Phase 2 Clinical Trial of Stereotactic Radiotherapy (SRT) and PD-1 or PD-L1 Inhibiting Therapy for Treatment of Advanced Solid Tumors After Disease Control on PD-1 or PD-L1 Inhibiting Therapy
Phase: PHASE2
Conditions: Solid Tumor
Sponsor: Virginia Commonwealth University

MCC-16-12436
Phase 2 Clinical Trial of Stereotactic Radiotherapy and
PD-1 or PD-L1 Inhibiting Therapy for Treatment of
Advanced Solid Tumors After Disease Control on PD-1
or PD-L1 Inhibiting Therapy
NCT03220854
Document Date: 12/19/2018

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Mb.$Nx Virginia Commonwealth University Massey Cancer Center
@VCU 
MCC Protocol#: MCC-16-12436 
Phase 2 Clinical Trial of Stereotactic Radiotherapy and PD-1 or PD-L 1 Inhibiting Therapy for 
Treatment of Advanced Solid Tumors After Disease Control on PD-1 or PD-L 1 Inhibiting Therapy 
Principal Investigator 
Alfredo Urdaneta, MD 
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TABLE OF CONTENTS 
REVISION HISTORY .................................................................................................................. 3 
LIST OF FIGURES ..................................................................................................................... 9 
LIST OF TABLES ....................................................................................................................... 9 
LIST OF ABBREVIATIONS ...................................................................................................... 10 
STUDY SCHEMA ..................................................................................................................... 11 
1 
BACKGROUND ......................................................................................................... 12 
1.1 
RADIOTHERAPY AND THE ABSCOPAL EFFECT ................................................................. 12 
1.2 
BIOLOGIC RATIONALE FOR COMBINING IMMUNOTHERAPY AND STEREOTACTIC 
RADIOTHERAPY ............................................................................................................ 12 
1.3 
CLINICAL EXPERIENCE WITH IMMUNOTHERAPY AND STEREOTACTIC RADIOTHERAPY ......... 13 
1.4 
RATIONALE FOR PD-1 AND PD-L1 INHIBITORS VERSUS CTLA-4 INHIBITORS .................... 13 
1.5 
INCLUSION OF MULTIPLE ADVANCED SOLID TUMORS ...................................................... 14 
1.6 
INCLUSION OF BRAIN METASTASES ................................................................................ 14 
1.7 
OPPORTUNITY FOR NOVEL INVESTIGATION ..................................................................... 14 
1.8 
VOLUMETRIC MEASUREMENTS FOR RESPONSE ASSESSMENT ......................................... 15 
1.9 
EVALUATION OF IMMUNOLOGIC CORRELATES USING BLOOD SAMPLES ............................ 15 
1.10 
RATIONALE FOR INCLUSION OF PATIENTS WITH STABLE DISEASE .................................... 19 
2 
OBJECTIVES ............................................................................................................ 20 
2.1 
PRIMARY OBJECTIVE .................................................................................................... 20 
2.2 
SECONDARY OBJECTIVES ............................................................................................. 20 
2.3 
EXPLORATORY OBJECTIVES .......................................................................................... 20 
3 
STUDY DESIGN ........................................................................................................ 20 
3.1 
GENERAL DESCRIPTION ................................................................................................ 20 
3.2 
STUDY ACCRUAL .......................................................................................................... 21 
3.3 
PRIMARY ENDPOINT ..................................................................................................... 21 
3.4 
SECONDARY ENDPOINTS .............................................................................................. 21 
4 
PATIENT SELECTION ............................................................................................... 22 
4.1 
INCLUSION CRITERIA .................................................................................................... 22 
4.2 
EXCLUSION CRITERIA ................................................................................................... 23 
5 
STUDY ENTRY AND WITHDRAWAL PROCEDURES .............................................. 24 
5.1 
STUDY ENTRY PROCEDURES ........................................................................................ 24 
5.2 
STUDY WITHDRAWAL .................................................................................................... 24 
6 
STUDY TREATMENT ................................................................................................ 24 
6.1 
BASELINE TESTS AND PROCEDURES .............................................................................. 24 
6.2 
SUMMARY OF STUDY TREATMENT ................................................................................. 25 
6.3 
STEREOTACTIC RADIOTHERAPY .................................................................................... 25 
6.4 
ADMINISTRATION OF THE PD-1 OR PD-L1 INHIBITING THERAPY ....................................... 29 
6.5 
PROHIBITED MEDICATIONS AND TREATMENTS ................................................................ 30 
6.6 
DURATION OF THERAPY ................................................................................................ 31 
6.7 
FOLLOW-UP PERIOD ..................................................................................................... 31 
7 
DOSING DELAYS/DOSING MODIFICATIONS.......................................................... 32 
7.1 
SRT ............................................................................................................................ 32 
7.2 
PD-1 OR PD-L1 INHIBITOR ............................................................................................ 32 

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ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS .............. 32 
8.1 
DEFINITIONS ................................................................................................................ 32 
8.2 
KNOWN AES ASSOCIATED WITH STEREOTACTIC RADIOTHERAPY ..................................... 34 
8.3 
KNOWN AES ASSOCIATED WITH PD-1 OR PD-L1 INHIBITING THERAPY ............................ 36 
8.4 
SECONDARY MALIGNANCY ............................................................................................ 36 
8.5 
TIME PERIOD AND GRADE OF AE CAPTURE .................................................................... 36 
8.6 
PROCEDURES FOR RECORDING AES, SAES, AND UPS ................................................... 36 
8.7 
EXPEDITED REPORTING PROCEDURES .......................................................................... 36 
9 
PHARMACEUTICAL INFORMATION ........................................................................ 38 
9.1 
PD-1 AND PD-L1 INHIBITORS ........................................................................................ 38 
9.2 
PD-1 AND PD-L1 PREPARATION, ADMINISTRATION, AND PATIENT MANAGEMENT ............. 38 
9.3 
DRUG SUPPLY.............................................................................................................. 38 
10 
MEASUREMENT OF EFFECT ................................................................................... 39 
10.1 
CRITERIA FOR TUMOR RESPONSE ................................................................................. 39 
10.2 
TUMOR RESPONSE REQUIREMENTS .............................................................................. 40 
10.3 
CENTRAL REVIEW FOR IMAGING INTERPRETATION .......................................................... 41 
11 
CORRELATIVE STUDIES ......................................................................................... 41 
11.1 
PATIENT PARTICIPATION ............................................................................................... 41 
11.2 
COLLECTION, PROCESSING, AND DISTRIBUTION OF SAMPLES .......................................... 41 
11.3 
BLOOD SAMPLE COLLECTION TIME POINTS .................................................................... 41 
11.4 
INSTRUCTIONS FOR BLOOD SAMPLE COLLECTION .......................................................... 42 
11.5 
BLOOD SAMPLE LABELING ............................................................................................ 42 
11.6 
TESTING AND ANALYSIS ................................................................................................ 42 
11.7 
TRACKING BLOOD SAMPLES .......................................................................................... 42 
12 
STUDY CALENDARS ................................................................................................ 42 
13 
STATISTICAL CONSIDERATIONS ........................................................................... 46 
13.1 
STUDY DESIGN ............................................................................................................. 46 
13.2 
SAMPLE SIZE AND ACCRUAL RATE ................................................................................ 46 
13.3 
STATISTICAL ANALYSIS OF PRIMARY OBJECTIVE ............................................................. 46 
13.4 
STATISTICAL ANALYSIS OF SECONDARY OBJECTIVES ..................................................... 47 
13.5 
ANALYSIS POPULATIONS ............................................................................................... 47 
14 
DATA AND SAFETY MONITORING .......................................................................... 47 
14.1 
STUDY TEAM ................................................................................................................ 47 
14.2 
MONITORING AND AUDITING .......................................................................................... 48 
15 
REGULATORY COMPLIANCE AND ETHICS ........................................................... 48 
15.1 
ETHICAL STANDARD ..................................................................................................... 48 
15.2 
REGULATORY COMPLIANCE .......................................................................................... 48 
15.3 
INSTITUTIONAL REVIEW BOARD ..................................................................................... 48 
15.4 
INFORMED CONSENT PROCESS ..................................................................................... 48 
15.5 
PATIENT CONFIDENTIALITY ............................................................................................ 49 
16 
DATA COLLECTION AND MANAGEMENT .............................................................. 49 
16.1 
DATA MANAGEMENT RESPONSIBILITIES ......................................................................... 49 
16.2 
CRFS AND DATA COLLECTION ...................................................................................... 50 
16.1 
ONCORE DATA ENTRY.................................................................................................. 50 
16.2 
STUDY RECORD RETENTION ......................................................................................... 50 
17 
REFERENCES ........................................................................................................... 51 

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APPENDIX 1. PERFORMANCE STATUS CRITERIA .............................................................. 60 
 
LIST OF FIGURES 
Figure 1. Exosomes Isolated from the Plasma of Patients with Lung Cancer Stimulate Fibroblast 
Proliferation ....................................................................................................................................17 
Figure 2. miR Analysis of Plasma Exosomes from Patients with Lung Cancer Normalized to 
Plasma Volume Extracted ...............................................................................................................18 
 
LIST OF TABLES 
Table 1. Expedited Reporting Requirements ...................................................................................37 
Table 2. Unidimensional Immune-Related Response Criteria .........................................................39 
Table 3. RANO-BM and iRANO Criteria for Brain Metastasis ..........................................................40 
Table 4. Study Calendar – Screening Requirements ......................................................................43 
Table 5. Study Calendar – On-Study, Study Treatment, and Follow-Up ..........................................44 

