Conditions: Metastatic Cancer
Keywords: stereotactic body radiation therapy checkpoint blockade immunotherapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 106
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether stereotactic body radiation therapy (SBRT) combined with checkpoint blockaded immunotherapy (CBI) will improve the response to the anticancer treatment compared to CBI alone in patients with advanced metastatic cancer.

Detailed description:
Patients who will receive anti-PD-1/PD-L1 immunotherapy with at least 1 site of measurable metastatic disease which will not be irradiated will be candidates for the study. Patients will be randomized (1:1) to CBI combined with SBRT or CBI alone. SBRT at 9.5Gy x3 fractions will be delivered within 1-21 days of the start of first cycle of CBI. The first six patients will be treated and observed for toxicity in the safety run-in phase for 30 days after radiation before continuing with further accrual. Radiation dose reduction is allowed if necessary to meet tissue constraints (6Gyx3 Minimum Dose). Response rates will be determined from the non-irradiated lesion/lesions. Blood draws will be obtained to analyze anti-tumor immune responses.

Arms:
arm 1: Checkpoint blockade immunotherapy (CBI) plus stereotactic body radiation therapy (SBRT) arm 2: Checkpoint blockade immunotherapy (CBI) alone

Interventions: intervention 1: Checkpoint blockade immunotherapy intervention 2: Checkpoint blockade immunotherapy plus SBRT
Intervention descriptions: intervention 1: Approved Checkpoint blockade immunotherapy (including anti-CTLA-4 and anti-PD-1/PD-L1 antibodies) intervention 2: SBRT at 28.5 Gy (9.5 Gy x3 fractions) will be delivered within 1 - 21 days of the start of Cycle 1 of the CBI plus CBI (approved CBIs including anti-CTLA-4 and anti-PD-1/PD-L1 antibodies)

Protocol document:
Prot_SAP_000.pdf: 
Randomized Phase II Study of Checkpoint Blockade Immunotherapy combined 
with Stereotactic Body Radiation Therapy in Advanced Metastatic Disease 
NCT Number: NCT02843165 
Document Date: March 4, 2019 (Version 9.0) 


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
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Randomized Phase II Study of Checkpoint Blockade 
Immunotherapy combined with Stereotactic Body 
Radiation Therapy in Advanced Metastatic Disease. 
IND Number
IND Exempt
Principal Investigator
Andrew Sharabi, M.D., Ph.D.
UC San Diego Moores Cancer Center
3855 Health Sciences Drive
La Jolla, CA 92093
Phone: (858) 822-6040
Email: ansharabi@ucsd.edu
Participating Research Sites:
University of California, San Diego
Rady Children’s Hospital, San Diego
Eisenhower Medical Center
Statisticians:
Chen Hu (JHU)
Amanda Blackford (JHU)
James Proudfoot
Project Manager: 
Ceonne Kim
Trial Coordinator: 
Daisy Perez
Regulatory Manager:
Renée Bailey, MA


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Table of Contents 
SCHEMA........................................................................................................................................................................4
1.
PROTOCOL SYNOPSIS........................................................................................................................................... 5
2.
ABBREVIATIONS AND DEFINITIONS OF TERMS......................................................................................... 6
3.
OBJECTIVES ......................................................................................................................................................7
3.1
PRIMARY OBJECTIVE....................................................................................................................................7
3.2
SECONDARY OBJECTIVES .............................................................................................................................7
4.
BACKGROUND .........................................................................................................................................................7
4.1
CANCER IMMUNOTHERAPY AND THE IMMUNE SYSTEM .................................................................................7
4.2
STEREOTACTIC BODY RADIATION THERAPY (SBRT)...................................................................................... 9
4.3
CHECKPOINT BLOCKADE IMMUNOTHERAPY (CBI) ...................................................................................... 11
4.4
SBRT COMBINED WITH CBI AND THE ABSCOPAL EFFECT ........................................................................... 12
5.
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES........................................................... 14
5.1
INCLUSION CRITERIA..................................................................................................................................14
5.2
EXCLUSION CRITERIA.................................................................................................................................15
6.
TREATMENT PLAN............................................................................................................................................... 15
6.1
DIAGNOSTIC PROCEDURES .........................................................................................................................15
6.2
THERAPEUTIC PROCEDURES .......................................................................................................................15
6.3
FOLLOW-UP PROCEDURES..........................................................................................................................17
6.4
DURATION OF THERAPY .............................................................................................................................17
6.5
DURATION OF FOLLOW-UP.........................................................................................................................17
6.6
CRITERIA FOR PATIENT REMOVAL ..................................................................................................17
6.7
Alternatives .…………………………………………………………………………..17
6.8
COSTS.........................................................................................................................................................18
6.9
COMPENSATION..........................................................................................................................................18
6.10
WITHDRAWAL FROM STUDY .............................................................................................................18
7.
CHECKPOINT BLOCKADE IMMUNOTHERAPY DRUG INFORMATION ............................................18
7.1
ANTI-CTLA-4 DRUG INFORMATION AND ADMINISTRATION ...................................................................... 18
7.2
ANTI-PD-1/ ANTI-PD-L1 DRUG INFORMATION AND ADMINISTRATION.................................................... 21
8.
DOSING DELAYS/DOSE MODIFICATIONS AND DISCONTINUATION CRITERION......................... 24
9.
CORRELATIVE/SPECIAL STUDIES.................................................................................................................. 26
9.1
Blood Sample Transport, Processing, and Storage............................................................................................................................26
9.2               Assessment of Immune Reponses ...………………………………………………………. …………. 26
10.
STUDY CALENDAR ............................................................................................................................................... 28
11.
MEASUREMENT OF EFFECT............................................................................................................................. 29
11.1
ANTITUMOR EFFECT-SOLID TUMORS .........................................................................................................29
11.2
DEFINITIONS...............................................................................................................................................29
11.3
DISEASE PARAMETERS ......................................................................................................                         29
11.4
METHODS FOR EVALUATION OF MEASURABLE DISEASE ............................................................................30
11.5
RESPONSE CRITERIA (VIA RECIST 1.1)......................................................................................................30


