Phase II Trial of Neutron Radiotherapy With Concurrent Checkpoint Inhibitor Immunotherapy (Pembrolizumab) in Patients With Advanced Urothelial Carcinoma
Phase: PHASE2
Conditions: Urothelial Carcinoma
Sponsor: University of Washington

1 
CLINICAL RESEARCH PROTOCOL 
Phase 
II 
Trial 
of 
Neutron 
Radiotherapy 
with 
Concurrent 
Checkpoint 
Inhibitor 
Immunotherapy 
(pembrolizumab) in Patients with Advanced Urothelial 
Carcinoma
Principal Investigator: 
Jing Zeng, MD 
Associate Professor 
Department of Radiation Oncology 
University of Washington Medical Center 
1959 NE Pacific Street, Box 356043 
Seattle, Washington 98195-6043 
Phone: 206-598-4100  
Fax: 206-598-6218 
Email: jzeng13@uw.edu 
Co-Investigators: 
Jay Liao, MD 
Ramesh Rengan, MD PhD  
Michael Schweizer, MD 
Petros Grivas, MD, PhD 
Evan Y. Yu, MD 
Michael T. Schweizer, MD 
Heather H. Cheng, MD, PhD 
Robert Bruce Montgomery, MD 
Andrew Hsieh, MD 
John Lee, MD 
Todd Yezefski, MD 
  Version: 01/08/2019 
IRO REC'D 1/30/2023
FHCRC IRB Approval  
2/23/2023 
Document Released Date
Printed on 10/29/2024

2 
Study Summary 
Title 
Phase II Trial of Neutron Radiotherapy with Concurrent Checkpoint 
Inhibitor Immunotherapy pembrolizumab) in Patients with Advanced 
Urothelial Carcinoma 
Short Title 
Neutron + Pembrolizumab in Advanced Urothelial Cancers 
Protocol Number 
CC 9940 
Phase 
II 
Methodology 
1 Arm Open-Label 
Study Duration 
2 yrs 
Study Center(s) 
University of Washington Medical Center 
Objectives 
To primary objective is to assess whether neutron radiation (with high 
relative biological effectiveness relative to standard photon radiation) to 
a single focus of disease in patients with advanced urothelial carcinoma, 
can improve the overall response rate to standard of care checkpoint 
inhibitor immunotherapy (pembrolizumab). The primary endpoint is the 
overall response rate per iRECIST. Secondary objectives are to 
evaluate toxicity, immune-related clinical responses and immune 
pharmacodynamic changes, progression-free survival, and overall 
survival. 
Number of Subjects 
20 evaluable subjects 
Diagnosis and Main 
Inclusion Criteria 
Patients diagnosed with advanced urothelial carcinoma, about to start 
checkpoint inhibitor immunotherapy (pembrolizumab) per standard of 
care, and eligible to undergo radiation to at least one site of disease with 
at least one additional site of disease that is measurable per RECIST 
criteria.  Patient may receive radiation to asymptomatic sites of disease.  
Study Product, 
Dose, Route, 
Regimen 
All treatments are approved standard of care for patients with advanced 
urothelial carcinoma, including pembrolizumab and neutron radiation to 
a metastatic site. Dosing of pembrolizumab will be in accordance with 
their FDA label. Neutron radiation will be administered at a palliative 
dose/fractionation regimen to a site of disease that is either 
symptomatic, likely to become symptomatic, or likely to cause minimal 
toxicity with radiation treatment.   
Duration of 
administration 
Checkpoint inhibitor immunotherapy will be given per standard clinical 
care until patients develop progression or intolerable toxicity.  Neutron 
radiation treatments will be given standard of care as well, for a 
maximum of 5 daily radiation treatments.   
Statistical 
Methodology 
Overall response rate will calculated as the percentage of patients 
achieving a PR or CR, and will be presented along with the 95% CI. 
Historical data suggest a response rate of 20%, and we hypothesize a 
true response rate of 40% with the proposed treatment. With 20 
patients, we’ll have 80% power to observe an estimated response rate 
that is statistically significantly higher (at the one-sided significance level 
of .05) than the fixed rate of 20%. 
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3 
Table of Contents 
1. Introduction
2. Study Objectives
3. Study Design
3.1. General Design
3.2. Statistical Plan
3.3. Eligibility
4. Study Registration
5. Radiation Therapy
5.1. Dose Specifications
5.2. Localization, simulation and immobilization
5.3. Target Volumes
5.4. Critical Structures
5.5. Treatment Planning
5.6. Radiation Quality Assurance Reviews
5.7. Radiation Toxicity