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LIST OF ABBREVIATIONS 
AE 
adverse event 
CBC 
complete blood count 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T lymphocyte-associated protein 4 
DSMC 
Data and Safety Monitoring Committee 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GTV 
gross tumor volume 
Gy 
gray 
IIT 
investigator-initiated trial 
irAE 
immune-related adverse event 
iRANO 
immunotherapy Response Assessment in Neuro-Oncology 
irRC 
immune-related response criteria 
IRB 
Institutional Review Board 
ITV 
Internal tumor volume 
MCC 
Massey Cancer Center 
NCI 
National Cancer Institute 
PD-1 
programmed death receptor-1 
PD-L1 
programmed death-ligand 1 
PR 
partial response 
PRMC 
Protocol Review and Monitoring Committee 
PTV 
planning target volume 
RANO-BM 
Response Assessment in Neuro-Oncology for Brain Metastases  
RECIST 
Response Evaluation Criteria in Solid Tumors 
RT 
radiation therapy 
SAE 
serious adverse event 
SBRT 
stereotactic body radiotherapy 
SD 
stable disease 
SRS 
stereotactic radiosurgery 
SRT 
stereotactic radiotherapy 
TRegs 
regulatory T cells 
UP 
unanticipated problem 
VCU 
Virginia Commonwealth University 
WCBP 
woman of childbearing potential 

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1 BACKGROUND 
1.1 Radiotherapy and the Abscopal Effect 
The immune system distinguishes “self” from “non-self,” and targets “non-self” for elimination. 
This process forms the basis of our immunity to pathogens and the primary barrier to organ 
transplantation. Cancer, however, is neither “self” nor “non-self,” but rather “altered-self” and 
evades detection and elimination by the immune system through multiple mechanisms. The 
ultimate goal of cancer immunotherapy is to target and reverse these tumor-induced 
immunosuppressive processes, allowing the activated immune system to eradicate the cancer 
and develop immunologic memory to combat future recurrences before they become clinically 
apparent (1). 
Radiotherapy has been a primary oncologic therapeutic modality for approximately a century, 
and it was recognized prior to 1950 that in rare circumstances, radiation of a single tumor 
resulted in regression of not only the irradiated tumor, but also regression of distant tumors not 
irradiated. This phenomenon was termed “The Abscopal Effect.” Contemporary preclinical 
work from various tumor immunology groups have demonstrated that the abscopal effect is 
mediated by the immune system (2, 3). 
1.2 Biologic Rationale for Combining Immunotherapy and Stereotactic Radiotherapy 
Stereotactic radiotherapy (SRT), in which large radiation doses per fraction are given, has 
been combined with immunotherapy to potentiate the abscopal effect of radiotherapy (1). A 
recent review describes the biologic rationale for combining immunotherapy and SRT. Tumor 
cells can downregulate major histocompatibility complex I (MHC I) expression to avoid 
immune system detection (4). One possible mechanism of the abscopal effect of radiation is 
upregulation of MHC I expression after radiation, which eliminates tumor cells’ ability to evade 
immune detection via this pathway (3, 5, 6). Radiation also increases the quantity of tumor-
specific antigens for immune presentation (7). However, upregulation of MHC I expression and 
increased antigen supply are insufficient – activated T cells must be present to recognize and 
kill the tumor cells (1, 6). 
Both cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, by keeping T cells 
activated for longer periods, and programmed death receptor-1 (PD-1) or programmed death-
ligand 1 (PD-L1) inhibitors, by preventing apoptosis of T cells, can potentiate the abscopal 
effect of radiotherapy. However, a documented mechanism of tumor resistance to CTLA-4 
inhibition is upregulation of PD-1 activity (8). Preclinical work has shown that PD-1 activity can 
moderate the abscopal effect of radiation therapy (9, 10), and that tumors can increase PD-1 
activity after radiotherapy (11). Correspondingly, a documented mechanism of tumor 
resistance to PD-1 inhibition is downregulation of MHC I expression (1). Therefore, the 
combination of SRT and PD-1 inhibiting therapy may offer enhanced tumor responses by 
disrupting known resistance mechanism to both individual therapies. 
In murine models, the combination of immune checkpoint inhibitors and SRT generated more 
robust treatment responses than either individually (9, 11-15). In murine melanoma and 
mammary carcinoma models, SRT augmented the response of combined PD-1 and  
CTLA-4 inhibition, even in cell lines previously resistant to CTLA-4 inhibition (8). 

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1.3 Clinical Experience with Immunotherapy and Stereotactic Radiotherapy 
Within the past 5 years, immune checkpoint inhibitors such as nivolumab and pembrolizumab 
(PD-1 inhibitors), atezolizumab and durvalumab (PD-L1 inhibitors), and ipilimumab (a CTLA-4 
inhibitor) have demonstrated improved outcomes in patients with advanced solid tumors, first 
in melanoma (16-21) and subsequently in non-small cell lung cancer (NSCLC), renal cell 
carcinoma (RCC), squamous cell carcinoma of head and neck (SCCHN), and bladder cancer 
(22-36), among others, leading to approval by the US Food and Drug Administration (FDA) for 
their use in these cancers with additional indications expected in the near future. 
Despite these dramatic improvements in patient outcomes, the majority of cancers progress 
on PD-1 and PD-L1 inhibitors, leaving them few options for treatment. While conventional 
thinking suggests that there is no further role for re-use of cytotoxic therapy or targeted 
therapy once tumors are resistant to those agents, immune checkpoint inhibitors may be 
different. As these agents do not target the tumor directly, the immune system may be more 
dynamic, and there may be modulations that can allow immune checkpoint inhibition to gain 
tumor control following initial progression while on these agents. Formal exploration of  
re-treatment strategies could begin to shed light on this process, and open new opportunities 
for therapy. 
Multiple groups have published case reports of patients who were failing immune checkpoint 
immunotherapy until they received SRT to a single lesion, after which regression of the 
irradiated lesion as well as lesions outside of the radiation field with attendant changes in 
molecular markers of immune activation was observed (1, 37, 38). Similarly, radiotherapy to 
oligo-progressive metastatic lesions has been shown to prolong the efficacy of tyrosine kinase 
inhibitors in lung cancer (39, 40). These reports have fueled a growing area of clinical 
investigation into the combination of radiotherapy and immunotherapy. 
1.4 Rationale for PD-1 and PD-L1 Inhibitors Versus CTLA-4 Inhibitors 
The efficacy of PD-1 inhibition versus CTLA-4 inhibition has rarely been directly evaluated. 
PD-1 inhibitors have been shown to be effective in patients with melanoma that has previously 
progressed on ipilimumab (41-43). In a three-arm phase 3 trial comparing ipilimumab (a CTLA-
4 inhibitor), nivolumab (a PD-1 inhibitor), and dual immune therapy in treatment-naïve patients 
with unresectable or metastatic melanoma, nivolumab demonstrated superior response rates 
and progression-free survival compared to ipilimumab (44). These results were replicated with 
pembrolizumab compared to ipilimumab (45). 
PD-1/PD-L1 inhibition and CTLA-4 inhibition target distinct pathways and have different 
mechanisms of action (46). Since PD-1 pathway inhibition has demonstrated superior 
response to CTLA-4 inhibition in melanoma (18, 44) and has proven effective in multiple 
cancer histologies after progression on CTLA-4 inhibition (8, 41-43), we have decided to 
pursue the combination of PD-1 or PD-L1 inhibiting therapy and SRT rather than CTLA-4 
inhibiting therapy and SRT. The toxicity profile of PD-1 inhibition appears to be more favorable 
than that of CTLA-4 inhibition (44). Should our initial study demonstrate favorable outcomes, 
then the combination of SRT and dual immune therapy could be evaluated in a subsequent 
study, given the excellent responses of dual immune therapy seen in melanoma. 
Although both classes of immune therapy have approval in melanoma, PD-1 inhibitors have 
FDA approval for use in NSCLC, RCC, and SCCHN, with additional indications expected in 
the near future. Also, the PD-L1 inhibitor, atezolizumab, has been approved by the FDA for 

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treatment of metastatic urothelial carcinoma, with additional indications expected in the near 
future. Therefore, the use of PD-1 and PD-L1 inhibitors, instead of CTLA-4 inhibitors, expands 
the eligible population now in this study and in the future. 
1.5 Inclusion of Multiple Advanced Solid Tumors 
PD-1/PD-L1 inhibiting therapy has demonstrated efficacy in multiple tumor types. Similarly, the 
abscopal effect has been seen in multiple tumor types (47-57). By limiting our population to 
patients who have demonstrated disease control on PD-1 or PD-L1 inhibiting therapy, we 
select patients with tumors that have the highest likelihood of responding to further immune 
modulation with radiotherapy and continued immunotherapy. This population is also consistent 
with the patients described in case reports of combining SRT and immunotherapy. Our plans 
for statistical methodology that includes both overall and disease-specific futility assessments 
increases the likelihood of identifying tumor types that respond to combination therapy. 
1.6 Inclusion of Brain Metastases 
While patients with brain metastases were excluded from most of the seminal studies leading 
to the adoption of PD-1 and PD-L1 inhibiting therapy, PD-1 inhibitors have demonstrated 
efficacy in brain metastases (58, 59), and the combination of SRT and PD-1 inhibitors in the 
treatment of brain metastases has been shown to be safe (60, 61). Additionally, the reduced 
blood brain barrier seen in brain metastases suggests that radiotherapy to these lesions offers 
a similar, if not identical, chance for immune reactivation compared to radiotherapy to 
extracranial sites (62).  
Our radiation oncology group is not comfortable with observing intracranial disease given the 
potential for these lesions to quickly cause debility and/or death. Therefore, patients with brain 
metastases will be included in this study provided all brain lesions can be treated with SRT 
and there is extracranial measurable disease that can be observed. Given the limited data on 
the immunogenicity of brain metastases, enrollment of patients who receive SRT to brain 
metastases alone will be limited and their data analyzed separately. 
1.7 Opportunity for Novel Investigation 
Most of the recent clinical trials evaluating the combination of SRT and immunotherapy are 
enrolling patients who are naïve to immunotherapy, and recently published studies in 
melanoma, prostate cancer, and other solid malignancies investigated immunotherapy-naïve 
patients (8, 63-65). However, in the seminal case report detailing the abscopal effect in a 
patient with metastatic melanoma, the patient, who had previously responded to ipilimumab 
but was progressing on immunotherapy, received SRT to a painful paraspinal metastasis while 
continuing immunotherapy (37). 
To date, no studies have prospectively examined combination therapy in patients with tumors 
that have progressed on prior immune checkpoint inhibiting therapy, recreating the conditions 
described in prior case reports. In this clinical trial, SRT and immunotherapy will be combined 
to treat patients who have had disease control from immunotherapy but did not continue to 
improve. 

