Radiation Enhancement of Local and Systemic Anti-Prostate Cancer Immune Responses
Phase: PHASE2
Conditions: Castration-Sensitive Prostate Carcinoma, Metastatic Malignant Neoplasm in the Bone, Metastatic Prostate Carcinoma, Prostate Adenocarcinoma, Prostate Small Cell Neuroendocrine Carcinoma, Stage IV Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8
Sponsor: University of Washington

CC9938 CLINICAL RESEARCH PROTOCOL 10/19/2020
Fred Hutch IRB
Approved
8/22/2023
FRED HUTCHINSON CANCER RESEARCH CENTER
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE
Radiation Enhancement of Local and Systemic Anti-Prostate Cancer Immune
Responses
Principal Investigator:
Co-Investigators:
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
Evan Y. Yu, MD
Professor, Department of Medicine
Division of Oncology
University of Washington School of Medicine
Seattle Cancer Care Alliance
Ramesh Rengan, MD PhD
Medical Director, SCCA Proton Therapy Center
Professor, Department of Radiation Oncology
University of Washington School of Medicine
Associate Member, Fred Hutchinson Cancer Research
Center
Jay Liao, MD
Associate Professor
Department of Radiation Oncology
University of Washington Medical Center
Kent Wallner, MD
Associate Professor
Department of Radiation Oncology
University of Washington Medical Center
Biostatistician:
Qian (Vicky) Wu, PHD
Assistant Member
Clinical Research Division
Public Health Sciences Division
Fred Hutchinson Cancer Research Center
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CC9938 Protocol Version: October 19, 2020
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Title
Short Title
Protocol Number
Phase
Methodology
Study Duration
Study Center(s)
Objectives
Number of Subjects
Diagnosis and Main
Inclusion Criteria
Study Product, Dose,
Route, Regimen
Duration of
administration
Statistical
Methodology
Study Summary
Radiation Enhancement of Local and Systemic Anti-Prostate Cancer Immune
Responses
Neutron radiation immune response in CSPC
CC9938
Pilot
2 Arm Randomized
2 yrs
University of Washington Medical Center
The primary objective of this study is to assess the systemic immune effects of
radiation with high relative biological effectiveness (RBE) in the form of
neutron radiation, in combination with androgen deprivation therapy (ADT) in
patients with newly diagnosed castration sensitive prostate cancer (CSPC).
Patients on ADT will be randomized to either standard of care abiraterone +
prednisone, or same plus radiation to 1-3 sites of metastatic disease and
undergo blood draws at multiple time points. The primary endpoint will
measure percent change in peripheral blood effector T-cells (CCR7-
/CD45RO-)-post-therapy (3 months after start of ADT, which is also 1 month
post-radiation in the radiation arm).
30 evaluable subjects
Patients diagnosed with CSPC, beginning ADT and abiraterone + prednisone
as first line therapy, eligible for neutron radiation therapy to at least one
metastatic site of disease. Site of radiation does not have to be symptomatic.
All treatments are approved standard of care for patients with CSPC, including
ADT, abiraterone, prednisone, and neutron radiation.
ADT and abiraterone will be given per standard clinical care for at least 6
months or until patients develop progression (unless treating oncologist feels
patient is still deriving benefit from therapy), or intolerable toxicity. Neutron
radiation treatments will be given standard of care as well, for a maximum of 5
daily radiation treatments.
In order to detect an estimated 10% increase in peripheral blood effector T-
cells (CCR7-/CD45RO-)in the neutron arm versus the no radiation arm with a
two-sided type I error rate of 5% and 80% power, while assuming a 10%
standard deviation in each patient group, around 15 patients are required per
arm.
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Table of Contents
1. Introduction                                                                                                                                   4
2. Study Objectives                                                                                                                            8
3. Study Design                                                                                                                                 8
3.1. General Design
3.2. Eligibility
4. Study Registration                                                                                                                         12
5. Radiation Therapy                                                                                                                         12
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. Drug Therapy                                                                                                                                14
6.1 Duration of Therapy
7. Adverse Event Reporting Requirements                                                                                        14