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12.
ADVERSE EVENT REPORTING REQUIREMENTS.................................................................................... 32
12.1
GENERAL....................................................................................................................................................32
12.2
DEFINITIONS...............................................................................................................................................32
12.3
POTENTIAL ADVERSE EVENTS ....................................................................................................................33
12.4
STEREOTACTIC BODY RADIATION TREATMENT..........................................................................................34
12.5
REPORTING PROCEDURES ...........................................................................................................................34
13.
DATA AND SAFETY MONITORING PLAN................................................................................................... 35
14.
REGULATORY CONSIDERATIONS ............................................................................................................... 35
14.1
PROTOCOL REVIEW AND AMENDMENTS.....................................................................................................35
14.2
INFORMED CONSENT ..................................................................................................................................35
14.3
ETHICS AND GCP........................................................................................................................................36
15.
STATISTICAL CONSIDERATIONS................................................................................................................. 36
15.1
ENDPOINTS.................................................................................................................................................36
15.2
SAMPLE SIZE/ACCRUAL RATE ....................................................................................................................37
15.3
SAFETY RUN-IN PHASE...............................................................................................................................37
15.4
EARLY STOPPING GUIDELINES....................................................................................................................37
15.5
ANALYSIS OF PRIMARY OBJECTIVE ............................................................................................................37
15.6
ANALYSIS OF SECONDARY OBJECTIVES......................................................................................................38
15.7
EVALUATION OF TOXICITY .........................................................................................................................38
15.8
EVALUATION OF RESPONSE ........................................................................................................................38
REFERENCES:................................................................................................................................................................ 39


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1. PROTOCOL SYNOPSIS 
TITLE
Randomized Phase II Study of Checkpoint Blockade 
Immunotherapy combined with Stereotactic Body 
Radiation Therapy in Advanced Metastatic Disease.
STUDY PHASE
Phase II
INDICATION
Patients who will receive CBI immunotherapy with at least 1 
site of measurable metastatic disease which will not be 
irradiated. 
PRIMARY OBJECTIVE
x
To determine whether SBRT combined with 
concurrent CBI improves the relative objective 
response rate (CR+PR) compared to CBI alone in 
patients with metastatic disease. 
SECONDARY OBJECTIVES
x
To assess the safety and toxicity of CBI used
concurrently with SBRT delivered in 3 fractions in 
patients with metastatic disease
x
To determine the progression free survival, overall 
survival, and rate of stable disease greater than or 
equal to 6 months in patients after completion of
SBRT in combination with CBI
x
To assess whether SBRT combined with concurrent 
CBI results in improvements in anti-tumor immune 
responses compared to CBI alone
HYPOTHESIS
Concurrent SBRT and CBI will increase the relative
objective response (CR+PR) rate by at least 33% 
compared to CBI alone. 
STUDY DESIGN
Patients who will receive CBI and have at least 1 site of 
measurable metastatic disease which will not be irradiated 
will be candidates for study. Patients will be randomized
(1:1) to CBI combined with SBRT or CBI alone. SBRT at 
9.5Gy x3 fractions will be delivered within 1-21 days of the 
start of Cycle #1 of CBI. The first six patients will be 
treated and observed for toxicity in the safety run-in phase
for 30 days after radiation before continuing with further 
accrual. Radiation dose reduction is allowed if necessary to 
meet tissue constraints (6Gyx3 Minimum Dose). Response 
rates will be determined from the non-irradiated
lesion/lesions and three blood draws will be obtained to 
analyze anti-tumor immune responses.
SAMPLE SIZE BY
TREATMENT GROUP
73 patients per group (146 patients total)