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1.8 Volumetric Measurements for Response Assessment 
Most criteria for evaluating treatment response use unidirectional or 2-dimensional tumor 
measurements to assess response. In this study, the feasibility of using volumetric 
measurements of tumor size will be explored. 
1.9 Evaluation of Immunologic Correlates Using Blood Samples 
1.9.1 Significance and Background 
The mechanisms underlying radiation therapy (RT)-induced antitumor immune 
responses are complex, but are likely related to secretion of certain immunostimulatory 
cytokines and chemokines, systemic immune response against tumor antigens, 
systemic signaling by exosomes released from tumor cells, and local inflammation 
contributing to a distant effect (66). For example, serum IFN-γ levels were found to 
increase in a dose-dependent fashion in patients with esophageal squamous cell 
carcinoma who were treated with RT alone. Type I interferons (IFN-α and IFN-β) not 
only play important roles in the immune responses to viral infection, but are also 
actively involved in antitumor immunity (67). RT can induce production of Type I 
interferons through activation of intracellular DNA sensors, such as the STING-
dependent pathway (68, 69). Induction of Type I interferon within the TME is required 
for generation of Type I interferon-dependent innate and adaptive antitumor immunity 
by potentiating the cross-priming capacity of tumor-infiltrating antigen-presenting cells, 
such as dendritic cells, as well as recruitment and effector function of CD8+ T effector 
cells (70, 71). 
Exosomes are small (30–150 nm) vesicles containing unique RNA and protein cargo, 
secreted by all cell types in culture. They are also found in abundance in body fluids 
including blood, saliva, and urine (72-74). Interest towards exosomes, from their 
function in the body to more practical applications, such as the use in diagnostics 
(based on analysis of their miRNA and protein content) and therapeutics development, 
has grown exponentially in the last 5 years (75). With the current advances the analysis 
of exosomal miRNA from biological samples such as blood is more feasible than ever 
before. Furthermore, the cargo contained in exosomes provides an enriched population 
of miRNA free of endogenous RNA contaminants such as ribosomal RNA (rRNA). 
Therefore, these exosomes contains a disease-specific miRNA signature, which is very 
attractive for diagnostic purposes (76-78). 
Investigators have also examined the interactions of cancer-derived exosomes with 
primary T-lymphocytes (79-82). For example, previous studies have demonstrated that 
these cancer-derived exosomes induce apoptosis in CD8+ T-lymphocytes through the 
FAS/FASL pathway. Other studies have demonstrated that tumor-derived exosomes 
up-regulate expression of inhibitory genes in conventional CD4+T cells and their 
conversion into CD4+ CD25high FOXP3+ CD39+ Treg (83, 84), which co-expressed  
IL-10 and TGF-β, CTLA-4, granzyme B/perforin and effectively mediated immune 
suppression. 
RT can also induce extensive immunogenic alterations of dying and surviving cancer 
cells within the tumor microenvironment. The resulting stress and death of tumor cells 
could stimulate tumor-specific immune responses through the liberation of ‘danger’ 
signals or damage-associated molecular patterns, together with tumor-associated 

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antigens. Specialized antigen-presenting cells can capture tumor antigens and 
concurrently activate the ‘danger’ signals by engaging their corresponding pattern 
recognition receptors, such as toll-like receptors on the surface of immune cells (85, 
86). The resultant antigen presentation can potentially lead to recruitment and priming 
of T cells and consequent immune-mediated destruction of tumors and/or metastases 
(87). 
1.9.2 Preliminary Studies 
The VCU Department of Radiation Oncology has an ongoing blood draw study (HM-
12181) collecting blood samples from patients receiving RT with curative intent for 
cancer of the thorax (lung, breast, prostate, rectal, cervical, head and neck). We have 
published a preliminary analysis of retrospective patient blood samples collected for 
single-nucleotide polymorphisms (SNPs) in genes encoding HO-1, eNOS, NRF2 and 
TGF-β1 (87). NRF2 is a transcription factor for HO-1 expression and NRF2 knock-out 
mice are sensitive to radiation-induced lung injury (88). We also analyzed position -509 
in the promoter of TGF-β1 because the minor allele is associated with enhanced 
promoter activity and TGF-β1 expression and previous studies had generated 
conflicting results of whether the minor allele was predictive for the late effects of 
radiotherapy. This study showed that polymorphisms of 3 genes involved in wound 
repair and response to radiation potentially predicted late normal tissue toxicity if racial 
differences in polymorphism frequencies are considered. Increased frequency of a long 
GT repeat in the promoter was associated with late effects in both African-Americans 
and Caucasian patient populations. SNPs in the TGFβ1 and NRF2 promoters were 
significantly associated with late effects in African-Americans but not Caucasians. 
These latter findings demonstrate that the demographics of the VCU patient population 
and tissue bank will allow us to test for racial differences in the response of tissues to 
radiation. 
In a preliminary study (Serrano et al, in preparation), exosomes were isolated from the 
plasma of patients with lung cancer on HM12181 the day before RT started, 3 weeks 
into RT and 6 months after the end of treatment (Figure 1). Exosomes from patients 
with recurrence isolated 6 months post-RT recovered their growth-promoting property 
in contrast to exosomes from patients who demonstrated no tumor recurrence. These 
results suggest the potential for exosomal biomarkers of tumor recurrence after 
therapy. 

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Figure 1. Exosomes Isolated from the Plasma of Patients with Lung Cancer Stimulate 
Fibroblast Proliferation 
The relative expression levels of 10 different miRs selected on the basis of their roles in 
lung cancer were also determined: let-7a-5p, miR-20a-5p, miR-21-5p,  
miR-30b-5p, miR-106a-5p, miR-146a-5p, miR-155-5p, miR-200b-5p, miR-203a, and 
miR-208a-5p. Expression of 6 miRs demonstrated significant difference between 
recurrent and non-recurrent groups of lung cancer patients (Figure 2). Results are 
shown as an average of miRs expression (Cq-values) for recurrent (3 patients) and 
non-recurrent (3 patients) lung cancer before, during, and 6 months after therapy. 
Given the exponential property of Cq, the differences observed between the recurrent 
and non-recurrent patients are orders of magnitude. The Cq-values were normalized 
with respect to plasma volume. If the Cq-values are converted into fold differences, 
there is a significant difference between miR expression before and after therapy in the 
non-recurrent group (eg, let-7a demonstrates >5-fold decrease, miR-21 demonstrates  
>10-fold decrease). miR-155 is most probably absent at all time points in the non-
recurrent group. When plasma exosome concentration numbers are determined, 
patients in the non-recurrent group consistently demonstrated only 3- to 5-fold 
decrease of exosome concentrations suggesting that the tumor cell is not an exclusive 
source of these exosomes, at least at 6 months post-therapy. 
 
 
 

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0.7 and 3.0 mg exosomal protein and 6-12 ng exosomal miR depending on the patient 
and time point. Quality and quantity of miR are assessed using a bioanalyzer and an 
Agilent small RNA chip and kit. Protein and miR are sequentially isolated from 
exosomes using the Norgen kit. From our prior experience, for example in Figure 1, we 
obtain sufficient amounts of exosomes from individuals to perform the proposed 
analyses, eg amount of exosomal miRs extracted from 0.7mL of serum is enough for at 
least 30,000 qPCR reactions. qRT-PCR is the gold standard for miR measurement. 
For functional analysis of exosomes, we will determine whether exosomes isolated 
from cancer patients as described above induce apoptosis of activated CD8+ T cells 
isolated from anonymized blood samples purchased from a local blood bank (79-82). 
Additional experiments will test whether tumor-derived exosomes mediate immune 
suppression by stimulating proliferation of conventional CD4+ T cells and their 
conversion to CD4+CD25highFoxP3+CD39+ Treg cells expressing IL-10, TGFβ, CTLA-
4, and granzymeB/perforin (83, 84). Experiments described above in Figure 1 
evaluating whether exosomes stimulate fibroblast proliferation will be continued. 
1.10 Rationale for Inclusion of Patients with Stable Disease 
SRT is often used clinically in individuals who have not had progression of disease, but who 
may still benefit from radiation. Some situations when this would be appropriate include but 
are not limited to: 
• 
Metastatic sites that, if left to grow, would cause clinical issues but are currently 
asymptomatic, such as spinal metastases that could cause cord compression 
• 
Metastatic sites that are causing symptoms such as pain, neurological changes, shortness 
of breath, hemoptysis, or rectal bleeding 
• 
Oligoprogressive metastasis in which most of the metastatic sites have responded to 
immunotherapy but one or more has grown larger. 
Recent studies indicate that the combination of the immunotherapy drugs and SRT is well 
tolerated, with toxicity similar to monotherapy (89-91). Preliminary results also indicate the 
presence of abscopal response in non-irradiated measurable lesions with concurrent 
pembrolizumab(90). Another study suggested that the addition of RT to immune therapy could 
“allow for a prolonged response to immune checkpoint inhibition” (92).  
Given the apparent low risk of combining immunotherapy with SRT, we have elected to 
expand the study population beyond those patients who have responded to and then 
progressed on immunotherapy, to include patients who have demonstrated disease control 
with immunotherapy but are no longer continuing to improve. In these cases, radiotherapy may 
provide improved disease control and symptom management. We will continue to explore the 
potential synergistic interactions of the immune-mediated abscopal effect with the anti-PD-
1/PD-L1 activity of the allowed immunotherapy drugs. 