7.1. Adverse Event Reporting
7.2. Expected Toxicities
8. Data and Safety Monitoring Plan                                                                                                  15
8.1. Early Stopping Rules
8.2. Interim Data Review
9. Data Management/Confidentiality                                                                                                16
10. Statistical Considerations                                                                                                              16
10.1. Study Population
10.2. Primary Objective
10.3. Secondary Objectives
10.4. Exploratory Objectives
11. References                                                                                                                                     19
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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.
Prostate cancer has seen limited success with immunotherapy, although there is suggestion of clinical
activity:
Prostate cancer remains the most common cancer in men in the United States and the number three cause
of cancer death1. Most patients initially present with disease that is sensitive to androgen deprivation
therapy (ADT), and for patients who present with metastatic disease, LHRH agonists such as leuprolide
or LHRH antagonists such as degarelix are commonly used as first line treatment.
Recent trials
LATITIDE and STAMPEDE showed that the addition of abiraterone plus prednisone to ADT in
castration sensitive prostate cancer (CSPC) as part of first line therapy can improve survival over ADT
alone.2,3 Response rate to first line ADT is high but many patients eventually develop metastatic
castration resistant prostate cancer (mCRPC) and therapeutic options become more limited. Although
immense strides have been made in systemic therapy options for mCRPC, there has been limited success
with immunotherapy4. Sipuleucel-T remains the only FDA approved immunotherapy for mCRPC5, with
two phase III trials comparing ipilimumab versus placebo unable to improve overall survival6,7. There
was, however, evidence of clinical activity, with superior progression free survival in the ipilimumab arm
in both trials. The trial by Kwon et al., gave standard photon radiation to a bony site prior to ipilimumab,
based on the hypothesis that radiation could stimulate an immune response and enhance the efficacy of
ipilimumab6,8. Multiple trials are ongoing in mCRPC testing new immunotherapy agents, combinations of
immunotherapy agents, as well as immunotherapy plus radiation4.
Radiation therapy could potentially improve survival in metastatic prostate cancer:
Historically, the only role of radiation therapy in metastatic prostate cancer has been for palliation, either
to address existing symptoms (such as pain from a metastasis in the bone), or prevent future symptoms
(such as radiation to the spine to prevent spinal cord compression). However, two trials were published in
2018-2019 that suggest radiation could improve survival in oligometastatic prostate cancer (limited
number of metastatic sites). The STAMPEDE trial randomized men with newly diagnosed metastatic
prostate cancer to standard of care systemic therapy (ADT with or without chemotherapy) plus or minus
radiation to the prostate9. For patients with limited metastatic disease burden, radiation to the prostate
improved overall survival (HR 0·68, 95% CI 0·52–0·90; p=0·007; 3-year survival 73% with control vs
81% with radiotherapy). Another trial called SABR-COMET randomized patients with oligometastatic
cancers (1-5 metastatic lesions) and controlled primary tumors to standard of care systemic therapy,
versus systemic therapy plus aggressive radiation (stereotactic ablative radiation therapy), and found
radiation improved median progression-free survival to 12.0 months from 6.0 months (HR = 0.47, P
= .0012), and median overall survival to 41 months (95% CI = 26 months–not reached) from 28 months
(95% CI = 19–33 months, HR = 0.57, P = .090)10. Prostate cancer was one of cancer types included in the
SABR-COMET trial. Multiple additional randomized trials are ongoing internationally to investigate the
role of radiation in prolonging survival in metastatic prostate cancer.
ADT has been shown to have an effect on the immune response in prostate cancer:
Although the primary anti-tumor effect of ADT on prostate cancer is directly inducing cancer cell
apoptosis, ADT also has an effect on the adaptive immune response.11 Patients on ADT show an increase
in naïve CD4+ T-cells in peripheral blood of almost 50% by 1 month after starting ADT, likely
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attributable to increased thymic output.12 At the same time, CD4+ and CD8+ T-cells show increased
proliferation in response to stimulation, suggesting the T-cells are not only increasing in number but also
responsiveness. This increased proliferation of around 10% was statistically significant in the effector