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SUMMARY OF SUBJECT
ELIGIBILITY CRITERIA
1. At least 1 site of measurable metastatic disease which will 
not be irradiated.
2. Plan to treat patient with CBI
3. Age > 3 years.
4. Lansky scale score of DJHV  3 or < 16 years) 
    OR
    .DUQRIVN\VFDOHVFRUHRIDJHV  16 or < 18
    years)
    OR
    ECOG performance VWDWXV (18 years or older).
5. Histologic confirmation of malignancy (primary or
metastatic tumor).
CBI PRODUCT DOSAGE
AND ADMINISTRATION
Commercially available checkpoint blockade 
immunotherapy will be administered intravenously as 
clinically indicated. 
CONTROL GROUP
CBI Alone
PROCEDURES
1. Physical exam
2. Three Research Blood draws
3. CT or MRI of Involved Site
4. PET-CT (optional)
5. SBRT
6. IV CBI administration
2. ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation
Definition
ADL
Activities of daily living
AE
Adverse event
BID
Twice daily
BSA
Body surface area
BMP
Basic Metabolic Panel
CBI
Checkpoint Blockade Immunotherapy
CBC
Complete blood count
CI
Confidence interval
CMAX
Maximum concentration of drug
CNS
Central nervous system
CRF
Case report/Record form
CR
Complete response
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
GI
Gastrointestinal


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Hgb
Hemoglobin
HPF
High-power field
HTN
Hypertension
IRB
Institutional Review Board
IV
Intravenous
LLN
Lower limit of normal
LFT
Liver Function Tests
MTD
Maximum tolerated dose
OS
Overall survival
PLT
Platelet
PD
Progressive disease
PFS
Progression free survival
PR
Partial response
QD
Once daily
RECIST
Response evaluation criteria in solid tumors
RR
Response rate
SAE
Serious adverse event
SBRT
Stereotactic body radiation therapy
SD
Stable disease
TTP
Time to progression
ULN
Upper limit of normal
UNK
Unknown
WBC
White blood cell
WHO
World Health Organization
3. OBJECTIVES 
3.1
Primary Objective
3.1.1  To determine whether SBRT combined with concurrent CBI improves the
relative objective response rate compared to CBI alone in patients with 
metastatic disease.
3.2
Secondary Objectives 
3.2.1  To assess the safety and toxicity of CBI used concurrently with SBRT delivered 
in 3 fractions in patients with metastatic disease
3.2.2  To assess progression free survival, overall survival, and rates of stable disease 
greater than or equal to 6 months in patients after completion of SBRT in 
combination with CBI
3.2.3  To determine whether SBRT combined with concurrent CBI results in 
improvements in anti-tumor immune responses compared to CBI alone
4. BACKGROUND 


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4.1
Cancer Immunotherapy and Immune System
The primary modalities of cancer treatment are Surgery, Chemotherapy, and 
Radiation therapy. Unfortunately, cancer continues to rise as a primary cause of death 
in the United States because these current modalities are unable to cure most patients 
once cancer has metastasized[1]. Recently the field of immunotherapy has gained 
significant interest as basic science discoveries have been translated to FDA 
approved clinical therapies, including checkpoint blockade immunotherapy[2, 3].
Checkpoint Blockade Immunotherapy (CBI), including anti-CTLA-4 and anti-PD-
1/PD-L1 antibodies, has received mainstream attention due to the potential for 
dramatic and durable clinical responses in certain patients with metastatic disease[4-
6]. CBI is now FDA approved for melanoma and lung cancers and is helping to 
establish immunotherapy as a new fourth modality of cancer care. Unfortunately, not 
all patients respond to single agent or dual agent CBI and the activity of current 
agents appears to be limited to certain disease types. Thus the next logical step is 
combining CBI with surgery, chemotherapy or radiation therapy and understanding 
how to best incorporate immunotherapy into palliative and definitive treatment 
regimens[7, 8].
It is now widely accepted that the immune system plays a critical role in tumor 
biology, as described by the three E's of cancer immunoediting, elimination, 
equilibrium, and escape[9]. The term elimination represents the classical paradigm 
of immuno-surveillance, where the immune system is seeking and eradicating cells 
which have undergone malignant transformation. Equilibrium represents a dynamic 
state potentially lasting years where malignant cells under internal and external stress 
adapt and respond to survive while interacting and modulating the immune system. 
Tumor escape denotes a phase where select cancer cells have overcome barriers to 
continued growth and can proliferate and spread in an immunocompetent host. As 
these interactions between the immune system and cancer cells becomes better 
understood additional targets and strategies for immuno-modulation have been 
discovered and translated for clinical benefit. Immunotherapy aims to provide a 
highly specific, efficacious, and well tolerated anti-cancer therapy. However, until 
very recently most immunotherapy approaches have not proven to be very potent. 
Methods which enhance the induction and potency of the immune response are 
needed in order to continue the progress of immunotherapy in the clinic.
Development of an immune response is a complex and highly regulated process 
which involves interaction of multiple different cell types. In a simplified example, an 
antigen presenting cell (APC) such as a macrophage or dendritic cell (DC) captures 
an antigen which it then presents via MHC on the cell surface[10]. The APC then 
migrates back to a lymph node where it interacts with CD4 T-helper cells. The T-cell 
receptor binds to the antigen presented on MHC and in the presence of proper co-
stimulation, a T- or B-cell is then signaled to propagate an immune response resulting 
in development of cytotoxic effector T-cells or tumor specific antibodies, 
respectively. There are classically two signals which are needed in order to induce a 
specific immune response: Signal 1 is the antigen; Signal 2 is the co-stimulatory 