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2 OBJECTIVES 
2.1 Primary Objective 
To determine if SRT and PD-1/PD-L1 inhibiting therapy can restore the benefit of PD-1/PD-L1 
inhibiting therapy in patients with an advanced solid tumor who had demonstrated disease 
control from PD-1/PD-L1 inhibiting therapy but did not continue to improve 
2.2 Secondary Objectives 
In patients who have received study treatment (SRT and PD-1/PD-L1 inhibitor): 
2.2.1 To determine the response rate of SRT and PD-1/PD-L1 inhibiting therapy per 
unidimensional immune-related response criteria (irRC) and, if brain metastases are 
present, per iRANO 
2.2.2 To determine the response rate at irradiated tumor sites 
2.2.3 To determine the response rate at non-irradiated tumor sites 
2.2.4 To determine the 2-year survival rate 
2.2.5 To assess the toxicity associated with the study treatment 
2.2.6 To assess the radiobiological and immunological characteristics of patients receiving 
study treatment using blood samples collected before and after SRT 
2.3 Exploratory Objectives 
2.3.1 To explore the use of volumetric measurements of tumor size for assessing response in 
patients who have received study treatment. 
3 STUDY DESIGN 
3.1 General Description 
This study is a phase 2 single-arm clinical trial of SRT delivered concurrently with PD-1 or PD-
L1 inhibiting therapy to determine if standard SRT potentiates the abscopal effect of PD-1 or 
PD-L1 inhibiting therapy in patients with an advanced solid tumor who previously achieved 
disease control from PD-1 or PD-L1 inhibiting therapy but are no longer continuing to improve. 
Eligible patients must have 1 to 5 metastatic, recurrent, or primary tumors that are clinically 
appropriate to receive SRT and at least one additional tumor that is measureable but will not 
be treated using SRT. 
SRT will be delivered over 1 to 2 weeks. Patients will continue to receive the same FDA-
approved PD-1 or PD-L1 inhibitor that they had been receiving previously until 52 weeks 
following completion of SRT. 

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Correlative blood samples will be collected at baseline, prior to the second SRT fraction, after 
the last SRT fraction (on the same day), and at 8, 24, and 52 weeks after the last SRT fraction. 
These samples will be used to determine the mechanistic immunologic effects of therapy. 
3.2 Study Accrual 
A Simon two-stage design will be employed to assess for treatment futility by examining 
treatment response in the first 11 patients at the 24-week post-SRT time point. If at least one 
patient has improved disease control, accrual will continue until a total of 41 patients have 
been enrolled in the study. Given the established safety profile of PD-1 pathway inhibition and 
SRT, an interruption in accrual after the first 11 patients have been accrued will not be 
required. 
Refer to Section 1.6 and Section 13.2 for accrual restrictions for patients who receive SRT to 
brain metastases alone. 
3.3 Primary Endpoint 
Proportion of patients with improved disease control (see Section 13.1) per Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) and, if brain metastases are 
present, per Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) 
criteria at 24 weeks following SRT 
3.4 Secondary Endpoints 
3.4.1 Proportion of patients alive and free from progression (ie, CR, PR, or SD) per 
unidimensional irRC and, if brain metastases are present, per iRANO criteria at 24 
weeks following SRT 
3.4.2 Proportion of patients with treatment response (ie, CR, PR, or SD) at irradiated tumor 
sites at 24 weeks following SRT (refer to Section 10.1 for response criteria) 
3.4.3 Proportion of patients with treatment response (ie, CR, PR, or SD) at  
non-irradiated tumor sites at 24 weeks following SRT (refer to Section 10.1 for 
response criteria) 
3.4.4 Proportion of patients who are alive at 2 years after completion of SRT 
3.4.5 Adverse events including the following: 
• 
All SRT-related and immunotherapy-related ≥ grade 3 adverse events per the most 
current National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events Version 5.0 (CTCAE v5.0) occurring from initiation of SRT until 8 weeks after 
the last SRT fraction 
• 
All immunotherapy-related adverse events (AEs) occurring from 8 weeks post-SRT 
until 2 years post-SRT requiring discontinuation of PD-1 or PD-L1 inhibiting therapy 
and concurrent initiation of immunosuppressive agents such as steroids as 
described in Section 8.5.2. 

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3.4.6 Radiobiological signature as described in Section 1.9.3 using blood samples collected 
prior to SRT (baseline), prior to the 2nd SRT fraction, immediately following completion 
of SRT (on same day); and at 8, 24, and 52 weeks following completion of SRT 
4 PATIENT SELECTION 
4.1 Inclusion Criteria 
A patient must meet all of the following inclusion criteria to be eligible for this study. 
4.1.1 Pathologically-proven diagnosis of a solid tumor malignancy 
4.1.2 One of the following criteria must be met: 
4.1.2.1 Clinical or radiographic evidence of disease control (defined as best response 
of SD or PR or combination of both for ≥ 16 weeks) without evidence of CR or 
progression 
OR 
4.1.2.2 Clinical or radiographic evidence of disease progression during treatment with 
PD-1 or PD-L1 inhibiting therapy, following previous tumor response (CR, PR, 
or SD for ≥ 16 weeks) to PD-1 or PD-L1 inhibiting therapy, 
and, for patients who discontinued PD-1 or PD-L1 inhibiting therapy during 
response to therapy, disease progression must have occurred following at 
least 8 weeks of re-treatment with PD-1 or PD-L1 inhibiting therapy 
Note: Both the treating medical oncologist and radiation oncologist must be in 
agreement with determination of disease progression. 
4.1.3 Administration of a PD-1 or PD-L1 inhibitor within 60 days prior to study registration 
4.1.4 Determination by the treating radiation oncologist that the patient is a candidate for 
SRT (ie, radiation therapy with a stereotactic setup) 
Note: All brain metastases will receive SRT. 
4.1.5 The total number of tumors requiring SRT must be ≤ 5 
Note: Regardless of the number of brain metastases that will be treated with SRT, the 
brain metastases will be considered to be one tumor. 

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4.1.6 Measurable disease by RECIST v1.1 that will not undergo SRT and that is amenable to 
monitoring 
Note: As noted in Section 4.1.6, all brain metastases will receive SRT. Therefore, a 
patient with brain metastases that will be treated with SRT must also have extracranial 
disease that will not undergo SRT and that is amenable to monitoring (also see Section 
1.6 and Section 13.2). 
4.1.7 Determination by the treating medical oncologist that the patient is a candidate to 
continue the PD-1 or PD-L1 inhibiting therapy that had previously provided disease 
control 
4.1.8 Age ≥ 18 years 
4.1.9 Karnofsky Performance Status score of ≥ 60 % (see Appendix 1 for criteria) 
4.1.10 A woman of childbearing potential (WCBP), defined as a woman who is < 60 years of 
age and has not had a hysterectomy, must have a documented negative serum 
pregnancy test within 14 days prior to initiating study treatment 
4.1.11 Ability to understand and willingness to sign the consent form 
4.2 Exclusion Criteria 
4.2.1 Other anti-cancer therapy administered between the time of tumor response to PD-1 or 
PD-L1 therapy and time of study enrollment 
Note: Patients treated with a combination of PD-1 or PD-L1 inhibiting therapy and other 
immunotherapy are eligible; patients taking hormonal anti-cancer therapies or steroids 
for central nervous system (CNS) edema management that, in the opinion of the 
investigator, are appropriate to continue are eligible. 
4.2.2 Any prior PD-1/PD-L1 therapy-related AE that, in the opinion of the investigator, 
warrants exclusion from participation in this trial 
4.2.3 Administration of any investigational agent within 4 weeks prior to initiating study 
treatment 
4.2.4 Known active hepatitis B or C 
4.2.5 Pregnancy or breastfeeding 
4.2.6 Medical, psychological, or social condition that, in the opinion of the investigator, may 
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5 STUDY ENTRY AND WITHDRAWAL PROCEDURES 
5.1 Study Entry Procedures 
5.1.1 Required Pre-Registration Screening Tests and Procedures 
Refer to the study calendar in Section 12 for the screening tests and procedures that 
are required prior to registration and for the timing of these events relative to the start of 
treatment. 
5.1.2 Registration Process 
Study registration will be performed by the study team 
 
. The following documents are required for study registration: 
• 
Completed, signed, and dated eligibility checklist 
• 
Signed and dated consent form 
The registrar will complete the registration process by assigning a study ID number. 
Study treatment may not begin until the Confirmation of Registration has been received 
and a study ID number has been assigned. 
The study team submitting registration documents to the registrar will enter the patient’s 
initial enrollment data (eg, demographics, consent, eligibility, on study) into the OnCore 
database within 24 hours following study registration (before the first SRT fraction). 
5.2 Study Withdrawal 
A patient may decide to withdraw from study participation at any time. Patients must be 
removed from the study when any of the following occurs: 
• 
The patient has withdrawn consent for study treatment and study procedures 
• 
If, in the investigator's opinion, continuation of the study requirements would be harmful to 
the patient's well-being 
• 
The patient is lost to follow-up 
• 
The sponsor has terminated the study 
The reason for and date associated with study withdrawal or removal from the study must be 
documented in source documents and in the OnCore database. 
6 STUDY TREATMENT 
6.1 Baseline Tests and Procedures 
Refer to the study calendar in Section 12 for requirements prior to initiation of study treatment. 
The tumor(s) anticipated to receive SRT (and at least one tumor that is measureable and will 
not be treated with SRT) and disease to be monitored should be identified using assessments 
completed prior to starting SRT. 