cell population at 1 month (Figure 1). However, after 2 years of ADT, a decrease was seen in Th1 and
Th17 effector memory subsets in peripheral blood. Therefore, ADT may induce an anti-tumor immune
response early in the treatment course but eventually contribute to an immunosuppressive environment.13
Standard photon radiation combined with immunotherapy augments anti-tumor activity in 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)14. Peripheral blood from patients
with metastatic melanoma receiving 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 monocytes8,15. Clinical reports
have been published with 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 immunotherapy8,16,17. Multiple ongoing trials
are testing the combination of immune check-
point blockade with radiation therapy in a variety
of disease sites (NCT01952769, NCT02289209,
NCT02298946).
Figure 1. Change in peripheral blood in 12 patients on ADT
showing statistically significant increase in effector T-cells
(CD4+/CCR7-/CD45RO-) after 1 month compared with
pretreatment (P). Cells were stimulated with anti-CD3 and anti-
CD28 antibodies. Adapted from Morse and McNeel. Human
Immunology 71 (2010): 496-504.
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 radiations such carbon ions and
fast neutrons.18-20 While the mainstay of radiation treatment worldwide is still photon therapy, particle
therapy is increasingly prevalent. 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 tissues21.
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.19-21 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 more aggressive prostate cancers22, 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 milieu23.
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Immunologic effects of high-RBE radiation compared with standard photon radiation:
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.24-26
High RBE therapy may cause a more immunogenic tumor microenvironment via release of more tumor
neoantigens27,28. 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 dose29.
Immunologic effects of standard photon therapy on patients receiving radiation for prostate cancer:
There is limited data on the immune response of patients with prostate cancer receiving palliative
radiation with standard photon therapy alone, without immunotherapy. Schaue et al., looked at peripheral
blood lymphocytes from 20 patients with localized prostate cancer receiving standard photon radiation
treatment. CD8+ T-cells able to bind survivin, which is overexpressed in prostate cancer, was detected in
peripheral blood and increased after therapy in some patients30.
Nesslinger et al., also looked at
peripheral blood in 73 patients with localized prostate cancer undergoing standard treatments including
standard photon radiation31, and found that 13.8% of patients developed treatment associated
autoantibodies detected via Western blot probing against LNCaP cell lysates. It is possible to detect
changes in immune response in peripheral blood after localized radiation therapy for prostate cancer.
Rationale for combination of ADT, abiraterone+prednisone, and neutron radiation for enhancing the
systemic immune response to prostate cancer:
Both ADT and radiation have been shown to modulate the systemic anti-tumor response. Although ADT
might contribute to an anti-tumor immunologic reaction earlier in the treatment course, the effects may
become more immunosuppressive over time.11      Radiation can also be immunosuppressive given that
lymphocytes are extremely sensitive to radiation killing, but the right dose of radiation to a limited area at
the right time can act similarly to a “vaccine” to enhance or induce an immune reaction.14 Adding a short
course of high-intensity radiation early in the ADT treatment course may enhance and prolong the anti-
tumor immunologic changes seen with ADT.
Although ADT with LHRH agonists or antagonists alone have been standard of care first-line therapy in
CSPC for years, results from LATITUDE and STAMPEDE show that the addition of abiraterone +
prednisone improves survival over ADT alone even in the first-line setting, and this treatment
combination is increasingly used to treat patients with newly diagnosed metastatic prostate cancer.2,3
Little is currently known regarding the immunologic effects of abiraterone + prednisone and there are
concerns about immunosuppressive effects of the low dose prednisone given with abiraterone. However,
a randomized phase 2 trial of sipuleucel-T with abiraterone + prednisone showed that concurrent
administration of both therapies did not blunt or alter the immune parameters seen with sipuleucel-T.32 In
vitro studies of abiraterone show it sensitizes prostate tumor cells to T-cell mediated lysis via an
androgen-receptor dependent pathway,33 and can act synergistically with immunotherapy in a mouse