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surface molecule. Professional APCs including DCs are the most potent antigen 
presenting cells capable of inducing immune responses due to their high antigen 
presentation capacity, high expression of co-stimulatory molecules and ability to 
secrete significant levels of co-stimulatory cytokines. The presence of these co-
stimulatory molecules cannot be understated as DCs, which do not express co-
stimulatory molecules, can cause T-cell anergy and actively suppress development of 
a specific immune response[10]. Unfortunately the tumor microenvironment is highly 
immunosuppressive and tumor cells use sophisticated mechanisms to inhibit immune 
responses. Indeed, there are a variety of different mechanisms used by tumors to 
suppress the immune response including physical barriers, loss of antigen or MHC, 
increasing expression of inhibitory cell surface molecules, secretion of inhibitory 
cytokines, and recruitment of suppressor cell populations such as T-regulatory cells 
(Tregs) or Myeloid derived suppressor cells (MDSC)[11-13]. The presence of these 
powerful 
inhibitory 
mechanisms 
highlights 
the 
need 
for 
combinatorial 
immunotherapy strategies to unlock the full potential of the immune system to fight 
cancer. 
While immunotherapy is establishing itself as a novel and effective modality of 
cancer treatment, the current use FDA approved indication for CBI is in patients 
with metastatic disease. The ability for cancers to metastasize depends on a number 
of factors including histology, location, time, as well as the genetics or biology of the 
cancer. Interestingly, some aggressive tumors metastasize early in the course of 
disease while other cancers behave more indolently and may never metastasize. 
Along these lines there is a term called oligometastatic disease in which metastases 
are limited in number and location (for example only 3 lung metastasis, or only 2 
liver metastasis). Although there is no strict definition of oligometastases, it is
commonly interpreted to be no more than 5 or 6 metastatic sites. The presence of 
an oligometastatic state was originally coined by Hellman et al., who hypothesized 
that patients with olgiometastatic disease might derive benefit from effective local 
therapy applied to all sites of disease[14]. Clinical data has supported this hypothesis 
and the aggressive treatment of metastatic disease with surgery and chemotherapy in 
patients with isolated pulmonary metastases or liver metastases has resulted in long 
term survival[15-17]. The optimal type of treatment for metastases depends on a 
number of factors including histology, location, size, and number of sites. However, 
options for definitive local therapy include surgery (metastectomy), other ablative 
therapies such as radiofrequency ablation (RFA) or cryotherapy, specific targeted 
systemic therapies including hormonal therapy, or ablative radiation therapy 
(Stereotactic Body Radiation Therapy (SBRT). In this trial we are investigating 
combining checkpoint blockade immunotherapy with focused radiation therapy 
(SBRT) in attempt to enhance response rates and improve clinical outcomes for 
these patients.
4.2
Stereotactic Body Radiation Therapy (SBRT)