5.8. Criteria for Removal/Withdrawal from Treatment
6. Systemic Therapy
7. Adverse Event Reporting Requirements
8. Data and Safety Monitoring Plan
8.1. Early Stopping Rules
8.2. Interim Data Review
9. Data Management/Confidentiality
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4 
1 Introduction 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 
and International Conference on Harmonization guidelines), applicable government regulations 
and Institutional research policies and procedures.  
Bladder cancer has seen success with immunotherapy, although life expectancy with metastatic 
bladder cancer remains poor: 
This trial tests whether the addition of focal radiation can act as a “vaccine” by releasing tumor 
neoantigens, with the goal of augmenting the immune response to immunotherapy.  Bladder 
cancer will be diagnosed in around 79,000 patients in the US in 2017 with around 17,000 
deaths1. For patients with metastatic urothelial bladder cancer, FDA has approved five immune 
checkpoint inhibitors as of 8/12/2017 targeting the PD-1/PD-L1 pathway, including atezolizumab 
(PD-L1 inhibitor), nivolumab (PD-1 inhibitor), pembrolizumab (PD-1 inhibitor), avelumab (PD-L1 
inhibitor), and durvalumab (PD-L1 inhibitor).  However, outcome for these patients remain poor. 
For metastatic urothelial bladder cancer, median overall survival (OS) is around 12 months2. For 
patients who relapse after chemotherapy, median survival is worse, with few effective systemic 
options. A phase 2 trial with atezolizumab in patients with metastatic urothelial carcinoma that 
progressed after platinum-based chemotherapy showed an improvement in response from 10% 
historically to 15% with atezolizumab (p=.0058)3.  Similarly, nivolumab was tested in a phase 2 
trial of advanced urothelial carcinoma and showed 19.6% response with median OS 8.7 
months4.  Pembrolizumab was given to patients who progressed after platinum-based 
chemotherapy in a phase 3 trial versus standard second line chemotherapy, and showed an 
improvement in OS (10.3 months vs. 7.4 months, p=0.002), with objective response of 21.1% in 
the pembrolizumab group versus 11.4% in the chemotherapy group5. Pembrolizumab has also 
been tested in a phase 2 trial in the first line setting in patients who are ineligible for platinum-
based chemotherapy, with an objective response rate of 24%6.  Although these results are 
improvements over historical controls, response rates of 20% and median survivals of less than 
a year leave room for improvement.    
Standard photon radiation can be combined with immunotherapy to augment anti-tumor activity 
in a variety of solid tumors: 
Radiation causes release of tumor antigens and cytokines into the tumor microenvironment, 
which leads to an inflammatory response and infiltration of immune cells including T-cells (both 
cytotoxic and regulatory), dendritic cells, macrophages, and myeloid-derived suppressor cells 
(MDSCs)7.  Peripheral blood from patients with metastatic melanoma receiving standard photon 
radiation to a single site of disease while on ipilimumab show that radiation induces an increase 
in percentage of CD4+ T-cells, ratio of CD8+ T-cells to Tregs, decrease in MDSCs, and 
increase in HLA-DR expression on monocytes8,9. Clinical reports have been published with 
standard photon radiation to one tumor causing an abscopal effect that leads to systemic 
regression of disease outside the radiation field, even in patients who have previously 
progressed on immunotherapy8,10,11. Although the exact mechanism of the radiation induced 
abscopal effect is unclear, published data supports it is partially due to T-cell effector function in 
the irradiated tumor, especially CD8+ T-cells9,12.  There is also growing evidence that cytokine 
release is a major mechanism, which can lead to a decrease in MDSCs8,13,14. 
Strengths and limitations of standard photon radiation as an immune-adjuvant: 
All of the published data on radiation and its ability to augment response to immunotherapy 
have been with standard photon radiation, which is sparsely ionizing with a relative biological 
effectiveness (RBE) of ~1, compared to 1.1 for protons and 3 or more for densely ionizing 
Printed on 10/29/2024