model to control prostate tumors.34     Large series of patients treated with checkpoint inhibitor
immunotherapy needing immunosuppressive therapy (prednisone taper) to manage toxicity have shown
that treatment efficacy is not diminished in patients who received immunosuppressive therapy versus
those who did not, suggesting low dose prednisone does not negate the changes and benefits of
immunotherapy.35,36 It is also plausible that the addition of abiraterone to the treatment regimen induces a
more robust immune response, as testosterone levels are lowered approximately 1-2 logs lower than can
be achieved with LHRH therapy alone37. Therefore, we propose this study to look at the ability of neutron
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typically had a low tumor
burden and higher fold
change in Ki67+ CD8
arbitrary cutoff of 2.2 fold
to a single index lesion and 4 cycles of anti-CTLA4
1+Eomes+CD8 T cells that are Ki67+GzmB+ after
treatment. Each circle represents a patient.
of immunotherapy. Adapted from
Sander FE et al. Oncotarget. 2016.
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radiation to enhance the anti-tumor immunologic changes seen with ADT plus abiraterone and prednisone
in first line therapy for advanced castration sensitive prostate cancer.
Rationale for peripheral blood effector T-cells as surrogate endpoint for systemic immune response:
Various studies have reported on correlations between changes in peripheral blood immune cell subsets
and clinical outcomes, with no current consensus on the most important population changes for prognosis
prediction. However, multiple studies have shown that an increase in peripheral effector T-cells is
correlated with improved clinical outcomes. Sander et al. looked at peripheral blood of 84 patients with
acute myeloid leukemia who were in first remission after chemotherapy, starting maintenance
immunotherapy with low dose IL-2 and histamine dihydrochloride38.
When comparing peripheral cell counts before and after the first
treatment cycle (C1D1 versus C1D21) as shown in Figure 2, patients
who did not ultimately develop disease relapse had an increase in
effector T-cells (CCR7-/CD8 T-cells) of approximately 10%, versus no
significant change in peripheral effector T-cell percentage in patients
who did develop disease relapse.
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 Figure 2. Change in percent CCR7-
receiving anti-PD-1 antibody pembrolizumab39.
At 3-weeks into CD8 effector T-cells after first cycle
therapy, frequency of Ki67+ CD8 effector 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 effector 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
3).
Clinical
response was correlated
with the fold change of
PD-1+        Ki67+        CD8
effector T-cells after anti-
PD-1 therapy, adjusted for
baseline tumor burden. Figure 3. Change in percent
Patients with longer PFS 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.
Figure 4. Change in peripheral blood in 10 patients
effector T-cells. Using an Nature 2017 (545):60-65.
with metastatic melanoma receiving photon radiation        change in Ki67+ PD-1+ CD8 T-cells after anti-PD-1
therapy. Percentage of Eomes+PD-1+ CD8 T cells in         therapy at weeks 3-12 compared to baseline, response rate
post-treatment blood vs change in%PD-                              was 40% (8/20) for patients with Ki67 change above the
fold, and 29% (2/7) for patients below the fold. T-cell
Progression-free survival (PFS) is proportional to
receptor repertoire was compared between pretreatment
circle size and quadrant boundaries are average values
tumor infiltrating T-cells and peripheral blood CD8 T-
for patients under the mean PFS. Concordance index
cells. Across 6 patients, at peak Ki67 expression after
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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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 effector
T-cells may peak around weeks 3-6 and be related to clinical outcome.
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
ipilimumab15. 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 effector T-cells after treatment (6-12%
increase), while the proportion of PD-1+ Eomes+ T-cells remained at or below the mean (Fig. 4). 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.
Taken together, the studies above suggest that it is possible to detect changes in effector T-cell
populations in the peripheral blood in response to therapies that affect the immune system, and increase in
effector T-cells may be correlated with improved clinical outcomes.
2
Study Objectives
Primary Objective:
Compare the percent change in peripheral blood effector T-cells (CCR7-/CD45RO-) between the ADT+
abiraterone arm and the ADT+ abiraterone+ radiation arm, measured at immediately prior to starting
abiraterone, and 1 month after start of abiraterone (which is also about 1 month after radiation treatment
in the radiation arm).
Secondary Objectives:

To evaluate the rate of patients with undetectable PSA (<0.2 ng/mL) at 6-months after start of
abiraterone.

To evaluate the frequency and severity of toxicities as measured by CTCAE 4.0.
Exploratory Objectives:

Changes in peripheral blood immune cell subpopulations measured via multi-parameter flow
cytometry at all specimen collection time points:
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.
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Randomization
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
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 (of an untreated site) in select patients who consent will be assessed for: cell death,
tumor infiltrating lymphocytes, expression of cell surface markers including HLA, PDL1, and
undergo multiparameter flow cytometry as well as TCR sequencing.
3
Study Design
3.1. General Design
This is a pilot study to test whether densely ionizing, high relative biological effectiveness (RBE)
radiation in the form of neutron radiation, can induce a more robust systemic immune response in
combination with ADT plus abiraterone + prednisone, than ADT plus abiraterone + prednisone alone, in
patients with advanced CSPC. The long-term goal is to improve the response rate to systemic therapy
with addition of focal radiation treatment as a “vaccine”. Trial schema is shown below in Figure 5 and
study calendar in Table 1. Patients with CSPC about to receive ADT plus abiraterone + prednisone
therapy as first-line treatment, and eligible to receive radiation treatment to 1-3 sites of disease, will be
enrolled and randomized onto one of 2 arms: 1) ADT plus abiraterone + prednisone alone; or 2) ADT
plus abiraterone + prednisone and neutron radiation.
Patients with
advanced
CSPC, starting
ADT plus
abiraterone +
prednisone as
first-line
therapy, and
eligible for
radiation
2 months
Start ADT
Arm 1: ADT plus abiraterone + prednisone
1 month
3 months
Start abiraterone + prednisone
Arm 2: Radiation + ADT plus abiraterone + prednisone
1 month
3 months
Radiation AND Start abiraterone + prednisone
= Peripheral blood draw
Figure 5. Clinical trial schema.
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2-Months After
Start of ADT4
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Table 1. Study Calendar
Informed
Consent
1-Month After Start 4-Months After Start Every 4-Weeks9 Until
of Abiraterone+          of Abiraterone+       6-Months After Start
Prednisone7
Prednisone8
of Abiraterone
X
Medical History
Physical Exam
ECOG
Performance
Status
Blood Draw1
Radiation
Treatment
Tumor biopsy
(optional)2
PSA
CT C/A/P3
Survival
X
X
X
X
X
X
X
X
X
X5
X
X
X6
X
X
X
X
X
X
X
X
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 non-radiated site will be performed for patients who consent.
3CT C/A/P is preferred but MRI or PET/CT also acceptable.
4Patients may be enrolled onto the trial up to 2 months after starting ADT, and ADT starts from the first
dose of LHRH agonists or antagonists. Patients must be enrolled prior to starting radiation treatment since
randomization must occur to determine if patient will receive radiation treatment. All pre-treatment
assessments must be performed within 30 days of protocol enrollment, except CT C/A/P which must be
within 60 days of protocol enrollment.
5First blood draw must take place after at least 7 weeks on ADT and be ≤1week prior to starting radiation
or abiraterone.
6Radiation treatment can happen between 8-10 weeks after starting ADT and must happen within 1-week
of starting abiraterone (could be either before or after).
7Acceptable date range is 3-5 weeks.
8Acceptable date range is 3-5 months.
9Acceptable date range is every 3-6 weeks.
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Time points for peripheral blood collection are based on prior studies, including Twyman-Saint Victor et
al.15,that show changes in peripheral blood immune cell populations after radiation treatment peak around
2-4 weeks but can persist for months after treatment. Tumor biopsy of a non-radiated site will be
performed for patients who consent, pre-radiation treatment and post-radiation treatment (2-4 weeks after
radiation).
After completion of radiation treatment, patients will continue to obtain PSA checks every 4 weeks per
standard of care until 6 months after start of abiraterone (see study calendar in Table 1), and a research
coordinator will collect survival data until that point. Patient may be followed by local physicians and
does not have to be seen within the UWMC/SCCA system, but will give permission for outside medical
records to be obtained. Patients are considered off-study as defined under section 6.1 Duration of
Therapy.
3.2. Eligibility Criteria
A. Inclusion Criteria

Pathologically proven (either histologic or cytologic) diagnosis of prostate adenocarcinoma with
<50% neuroendocrine differentiation or small cell histology

At least one site of nodal or distant metastatic disease that is measurable by RECIST 1.1 criteria, or a
bony metastasis that is evaluable on both CT and bone scan

No prior orchiectomy.