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Radiation therapy has a long and established history in the field of oncology[18].
Recently, technological advances have allowed radiation oncologists to effectively treat
tumors anywhere in the body using SBRT[19]. This ability to deliver high tumoricidal 
doses while limiting dose to surrounding normal structures has been a major advance 
and fundamental shift in the field of radiation oncology. The term stereotactic radiation 
or stereotaxy refers to the use of a referenced three-dimensional coordinate system to 
locate targets inside the body and deliver highly focused beams of radiation to that site 
with millimeter accuracy. Stereotactic delivery of radiation is usually termed 
stereotactic body radiation therapy (SBRT) for extracranial tumors, and referred to as 
Stereotactic Radiosurgery (SRS) for intracranial tumors. Because of the accuracy and 
ability to precisely modify the radiation dose distribution to minimize radiation to 
normal tissue, stereotactic radiation allows for "hypofractionation" or delivery of very 
high doses of radiation during each fraction of treatment. In the United States, clinical 
stereotactic radiation courses are currently completed in 1 to 5 fractions total. This is a 
dramatic shortening of total treatment time compared to conventionally fractionated 
radiation which can range from between 2-8 weeks or 10-40 fractions to complete. 
Clinically, stereotactic radiation achieves excellent local control rates, for example SRS 
for AVMs[20], trigeminal neuralgia[21], pituitary adenoma[22], brain metastases[23].
SBRT for early stage lung cancer has local control rates rivaling those of surgery[24].
SBRT is also being increasingly used as an effective local therapy for metastatic lesions 
or in patients with oligometastatic disease. Local control rates greater than 75% have 
been reported for metastatic tumors of the lung, liver, and spine, which is significantly 
higher than standard conventional moderate dose radiation[25-27]. Given these 
response rates, SBRT is being used in place of surgery for oligometastatic disease to 
target pulmonary metastasis, especially in patients who are not optimal surgical 
candidates. A number of institutions have reported favorable outcomes using either 
single or multi-fraction SBRT for oligometastatic sites within the lung. For example, a 
90% control rate at 9 months was reported with SBRT was prescribed to 26 Gy in a 
single fraction[28].  Hof et al, reported a 63% progression free survival at 3 years when 
SBRT was prescribed to 12-30Gy[29]. Le et al, treated early stage and metastatic lung 
tumors with SBRT using doses of 15-30 Gy and report a local control of 91% for doses 
greater than 20 Gy and 54% for doses less than 20 Gy[26].  However, toxicity was rare 
when doses of less than 25 Gy were given[26]. Thus a dose of 9.5 Gy x 3 will allow for 
safe targeting of pulmonary metastases. Radiosensitizing effects of checkpoint blockade 
may result in synergistic effects and may improve the local control rates radiation while 
providing acceptable toxicity. There have been reports of high grade pneumonitis in 
patients receiving anti-PD-1/PD-L1 checkpoint blockade, although there has been no 
definitive evidence of supra-additive toxicity when radiation is combined with CBI[30, 
31].
Regarding liver metastases, systemic chemotherapy or molecular-targeted agents rarely 
achieve long term control. On the other hand, surgical removal of colorectal liver 
metastases has resulted in reported 5-year survival rates approaching 50%, 
demonstrating that local therapy has a potential curative role in patients with 
oligometastatic disease[17, 25, 32]. In inoperable patients, the benefit of local therapy is 


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less clear, however long-term survival has been reported after the resection of liver 
metastases from sarcoma, breast cancer, and other histologies [33]. Classically the dose 
limiting toxicity with radiation therapy to the liver has been radiation-induced liver 
disease (RILD). However, with the technological advances in radiation therapy and 
image guidance SBRT can now be delivered safely resulting in high tumor doses to 
portions of the liver while sparing other portions of the liver. For example, no cases of 
RILD after radiation for colorectal liver metastases were seen when the mean liver dose 
was <31 Gy at the University of Michigan[34]. A phase I dose-escalation trial of single 
fraction treatment for liver metastases reported even high doses up to 30Gy in 1 fraction 
with no dose-limiting toxicity and a 2 year actuarial survival rate of 50% at a medial 
followup of 17 months[35].
In summary, SBRT has been well tolerated and efficacious with minimal toxicity in 
national and international trials. This significant advancement in radiation technology 
and capability calls for a re-evaluation of the effects of focused radiation on the immune 
system and in combination with immunotherapy.  Based on data above, in this study we 
will evaluate whether CBI plus 28.5Gy of SBRT (9.5Gy x 3 fractions) improves 
objective response rates and local as well as distant control.


