform 
slice thickness of less than or equal to 3 mm. The use of IV contrast is at the 
discretion of the treating physician. 
 
All lesions with the potential for respiratory motion should be evaluated by 
appropriate means, such as with a 4D-CT scan and/or implanted 
beacon(s)/marker(s). Respiratory motion management, including—but not 
limited to—methods such as breath hold, respiratory gating, and fiducial marker 
tracking, will be employed for applicable patients per standard clinical practice. 
 
Daily image guidance will be employed for target localization. Typically this will 
include volumetric imaging (cone-beam CT) when possible, as well as any 
additional techniques deemed helpful. 
 
5.3.3 
Target Volumes 
 
The gross tumor volume (GTV) is defined as all known gross disease 
corresponding to the selected lesion as visualized on the planning CT scan and 
aided by any additional relevant imaging studies (e.g. additional CT scans, 
PET/CT, MRI, etc.). The use of additional diagnostic imaging studies is 
dependent on the location of the lesion and is left to the discretion of the treating 
physician. An internal target volume (ITV) is defined for mobile lesions at the 
discretion of the treating physician. A 4D-CT scan will be acquired in order to 
account for the motion of the lesion if necessary. Breath hold techniques are 
also acceptable. For moving lesions, the ITV will be defined as the union of the 
visualized lesion on all gated CT datasets. 


20 
 
The clinical target volume (CTV) will equal the GTV/ITV with additional margin 
added to account for subclinical disease extension where appropriate as per 
standard practice. In the case of a lung metastasis, for example, the CTV would 
generally be equal to the GTV/ITV, whereas for a bone metastasis a margin may 
be added to account for disease that may extend further into the marrow than 
visible on imaging. 
 
The planning target volume (PTV) will be defined as per the convention for 
photon beam radiotherapy. A 3-dimensional margin will be created on the CTV to 
allow for daily set-up variation. 
 
5.3.4 
Normal Structures 
 
Organs at risk (OARs) in the vicinity of the target lesion will be delineated as 
visualized on the planning CT scan. When applicable, an expansion of 1-5 mm 
may be used to generate a planning organ-at-risk volume (PRV) to account for 
setup uncertainty and motion. 
 
5.3.5 
Treatment Planning 
 
Acceptable planning techniques include 3D-conformal radiotherapy and intensity- 
modulated radiotherapy (including volumetric arc radiotherapy [VMAT]). For 3D- 
conformal radiotherapy, static 3D coplanar and/or non-coplanar beam 
arrangements as well as dynamic conformal arcs are permitted. 
 
In the case of 3D coplanar or non-coplanar beam arrangements, these plans will 
be customized for each case to deliver highly conformal prescription dose 
distributions. Non-opposing, non-coplanar beams are frequently advantageous. 
Often, ≥ 7-10 beams of radiation will be used with roughly equal weighting. More 
beams are typically used for larger lesion sizes. When static beams are used, a 
minimum of 7 non-opposing beams is encouraged. For arc rotation techniques, a 
minimum of 340 degrees (cumulative for all beams) is encouraged. 
 
In order to obtain acceptable coverage for 3D conformal techniques, field 
aperture size and shape should generally correspond nearly identically to the 
projection of the PTV along a beam’s eye view (i.e., no additional “margin” for 
dose buildup at the edges of the blocks or MLC jaws beyond the PTV). An 
exception should be when observing the minimum field dimension when treating 
small lesions. As such, prescription lines covering the PTV will typically be the 
60-90% line for 3D conformal plans (where the maximum dose is 100%); 
however, higher isodoses (hotspots) must be manipulated to occur within the 
target and not in adjacent normal tissue. The treatment isocenter or setup point 
in stereotactic coordinates will be determined from system fiducials (and can be 
adjusted pre-treatment depending on the results from localization imaging 
studies) and translated to the treatment record. 
 
All dose calculations will include corrections for tissue heterogeneities as 
specified by IROC Houston. 
 
Maximum Dose: 
The treatment plan should be created such that the maximum point dose (to a 
volume of at least 0.03cc) is ≤130% of the prescription dose. This point must 
exist within the PTV. 
 
Prescription Isodose: 
This is variable, but for 3D conformal plans the prescription isodose surface will 
typically be 60-90% of the maximum dose. 
 
Prescription Isodose Surface Coverage: 


21 
 
The prescription isodose surface will, ideally, be chosen such that ≥95% of the 
target volume (PTV) is conformally covered by the prescription isodose surface 
(PTV V(Rx dose in Gy) ≥95%) and ≥99% of the PTV receives a minimum of 90% 
of the prescription dose (PTV V(90%Rx dose in Gy) ≥99%). Additionally, every 
effort should be made to ensure that 100% of the GTV/ITV should receive ≥100% 
of the Rx dose when possible. However, target coverage will be a priority 2 
planning goal, and will therefore be secondary to priority 1 goals for critical 
organs at risk. 
 