5 
radiations such carbon ions and fast neutrons.15-17 While the mainstay of radiation treatment 
worldwide is still photon therapy, particle therapy is increasingly prevalent.  There are 25 proton 
therapy centers in operation across the United States with dozens more under construction. 
Densely ionizing (high RBE) particles are becoming more prevalent as well, with 10 carbon ion 
centers operational worldwide, and one announced in the US with more expected over the next 
decade.  The main attraction of particle therapy is the ability to improve dose conformality by 
depositing most of the radiation in the tumor and less radiation in normal tissues18.  Although 
protons are more widely available than carbon or other high RBE particles, protons have similar 
biologic efficacy as standard photon therapy (proton RBE ~ 1.1), but fast neutrons and carbon 
ions have higher RBE of 3 or more.16-18  Higher RBE particles have a unique ability to overcome 
hypoxia, cell cycle radiosensitivity, and other effects that enable some tumors to resist standard 
photon treatments. For example, p53 mutated cells, which are associated with higher grade and 
higher stage bladder cancers19, are relatively radioresistant to standard photon therapy but 
more susceptible to high RBE radiation, meaning it is likely that high RBE radiation has a 
greater impact on the tumor microenvironment and immune milieu20.   
Immunologic effects of high-RBE radiation compared with standard photon radiation: 
Although classical radiation biology states that the cytotoxic effects of radiation on tumor cells 
are primarily initiated by DNA double strand breaks, there is an emerging understanding of the 
importance of an “immunogenic cell death” (ICD) as a significant in vivo cell death mode. 
Radiation has been shown to induce all 3 key components of ICD: cell surface translocation of 
calreticulin to signal dendritic cells, and release of danger signals such as HMGB1 and ATP, 
which result in priming of CD8+ T-cells21. Tumor mutational burden and defects in the DNA 
repair pathway have been linked to tumor response rate to checkpoint inhibitors such as anti-
PD-1 therapy. While bladder cancer is the third highest mutated cancer22, high RBE particle 
therapy such as neutrons cause qualitative changes in the sub-cellular distribution and types of 
DNA damage, and have the potential to shift cells from an apoptotic cell death mode towards 
the more inflammatory, and possibly immunogenic, mitotic catastrophe and necrotic cell death 
modes.23-25 High RBE therapy may cause a more immunogenic tumor microenvironment via 
release of more tumor neoantigens26,27. Mouse total body radiation experiments in the 1970s 
with neutrons versus standard photons found that the degree of immunosuppression was 
dependent on the LET of the radiation (neutrons have high LET), and mortality from total body 
radiation differs based on LET, for the same delivered radiation dose28. 
Immunologic changes in peripheral blood of patients receiving 
immunotherapy: 
Immune profiling of peripheral blood from patients on checkpoint 
inhibitor immunotherapy has not been widely explored.  Huang et 
al. looked at peripheral blood of 29 patients with metastatic 
melanoma receiving anti-PD-1 antibody pembrolizumab29.  At 3-
weeks into therapy, frequency of Ki67+ CD8 T-cells peaked and 
then declined, with highest percent of Ki67+ CD8 T-cells around 
weeks 3-6 after start of pembrolizumab (Ki67+ CD8 T-cells 
increased from around 7% at baseline to around 14-19% at weeks 
3-6 post-pembrolizumab). The increase in Ki67 expression was
mostly seen in the PD-1+ versus PD-1 negative CD8 T-cells, with
Ki67 increasing from around 9% at baseline to around 23% at 3-
weeks (peak response) in the PD-1+ CD8 T-cells population, and
non-statistically significant increase in Ki67+ cells in the PD-1
negative CD8 T-cell population (Figure 1).  Clinical response was
correlated with the fold change of PD-1+ Ki67+ CD8 T-cells after
Figure 1. Change in percent
Ki67+ CD8 T-cells after start
of 
pembrolizumab 
therapy
(n=29). Red line=PD-1+ cells,
blue line=PD-1 negative cells.
Adapted from Huang AC et al.
Nature 2017 (545):60-65. 
Printed on 10/29/2024