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4.3
Checkpoint Blockade Immunotherapy
Recently, there have been several significant and critical advancements in the 
immunotherapy field[37, 38] including adoptive T-cell transfer, dendritic cell 
vaccines, peptide vaccines, oncolytic viruses, cytokine therapy, agonist monoclonal 
antibodies, and small molecules. Of these new advancements, checkpoint blockade 
Immunotherapy (CBI) is perhaps one of the most exciting in recent years. The 
significant interest in checkpoint blockade immunotherapy (CBI) stems from the 
dramatic and durable responses observed in a subset of patients with metastatic 
disease who have been heavily pre-treated.  At its core, CBI functions to inhibit 
negative regulators of immune responses, or in other words removing the brakes on 
the immune system. For decades immunotherapy approaches have focused on 
attempting to positively stimulate the immune responses without necessarily 
addressing the powerful negative regulatory systems that are in place which dampen 
or prevent excessive immune responses. It is now understood that disabling these 
negative regulators or checkpoints can result in robust and clinically efficacious 
immune responses which in some cases can control widely metastatic disease. CTLA-
4 (Cytotoxic lymphocyte antigen 4) is a receptor present on the surface of T-cells 
which binds the co-stimulatory molecules B7-1 and B7-2 on APCs with a much 
higher affinity than CD28. Instead of transmitting a positive co-stimulatory signal to 
the T-cell, ligation of CTLA-4 transmits a powerful inhibitory signal to T cells which 
can block T-cell activation. Indeed, CTLA-4 is one of the most powerful negative 
regulatory molecules on the cell surface of T-cells[36]. Similarly, Programmed death 
receptor 1 (PD-1) is a receptor on T-cells which binds PD-L1 or PD-L2 and recruits 
SHP phosphatases to impose a powerful inhibitory signal on T-cell activation and 
proliferation. Inhibiting the CTLA-4 and PD-1 pathways is now FDA approved for 
metastatic melanoma, NSCLC cell lung cancer and Kidney Cancer. 
In 2011 the FDA granted approval to the anti-CTLA-4 drug ipilimumab (Yervoy, 
Bristol-Myers Squibb) for the treatment of unresectable or metastatic melanoma. In 
Sept 2014 the FDA granted approval to the anti-PD-1 drug pembrolizumab
(Keytruda, Merck Sharp & Dohme Corp.) for the treatment of patients with 
unresectable or metastatic melanoma. 
In Dec 2014 the FDA granted accelerated approval for the anti-PD-1 drug nivolumab 
(Opdivo, Bristol-Myers Squibb) for patients with progressive unresectable or 
metastatic melanoma after treatment with ipilimumab or BRAF inhibitor. Nivolumab 
received FDA approval on March 4th 2015 for treatment of advanced squamous 
NSCLC that has progressed after treatment with platinum-based chemotherapy. In 
the phase II clinical trial CheckMate-063, tumors shrank in 15% of patients who 
took Opdivo, and 26% had stable disease. Additionally the phase III CheckMate-017 
trial in which NSCLC patients received either docetaxel chemotherapy or Opdivo 
was stopped early after it became evident that nivolumab outperformed docetaxel. In 
Sept 2015 the FDA granted accelerated approval to nivolumab in combination with 
ipilimumab for the treatment of patients with BRAF V600 wild-type, unresectable or 
metastatic melanoma.
Along the same lines, the anti-PD-1 drug Keytruda 


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(Pembrolizumab) received FDA approval on Oct 2nd, 2015 for advanced (metastatic) 
non-small cell lung cancer (NSCLC) whose disease has progressed after other 
treatments and with tumors that express a protein called PD-L1. In the KEYNOTE-
001 trial Keytruda resulted in an overall response rate of 41% (n=25/61) in patients 
who had PD-/SRVLWLYHWXPRUV7XPRUSURSRUWLRQVFRUH,Q1RYWKH
FDA approved Nivolumab to treat patients with advanced (metastatic) renal cell 
carcinoma. Additionally CBI has demonstrated clinical activity in a variety of tumor 
types including bladder cancer, Hodgkin's lymphoma, and prostate cancer among 
many others [4-6, 30, 37-42]. The body of clinical data evaluating the activity of CBI 
is established and remarkable[39-46] with additional FDA approved indications for 
different disease sites anticipated.
Immunotherapies and CBI can have unique profile of side effect termed termed 
immune-related adverse events (irAEs). Examples of irAE include dermatologic (rash), 
gastrointestinal (colitis), hepatic (hepatitis), endocrine (hypophysitis), pulmonary 
(pneumonitis) and are thought to relate to general increased activity of the immune 
system and inflammation. CBI has been studied in Phase III clinical trials with large 
numbers of patients evaluated and the general frequencies of irAE have been reported. 
These reported frequencies serve as reference values for estimating any increased 
toxicity with combinatorial therapies. 
4.4
Rationale for SBRT combined with CBI
There is now an established body of pre-clinical literature demonstrating that radiation 
can modify anti-tumor immune responses. Radiation has been demonstrated to cause 
upregulation of Major Histocompatibility Complex (MHC) and increase presentation of 
antigens on surface of tumor cells [43-48]. The DNA damage and reactive oxygen 
species induced by radiation have been shown to result in inflammatory tumor cell 
death and release of damage associated molecular patterns (DAMPs), including high 
mobility group box chromosomal protein 1 (HMGB1), which can activate antigen 
presenting cells[49-51]. Radiation induced activation of antigen presenting cells has 
also been demonstrated in animal models to enhance tumor antigen cross-presentation 
in the draining lymph node and result in activation and proliferation of tumor specific 
cytotoxic T-cells[47, 52-57]. Radiation has also been shown to influence expression of 
cytokines and chemokines, such as IL-1, IL-2, L-6, TNF-alpha, TGF-beta, CXCL-16, as 
well as Type I and Type II Interferons which may play a critical role in modulating 
immune responses[58-65]. Undoubtedly due to the culmination of these effects, 
multiple groups have demonstrated that radiation can cause tumor cells to become more 
susceptible to immune mediated attack[44, 45, 66]. Indeed some authors have suggested 
that the therapeutic effects of radiation alone may depend on the status of the host 
immune system and anti-tumor immune responses in the radiation field[54, 63, 67-69].
Given these effects using radiation alone there has been a significant effort to combine 
radiation with various immunotherapies with sometimes striking results within the 
radiation field (radiosensitizing immunotherapy), as well as distantly outside the 
radiation field (abscopal responses)[44, 47, 53, 65, 66, 69-78]. A number of excellent 