(i) 
High dose spillage: The cumulative volume of all tissue outside the PTV 
receiving a dose > 105% of prescription dose should be no more than 15% 
of the PTV volume. Conformality of PTV coverage will be judged such that 
the ratio of the volume of the prescription isodose to the volume of the PTV 
is ideally < 1.2. This may not be possible for very small tumors (< 2.5 cm 
axial CTV dimension or < 1.5 cm craniocaudal CTV dimension) due to the 
required minimum field size. 
(ii) 
Intermediate dose spillage: The falloff gradient beyond the PTV extending 
into normal tissue structures must be rapid in all directions and should 
ideally meet the following (suggested) criteria: 
 
Location: 
The maximum total dose over all fractions in Gray (Gy) to any 
point 2 cm or greater away from the PTV in any direction should 
be no greater than D2cm where D2cm is given by the table below. 
 
Volume: 
The ratio of the volume of the 50% isodose volume to the volume 
of the PTV (R50%) should meet the criteria in the table below if 
possible (adapted from RTOG 0915), although in some cases 
this may not be achievable. This table is used for all prescription 
requirements irrespective of calculation algorithm and total 
treatment dose. 
 
Critical Organ Doses: 
Ideal 
Good 
Ideal 
Good 
Ideal 
Good 


22 
 
Critical organ dose-volume limits with be those used in standard practice at the 
University of Michigan. 
 
Planning Priorities: 
Every attempt will be made to successfully satisfy all of the planning goals and 
OAR criteria. In some circumstances, it may not be possible to meet all the ideal 
criteria. In these cases, spinal cord, cauda equina, sacral plexus (when 
applicable), and brachial plexus dose constraints must be respected over PTV 
coverage. In the case of other OAR constraints, which are not well validated, 
PTV coverage and OAR constraints must be balanced per clinical practice at the 
discretion of the treating physician. 
 
 
5.4 
Concomitant Medications/Treatments 
 
Systemic corticosteroids greater than the equivalent of 10mg of prednisone or equivalent 
alternative steroid (except physiologic dose for adrenal replacement therapy) or other 
immunosuppressive agents (such as cyclosporine or methotrexate) and any other 
medications that could potentially impact the efficacy or safety of the study as judged by 
the treating investigator are NOT permitted from time of registration to subjects 
completing protocol therapy unless clinically indicated to manage adverse events or life 
threatening or serious conditions as determined by the treating investigator. 
Additional palliative radiation for pain, bleeding, airway compromise, or other needs is 
permitted. 
 
 
5.5 
Other Modalities or Procedures 
 
Pembrolizumab should be held for any surgery until subject is judged to be stable to 
resume by treating investigator as adequate information does not exist on its effects on 
wound healing. When resumed, same dose level will be maintained. Percutaneous 
procedures like imaging guided biopsies and central line placements do not require 
pembrolizumab to be held. 
 
 
5.6 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment will continue for 17 
cycles or until one of the following criteria apply: 
● 
Disease progression as defined in Section 7.0 
● 
Patients may continue on pembrolizumab beyond the first progression by imaging as 
long as investigator deemed clinical benefit continues 
● 
Inter-current illness that prevents further administration of treatment 
● 
Unacceptable adverse event(s) or death 
● 
Patient voluntarily withdraws from treatment 
● 
General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
 
5.7 
Off Treatment Criteria 
Patients will be removed from protocol therapy when any of the criteria listed in Section 
5.6 apply. Document in the source the reason for ending protocol therapy and the date 
the patient was removed from treatment. All patients who discontinue treatment should 
comply with protocol specific follow-up procedures as outlined in Section 5.8. The only 
exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 


23 
 
5.8 
Duration of Follow-Up 
Continued follow-up after end of treatment is for patients who discontinue study treatment 
for reasons other than progressive disease or death (such as patients who discontinue 
treatment due to toxicity) AND patients who continue on treatment past 17 cycles. These 
patients should continue to be followed by imaging every 12 weeks with standard of care 
CT chest, abdomen/pelvis until documentation of progressive disease, death, withdrawal 
of consent, or initiation of a new anti-cancer treatment for up to 2 years. 
 
5.9 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation from study will be documented and may 
include: 
 
• 
Patient withdraws consent (termination of treatment and follow-up); 
 
• 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
 
• 
Patient is unable to comply with protocol requirements; 
 
• 
Treating physician judge’s continuation on the study would not be in the patient’s 
best interest; 
 
• 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
 
• 
Development of second malignancy (except for basal cell carcinoma or squamous 
cell carcinoma of the skin) that requires treatment, which would interfere with this 
study; 
 
• 
Lost to Follow-up. If a research subject cannot be located to document progression 
free survival after a period of 2 years, the subject may be considered “lost to follow- 
up.” All attempts to contact the subject during the two years must be documented. 
 
• 
Termination of the study by The University of Michigan; 
 
• 
Patient completes protocol treatment and follow-up criteria. 
 