6 
anti-PD-1 therapy, adjusted for baseline tumor burden.  Patients with longer PFS typically had a 
low tumor burden and higher fold change in Ki67.  Using an arbitrary cutoff of 2.2 fold change in 
Ki67+ PD-1+ CD8 T-cells after anti-PD-1 therapy at weeks 3-12 compared to baseline, 
response rate was 40% (8/20) for patients with Ki67 change above the fold, and 29% (2/7) for 
patients below the fold.  T-cell receptor repertoire was compared between pretreatment tumor 
infiltrating T-cells and peripheral blood CD8 T-cells.  Across 6 patients, at peak Ki67 expression 
after anti-PD-1 treatment, 14 clones were present among the top 10 clones in both tumor and 
blood, supporting the notion that Ki67+ T-cells in the blood are reinvigorated by anti-PD-1 
therapy and contain T-cell clones that are also present in the tumor.  This study shows that it is 
possible to detect immunologic changes in peripheral blood after treatment with anti-PD-1 
therapy, and changes in Ki67+ CD8 T-cells may peak around weeks 3-6 and be related to 
clinical outcome. 
Immunologic changes in peripheral blood of patients receiving immunotherapy plus photon 
radiation: 
Twyman-Saint Victor et al. reported on 22 patients 
with 
metastatic 
melanoma 
treated 
with 
hypofractionated photon radiation to a single index 
lesion, followed by 4 cycles of anti-CTLA4 antibody 
ipilimumab9.  Radiation was found to increase the 
diversity of the T-cell receptor repertoire while anti-
CTLA4 therapy inhibited T-regulatory (Treg) cells 
and increased the CD8/Treg ratio.  For 10 patients 
with available pre- and post-treatment blood, two had 
partial responses 
in 
unirradiated 
tumors 
and 
progression-free survival significantly longer than the 
median. For both of these patients, the percentages 
of Ki67+ GzmB+ cells increased in PD-1+ Eomes+ 
CD8 T-cells after treatment (6-12% increase), while 
the proportion ofPD-1+ Eomes+ T-cells remained at 
or below the mean (Fig. 2). In contrast, patients with 
a high percentage of PD-1+ Eomes+ T-cells post-
treatment did not have partial responses and had a 
short 
progression-free 
survival, 
regardless 
of 
reinvigoration.   Peripheral blood was collected post-
radiation treatment and pre-anti-CTLA4 therapy, as 
well as every 3 weeks with anti-CTLA4 therapy for 4 
cycles.   
Immunologic effects of standard photon radiation on patients receiving immunotherapy for 
bladder cancer: 
Although no clinical data has been published on the effect of standard photon radiation on 
patients receiving immunotherapy for metastatic bladder cancer, multiple trials are ongoing to 
test this combination (NCT02826564, NCT02992912, NCT02289209).  It is expected that these 
clinical trials will be looking at immunologic correlates of response as well as overall disease 
response and survival.     
Figure 2. Change in peripheral blood in 10
patients with metastatic melanoma receiving
photon radiation to a single index lesion and 4
cycles of anti-CTLA4 therapy. Percentage of
Eomes+PD-1+ CD8 T cells in post-treatment
blood vs change in%PD-1+Eomes+CD8 T cells
that are Ki67+GzmB+ after treatment. Each circle
represents a patient. Progression-free survival
(PFS) is proportional to circle size and quadrant
boundaries are average values for patients under
the mean PFS. Concordance index of the random
forest model is 0.59. Adapted from Twyman-Saint
Victor C et al. Nature 2015 (520):373-377. 
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7 
2 
Study Objectives 
Primary Objective 
The primary objective is to assess the overall response rate to neutron radiation (with high 
relative biological effectiveness relative to standard photon radiation) to a metastatic focus in 
combination with standard of care checkpoint inhibitor immunotherapy (pembrolizumab), in 
patients with advanced urothelial carcinoma.  Primary endpoint is clinical response as quantified 
by iRECIST30.  Response will be assessed on non-radiated, RECIST evaluable lesions. Key 
iRECIST criteria as detailed by Seymour et al. are detailed below.30  
Figure 1A-C. Key iRECIST Criteria. Published by Seymour et al. iRECIST: guidelines for 
response criteria for use in trials testing immunotherapeutics. The Lancet Oncology. Mar 
2017;18(3):e143-e152. 
A 
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8 
Secondary Objectives: 
•
Progression free survival.
•
Overall survival.
•
Safety and tolerability as evaluated by the incidence, severity, duration, causality,
seriousness, and type(s) of adverse events as assessed by CTCAE version 4.0
Exploratory Objectives: 
C 
B 
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9 
•
Changes in peripheral blood immune cell subpopulations measured via multi-parameter
flow cytometry:
o
Important 
T-cell 
subsets 
using 
markers 
such 
as: 
CD3/CD8/CD4/Foxp3/CD45RA/CD45RO/CCR7/CD28/CD27/CD57/CD25/HLA-
DR/CTLA4/PD-1
o
NK cells will be assessed using CD16/CD56/CD69.
o
B-cells and dendritic cells will be analyzed using: CD19, CD123, CD11c, CD86,
MHC class I and II, CD70, and CD54.
o
MDSC will be assessed using: CD11b, CD 14, CD33.
•
Next generation sequencing of the T-cell receptor-β locus in genomic DNA from sorted
CD4+ and CD8+ T cell subsets from blood samples using the TRB ImmunoSeq kit
(Adaptive Biotechnologies).
•
Tumor biopsies (pre- and post-treatment of a non-radiated site) in select patients who
consent will be assessed for: cell death, tumor infiltrating lymphocytes, expression of cell
surface markers including HLA, PDL1, etc., and undergo multiparameter flow cytometry
as well as TCR sequencing.
3 
Study Design
3.1 General Design 
This is a study to test whether densely ionizing, high relative biologic equivalence (RBE) 
radiation in the form of neutron radiation, can improve the response rate to checkpoint inhibitor 
immunotherapy in patients with advanced urothelial carcinoma.  In this trial, the addition of focal 
radiation is hypothesized to act as a “vaccine” by releasing tumor neoantigens, with the goal 
being to augment the immune response.  Trial schema is shown below in Figure 1 and study 
calendar in Table 1.  Patients with advanced urothelial carcinoma about to receive checkpoint 
inhibitor therapy (pembrolizumab), with at least two sites of measurable disease per RECIST 
1.1, will undergo neutron radiation to 1-3 sites of disease.  At least one site of RECIST 1.1 
evaluable disease must remain untreated31, as only non-radiated sites will serve as index 
lesions to assess for response rate per iRECIST criteria.30 Asymptomatic lesions are eligible for 
radiation as the primary goal of the radiation therapy is to induce an immune response.   
= Blood draw; 
  = Radiation Treatment 
Figure 2. Clinical trial schema. 
TIMELINE
Study Enrollment 
Day 1, 1st Dose of 
Pembrolizumab 
Day 0: Baseline 
Peripheral Blood Draw 
Day 23-42: Peripheral 
Blood Draw and Optional 
Tumor Biopsy Prior to 
Starting 
Radiation 
Therapy with Neutrons 
Between 2nd & 3rd Dose 
of Immunotherapy: 2.7 
Gy Times 3 Fractions, 
Biologically Equivalent to 
8 Gy Times 3 Fractions.  
Standard 
of 
Care 
Pembrolizumab Until Disease 
Progression, With Peripheral 
Blood Draw at 4 Weeks and 16 
Weeks 
Post-Radiation, 
and 
Imaging 
Assessment 
Per 
Standard of Care Every 12 
Weeks. 
 