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
14
reviews have also highlighted the potential benefits and ongoing clinical trials of 
radiation combined with immunotherapy[61, 79-83].
Along these lines, recent evidence has demonstrated that focused radiation can in fact 
stimulate an anti-tumor immune response outside of the radiation field, termed the 
abscopal effect. This phenomenon was originally coined by Dr. R.H. Mole in 1953 as an 
effect of radiation away from the primary target, or in other words, an action at a 
distance (49).  Work by Silvia Formenti and colleagues from New York University has
further characterized the abscopal effect (50) (51). Demaria et al. found that growth of a 
non-irradiated mammary carcinoma was impaired with the use of Flt3-ligand and 
radiation to a contralateral tumor (50). The authors also provided evidence that this
effect was T-cell dependent as it was not observed in T-cell deficient hosts. Given that 
radiation is capable of inducing inflammation, apoptosis, cell death, and release of tumor 
antigens (53), this would create an ideal local environment for induction of a potent 
immune response (50) (54) (55) (56). Thus the preponderance of pre-clinical data would 
suggest that adding SBRT to CBI has the potential to enhance systemic anti-tumor 
immune responses which could help to control systemic metastatic disease and improve 
objective response rates. Indeed, a number of ongoing clinical trials are evaluating 
radiation therapy combined with CBI. 
On the basis of this preclinical and clinical evidence, we propose a phase II study
of CBI combined with SBRT in patients with metastatic disease. With published data
establishing the relative safety of multi-fraction SBRT to the brain, lungs, liver, 
prostate, and pancreas, we have decided to proceed with 28.5 Gy of SBRT (9.5Gy x3
fractions) concurrently with CBI. However, the use of a three fractions concurrent
with CBI is not of proven benefit. This investigation aims to confirm the safety and
efficacy for SBRT used concurrently with a CBI in the setting of metastatic
disease. The dose selected has been c a r e f u l l y  chosen with the belief that it is
safe and effective based on prior experience with SBRT. All patients will be
treated with three fractions, targeted to the lesion concurrently with CBI. 
Patient’s with metastatic disease have a poor prognosis. Current treatment modalities are 
generally palliative and patients are rarely cured, thus additional treatment modalities are 
certainly needed. This proposed study represents a logical extension of the current 
understanding of immunotherapy and radiation therapy and potential for synergy 
between these two modalities. This study will refine the current understanding of 
radiation tolerance for normal tissues in 3 fractions, thereby making it possible to treat 
future patients more safely and aggressively. Additionally, this study could identify a 
new indication for SBRT in specifically for enhancing the systemic effects of 
immunotherapy. Finally, this study has the potential to translate into improved local as 
well as distant control ultimately improved overall survival.
5. PARTICIPANT SELECTION AND ENROLLEMENT CRITERION 


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March 4, 2019 (Version 9.0)
15
5.1
Inclusion Criteria
5.1.1
The PI or Co-Investigator Radiation Oncologist states that one of the lesions can be 
treated with SBRT. 
5.1.2
Patient must have at least 1 site of measurable disease by Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 criteria on computed tomography (CT) or 
Magnetic resonance imaging (MRI) which will not be irradiated. 
5.1.3
Histological confirmation of malignancy (primary or metastatic tumor).
5.1.4
Patient may have any prior therapy allowed aside from having had prior
radiotherapy to the treatment site (see exclusion criteria 5.2.3).
5.1.5
Patient must be 3 years of age.
5.1.6
/DQVN\VFDOHVFRUHRIDJHVRU\HDUV- OR - Karnofsky scale score 
RIDJHVRU\HDUV– OR - (&2*SHUIRUPDQFHVWDWXV\HDUV
or older).
5.1.7
Patient’s screening laboratory values must meet the following criteria:
Leukocytes
>ȝ/
Absolute Neutrophil Count
>ȝ/
Platelets
>ȝ/
Total bilirubin                      
<2x institutional upper limit of normal
AST(SGOT)/ALT(SGPT)   
<2.5 X institutional upper limit of 
normal 
Serum creatinine 
[8/1or creatinine clearance 
&U&OP/PLQXVLQJWKH
Cockcroft-Gault formula):
(1) Female CrCl = (140 - age in years) x weight in kg x 0.85 /72 x serum 
creatinine in mg/dL
(2) Male CrCl = (140 - age in years) x weight in kg x 1.00/72 x serum
creatinine in mg/dL
Pulse Oximetry
RQ5RRP$LUDW5HVW
5.1.8
Patient or parent/legal guardian must have the ability to understand and the
willingness to sign a written informed consent document.
5.1.9
For Patients <18 years of age, enrollment on trial and potential for use of CBI 
or CBI combined with SBRT must be agreed upon by consensus opinion of a 
multidisciplinary pediatric tumor board.
5.2
Exclusion Criteria
5.2.1
Patient has had chemotherapy or radiotherapy within 4 weeks prior to entering
the study or those who have not recovered from adverse events due to agents