 
5.10 
Patient Replacement 
A patient is evaluable for feasibility and safety if they receive at least one dose of 
pembrolizumab. Patients who achieve a complete response prior to SBRT are not 
evaluable for feasibility. Non-evaluable patients will be replaced. 


24 
 
6.0 
STUDY PROCEDURES 
 
6.1 
Follow-Up Procedures 
Continued follow-up after end of treatment is for patients who discontinue study treatment 
for reasons other than progressive disease or death (such as patients who discontinue 
treatment due to toxicity) AND patients who continue on treatment past 17 cycles. These 
patients should continue to be followed by imaging every 12 weeks with standard of care 
CT chest, abdomen/pelvis until documentation of progressive disease, death, withdrawal 
of consent, or initiation of a new anti-cancer treatment for up to 2 years. 
 
6.2 
Time and Events Table 
All assessments have a window of ± 5 business days except for imaging/tumor 
measurements where a window of ± 7 business days will apply. 
 
Study Calendar 
 
Screening period 
(within 28 days) 
C1 
D1 1 
SBRT (will 
commence no later 
than initiation of 
cycle 2)3 
C2 
D1 
C3 
D1 
C4 
D1 
Week 
12 
C5 
D1 
Cycles per std 
frequency for drug 
Every 12 weeks 
End of Treatment 
Follow-up (every 
12weeks for up to 
24 months5 
Informed Consent for 
FAST 
X 
Informed Consent for 
MI-Oncoseq4 
X 
Archival Tissue 
identified 
X 
Serum and Plasma 
banking 
X2 
Optional Biopsy at 
Progression 
X 
History and Physical 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor 
Measurements 
X 
X 
X 
X 
Toxicity Evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
CBC 
with diff and 
platelet count 
X 
X 
X 
X 
X 
X 
X 
X 
Comp 
metabolic 
panel 
X 
X 
X 
X 
X 
X 
X 
X 
Amylase/Lipase 
X 
X 
X 
X 
TSH, free T3, free T4 
(IF clinically indicated: 
FSH, LH, ACTH) 
X 
X 
X 
X 
HIV, 
Hepatitis 
B 
Surface Antigen 
X 
Pregnancy test for 
WOCBP 
X 
CT Chest 
X 
X 
X 
X 


25 
 
CT or MRI 
Abdomen/Pelvis 
X 
X 
X 
X 
Pembrolizumab 
X 
X 
X 
X 
X 
X 
SBRT 
X 
 
1Cycles are 21 days in duration. 
2 Serum and plasma banking will be collected C1D1 prior to first dose 
3SBRT cannot overlap with C1D1 
4Optional 
5 Continue follow-up after end of treatment is for patients who discontinue study treatment for reasons other than 
progressive disease or death AND patients who continue on treatment past 17 cycles. These patients should continue 
to be followed by imaging every 12 weeks with standard of care CT chest, abdomen/pelvis until documentation of 
progressive disease, death, withdrawal of consent, or initiation of a new anti-cancer treatment for up to 2 years. 
 
 
7.0 
MEASUREMENT OF EFFECT 
 
7.1 
Antitumor Effect- Solid Tumors 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria. 
 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with study drug. 
 
Evaluable for objective response. Only those patients who have measurable 
disease present at baseline, have received at least 1 dose of pembrolizumab and 
have had their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the definitions 
stated below. (Note: Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
 
● 
10mm by CT scan (irrespective of scanner type) for studies with a slice 
thickness of <5mm or twice the slice thickness or MRI 
● 
10mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as 
non-measurable) 
● 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters) 
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 


26 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
CT scan), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organ, 
but in addition should be those that lend themselves to reproducible repeated 
measurements. 
 
Lymph nodes merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. Pathological 
nodes which are defined as measurable and may be identified as target lesions 
must meet the criterion of a short axis of ≥15mm by CT scan. Only the short axis 
of these nodes will contribute to the baseline sum. The short axis of the node is 
the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as 
being 20mm x 30mm has a short axis of 20mm and qualifies as a malignant, 
measurable node. In this example, 20mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 
mm) should be considered non-target lesions. Nodes that have a short axis 
<10mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum. The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required and these lesions should 
be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start and never more than 4 weeks before the 
beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging based evaluation should always be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial and >10mm diameter as assessed using calipers (e.g. skin 


27 
 
nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is suggested. As noted above, 
when lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, 
particularly in identifying new lesions. However, lesions on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated 
lung. 
 
CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5mm or less. When CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique 
and measurements will be taken from one assessment to the next. If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response or surgical resection is an 
endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they 
must normalize for a patient to be considered in complete response. Because 
tumor markers are disease specific, instructions for their measurement should be 
incorporated into protocols on a disease specific basis. Specific guidelines for 
both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer), have been published. In addition, the Gynecologic 
Cancer Intergroup has developed CA125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian 
cancer. 
 