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6.2 Summary of Study Treatment 
• 
Patients will receive a standard treatment regimen of SRT (refer to Section 6.3). The term 
SRT encompasses all radiotherapy using a stereotactic setup, both stereotactic 
radiosurgery (SRS) for metastatic lesions in the brain and stereotactic body radiotherapy 
(SBRT) for SRT delivered to all other locations. Registered patients will be designated as 
belonging to subgroups as follows: 
A. Patients receiving SBRT (body) irradiation only 
B. Patients receiving SBRT and SRS (body and brain) irradiation 
C. Patients receiving SRS (brain) irradiation only 
• 
The same PD-1 or PD-L1 inhibitor that the patient was receiving prior to study registration 
will be continued after study registration. The PD-1 or PD-L1 inhibitor will be administered 
after the last SRT fraction (on the same day) and will continue to be given according to the 
schedule the patient was receiving prior to study registration through 52 weeks after the 
last SRT fraction. At the investigator’s discretion, administration of the PD-1 or PD-L1 
inhibitor may continue during Year 2 or longer (refer to Section 6.4 for additional 
scheduling information). 
• 
At the treating medical oncologist’s discretion, one dose of PD-1 or PD-L1 inhibitor may be 
given after study registration but prior to receiving SRT. 
• 
All doses of the PD-1 or PD-L1 inhibitor administered after study registration will be given 
at the VCU Massey Cancer Center. 
6.3 Stereotactic Radiotherapy 
For the purposes of data collection and management, only the radiotherapy data required by 
the eCRFs for this trial will be captured in the database. The radiation treatment plan herein 
described is standard. 
6.3.1 Radiation Oncology Department 
All study patients will receive SRT in the MCC Radiation Oncology Department. 
6.3.2 Dose Specifications 
• 
Treatment will be planned to deliver a total of 18 to 60 Gy to the planning target 
volume (PTV) in up to 10 fractions over 1 to 2 weeks. 
• 
The dose per fraction is to be prescribed so that at least 95% of the PTV receives 
the prescription dose. 
Note: Metastases in different locations may be treated to different doses in the same 
patient. 
6.3.3 SRT Treatment Schedule 
• 
SRT must begin within 4 weeks following study registration and be completed 
within 3 weeks after the first SRT fraction. 

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• 
The dates of computerized tomography (CT) simulation, start of RT, and completion 
of RT must be documented. 
• 
The timing of treatment initiation should be coordinated with administration of the 
PD-1 or PD-L1 inhibitor, which must be given on the same day, after the last SRT 
fraction. 
6.3.4 Treatment Planning 
• 
Planning Constraints 
Planning constraints are provided in this section for both the PTV as well as critical 
normal structures to be spared. Acceptable treatment plans will be established from 
a DVH-based analysis of the volumetric dose to both the PTV and critical normal 
structures to ensure that minimally acceptable constraints for each volume of 
interest have been met. 
• 
Planning Techniques 
Planning techniques may differ for each lesion to be treated provided that the tumor 
motion is properly accounted for with each technique when the target or targets are 
in or near the thorax region. 
• 
Planning SRT Near Prior Radiotherapy Volumes 
The toxicity of delivering SRT to multiple metastases in close proximity to prior 
conventionally-fractionated external beam RT volumes is not known. Every effort 
should be made to limit the dose to organs at risk that have previously received 
radiation. 
6.3.5 Technical Factors 
• 
Megavoltage equipment capable of delivering static intensity modulation with a 
multileaf collimator or dynamic intensity modulation, using a multileaf collimator or 
tomotherapy, is required.  
• 
Daily image guidance is required. This can take the form of electronic portal 
imaging, orthogonal KV imaging, or cone beam CT. 
6.3.6 Localization, Simulation, and Immobilization 
• 
A custom immobilization device is suggested to minimize set-up uncertainty. 
• 
CT-based simulation (maximum 3 mm slice thickness) is required. 
6.3.7 Target Volumes and Contouring 
• 
The gross tumor volume (GTV) is defined as all known gross disease as determined 
from a combination of clinical and radiographic examination. 
• 
The internal target volume (ITV) is defined as all regions that are likely to harbor 
microscopic metastatic disease based on location and histology of the tumor and 
other involved sites as well as compensation for tumor motion. 
• 
Normal structures should be contoured according to consensus guidelines such as 
Radiation Therapy Oncology Group contouring atlases, if available, or according to 
other commonly accepted contouring guidelines. 

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• 
The PTV will provide a margin around the ITV to compensate for the inter- and intra-
fraction uncertainty consequent to daily set-up uncertainty and to potential internal 
organ motion. Depending on the site of the treated lesion and the immobilization 
technique used, the PTV will consist of a symmetrical 1-5 mm expansion around the 
ITV. In the event that PTVs extend outside of the skin surface, the clinician should 
manually trim the PTV contours to be 3-5 mm inside the outer skin (unless there is 
direct skin involvement). 
6.3.8 Critical Structure Constraints 
• 
Critical structure constraints will be specified according to the American Association 
of Physicists in Medicine Task Group (AAPM TG101) report (93). In the event that 
constraints for the number of fractions used are not listed in the report, dose 
constraints will be linearly interpolated from TG101 constraints. 
• 
Use TG101 as a guide for dose limits to normal tissue. At a minimum, no organ at 
risk should receive greater than 105% of the prescription dose. 
• 
In the event that a critical structure is encompassed in the PTV, the area of overlap 
will be limited to 105% of the prescription dose. 
6.3.9 Metastasis Location Definition for Treatment Planning 
Each metastasis targeted with SRT will be assigned to one of the 8 “Metastasis 
Locations” as described in this section. 
6.3.9.1 Lung Central 
• 
GTV within 2 cm of proximal bronchial tree: Tumor within or touching the 
zone of the proximal bronchial tree, defined as a volume 2 cm in all 
directions around the proximal bronchial tree (carina, right and left main 
bronchi, right and left upper lobe bronchi, intermedius bronchus, right 
middle lobe bronchus, lingular bronchus, right and left lower lobe bronchi) 
• 
Tumors that are immediately adjacent to mediastinal or pericardial pleura 
(ie, PTV touching the pleura) also are considered central tumors 
6.3.9.2 Lung Peripheral 
Metastases within the lung parenchyma with GTV outside of the proximal 
bronchial tree as described above 
6.3.9.3 Mediastinal/Cervical Lymph Nodes 
• 
Mediastinal 
GTV arising within the anatomic space between the lungs, above the 
diaphragm, and below the thoracic inlet at the level of the top of the sternal 
notch 
• 
Cervical lymph nodes 
GTV occurring within cervical lymph node Levels I-VI and/or 
retropharyngeal spaces; superior border skull base 
• 
Sternal metastases 

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Assigned to the mediastinal/cervical lymph node location based on 
potential for normal tissue toxicity 
6.3.9.4 Liver 
• 
GTV arising within the liver 
• 
Rib metastases immediately adjacent to the liver assigned to the liver 
metastasis location 
6.3.9.5 Spinal 
• 
Metastases assigned to the spinal/paraspinal site if the GTV arises within 
the vertebral bodies expanded by 1 cm. Spinal metastases can involve the 
vertebral body only or the vertebral body and pedicle or posterior elements 
only. 
For each of these metastases, the PTV delineation will include: 
− 
Involved vertebral body and both pedicles or 
− 
More generous delineation of the involved vertebral body and 
both pedicles or 
− 
Involved vertebral body, both pedicles, and the anterior and 
posterior elements of the spine or 
− 
Spinous process and laminae 
The target volume may be chosen at the discretion of the treating radiation 
oncologist based on the extent of tumor involvement. 
• 
Spinal metastases with epidural extension will only be included if there is > 
3 mm gap between the edge of the epidural metastasis and edge of the 
spinal cord. 
• 
Metastases arising in the ribs within 1 cm of the edge of the vertebral body 
should be included in the spinal metastasis location, but osseous 
metastases planning guidelines are to be used. 
6.3.9.6 Osseous 
• 
GTV arising within an osseous structure, part of the axial skeleton, not 
included in the spinal definition. 
• 
Rib metastases that are within 1 cm of the vertebral bodies are to be 
classified into the spinal metastasis location given the similar normal 
tissues at risk. 
• 
Rib/scapular metastases within the thorax adjacent to lung parenchyma are 
to be classified into the lung metastasis location given the similar normal 
tissues at risk. 
• 
Rib/osseous metastases adjacent to mediastinal or cervical structures are 
to be classified into the mediastinal/cervical lymph node location given the 
similar normal tissues at risk. 