Optional 
Tumor 
Biopsy at Progression, Or In 
Extraordinary Responders. 
Day 22, 2nd Dose of 
Pembrolizumab 
Day 43, 3rd Dose of 
Pembrolizumab 
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10 
Table 1. Study Calendar. 
Pre-
treatment4 
Between Dose 2 
and 3 of 
Immunotherapy5 
4-Weeks After End
of Radiation6
16-Weeks After End
of Radiation7
Informed 
Consent 
X 
Medical 
History 
X 
X 
X 
Physical 
Exam 
X 
X 
X 
ECOG 
Performance 
Status  
X 
X 
X 
Blood Draw1 
X 
X 
X 
X 
Radiation 
Therapy 
X 
Tumor biopsy 
(optional)2 
X 
X 
CT C/A/P3 
X 
X 
X 
1Blood draw will consist of 9 tubes: 8 yellow top tubes (BD Vacutainer #364606 Acid citrate dextrose 
additives ACD Solution A) and 1 red top tube (BD Vacutainer #367820 Clot Activator) to collect and store 
the following: 1) 6 tubes of 0.5 ml serum; 2) 2 tubes of 1.0 ml plasma; 3)  4 tubes of 0.5 ml PBMC; and 4) 
6 tubes of 1 ml PMBC. 
2Tumor biopsy of a radiated or non-radiated site will be performed for patients who consent. 
3CT C/A/P is preferred but MRI or PET/CT also acceptable.   
4All pre-treatment assessments must be performed within 30 days of protocol enrollment, except CT 
C/A/P which must be within 45 days of protocol enrollment.   
Pembrolizumab is typically given every 3 weeks. Dose 2 must happen between 2.5-5 weeks after dose 1, 
and dose 3 must happen between 6-9 weeks after dose 1. 
6Acceptable date range is 3 to 6 weeks after radiation ends. 
7Acceptable date range is 12 to 24 weeks after radiation ends. 
Time points for peripheral blood collection are based on prior studies, including Huang et al. and 
Twyman-Saint Victor et al. described above9,29, that show peak changes in peripheral blood 
immune cell populations around 3-6 weeks post start of therapy for checkpoint inhibitor 
immunotherapy, and changes after radiation treatment that peak around 2-4 weeks but can 
persist for months after treatment.  
After the study period as outlined above, all patients will be followed at least once every 3 
months by the treating oncologist per standard of care. Toxicity, disease response, and survival 
will be recorded at each clinic visit.  Patients are considered off-study once disease progression 
is detected per iRECIST30. Follow up with radiation oncology is not required but records will be 
obtained from treating oncologist.  All correlative studies will be batched for analysis.   
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11 
3.2. Statistical Plan 
This is a single-arm phase 2 study with the primary endpoint of overall response rate per 
iRECIST. Overall response rate will calculated as the percentage of patients achieving a PR or 
CR, and will be presented along with the 95% CI. Historical data suggest a response rate of 
20%, and we hypothesize a true response rate of 40% with the proposed treatment. With 20 
patients, we’ll have 80% power to observe an estimated response rate that is statistically 
significantly higher (at the one-sided significance level of .05) than the fixed rate of 20%. 
Secondary endpoints overall and progression-free survival will be estimated using the method of 
Kaplan and Meier with 95% CI obtained using Greenwood estimates of variance. Toxicities as 
assessed by CTCAE version 4.0 will be summarized as the proportion of patients with such 
toxicities, in addition to total number of toxicities (allowing for multiple toxicities within a patient) 
among all patients. The exploratory endpoints, change in peripheral blood cell populations will 
be assessed by estimating the average change between pre- and post-treatment, and these 
differences will be calculated for each time point; the one-sample t-test will be used to test the 
null hypothesis that the change is equal to zero. Trends for changes in differences from pre-
treatment to post-treatment across time will be assessed using generalized linear models. 
Similar methods will be used to assess change in tumor biopsies for patients who consent to 
such analyses, where changes from pre- to post-treatment will be examined for cell death, 
tumor-infiltrating lymphocytes and expression of various cell-surface markers.   
Should this regimen be deemed to be potentially efficacious as defined above, consideration will 
be given to conduct a subsequent randomized study designed to compare neutron radiation 
plus checkpoint inhibitors versus checkpoint inhibitors alone. 
3.3. Eligibility Criteria 
A. Inclusion Criteria
•
Pathologically proven (either histologic or cytologic) diagnosis of urothelial carcinoma
•
At least two sites of disease that are measurable by RECIST 1.1 criteria
•
Eligible for checkpoint inhibitor immunotherapy (pembrolizumab) per standard of care
o
No history of autoimmune disease requiring systemic therapy (e.g. steroids or biologic
agents).
o
Adequate organ function