Cytology, Histology: These techniques can be used to differentiate between PR 
and CR in rare cases if required by protocol (for example, residual lesions in 
tumor types such as germ cell tumors, where known residual benign tumors can 
remain). When effusions are known to be a potential adverse effect of treatment 
(e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable 
disease) and progressive disease. 


28 
 
Response Criteria 
 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions, plus a minimum 5 mm increase, taking as reference the 
smallest sum LD recorded since the treatment started, or the 
appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesion(s) and/or maintenance of tumor marker level above the 
normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions. 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The patient's best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
Target 
Lesions 
Non- 
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non- 
CR/SD 
No 
PR 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
Documented 
at least once 
>4 wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, 
PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 


29 
 
 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started. 
 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression or death, whichever occurs first. Patients 
without progression or death will be censored at the date of their last scan. 
 
7.2 
Immune Related Response Criteria 
As a secondary endpoint, this study will evaluate concordance of the Immune Related 
Response Criteria (irRC) with RECIST 1.1. These response criteria were developed to 
overcome the variable and unusual patterns of response to immunotherapeutic agents, in 
particular, ipilimumab. The development of the guidelines was prompted by observations, 
mostly in subjects with metastatic melanoma, of initial disease progression followed by 
later response, late responses, and mixed responses with an overall decrease in tumor 
burden. 
 
Antitumor response based on total measurable tumor burden 
For the irRC, only index and measurable new lesions are taken into account (in contrast 
to conventional WHO criteria, which do not require the measurement of new lesions, nor 
do they include new lesion measurements in the characterization of evolving tumor 
burden). At the baseline tumor assessment, the sum of the products of the two largest 
perpendicular diameters (SPD) of all index lesions (5 lesions per organ, up to 10 visceral 
lesions) is calculated. At each subsequent tumor assessment, the SPD of the index 
lesions and of new, measurable lesions (up to 5 new lesions per organ; 10 visceral 
lesions) are added together to provide the total tumor burden: 
 
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions 
Note: 
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of 
treatment. 


30 
 
Table: Comparison of WHO and irRC criteria 
WHO 
irRC 
New, 
measurable 
lesions 
Always represent PD 
Incorporated into tumor 
burden 
New, 
nonmeasurable 
lesions 
Always represent PD 
Do not define progression 
(but preclude irCR) 
Non-index 
lesions 
Changes contribute to defining 
BOR of CR, PR, SD, and PD 
Contribute to defining irCR 
(complete disappearance 
required) 
CR 
Disappearance of all lesions in two 
consecutive observations not less 
than 4 wk apart 
Disappearance of all lesions 
in two consecutive 
observations not less than 4 
wk apart 
PR 
≥50% decrease in SPD of all index 
lesions compared with baseline in 
two observations at 
least 4 wk apart, in absence of new 
lesions or unequivocal progression 
of non-index lesions 
≥50% decrease in tumor 
burden compared with 
baseline in two observations 
at least 4 wk apart 
SD 
50% decrease in SPD compared 
with baseline 
cannot be established nor 25% 
increase compared with nadir, in 
absence of new lesions or 
unequivocal progression of non- 
index lesions 
50% decrease in tumor 
burden compared with 
baseline cannot be 
established nor 
25% increase compared with 
nadir 
PD 
At least 25% increase in SPD 
compared with nadir and/or 
unequivocal progression of non- 
index lesions and/or appearance of 
new lesions (at any single time 
point) 
At least 25% increase in 
tumor burden compared with 
nadir (at any single time 
point) in two consecutive 
observations at least 4 wk 
apart 
 
Time-point response assessment using irRC 
Percentage changes in tumor burden per assessment time point describe the size and 
growth kinetics of both conventional and new, measurable lesions as they appear. At 
each tumor assessment, the response in index and new, measurable lesions is defined 
based on the change in tumor burden (after ruling out irPD). Decreases in tumor burden 
must be assessed relative to baseline measurements (i.e., the SPD of all index lesions at 
screening). The irRC were derived from WHO criteria and, therefore, the thresholds of 
response remain the same. However, the irRC response categories have been modified 
from those of WHO criteria. 
 
Overall response using the irRC 
The sum of the products of diameters at tumor assessment using the immune-related 
response criteria (irRC) for progressive disease incorporates the contribution of new 
measurable lesions. Each net Percentage Change in Tumor Burden per assessment 
using irRC criteria accounts for the size and growth kinetics of both old and new lesions 
as they appear. 
 
Definition of Index Lesions Response Using irRC 
• 
irComplete Response (irCR): Complete disappearance of all index lesions. 
This category encompasses exactly the same subjects as “CR” by the 
mWHO criteria. 
• 
irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater 
in the sum of the products of the 2 largest perpendicular diameters of all 


31 
 
index and all new measurable lesions (ie, Percentage Change in Tumor 
Burden). Note: the appearance of new measurable 
• 
irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the 
absence of progressive disease. 
• 
irProgressive Disease (irPD): At least 25% increase Percentage Change in 
Tumor Burden (i.e., taking sum of the products of all index lesions and any 
new lesions) when compared to SPD at nadir. 
 