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• 
Rib metastases adjacent to the liver are to be classified into the liver 
location given the similar normal tissues at risk. 
• 
Rib metastases adjacent to the stomach/abdominal wall are to be classified 
into the intra-abdominal location given the similar normal tissues at risk. 
• 
Sternal metastases are to be considered part of the mediastinal/cervical 
lymph nodes location given the similar normal tissues at risk. 
• 
Metastases arising in the bones of the skull are to be included in the brain 
metastasis location but osseous metastases planning guidelines are to be 
used. 
6.3.9.7 Abdominal-pelvic 
GTV arising within the anatomic space defined by the diaphragm superiorly, 
the genitourinary diaphragm inferiorly including the peritoneal and 
retroperitoneal spaces, not including the liver, osseous, or spinal metastases 
6.3.9.8 Brain 
• 
GTV arising within the anatomic space defined by skull base inferiorly, 
within 1 cm of brain parenchyma, and not including osseous metastases 
• 
If above skull base but not within 1 cm of brain parenchyma, then include 
as osseous metastasis 
6.3.10 Labeling Target Structures 
Target structures will be labeled as gross tumor volume (GTV), internal target volume 
(ITV) if applicable, and planning target volume (PTV). The prescription dose in cGy will 
follow the structure names separated by an underscore. Each should be labeled 
according to numerical order of the anatomical sites described in Section 6.3.9 (eg, 
PTV_5000_2 is a peripheral lung lesion receiving 50 Gy while PTV_5000_4 is a liver 
lesion receiving 50 Gy). If multiple lesions exist within a single anatomical site, each 
lesion can be distinguished by adding a letter to the end of the PTV name  
(eg, PTV_5000_1a and PTV_5000_1b). Brain lesions can also include an anatomic 
descriptor (eg, PTV_2700_8a_ left parietal). 
6.3.11 Supportive Care 
Supportive care for management of symptoms related to SRT is at the discretion of the 
radiation oncologist. 
6.4 Administration of the PD-1 or PD-L1 Inhibiting Therapy 
The following instructions regarding the administration of the PD-1 or PD-L1 inhibitor will be 
followed: 
6.4.1 PD-1 or PD-L1 Inhibitor 
The patient must continue to receive the same PD-1 or PD-L1 inhibitor that had been 
administered prior to study registration. 

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6.4.2 Preparation and Administration of the PD-1 or PD-L1 Inhibitor 
Refer to the current agent-specific prescribing information for instructions regarding 
preparation and administration of the PD-1 or PD-L1 inhibitor. 
6.4.3 PD-1 or PD-L1 Inhibitor Treatment Schedule 
• 
The timing of the pre-SRT dose of the PD-1 or PD-L1 inhibitor (if given) must be 
planned to allow the second PD-1 or PD-L1 inhibitor dose to be administered on the 
last day of SRT (following the last SRT fraction). 
Note: Administration of an on-study PD-1 or PD-L1 inhibitor prior to initiation of the 
SRT is not required, but one pre-SRT dose is permitted. (See Section 4.1.4 
regarding requirements prior to study registration.) 
• 
The PD-1 or PD-L1 inhibitor will continue to be administered according to the 
prescribing information for the agent the patient is receiving. At the discretion of the 
treating medical oncologist, modifications in treatment schedule are permitted. 
6.4.4 Duration of PD-1 or PD-L1 Inhibiting Therapy 
The PD-1 or PD-L1 inhibitor will continue until 12 months following completion of SRT. 
At the treating investigator’s discretion, the PD-1 or PD-L1 inhibitor may be continued 
during Year 2 (or longer) if the patient continues to tolerate treatment and is receiving 
clinical benefit. 
6.4.5 Assessment and Management of PD-1 or PD-L1 Inhibiting Therapy Side Effects 
Information and instructions found in the applicable prescribing information should be 
followed. However, management of side effects is at the discretion of the treating 
medical oncologist. 
6.4.6 Supportive Care 
Patients should receive appropriate supportive care measures as deemed necessary 
by the treating medical oncologist. Supportive care measures for the management of 
AEs with potential immunologic etiology are provided in the prescribing information for 
the specific PD-1 or PD-L1 inhibitor. 
6.5 Prohibited Medications and Treatments 
6.5.1 Cancer Treatment 
Once study therapy is initiated, cancer treatment (eg, chemotherapy, biological therapy, 
immunotherapy, RT) other than the treatment specified in the protocol for this study is 
not permitted until disease progression. Continuation of hormonal anti-cancer therapy is 
permitted at investigator discretion. Steroids for CNS edema management are 
considered supportive care, not anti-cancer treatment.  

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6.5.2 Other Medications 
• 
Live vaccines (examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine) are prohibited. 
• 
Administration of investigational agents is not permitted until disease progression 
(see Section 5.2 regarding study withdrawal). 
6.5.3 Concurrent Medications 
Concurrent medications will be recorded in source documents at visits in accordance 
with the study calendar. The only concurrent medications required to be captured in 
eCRFs are: 
• 
Oral or parenteral steroids 
• 
Any immunotherapy given other than PD-1 or PD-L1 inhibitor (see Section 4.2.1) 
• 
Any hormonal therapy being used for cancer control (see Section 4.2.1) 
• 
Any prohibited medication (see Sections 6.5.1 and 6.5.2) 
6.6 Duration of Therapy 
Study treatment will be administered as described in Sections 6.3 and 6.4 unless one of the 
following occurs (also see study withdrawal criteria in Section 5.2): 
• 
AE that requires discontinuation of study treatment 
• 
Pregnancy 
• 
Determination by the investigator that discontinuation is in the patient’s best medical 
interest 
• 
Patient decision to discontinue study treatment 
• 
Withdrawal of study sponsor support 
The reason for discontinuation of study treatment must be documented in the source 
documents and in the OnCore database. 
6.7 Follow-Up Period 
6.7.1 For AE Evaluation and Reporting 
6.7.1.1 AEs Related to SRT and/or PD-1 or PD-L1 Inhibiting Therapy 
Assessment and reporting for all ≥ grade 3 AEs will continue through 8 weeks 
following the last SRT fraction (Section 8.5.1). 
6.7.1.2 AEs Related to PD-1 or PD-L1 Inhibiting Therapy 
Assessment and reporting of selected AEs related to the PD-1 or PD-L1 
inhibiting therapy as described in Section 8.5.2 will continue until the PD-1 or 

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PD-L1 inhibitor has been discontinued (for any reason) or until 2 years after 
completion of SRT, whichever occurs first. 
6.7.2 Follow-up for Treatment Response and Survival 
Patients who remain on study will be assessed according to the study calendar (Table 
5) through 2 years after completion of SRT. 
7 DOSING DELAYS/DOSING MODIFICATIONS 
7.1 SRT 
There are no study-specified requirements for modification in the SRT treatment plan. 
However, the treating radiation oncologist may modify the fraction dose and/or schedule if 
necessary for patient safety. 
7.2 PD-1 or PD-L1 Inhibitor 
Dose reductions and/or treatment delays due to immune-related side effects of the PD-1 or 
PD-L1 inhibitor will be permitted at the discretion of the treating medical oncologist. The 
instructions for dosing delays and/or modifications provided in the prescribing information for 
the specific PD-1 or PD-L1 inhibitor can be referred to in making treatment modification 
decisions. 
8 ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
8.1.2 Serious AE (SAE) 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: 
• 
death, 
• 
a life-threatening AE, 
An AE is considered to be “life-threatening” if, in the view of either the investigator or 
sponsor, its occurrence places the patient at immediate risk of death. It does not 
include an AE that, had it occurred in a more severe form, might have caused death. 
• 
inpatient hospitalization or prolongation of existing hospitalization, 
Planned inpatient hospitalizations, eg, for planned surgery, or those that occur for 
logistical reasons, eg, to complete a therapy that cannot be completed due to 
outpatient clinic business hours, are exempt from SAE reporting. Events that 

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prolong such hospitalizations and otherwise meet reporting criteria are, however, 
still subject to SAE reporting requirements. 
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• 
a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgement, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
8.1.3 Unanticipated Problem 
An unanticipated problem (UP) includes any incident, experience, or outcome that 
meets all of the following criteria: 
• 
unexpected (in terms of nature, severity, frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
research protocol and informed consent document approved by the institutional 
review board (IRB); and (b) the characteristics of the patient population being 
studied; 
• 
related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
suggests that the research places patients or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
8.1.4 AE Description and Grade 
The descriptions and grading scales found in the revised CTCAE v5.0 will be utilized for 
AE reporting. 
8.1.5 AE Expectedness 
AEs can be ‘Unexpected’ or ‘Expected’. 
• 
Expected AEs are those AEs, the specificity and severity of which, are listed or 
described in the current version of the FDA-approved prescribing information for the 
specific PD-1 or PD-2 inhibitor. 
• 
Unexpected AEs are those AEs occurring in one or more patients participating in the 
study, the nature, severity, or frequency of which is not consistent with either: 
− 
The known or foreseeable risk of AEs associated with the procedures involved in 
the research that are described in (a) the protocol-related document, such as the 
IRB-approved research protocol and the current IRB-approved informed consent 
document, and (b) the FDA-approved prescribing information. 
− 
The expected natural progression of any underlying disease, disorder, or condition 
of the patient(s) experiencing the AE and the patient’s predisposing risk factor 
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8.1.6 AE 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. 
8.2 Known AEs Associated with Stereotactic Radiotherapy 
Fatigue is likely to occur for all treatment locations with an expected duration of  
< 8 weeks. Other AEs related to SRT for the treatment of metastases depend on the location 
of the lesions treated and exposure of surrounding normal tissues. The following list contains 
examples of possible SRT-related AEs but is not all-inclusive, given the diversity of sites that 
may be irradiated in this trial. 
8.2.1 Lung (Central and Peripheral), Mediastinal/Cervical Lymph Node Metastases 
• 
Cardiac and pericardial injury 
Cardiac and pericardial injury is uncommon in the conventionally-fractionated 
course of RT, side effects can be seen with large doses per fraction of SRT. 
• 
Gastrointestinal/Esophageal injury 
Esophagitis (ie, dysphagia causing pain on swallowing) relatively soon after SRT is 
completed; typically resolves on its own within days to a week or longer 
• 
Central Airway/Bronchial injury 
Bronchial toxicity includes: 
− 
Cough 
− 
Dyspnea 
− 
Hypoxia 
− 
Pleural effusion 
− 
Pleuritic pain associated with collapse 
− 
Bronchial necrosis/fistula 
− 
Hemoptysis/pulmonary hemorrhage 
• 
Lung injury 
Radiation pneumonitis (ie, inflammation of the end bronchioles and alveoli); 
toxicities include: 
− 
Fever 
− 
Shortness of breath 
− 
Pulmonary infiltrate on chest x-ray 
8.2.2 Liver/Abdominal-Pelvic Metastases 