Hematologic
•
ANC ≥1500 /mcL
•
Platelets ≥ 100,000/mcL
•
Hemoglobin > 9 g/dL

Renal
•
Creatinine ≤1.5 x upper limit of normal (ULN) OR ≥60 mL/min

Hepatic
•
Total bilirubin ≤1.5 ULN OR direct bilirubin ≤ULN if total bilirubin >1.5
x ULN
•
AST and ALT ≤2.5 x ULN OR <5 x ULN if patient has live metastasis
•
Albumin ≥ 2.5 g/dL

Coagulation
•
INR or PT ≤1.5 x ULN unless on anticoagulation therapy, in which
case PT or PTT should be in the therapeutic range
•
PTT ≤1.5 x ULN unless on anticoagulation therapy, in which case PT
or PTT should be in the therapeutic range
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12 
•
Eligible for neutron radiation treatment to 1-3 sites of metastatic disease (lesions do not
have to be symptomatic)
•
No steroids for at least 2 weeks prior to enrollment, and patient must not be expected to
require steroids during the study period
•
Zubrod Performance Status 0-2
•
Age ≥ 18
•
Patient must sign study specific informed consent prior to study entry
•
Patients who are sexually active must use medically acceptable forms of contraception
•
Life expectancy must be > 3 months
B. Exclusion Criteria
•
Has a known history of active TB (Bacillus Tuberculosis)
•
Hypersensitivity to pembrolizumab or any of its excipients
•
Has a known additional malignancy that is progressing or requires active treatment
•
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
•
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
•
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
•
Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
•
Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject’s participation for the
full duration of the trial, or is not in the best interest of the subject to participate, in the
opinion of the treating investigator.
•
Has known history of, or any evidence of active, non-infectious pneumonitis.
•
Has an active infection requiring systemic therapy.
•
Has received a live vaccine within 30 days of planned start of study therapy.
•
Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
there is no evidence of new or enlarging brain metastases, and are not using steroids for
at least 7 days prior to trial treatment. This exception does not include carcinomatous
meningitis which is excluded regardless of clinical stability.
4 
Study Registration
Subjects will be registered by the FHCRC/UW Study Coordinator and entered into the Protocol 
Accrual Tracking System (PATS). Information regarding the PATS system is available at 
http://www.cancerconsortiumorg/rto/protocol_office/pats/. A complete, signed, study consent 
and HIPAA consent are required for registration. 
5 
Radiation Therapy 
All radiation treatments will be administered at the University of Washington Medical Center. All 
other appointments (medical oncology visits, labs, scans, etc.) can occur at either UWMC or 
SCCA.  Protocol treatment must begin within 30 days of study enrollment.   
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13 
5.1 Dose Specifications 
Radiation treatments will meet all requirements considered standard clinical care.  Patients 
should ideally be treated with 3 fractions of radiation but up to 5 fractions may be allowed if 
treating radiation oncologist is concerned with toxicity. All radiation treatments must complete 
within a 2 week period.  Up to 3 sites may be treated concurrently.  For neutron radiation, 2.8 
Neutron Gy x 3 fractions is the goal dose, but may be decreased to 1.5 Gy x 3-5 fractions at 
discretion of treating radiation oncologist.   
5.2 Localization, simulation, and immobilization 
•
All patients will undergo CT based treatment planning at initial simulation per standard
clinical care. Immobilization devices will be used as applicable to treated anatomic region.
The CT scan must capture the region of interest as well as surrounding organs at risk (OAR)
with sufficient margin for treatment planning. The CT scan should be obtained with a uniform
slice thickness of less than or equal to 3 mm throughout. The use of IV contrast is left to the
discretion of the treating physician.
•
All lesions with potential for respiratory motion should be evaluated by appropriate means
including 4D CT scan and/or implanted fiducial marker(s). Respiratory motion management
including but not limited to active-breathing control, respiratory gating, and fiducial marker
tracking, will be employed for qualifying patients per standard clinical practice.
•
Daily image guidance will be employed for target localization.
5.3 Target Volumes
•
The gross tumor volume (GTV) is defined as all known gross disease encompassing the
selected index lesion as visualized the planning CT scan and aided by additional diagnostic
imaging studies (PET/CT or MRI). The use of additional diagnostic imaging studies is
dependent on the location of the index lesion and is left to the discretion of the treating
physician.
•
An internal gross tumor volume (IGTV) is defined for mobile index lesions at the discretion of
the treating physician. A 4-D CT scan will be acquired in order to account for the motion of
the lesion during treatment. The IGTV will be defined as the union of the visualized index
lesion on all gated CT data sets.
•
The clinical target volume (CTV) can include a margin of 0-10 mm at the discretion of the
treating physician.
•
The planning target volume (PTV) will be defined as per standard of care.
5.4 Critical Structures
Organ at risk volume (OAR) is contoured as visualized on the planning CT scan.  Applicable 
OARs will be contoured as clinically appropriate based on site treated. 
5.5 Treatment Planning 
•
Any clinically acceptable, standard of care planning technique may be employed to deliver
radiation to the index lesion, including 3D conformal treatment, intensity modulated radiation
therapy, and stereotactic radiosurgery.  Typically, patients should not be treated with two
directly opposed beams due to the volume of tissue receiving high dose radiation, and using
at least 3 beams or 2 non-opposed beams is encouraged.  All plans are subject to review by
the PI.  All dose calculations will include corrections for tissue heterogeneities as specified
by IROC Houston.
Printed on 10/29/2024