Definition of Non-Index Lesions Response Using irRC 
• 
irComplete Response (irCR): Complete disappearance of all non-index 
lesions. This category encompasses exactly the same subjects as “CR” by 
the mWHO criteria. 
• 
irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) 
are not considered in the definition of PR, these terms do not apply. 
• 
irProgressive Disease (irPD): Increases in number or size of non-index 
lesion(s) does not constitute progressive disease unless/until the Percentage 
Change in Tumor Burden increases by 25% (i.e., the SPD at nadir of the 
index lesions increases by the required amount). 
 
Impact of New Lesions on irRC New lesions in and by themselves do not qualify as 
progressive disease. However, their contribution to total tumor burden is included in the 
SPD, which in turn feeds into the irRC criteria for tumor response. Therefore, new non- 
measurable lesions will not discontinue any subject from the study. 
 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria: 
• 
Immune-Related Complete Response (irCR): Complete disappearance of 
all tumor lesions (index and non-index together with no new 
measurable/unmeasurable lesions) for at least 4 weeks from the date of 
documentation of complete response. 
• 
Immune-Related Partial Response (irPR): The sum of the products of the 
two largest perpendicular diameters of all index lesions is measured and 
captured as the SPD baseline. At each subsequent tumor assessment, the 
sum of the products of the two largest perpendicular diameters of all index 
lesions and of new measurable lesions are added together to provide the 
Immune Response Sum of Product Diameters (irSPD). A decrease, relative 
to baseline of the irSPD compared to the previous SPD baseline, of 50% or 
greater is considered an immune Partial Response (irPR). 
• 
Immune-Related Stable Disease (irSD): irSD is defined as the failure to 
meet criteria for immune complete response or immune partial response, in 
the absence of progressive disease. 
• 
Immune-Related Progressive Disease (irPD): It is recommended in difficult 
cases to confirm PD by serial imaging. Any of the following will constitute 
progressive disease: 
o 
At least 25% increase in the sum of the products of all index lesions 
over nadir SPD calculated for the index lesions. 
o 
At least a 25% increase in the sum of the products of all index 
lesions and new measurable lesions (irSPD) over the baseline SPD 
calculated for the index lesions. 
• 
Immune-Related Best Overall Response Using irRC (irBOR) irBOR is the 
best confirmed irRC overall response over the study as a whole, recorded 
between the date of first dose until the last tumor assessment before 
subsequent therapy (except for local palliative radiotherapy for painful bone 
lesions) for the individual subject in the study. For the assessment of irBOR, 
all available assessments per subject are considered. irCR or irPR 
determinations included in the irBOR assessment must be confirmed by a 
second (confirmatory) evaluation meeting the criteria for response and 
performed no less than 4 weeks after the criteria for response are first met. 


32 
 
Derivation of irRC overall responses 
Measurable Response 
Nonmeasurable Response 
Overall 
Response 
Index and new, 
measurable lesions (tumor 
burden),*% 
Non-index lesions 
New, non- 
Measurable lesions 
Using irRC 
↓100 
Absent 
Absent 
irCR† 
↓100 
Stable 
Any 
irPR† 
↓100 
Unequivocal Progression 
Any 
irPR† 
↓≥50 
Any/Stable 
Any 
irPR† 
↓≥50 
Unequivocal Progression 
Any 
irPR† 
↓<50 to <25↑ 
Any/Stable 
Any 
irSD 
↓<50 to <25↑ 
Unequivocal Progression 
Any 
irSD 
25 
Any 
Any 
irPD† 
*Decreases assessed relative to baseline (scan prior to start of any protocol therapy), 
including measurable lesions only 
†Assuming response (irCR) and progression (irPD) are confirmed by a second, 
consecutive assessment at least 4 wk apart. 
 
7.3 
Safety/Tolerability 
 
Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 4.03 for reporting of non-hematologic 
adverse events (http://ctep.cancer.gov/reporting/ctc.html) and modified criteria for 
hematologic adverse events. 
 
 
8.0 
ADVERSE EVENTS 
 
8.1 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Data on adverse events will be collected from 
the time of the initial study treatment administration through 30 days after the last [dose 
of study treatment. Any serious adverse event that occurs more than [30] days after the 
last study treatment and is considered related to the study treatment must also be 
reported. Serious Adverse Events (SAEs) will continue to be followed until: 
● 
Resolution or the symptoms or signs that constitute the serious adverse 
event return to baseline; 
● 
There is satisfactory explanation other than the study treatment for the 
changes observed; or 
● 
Death. 
 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration is considered to be pre-existing in nature. Any known pre- 
existing conditions that are ongoing at time of study entry should be considered medical 
history. 
 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, 
occurring from the initial study treatment through 30 days following the last dose of the 
study treatment must be recorded as an adverse event in the patient’s source documents 
and on the CRF regardless of frequency, severity (grade) or assessed relationship to the 
study treatment. 