No androgen deprivation therapy such as treatment with antiandrogens, LHRH agonists or antagonists
for at least one year prior to trial enrollment, and testosterone must be inside normal range prior to
trial enrollment if there is prior history of ADT.

No other systemic anti-cancer therapy, including ADT, for at least 1-year prior to enrollment.

Prior prostate-directed therapies such as prostatectomy or cryotherapy are allowed.

Prior radiation treatments are allowed (prostate or metastatic sites) but must have been completed at
least 3 months prior to starting ADT for this trial.

Patients must have normal organ and marrow function as defined below:
o WBC>3000/mm3
o ANC>1000/mm3
o Platelets > 100,000/mm3
o Creatinine <1.5 institutional ULN or calculated creatinine clearance >30 ml/min
o AST, ALT, and total bilirubin < 3x institutional ULN (unless patient has documented
Gilbert’s syndrome)

No steroids for at least 2 weeks prior to enrollment, and patient must not be expected to require
steroids during the study period, other than the typical low dose steroid that is given with abiraterone
(typically prednisone or prednisolone at 5 mg twice daily).

Zubrod Performance Status 0-2

Age ≥ 18

Patient must sign study specific informed consent prior to study entry

Men who are sexually active must use medically acceptable forms of contraception
B. Exclusion Criteria

Other illnesses with a life expectancy of less than 6 months, including but not limited to unstable
angina, symptomatic congestive heart failure, cardiac arrhythmias.

Psychological or social issues that would prevent patients from informed consent or complying with
study requirements.
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
Subject has a history of unexplained loss of consciousness or transient ischemic attack within 12
months of treatment start.

Individuals on active treatment for a different cancer are excluded. Individuals with a history of other
malignancies are eligible if they are deemed by the investigator to be at low risk for recurrence of that
malignancy.

Known brain metastasis.

Known allergies, hypersensitivity, or intolerance to abiraterone or prednisone.

Prior ADT less than a year, or greater than two months, prior to trial enrollment or prior ADT with
testosterone less than normal.

Must not have a gastrointestinal condition that would interfere with absorption.

There is a potential drug interaction when abiraterone is concomitantly used with a CYP2D6 substrate
narrow therapeutic index (e.g., thioridazine, dextromethorphan), or strong CYP3A4 inhibitors (e.g.,
atazanavir, erythromycin, indinavir, itraconazole, Ketoconazole, nefazodone, nelfinavir, ritonavir,
saquinavir, telithromycin, and voriconazole) or strong inducers (e.g., carbamazepine, Phenobarbital,
phenytoin, rifabutin, rifampin, rifapentine). Caution should be used when patients are on one of these
drugs.

Patients with a history of pituitary or adrenal dysfunction, active or symptomatic viral hepatitis, HIV,
or chronic liver disease are not eligible.

Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg
prednisone/prednisolone once daily
4
Study Registration
Subjects will be registered by the FHCRC/UW Study Coordinator and entered into the OnCore Clinical
Trial Management System (CTMS). 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.
5.1. Dose Specifications
Radiation treatments will meet all requirements considered standard clinical care. Although the neutron
radiation treatment is the study procedure in this clinical trial, it is routinely given as standard clinical care
in patients with metastatic prostate cancer, either for palliation of existing symptoms (such as pain from a
bone metastasis), or to prevent development of symptoms from a metastatic lesion (such as preventing
future fracture from a bone metastasis), or to potentially improve survival (as seen in the STAMPEDE
and SABR-COMET trials discussed in the Introduction section). The exact role of radiation therapy in
metastatic prostate cancer is controversial (multiple randomized studies are ongoing) and both arms of
this study are acceptable as 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, 2.7 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.
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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 or MR 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.

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
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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 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.
6
Drug Therapy
Patients will receive ADT and abiraterone + prednisone per standard of care with medical oncology.