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• 
Skin irritation, redness, itchiness, discomfort 
• 
Asymptomatic decrease in blood counts 
• 
Asymptomatic increase in liver enzymes 
• 
Nausea and vomiting 
• 
Gastric, esophageal, small bowel or large bowel irritation, ulceration, and/or 
bleeding 
• 
Fistula 
• 
Obstruction or changes in motility following therapy 
• 
Chest wall pain 
• 
Radiation-induced liver disease (RILD) 
− 
Classic RILD: Anicteric ascites, hepatomegaly, and elevation of alkaline 
phosphatase relative to other transaminases that may occur following SRT 
to the liver 
− 
Non-classic RILD: Elevation of liver enzymes and/or any decline in liver 
function 
• 
Liver failure 
• 
Permanent thrombocytopenia 
• 
Bleeding 
8.2.3 Spinal Metastases 
• 
Radiation myelitis 
• 
Radiation esophagitis 
• 
Radiation laryngitis or pharyngitis 
• 
Radiation pneumonitis 
8.2.4 Osseous 
• 
Erythema 
• 
Desquamation 
• 
Pain 
• 
Edema 
• 
Neuralgia 
8.2.5 Brain 
• 
Nausea/vomiting 
• 
Seizure 
• 
Headache 

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8.3 Known AEs Associated with PD-1 or PD-L1 Inhibiting Therapy 
Refer to the current prescribing information for the known AEs associated with the PD-1 or 
PD-L1 inhibitor the patient is receiving. 
8.4 Secondary Malignancy 
A secondary malignancy is a new cancer caused by previous treatment for a malignancy, eg, 
chemotherapy or RT. Metastatic disease is not a secondary malignancy. Any secondary 
malignancy should be reported via expedited reporting mechanisms. 
8.5 Time Period and Grade of AE Capture 
8.5.1 From Initiation of SRT Until 8 Weeks Post-SRT 
All SRT-related and immunotherapy-related ≥ grade 3 AEs will be recorded beginning 
at the time of the first SRT fraction and continuing until 8 weeks following completion of 
SRT. 
8.5.2 After 8 Weeks Post-SRT 
Only AEs requiring that the PD-1 or PD-L1 inhibitor be discontinued and that steroids 
be administered will be recorded beginning after the 8-week post-SRT AE assessment. 
8.6 Procedures for Recording AEs, SAEs, and UPs 
All AEs, SAEs, and UPs will be recorded in MCC’s OnCore Clinical Trials Management 
System. In most cases, it is acceptable to record in OnCore only the highest grade of a toxicity 
occurring during a particular study segment when an event has serial fluctuations in grade 
over time. 
SAE’s will be entered into the OnCore SAE domain. UPs will be entered into the OnCore 
Deviations domain. An SAE that is both an SAE and a UP will be entered in both domains. For 
all SAEs, a corresponding entry should be made in the routine AE record to match the event 
entries in the SAE domain. 
8.7 Expedited Reporting Procedures 
Refer to Table 1 for expedited reporting requirements and instructions. 

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10.2.2 Imaging 
Only imaging of the initial sites of disease is required at subsequent time points to 
provide tumor measurements for assessment of antitumor effect. The same type of 
imaging used at baseline should be used at each scheduled assessment. 
10.2.3 Clinical Examination 
• 
Per RECIST v1.1 and unidimensional irRC, imaging-based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but can be assessed by clinical exam. 
• 
Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in diameter as assessed using calipers (eg, skin nodules). 
10.3 Central Review for Imaging Interpretation 
Central radiologic review for evaluation of tumor response will only be conducted for patients 
who have CR, PR, or SD by internal review at the 24-week disease assessment time point. 
11 CORRELATIVE STUDIES 
Refer to Section 1.8 for a description of the plans for correlative studies using collected blood 
samples. 
11.1 Patient Participation 
Participation in the correlative studies using blood samples is a study requirement for all 
patients. 
11.2 Collection, Processing, and Distribution of Samples 
• 
The study team will coordinate collection and de-identification of all correlative blood 
samples. 
• 
Questions regarding study requirements should be directed to the study team. The 
Principal Investigator should be contacted in the event that a correlative sample must be 
missed or is found to be inadequate. 
11.3 Blood Sample Collection Time Points 
Blood samples will be collected at the following 6 time points: 
• 
Prior to initiation of SRT (after study registration) 
• 
Prior to the 2nd SRT fraction 
• 
After the last SRT fraction (on the same day) 
• 
At the following time points after the last SRT fraction: 
− 
At 8 weeks (+/- 2 weeks) 
− 
At 24 weeks (+/- 2 weeks) 

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− 
At 52 weeks (+/- 4 weeks) 
11.4 Instructions for Blood Sample Collection 
At each time point: 
• 
Collect 10 mL of blood in a purple-top tube 
• 
Invert 8-10 times after collection and deliver at ambient temperature within  
2 hours following collection to the laboratory of Ross Mikkelsen, PhD in the Department of 
Radiation Oncology. 
11.5  Blood Sample Labeling 
Each collected blood sample should be labeled as follows: 
• 
Study number 
• 
Patient study identification number 
• 
Date of sample collection 
• 
Time of sample collection 
• 
Study time point 
11.6  Testing and Analysis 
Testing and analysis of the blood samples will be performed by Dr. Ross Mikkelsen and Dr. 
Xiang-Yang (Shawn) Wang. 
11.7 Tracking Blood Samples 
Collection and distribution of all blood samples will be logged by the study team in OnCore. 
12 STUDY CALENDARS 
Required tests, exams, collection of samples for correlative studies, and study treatment are listed 
on 2 tables: requirements during screening on Table 4 and requirements during treatment and 
follow-up on Table 5. At the discretion of the treating radiation oncologist, additional SRT-related 
standard tests and exams may be performed. At the discretion of the treating medical oncologist, 
additional tests may be performed to continue the standard care the patient was receiving during 
PD-1 or PD-L1 inhibiting therapy prior to study registration. 

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Table 5 Footnotes: 
A. Within +/- 1 week. 
B. Within +/- 2 weeks. 
C. Within +/- 4 weeks. 
D. Assessment and reporting limited to AEs that required discontinuation of the PD-1/PD-L1 inhibitor and steroid management. 
E. AEs will continue to be assessed every 2-6 months through end of year 2 in those who continue on PD-1 or PD-L1 inhibitor therapy in 
accordance with Section 6.7. 
F. Refer to Section 6.5.3. 
G. Serum chemistry includes the following panels and tests: basic metabolic panel (sodium, potassium, carbonate, chloride, glucose, 
calcium, BUN, and creatinine); hepatic panel (ALT, AST, ALP, total bilirubin, direct bilirubin, albumin, and total protein). 
H. After week 4, labs are done as part of routine care assessments, and these lab values are not required to be entered in eCRFs. They will be 
reviewed as part of AE assessments and, as applicable, AE eCRF entry. 
I. 
For WCBP, the pregnancy test must be repeated if the pre-entry test was performed more than 14 days prior to initiation of SRT. If required, 
either a urine or serum qualitative pregnancy test may be performed. 
J. The imaging (and/or clinical assessment) used at baseline should be used at each subsequent time point; refer to Section 10.1 for information 
regarding the response criteria to be used. For patients with brain metastasis receiving SRS, disease assessment includes documentation of 
neurologic status and dosing history of steroids used for CNS edema management. 
K. A goal of imaging at 8 weeks post-SRT is to rule out progressive disease. 
L. Imaging findings at the 24-week time point will be used for analysis of the primary endpoint (Section 13.3). Refer to Section 10.3 
regarding central review requirements. An optional disease assessment may be done at approximately 28 weeks (at least 4 weeks 
after the 24-week disease assessment) if needed to confirm response status. 
M. In the absence of post-SRT disease progression, continue with imaging and disease assessment every 2-3 months until 12 months 
following completion of SRT. 
N. In the absence of post-SRT disease progression, continue with imaging every 2-6 months until 2 years following completion of SRT. (If 
the patient has initiated a new cancer treatment, imaging is no longer required.) 
O. If the patient is available and willing to have a final blood sample collected for the correlative studies. 
P. SRT must be administered by VCU Radiation Oncology and must begin within 4 weeks following study registration; refer to Section 6.3 for 
additional SRT requirements and instructions. 
Q. If one dose of the PD-1 or PD-L1 inhibitor needs to be given after study registration (before the first SRT fraction), the pre-SRT dose (if given) 
must be timed so that the next dose is given on the same day as the last SRT fraction. 
R. At the discretion of the treating medical oncologist, the PD-1 or PD-L1 inhibitor may continue to be administered after 52 weeks following 
completion of SRT if there has not been disease progression following SRT. 
S. For patients with post-SRT disease progression, follow-up can be limited to assessment of vital status until 2 years after completion of SRT. 