33 
 
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of 
a pre-existing condition that occurs after the patient begins study treatment is also 
considered an adverse event. 
8.2 
Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention. 
 
● 
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) 
procedures will not be reported as adverse events. However, the medical 
condition for which the procedure was performed must be reported if it meets 
the definition of an adverse event unless it is a pre-existing (prior to protocol 
treatment) condition. 
 
● 
Abnormal laboratory values or test results constitute adverse events if they 
induce clinical signs or symptoms or require therapy. They are to be captured 
under the signs, symptoms or diagnoses associated with them. 
 
Serious Adverse Event 
An adverse event is considered “serious” if, in the view of either the investigator it results 
in any of the following outcomes: 
 
• 
Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
• 
A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of either the 
investigator [or sponsor], its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event that, had it 
occurred in a more severe form, might have caused death. 
 
• 
Inpatient hospitalization or prolongation of existing hospitalization for > 24 
hours. 
 
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
• 
A congenital anomaly/birth defect 
• 
Important medical event 
Any event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition 
of “Serious Adverse Event”. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should not be 
reported as SAEs unless the underlying medical condition has worsened during the 


34 
 
course of the study. Preplanned hospitalizations or procedures for preexisting conditions 
that are already recorded in the patient’s medical history at the time of study enrollment 
should not be considered SAEs. Hospitalization or prolongation of hospitalization without 
a precipitating clinical AE (for example, for the administration of study therapy or other 
protocol-required procedure) should not be considered SAEs. However, if the preexisting 
condition worsened during the course of the study, it should be reported as an SAE. 
 
Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
● 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label). 
● 
For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochure. 
● 
In clinical research studies, information on expected adverse events is also 
summarized in the protocol and in the consent document. See section 9.1 
for the list of expected adverse events related to the drug under study. 
 
Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the Package 
Insert, Investigator’s Brochure, in published medical literature, in the protocol, or in the 
informed consent document. 
8.3 
Adverse Event Characteristics 
CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized 
for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.03. A copy of the CTCAE version 4.03 can be down loaded from the 
CTEP web site. (http://ctep.cancer.gov). 
 
Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment 
Probable – The AE is likely related to the study treatment 
Possible – The AE may be related to the study treatment 
Unlikely – The AE is doubtfully related to the study treatment 
Unrelated – The AE is clearly NOT related to the study treatment 


35 
 
8.4 
Serious Adverse Event Reporting Guidelines 
 
The Principal Investigator must be notified within 2 business day of study team’s 
knowledge of any event meeting the criteria and definition of a serious adverse event, 
regardless of attribution, occurring during the study or within 30 days of the last 
administration of the study related treatment. 
 
The investigator must report all events meeting the criteria and definition of a serious 
adverse event that are unexpected and possibly related (definite, probable or possible) to 
study treatment within 7 business days of study team’s knowledge if death or life 
threatening, and within 14 calendar days for all others. Events that meet the FDA 
reporting requirements will be reported to the FDA according to 21CFR312.32.if the study 
is conducted under an IND. 
 
All Serious Adverse Events that are unexpected and possibly related (definite, probable 
or possible) to study treatment administration will be reported to the IRB using the 
OCTSU Serious Adverse Event form. 
 
8.5 
Routine Reporting 
All other adverse events- such as those that are expected, or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data 
submission. 
 
8.6 
Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the conduct of 
human subjects research that represent unanticipated problems but are not considered 
adverse events. For example, some unanticipated problems involve social or economic 
harm instead of the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased risk of harm, 
but no harm occurs. 
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem, the investigator should assess 
whether the incident, experience, or outcome represents an unanticipated problem. The 
incident, experience or outcomes is considered unanticipated if it meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm 
than was previously known or recognized. 
 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB within 7 calendar days of 
the study team becoming aware of the problem. 


36 
 
9.0 
DRUG INFORMATION 
 
9.1 
Pembrolizumab (Keytruda®) 
• 
Other names for the drug: Keytruda® 
• 
Description: Injection: 100 mg/4 mL (25 mg/mL) solution in a single-dose vial 
• 
Classification: type of agent: Immunomodulatory; checkpoint inhibitor 
• 
Mode of action: Pembrolizumab is a monoclonal antibody that binds to PD-L1 and 
blocks its interactions with both PD-1 and B7.1 receptors. This releases the PD- 
L1/PD-1 mediated inhibition of the immune response, including activation of the anti- 
tumor immune response without inducing antibody dependent cellular cytotoxicity. 
 
• 
Pharmacokinetics: Based on a population analysis that included 2,841 patients in 
various dose range, the typical population clearance was 212 mL/day, volume of 
distribution at steady state was 6.1 L, and the terminal half-life was 23 days. The 
population PK analysis suggests steady state is obtained by 19 weeks with an every 
3-week regimen and the systemic accumulation was 2.2-fold. The systemic 
accumulation in area under the curve (AUC), maximum concentration (Cmax) and 
trough concentration (Cmin) of pembrolizumab increased dose proportionally in the 
dose range of 2 to 10 mg/kg every 3 weeks. 
 