ADT will be given as LHRH agonists or antagonists (i.e. leuprolide).

First-generation androgen receptor antagonists such as bicalutamide may be given for up to two
months concurrently when the LHRH agonist is started, but must be discontinued after two
months to minimize potential immunologic impact on subsequent radiation treatment.

Abiraterone acetate will be given per standard clinical care, with prednisone.

Dose adjustments are allowed at the discretion of the treating oncologist after patients have
started on treatment.

No other anti-cancer therapy may be administered during the study.

Bone protective therapy with zoledronic acid or denosumab is allowed.
Abiraterone + prednisone will be administered for at least 6 months, or until disease progression as
defined below, unless treating oncologist feels patient is still deriving a benefit from therapy:

PSA progression per PCWG3 criteria: ≥ 25% and ≥ 2 ng/mL above the nadir, confirmed by a
second value ≥ 3 weeks later

Radiographic progression based on RECIST 1.1 and PCWG3 criteria

Symptomatic progression e.g. worsening pain or investigator discretion
6.1. Duration of Therapy

Disease progression (see above under section 6. Drug Therapy) unless treating oncologist feels
patient is still deriving a benefit from therapy.

Intercurrent illness that prevents further administration of treatment.

Unacceptable adverse event(s).

Subject decides to withdraw from the study.

General or specific changes in the subject's condition render the patient unacceptable for further
treatment in the judgment of the investigator.
7
Adverse Event Reporting Requirements
7.1. Adverse Event (AE) Reporting
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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
ADT and abiraterone + prednisone will be given per standard of care and is generally well-tolerated based
on
phase
III
data.
Full
prescribing
information
for
abiraterone
can
be
found
at:
https://www.zytiga.com/shared/product/zytiga/zytiga-prescribing-information.pdf.
Prescribing information for prednisone can be found at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202020s000lbl.pdf,
Prescribing information for leuprolide can be found at: http://www.rxabbvie.com/pdf/lupronuro_pi.pdf.
Neutron radiation will also be given per standard of care at palliative dosing, which is also 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 ADT,
abiraterone, and prednisone-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.
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
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Early stopping of this trial will be any grade 5 adverse events (AEs) or multiple grade 4 (2 or more) 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 3 or higher must be reported to the PI within 24
hours.
8.2. Interim Data Review
All immunologic correlate analysis will be batched. Interim reports 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.
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.
10
Statistical Considerations
10.1. Study Population
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This is a pilot study comparing the immunologic response to neutron radiation plus ADT and abiraterone
+ prednisone versus ADT and abiraterone + prednisone alone. Patients are expected to receive ADT per
standard clinical care, and study enrollment is allowed up to two months on ADT. After enrollment,
patients are randomized in a 1:1 ratio to two arms to receive either: 1) abiraterone in addition to ADT, or
2) abiraterone+radiation in addition to ADT. There will not be stratification factors. Target accrual is 30
patients receiving treatment per randomization. If a patient enrolls but cannot be randomized or cannot
receive treatment per randomization, they will be off study. Data analysis will be per treatment arm.
10.2. Primary Objective
The primary objective will compare the percent change in peripheral blood effector T-cells (CCR7-
/CD45RO-) between the ADT+abiraterone arm and the ADT+abiraterone+radiation arm, measured at
immediately prior to starting abiraterone, and 1 month after start of abiraterone (which is also about 1
month after radiation treatment in the radiation arm). Percent change in peripheral blood effector T-cells
will be calculated by measuring the difference of the percent peripheral blood effector T-cells for each
patient between two time points: pre-abiraterone treatment and 1 month post-abiraterone treatment (which
is also 1 month post-radiation in the radiation arm). No one has published on the effect of abiraterone on
immune cell populations in the peripheral blood. Depending on distribution of the percent change,
unpaired two-sample t-test, or Wilcoxon rank-sum test, or log transformation will be used to test the null
hypothesis that the percent change in peripheral blood effector T-cells is equal between the two arms.
In order to detect an estimated 10% larger increase in peripheral blood effector T-cells (CCR7-
/CD45RO-) in the radiation arm versus the no radiation arm at 1-month post-abiraterone+radiation, to
achieve 80% power at two-sided type I error of 5%, while assuming a 10% standard deviation in each
patient group, around 15 patients are required per arm. A study by Morse et al. described above in
section 1 saw approximately 10% increase in peripheral blood effector T-cells (CCR7-/CD45RO-) in
response to ADT in patients with prostate cancer at 1-month after starting ADT. Abiraterone further
suppresses testosterone levels in addition to ADT and could cause further changes in peripheral blood
effector T-cells. Multiple other studies referenced above in section 1 show that an approximately 10%
increase in peripheral blood T-cells could be correlated with improved clinical outcomes.
10.3. Secondary Objectives