14 
•
Dose specifications: at least 95% of the target volume (PTV) is covered by at least 90% of
the prescription dose.
•
Critical Organ Doses: All standard of care critical organ dose-volume limits will be respected.
5.6 Radiation Quality Assurance Reviews
All patients treated on this protocol will undergo standard review in the Department of Radiation 
Oncology.  At least two physicians will review the patient history, imaging findings, tumor 
contours, and radiation plan.   
5.7 Radiation Toxicity 
Toxicity will be graded based on CTCAE 4.0.  
5.8 Criteria for Removal/Withdrawal from Treatment 
Patients will be withdrawn from radiation treatment if their clinical conditions decline so they are 
no longer able to tolerate radiation, or are unlikely to clinically benefit from further therapy. 
Patients will still receive follow up care per standard of care even if they withdraw from the 
study.  If a subject withdraws consent to participate in the study or aspects of the study, 
attempts will be made to obtain permission to record at least survival data up to 6 months post-
treatment.  Details for withdrawal from immunotherapy is detailed below in section 6.1 
6 
Drug Therapy 
Patients will pembrolizumab per standard of care. Prescribing information for pembrolizumab 
can be found at: https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. 
Dose 
modification 
and 
discontinuation 
information 
can 
be 
found 
at: 
https://www.keytruda.com/static/pdf/guide-for-keytruda.pdf.  Standard dosing is 200 mg fixed 
dose IV infusion every 3 weeks. 
6.1 Duration of Therapy  
Pembrolizumab therapy will continue until one or more of the following conditions are met: 
•
The subject withdraws consent.
•
Confirmed radiographic disease progression
•
Unacceptable adverse experiences
•
Intercurrent illness that prevents further administration of treatment
•
Investigator’s decision to withdraw the subject
•
The subject has a confirmed positive serum pregnancy test
•
Noncompliance with trial treatment or procedure requirements
•
The subject is lost to follow-up
•
Administrative reasons
6.2 Pembrolizumab Supportive Care Guidelines 
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15 
Subjects should receive appropriate supportive care measures per standard clinical care as 
deemed necessary by the treating oncologist. Suggested supportive care measures for the 
management of adverse events with potential immunologic etiology are outlined below. Where 
appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids. Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care.  The treatment guidelines are 
intended to be applied when the oncologist determines the events to be related to 
pembrolizumab. 
•
Pneumonitis:
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve
to Grade 1 or less, steroid taper should be started and continued over no less
than 4 weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids. Administer
additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of prolonged
steroid administration.
•
Diarrhea/Colitis: Subjects should be carefully monitored for signs and symptoms of
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without
fever) and of bowel perforation (such as peritoneal signs and ileus).
o
All subjects who experience diarrhea/colitis should be advised to drink liberal
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and
electrolytes should be substituted via IV infusion.
o
For Grade 2 or higher diarrhea, consider GI consultation and endoscopy to
confirm or rule out colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral
corticosteroids.
o
For Grade 3 or 4 diarrhea/colitis treat with intravenous steroids followed by high
dose oral steroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and
continued over no less than 4 weeks.
•
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade
3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA)
o
For T1DM or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for Type I diabetes mellitus
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or
ketonuria.

Evaluate patients with serum glucose and a metabolic panel, urine
ketones, glycosylated hemoglobin, and C-peptide.
•
Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade
1 or less, steroid taper should be started and continued over no less than 4
Printed on 10/29/2024

16 
weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper
should be started and continued over no less than 4 weeks. Replacement of
appropriate hormones may be required as the steroid dose is tapered.
•
Hyperthyroidism or Hypothyroidism: Thyroid disorders can occur at any time during
treatment. Monitor patients for changes in thyroid function (at the start of treatment,
periodically during treatment, and as indicated based on clinical evaluation) and for
clinical signs and symptoms of thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are
suggested as initial therapy.

In 
hypothyroidism, 
thyroid 
hormone 
replacement 
therapy, 
with
levothyroxine or liothyroinine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism

Treat with an initial dose of IV corticosteroid followed by oral
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper
should be started and continued over no less than 4 weeks. Replacement
of appropriate hormones may be required as the steroid dose is tapered.
•
Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned to
baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.
o
When symptoms improve to Grade 1 or less, a steroid taper should be started
and continued over no less than 4 weeks.
•
Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and
continued over no less than 4 weeks.
•
Management of Infusion Reactions: Signs and symptoms usually develop during or
shortly after drug infusion and generally resolve completely within 24 hours of
completion of infusion.
Table 2 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
Table 2. Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
None 
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17 
intervention not indicated 
in the opinion of the oncologist. 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
•
IV fluids
•
Antihistamines
•
NSAIDS
•
Acetaminophen
•
Narcotics
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the oncologist. 
If symptoms resolve within one 
hour of stopping drug infusion, the 
infusion may be restarted at 50% 
of the original infusion rate (e.g., 
from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until 
symptoms resolve and the subject 
should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
Subject may be premedicated 
1.5h (±30 minutes) prior to 
infusion of pembrolizumab 
with: 
• 
Diphenhydramine 50
mg po (or equivalent 
dose of antihistamine). 
•
Acetaminophen 500-
1000 mg po (or
equivalent dose of
antipyretic).
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilator support 
indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
•
IV fluids
•
Antihistamines
•
NSAIDS
•
Acetaminophen
•
Narcotics
•
Oxygen
•
Pressors
•
Corticosteroids
•
Epinephrine
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the oncologist. 
Hospitalization may be indicated. 
Subject is permanently 
No subsequent dosing 
Printed on 10/29/2024