• 
Side effects: Please see the package insert(s) for pembrolizumab. For the most 
recent safety update, please refer to the current package insert(s). 
 
• 
Drug Interactions Please see the package insert for pembrolizumab for information 
regarding drug interactions. 
 
• 
Contraindications: Please see the package insert for pembrolizumab for information 
regarding contraindications. 
 
• 
Special Warnings and Precautions for Use: Please see the package insert(s) for 
pembrolizumab for information regarding special warnings and precautions for use. 
 
• 
Storage and stability: Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in 
original carton to protect from light. This product does not contain a preservative. 
Administer immediately once prepared. If diluted pembrolizumab infusion solution is 
not used immediately, it can be stored either: 
 
o 
At room temperature for no more than 6 hours from the time of preparation. 
This includes room temperature storage of the infusion in the infusion bag and 
time for administration for infusion. 
 
o 
Under refrigeration at 2°C–8°C (36°F–46°F) for no more than 24 hours. Do not 
freeze. Do not shake. If refrigerated, allow the diluted solution to come to room 
temperature prior to administration. 
 
• 
Preparation and Dispensing: 
Visually inspect drug product for particulate matter and discoloration prior to 
administration whenever solution and container permit. Pembrolizumab is a colorless 
to slightly yellow solution. Discard the vial if the solution is cloudy, discolored, or 
visible particles are observed. Do not shake the vial. Prepare the solution for infusion 
as follows: Add 2.3 mL of Sterile Water to vial. Withdraw the required volume of 
pembrolizumab from the vial and transfer into an intravenous (IV) bag containing 
0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted 
solution by gentle inversion. Do not shake. The final concentration of the diluted 
solution should be between 1 mg/mL to 10 mg/mL. Discard partially used or empty 


37 
 
vials of pembrolizumab. 
 
• 
Administration: 
Administer the initial infusion over 30 minutes through an intravenous line with or 
without a sterile, non-pyrogenic, low-protein binding in-line filter (pore size of 0.2– 
0.22 micron). If the first infusion is tolerated, all subsequent infusions may be 
delivered over 30 minutes. Do not co-administer other drugs through the same 
intravenous line. 
 
• 
Availability: Commercially available through Merck & Co., Inc. Standard of care in 
metastatic platinum refractory urothelial carcinoma. 
 
 
10.0 
CORRELATIVES/SPECIAL STUDIES 
 
10.1 
Sample Collection Guidelines 
Tumor tissue should be identified prior to registration. An archived formalin-fixed paraffin 
embedded tissue block and/or fresh tissue will be submitted for each subject from prior 
cystectomy or biopsy of metastatic lesion (estimated tumor content >30% of nucleated cells 
in specimen). This tissue may be used for: 
• 
PD-L1 testing of tumor cells and tumor infiltrating immune cells 
• 
Next generation sequencing via MI-ONCOSEQ 
• 
Tumor immune infiltrate sequencing via CIBERSORT 
 
Plasma sample (5-10mL) at baseline only: 
• 
5-10 mL will be banked 
• 
See below for collection and processing instructions 
 
Serum samples (5-10 mL) at baseline only: 
• 
For banking 
• 
See below for collection and processing instructions 
 
Serum collection and processing 
Collect whole blood in a covered test tube. If commercially available tubes are to be 
used, the researcher should use the red topped tubes. These are available from Becton 
Dickinson (BD). BD’s trade name for the blood handling tubes is Vacutainer. After 
collection of the whole blood, allow the blood to clot by leaving it undisturbed at room 
temperature. This usually takes 15-30 minutes. Remove the clot by centrifuging at 1,000- 
2,000 x g for 10 minutes in a refrigerated centrifuge. 
 
The resulting supernatant is designated serum. Following centrifugation, it is important to 
immediately transfer the liquid component (serum) into a clean polypropylene tube using 
a Pasteur pipette. The samples should be maintained at 2-8°C while handling. The serum 
should be apportioned into 0.5 ml aliquots, stored, and transported at –20°C or lower. It is 
important to avoid freeze-thaw cycles because this is detrimental to many serum 
components. Samples which are hemolyzed, icteric or lipemic can invalidate tests. 
 
Plasma samples collection and processing 
Collect whole blood into commercially available anticoagulant-treated tubes e.g., EDTA- 
treated (lavender tops) or citrate-treated (light blue tops). Heparinized tubes (green tops) 
are not permitted. Cells are removed from plasma by centrifugation for 10 minutes at 
1,000-2,000 x g using a refrigerated centrifuge. Centrifugation for 15 minutes at 2,000 x g 
depletes platelets in the plasma sample. 
 