To evaluate the rate of patients with undetectable PSA (<0.2 ng/mL) at 6-months after start of
abiraterone.
o This rate will be calculated using Kaplan-Meier estimates and reported for all patients on the
trial and for each treatment arm individually. Based on past publications in patients receiving
ADT+abiraterone as first-line therapy, the expected rate of undetectable PSA at 6-months is
around 95%2. This study is not powered to detect a difference between the two arms in this
endpoint, and no comparison is planned for this endpoint between the two arms.

To evaluate the frequency and severity of toxicities as measured by CTCAE 4.0.
o Descriptive statistics will be used to report the frequency and severity of toxicities for all
patients on the trial and for each treatment arm individually.
o Based on past publications in patients receiving ADT+abiraterone as first-line therapy2, 99%
of patients are expected to experience toxicity of any grade, with approximately 50% of
patients experiencing grade 3 or higher toxicity.
o The most common toxicities of any grade include hot flashes (90%), fatigue (77%),
musculoskeletal disorders (72%), impotence (55%), blood count changes (45%), and
cardiovascular disorders (43%).
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o The most common grade 3 or higher toxicities include endocrine disorders (including hot
flashes and impotence) 15%, cardiovascular disorders (10%), musculoskeletal disorders
(7%), and hepatic disorders (7%).
o The radiation treatment is expected to cause toxicity related to palliative radiation, which are
usually mild and transient. Typical toxicities include grade 2 or less fatigue and dermatitis.
Depending on body site treated, nausea, esophagitis, and musculoskeletal pain can also be
seen.
10.4. Exploratory Objectives

Changes in peripheral blood immune cell subpopulations measured via multi-parameter flow
cytometry at all three specimen collection time points will be compared between the arms. Percent of
each immune cell subpopulation in the peripheral blood will be calculated at three time points for
each patient: pre-abiraterone treatment, 1 month post-abiraterone treatment (which is also 1 month
post-radiation in the radiation arm), and 4 months post-abiraterone treatment (also 4 months post-
radiation in the radiation arm). The percent change from pre-treatment to 1-month post-treatment,
and the percent change from pre-treatment to 4-months post-treatment will be calculated for each
patient and compared between the two arms. No one has published on the effect of abiraterone on
immune cell populations in the peripheral blood. Depending on distribution of the percent change,
unpaired two-sample t-test, or Wilcoxon rank-sum test, or log transformation will be used to test the
null hypothesis that the percent change in peripheral blood immune cell subpopulations is equal
between the two arms.
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 (TCR)-β locus in genomic DNA from sorted CD4+
and CD8+ T cell subsets from blood samples using the TRB ImmunoSeq kit (Adaptive
Biotechnologies). TCR diversity and clonality for each patient will be compared at the three sample
collection time points: pre-abiraterone treatment, 1 month post-abiraterone treatment (which is also 1
month post-radiation in the radiation arm), and 4 months post-abiraterone treatment (also 4 months
post-radiation in the radiation arm). Hypothesis generating differences will be sought between the
two treatment arms. With 15 patients per arm, we do not expect statistically significant differences
between the two arms.

Tumor biopsies (of an untreated site) in select patients who consent will be assessed for: cell death,
tumor infiltrating lymphocytes, expression of cell surface markers including HLA, PDL1, and
undergo multiparameter flow cytometry as well as TCR sequencing. TCR clonotypes will be
compared in tumor biopsies and peripheral blood.
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