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13 STATISTICAL CONSIDERATIONS 
13.1 Study Design 
This is a single-arm phase 2 study of SRT and PD-1 or PD-L1 inhibiting therapy for 
patients with advanced solid tumors who achieved disease control during PD-1 or PD-L1 
inhibiting therapy. The primary objective is to determine if SRT can restore the benefit of 
PD-1 or PD-L1 inhibiting therapy in patients with an advanced solid tumor who had disease 
control from PD-1 or PD-L1 inhibiting therapy but did not continue to improve. For patients 
enrolled with progression, this would mean SD, PR, or CR. For patients enrolled with 
stable or plateaued disease, restoration of benefit would be an objective response, ie PR 
or CR. 
13.2 Sample Size and Accrual Rate 
Given that only approximately 10% of patients who continue PD-1 or PD-L1 inhibition after 
progression or plateau on a prior PD-1 or PD-L1 inhibiting agent experience improved 
disease control (18, 45, 98), we would consider an improved disease control rate of 25% 
(relative to 10% of patients who do not receive radiotherapy) with the combination of SRT 
and PD-1 or PD-L1 inhibiting therapy to be promising and worthy of further study. To 
statistically test whether the disease control improvement rate meets our disease control 
criteria, the study will require a sample size of 42 evaluable patients to have 80% power at 
5% level of significance. We anticipate that 10% of enrolled patients may be inevaluable; 
therefore, up to 46 patients are required to ensure that sufficient patients will be evaluable. 
Patients who are not evaluable for efficacy as defined in Section 13.5.2 will be replaced. 
Given the limited data on the immunogenicity of brain metastases, enrollment of patients 
who receive SRT to brain metastases alone will be limited to no more than 4 of the first 14 
evaluable patients and no more than 11 of the 37 evaluable patients. Patients who receive 
SRT to other sites as well as to brain metastases will not be counted towards this 
allotment. 
Accrual is anticipated to be about 1 patient every 1-2 months over a period of about 4.5 
years. 
13.3 Statistical Analysis of Primary Objective 
We will employ a Simon two-stage design to assess for treatment futility by examining the 
rate of improved disease control at 24 weeks following completion of SRT. Therefore, 14 
patients will be evaluated for the primary endpoint (ie, improved disease control) at 24 
weeks. If at least 2 successes are observed, we will continue to recruit a total of 42 
evaluable patients. If fewer than 2 successes are observed, then the study will close to 
further accrual. If 8 or more success are observed in the total population of 42 evaluable 
patients, further investigation of this treatment regimen will be considered warranted. 
At the end of the first stage, all primary and secondary endpoints will be summarized and 
shared with the Data Safety and Monitoring Committee (DSMC). If the study goes into the 
second stage of accrual, this will be the interim analysis. If early termination of the study is 
recommended, this will be the final analysis.   

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The rate of improved disease control will be reported with a point estimate and 95% 
confidence interval. Analysis of the primary objective will include all efficacy-evaluable 
patients; however, a subset analysis of efficacy-evaluable patients who only receive SRT 
to brain metastases will also be performed. 
13.4 Statistical Analysis of Secondary Objectives 
Patients’ demographics, AEs and SAEs, disease status, treatment status, clinical 
response, etc will be listed and summary descriptive statistics will be calculated. Rate of 
higher grade AEs will be reported at each follow-up visit. 
Time to death, time to progression at the irradiated site, and time to progression at a  
non-irradiated site will be summarized using the Kaplan Meier survival curve. Overall 
survival probabilities will be estimated with 95% confidence intervals at each follow-up time 
point during the 2-year follow-up. Analysis of the secondary objectives will include all 
evaluable patients; however, a subset analysis of evaluable patients who only receive SRT 
to brain metastases will also be performed. 
13.5 Analysis Populations 
13.5.1 Safety-Evaluable Population 
Patients who have received at least 1 SRT fraction and at least one dose of PD-1 or 
PD-L1 inhibiting therapy after SRT will be evaluable for safety and toxicity analyses. 
13.5.2 Efficacy-Evaluable Population 
Patients will be evaluable for analysis of the primary endpoint if they meet all of the 
following criteria: 
• 
Received at least 50% of the prescribed SRT 
• 
Received at least one dose of PD-1 or PD-L1 inhibiting therapy after SRT 
• 
Had baseline and at least one subsequent response assessment to measure the 
SRT-treated tumor and the non-SRT-treated tumor following the last dose of 
SRT as follows: 
• 
Patients with documented unequivocal progression of disease prior to 
the 24-week time point will be evaluable. 
• 
Patients who do not have documented unequivocal progression of 
disease prior to the 24-week time point and have not had an objective 
response assessment at the 24-week time point will not be evaluable 
for efficacy and will be replaced. 
14 DATA AND SAFETY MONITORING 
14.1 Study Team 
The study team minimally consists of the Principal Investigator, the research nurse, the 
clinical research associate, and the study biostatistician. While patients are on treatment, 

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the Principal Investigator, the research nurse, and the clinical research associate will meet 
at least monthly to review study status; quarterly meetings will be held with the study 
biostatistician. This review will include, but not be limited to, reportable SAEs and UPs and 
an update of the ongoing study summary that describes study progress. All meetings, 
including attendance, are documented. 
14.2 Monitoring and Auditing 
14.2.1 MCC Compliance Office 
Compliance specialists in the MCC Compliance Office will provide ongoing 
monitoring and auditing for this study. 
14.2.2 Data Safety and Monitoring Committee 
The study will be reviewed by the MCC DSMC initially according to the risk level 
specified by the MCC Protocol Review and Monitoring Committee (PRMC) and then 
according to a schedule based on study status and quality indicators. The DSMC 
will review reports provided by the Principal Investigator/study team and the MCC 
Compliance Office focusing on data integrity and patient safety. 
15  REGULATORY COMPLIANCE AND ETHICS 
15.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Patients of Research 
(US National Commission for the Protection of Human Patients of Biomedical and 
Behavioral Research, April 18, 1979). 
15.2 Regulatory Compliance 
This study will be conducted in compliance with the clinical trial protocol and with federal 
regulations, as applicable, including: 21 CFR 50 (Protection of Human Patients/Informed 
Consent); 21 CFR 56 (Institutional Review Boards); 21 CFR 312 (IND Application); and 45 
CFR 46 Subparts A (Common Rule), B (Pregnant Women, Human Fetuses and 
Neonates), C (Prisoners), and D (Children). 
15.3 Institutional Review Board 
The VCU IRB, which is registered with the Office for Human Research Protections 
(OHRP), must review and approve the protocol, the associated informed consent 
document, and recruitment material (if any). Any amendments to the protocol or consent 
form must also be approved. 
15.4 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Discussion of risks and possible benefits of this therapy will be provided to patients and 

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their families. Consent forms describing the study interventions/study procedures and risks 
are given to the patient and written documentation of informed consent is required prior to 
starting intervention/administering study product. Presentation, discussion, and completion 
of the consent form will occur at the MCC. 
Consent forms will be IRB-approved and the patient will be asked to read and review the 
document. Upon reviewing the document, the investigator will explain the research study to 
the patient and answer any questions that may arise. The patient will sign the informed 
consent document prior to any procedures being done specifically for the study. Patients 
should have the opportunity to discuss the study with their surrogates or think about it prior 
to agreeing to participate. Patients may withdraw consent at any time throughout the 
course of the trial. A copy of the informed consent document will be given to patients for 
their records; the original consent form will be maintained in the research records. The 
rights and welfare of patients will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. 
15.5 Patient Confidentiality 
Patient confidentiality is strictly held in trust by the Principal Investigator, participating 
investigators, staff, and the sponsor and its agents. This confidentiality includes the clinical 
information relating to participating patients, as well as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the Principal Investigator. 
The Principal Investigator will allow access to all source data and documents for the 
purposes of monitoring, audits, IRB review, and regulatory inspections. Source documents 
provided for the purpose of auditing or monitoring will be de-identified and labeled with the 
study number, patient ID number, and patient initials. 
The study monitor or other authorized representatives of the Principal Investigator may 
inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
patients in this study. The clinical study site will permit access to such records. 
16 DATA COLLECTION AND MANAGEMENT 
16.1 Data Management Responsibilities 
The Principal Investigator is responsible for: (i) reviewing SAE reports; and if so, filing the 
report; 
The Principal Investigator is responsible for: (i) the overall conduct of the investigation; (ii) 
ongoing review of trial data including all safety reports; and (iii) apprising participating 
investigators of any UPs. 
The Principal Investigator is responsible for: (i) the data management; and (ii) reporting 
SAEs, UPs, and other events requiring expedited reporting as described in Section 8.7. 

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Any laboratory conducting correlative studies must maintain the laboratory records and 
documentation (laboratory notebooks, laboratory protocols, print-outs, recordings, 
photographs, etc.) 
16.2 CRFs and Data Collection 
MCC OnCore data management will provide standard electronic CRFs (eCRFs) and create 
study-specific eCRFs to be able to capture all information required by the protocol. The 
eCRFs will be approved by the study team to ensure the most effective data acquisition. 
The investigator(s) and study coordinator(s) must maintain source documents for each 
patient in the study. All information on eCRFs will be traceable to these source documents, 
which are generally maintained in the patient’s file. 
All eCRFs should be completed and available for collection within a timely manner, 
preferably no more than 14 days after the patient’s visit. 
16.1 OnCore Data Entry 
Data will be entered into MCC’s OnCore database on an ongoing basis by the study team. 
The study team is responsible for updating data to allow for data compilation and review. 
The electronic data submissions will be reviewed periodically for data timeliness and 
accuracy. 
16.2 Study Record Retention 
As applicable, study records will be maintained a minimum of 6 years beyond the 
publication of any abstract or manuscript reporting the results of the protocol or submission 
of a final report to clinicaltrials.gov. 

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