18 
discontinued from further trial 
treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration. 
7 
Adverse Event Reporting Requirements 
7.1 Adverse Event (AE) Reporting 
An AE is any undesirable sign, symptom or medical condition or experience that develops or 
worsens in severity after starting the first dose of study treatment or any procedure specified in 
the protocol, even if the event is not considered to be related to the study. Abnormal laboratory 
values or diagnostic test results constitute AEs only if they induce clinical signs or symptoms or 
require treatment or further diagnostic tests.  
AEs of Grade 3 and above (per CTCAE v4.0) will be monitored and recorded in study-specific 
case report forms (CRFs) in the REDCap system from the time of the first study treatment 
through 30 days following the end of study treatment, or until the patient receives an alternative 
anti-cancer therapy, whichever date comes first. AEs related to tumor biopsies that are done 
solely for research will be monitored, recorded, and reported according to the same standards. 
7.2 Expected Toxicities 
Pembrolizumab will be given per standard of care and toxicity information is available from 
phase III data. Full prescribing information for pembrolizumab can be found at: 
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. 
Neutron radiation will also be given per standard of care at palliative dosing, which is generally 
well tolerated.  Exact toxicity depends on site of treatment and typically includes fatigue and 
dermatitis in the treatment field.   
The grade and severity of the event will be determined using CTCAE v.4.0. The event will be 
determined to be expected or unexpected. The determination of whether an AE is expected is 
based on pembrolizumab-specific adverse event information per prescribing information, as well 
as site specific toxicity listed on radiation treatment consent form for patients receiving radiation 
treatment. Unexpected AEs are those not listed in the agent-specific adverse event information 
nor radiation consent form.  The event will be evaluated for relationship to the medical treatment 
or procedure. The Investigator should document his/her opinion of the relationship of the event 
to study medication as follows: 
• Unrelated- The adverse event is clearly not related to the investigational agent(s).
• Possible-The adverse event may be related to the investigational agent(s).
• Probable-The adverse event is most likely related to the investigational agent(s).
• Definite- The adverse event is clearly related to the investigational agent(s).
Based on this information, institutional guidelines will be followed regarding whether an adverse 
event should be reported as an expedited report in addition to the routinely reported clinical 
data.  
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19 
8 
Data and Safety Monitoring Plan 
Oversight for this study will be provided by the Principal Investigator with delegation of 
appropriate responsibilities to sub-investigators and designated study personnel.  They will 
ensure all entry criteria are met prior to the initiation of the protocol and all study procedures and 
reporting of adverse events are performed according to the IRB-approved protocol.  
8.1 Early Stopping Rules 
Early stopping of this trial will be any grade 5 adverse events (AEs) or multiple (2 or more) 
grade 4 AEs occurring within ≤ 30 days after the end of treatment defined as possibly, probably, 
or definitely related to radiation treatment (per CTCAE, v.4.0).  All AE’s grade 4 or higher must 
be reported to the PI within 24 hours. All grade 3 AEs must be reported to the PI within 48 hours  
8.2 Interim Data Review 
Interim reports with statistical analyses will be prepared twice per year until the initial treatment 
results have been presented or published. In general, the interim reports will contain the 
following information: 
•
Patient accrual rate with a projected completion date (while the study is still accruing)
•
Total patients accrued
•
Frequencies and severity of adverse events
•
Compliance rates of treatment delivery
Institutional support of trial monitoring will be in accordance with the FHCRC/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan.  Under the 
provisions of this plan, FHCRC Clinical Research Support (CRS) coordinates data and 
compliance monitoring conducted by consultants, contract research organizations, or FHCRC 
employees unaffiliated with the conduct of the study.  Independent monitoring visits occur at 
specified intervals determined by the assessed risk level of the study and the findings of 
previous visits per the institutional DSMP.  
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and 
Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and the 
FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB).  The 
review committees evaluate accrual, adverse events, stopping rules, and adherence to the 
applicable data and safety monitoring plan for studies actively enrolling or treating subjects.  
The IRB reviews the study progress and safety information to assess continued acceptability of 
the risk-benefit ratio for human subjects.  Approval of committees as applicable is necessary to 
continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory committees and 
other institutional, state and federal guidelines. 
Printed on 10/29/2024

20 
9 
Data Management/Confidentiality 
The investigator will ensure that data collected conform to all established guidelines. Each 
subject is assigned a unique patient number to assure subject confidentiality. Subjects will not 
be referred to by this number, by name, or by any other individual identifier in any publication or 
external presentation. The licensed medical records department, affiliated with the institution 
where the subject receives medical care, maintains all original inpatient and outpatient chart 
documents. 
Subject research files are stored in a secure place (or database). Access is restricted to 
authorized personnel. 
Printed on 10/29/2024

21 
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