The resulting supernatant is designated plasma. Following centrifugation, it is important 
to immediately transfer the liquid component (plasma) into a clean polypropylene tube 
using a Pasteur pipette. The samples should be maintained at 2-8°C while handling. If 
the plasma is not analyzed immediately, the plasma should be apportioned into 0.5 ml 


38 
 
aliquots, stored, and transported at –20°C or lower. It is important to avoid freeze-thaw 
cycles. Samples which are hemolyzed, icteric, or lipemic can invalidate certain tests. 
 
Tissue samples and banked serum/plasma should be delivered for analysis/storage to: 
Attention: Javed Siddiqui, MS, MT (ASCP, CLsp (MB)) 
Michigan Center for Translational Pathology 
 
 
Phone: 
 
Fax: 
 
 
 
10.2 
Specimen Banking 
Banked patient samples (tissue, blood, serum, plasma) collected for this study will be 
retained at the University of Michigan. Coded specimens will be stored indefinitely or until 
they are used up. If consent for future use of specimens is withdrawn by the subject, best 
efforts will be made to stop any additional studies and to destroy the specimens. 
 
Specimens being stored long-term for potential use not outlined in the protocol are 
subject to University Policy Governing Tissue Sample Collection, Ownership, Usage, and 
Disposition within all UMMS Research Repositories 
[http://msa.med.umich.edu/policies/tissue-sample-collection-ownership-usage- 
disposition-within-all-umms-research-biorepositories]. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design/Study Endpoints, Sample Size and Accrual 
The primary aim of this study is to determine the feasibility of treating patients with 
metastatic urothelial carcinoma who have progressed after platinum based chemotherapy 
with sequential pembrolizumab and SBRT. Treatment success will be defined as 
completion of 4 cycles of pembrolizumab and at least one course of treatment of SBRT 
within 15 weeks from first dose of pembrolizumab. The trial will define the combination 
treatment as feasible if 70% of the patients receive the treatment as defined. With 20 
evaluable patients, if 14 out of 20 (70% [95% Confidence Interval: 50% - 90%]) achieve 
successful treatment then the trial will conclude that further evaluation of sequential 
pembrolizumab and SBRT should be explored. A patient is evaluable for feasibility and 
safety if they receive at least one dose of pembrolizumab. Patients who achieve a complete 
response prior to SBRT are not evaluable for feasibility. Non-evaluable patients will be 
replaced. With accrual of 1-2 patients per month the trial accrual is expected to take up to 
24 months. 
 
Secondary endpoints will include efficacy and safety. Efficacy will be measured using the 
following endpoints: best overall response by RECIST and Immune Related Response 
Criteria and progression-free survival by RECIST and Immune Related Response Criteria. 
Safety endpoints will measure the frequency and severity of grade 3-5 drug-related 
adverse events of the combination of SBRT and pembrolizumab. 
 
Correlative plans are described separately below. 
 
11.2 
Data Analyses Plans 
The primary analysis will report the count, proportion and corresponding 95% binomial 
confidence interval of evaluable patients who completed 4 cycles of pembrolizumab and 
at least one course of treatment of SBRT within 15 weeks from first dose of 
pembrolizumab. 


39 
 
The best overall response (CR + PR) by RECIST and Immune Related Response Criteria 
will be reported separately with counts, proportions and corresponding 95% binomial 
confidence intervals. Progression-free survival endpoints will be described with medians 
and Kaplan-Meier plots using product-limit estimates and associated 95% confidence 
intervals using RECIST and Immune Related Response Criteria separately. Frequency 
and severity of drug-related adverse events will be described. Each of the secondary 
endpoints will be described in the evaluable population and in the population who achieve 
treatment success as defined in the primary endpoint. 
 
 
Correlative Analyses 
PD-L1 expression on tumor cells and immune cells infiltrating tumor, and 
CIBERSORT/TIMER gene expression profiling correlatives will be analyzed with 
association to clinical outcomes using exact chi-square tests, t-tests, or Kaplan-Meier 
methods as is appropriate for each independent covariate and clinical outcome. Tumor 
mutational status and burden by tissue based next generation sequencing (MI- 
ONCOSEQ) results will be descriptive. 
 
 
12.0 
DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the NCI approved University of Michigan 
Comprehensive Cancer Center Data and Safety Monitoring Plan. 
 
The study team will meet quarterly or more frequently depending on the activity of the protocol. 
The discussion will include matters related to the safety of study participants (SAE/UaP 
reporting), validity and integrity of the data, enrollment rate relative to expectations, 
characteristics of participants, retention of participants, adherence to the protocol (potential or 
real protocol deviations) and data completeness. At these regular meetings, the protocol specific 
Data and Safety Monitoring Report form will be completed and signed by the Principal 
Investigator or by one of the co-investigators. 
 
Data and Safety Monitoring Reports will be submitted to the University of Michigan 
Comprehensive Cancer Center Data and Safety Monitoring Committee on a quarterly basis for 
independent review. 


40 
 
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