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March 4, 2019 (Version 9.0)
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administered more than 4 weeks earlier.
5.2.2
Patient receiving any investigational or experimental agents other than 
immunotherapy.  
5.2.3
Patient who has had any prior radiotherapy to the treatment site(s).
5.2.4
Patient is a pregnant woman (pregnant women are excluded from this study
because radiation treatment has known potential for teratogenic or abortifacient
effects).
5.2.5
Patient refuses to sign informed consent.
6. TREATMENT PLAN 
6.1
Diagnostic Procedures
A
CT
scan or
MRI will
be performed
for
tumor
localization using
rigid
immobilization appropriate for stereotactic treatment. A separate PET-CT may be
performed (optional) for diagnostic purposes and can be used for treatment planning
with fusion – the identical study would be performed if the patient were having
standard conventional dose radiation.
6.2
Therapeutic Procedures
Patients will be pre-screened for eligibility and should be enrolled and randomized prior 
to starting immunotherapy. However, patients who have started immunotherapy up to 5 
days prior to enrollment will be still be eligible for screening, randomization, and 
enrollment.
Upon confirmation of eligibility and enrollment in the study, the following will
be completed:
1)
Demographics review, medical history and clinical exam
2)
Review of concurrent medications
3)
Vital signs, height and weight
4)
Laboratory Bloodwork including: CBC, BMP, LFT.
5)
Plasma and Peripheral
blood
mononuclear
cells
will
be
collected
and
subsequently frozen for immune monitoring assays. 
6)
Tumor measurements (Recist 1.1) within 4 weeks prior to start of CBI
Upon randomization into the SBRT arm of the protocol, patients will be seen by at 
least one of the Co-Investigator Radiation Oncologists. CT simulation will be
performed with fabrication of a radiation therapy immobilization device (such as a 
Vac-Lok) which will be custom made for each patient. The treating radiation 


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Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
17
oncologist will identify the location of the tumor. Gross tumor volume (GTV) 
delineation will be performed on sequential axial computed tomography images. An 
SBRT treatment plan will be developed based on tumor size and location. The dose 
will be prescribed to the minimal isodose line that completely covers the GTV plus a 5 
mm margin. Adjacent normal structures including but not limited to the chest wall, 
spinal cord, heart, esophagus, aorta, kidneys, rectum, bowel, liver, and stomach within 
5 cm of the GTV will be identified for the purpose of limiting incidental radiation to 
these structures.
In addition, prior to treatment delivery, a four-dimensional cone beam CT study will
be performed on individual patients to assess respiration in these patients and to
determine tumor targeting accuracy for those tumors that may be subject to respiratory
motion such as those in the lung, abdomen, or liver. If tumor motion is greater than
5 mm, the planning target volume (PTV) will be expanded to account for respiration.
Within three weeks of the 1st cycle of checkpoint blockade, SBRT will be administered
using image-guidance. An Vac-Lok (or equivalent immobilization device such as 
Alpha-Cradle) will be used to minimize movement of the chest, spine, and
abdomen during treatment. During treatment, cone beam CT images of the patient’s
body site of interest will be obtained. Cone beam CT scan will be obtained
immediately prior to treatment and will be repeated until the treatment shift, required
to align the CT planning scan and the cone beam CT scan performed on the day of
treatment cone beam CT, is within tolerance for the body site per standard clinical 
practice. 
The patient will receive SBRT within 1-21 days of the start of Cycle#1 of CBI.
Afterwards, the patient will continue to receive CBI as indicated and recommended 
by the treating medical oncologist.
Patients
will
be
evaluated
for
adverse
events/toxicities during their treatment.
6.2.1
The dose limits for surrounding critical structures are as follows [Base in part from 
Stereotactic body radiation therapy: The report of AAPM Task Group 101, Med. 
Phys. 37(8), August 2010]:
x
Spinal Cord: maximal allowable total point dose is 2190cGy (7.3Gy/fx)
x
Lung: Combined mean lung dose < 400 cGy, V20<4%, and at least 1500cc 
< 1160 cGy
x
Heart: Volume of heart receiving 24 Gy should be <15cc 
x
Esophagus: 50% of the esophagus volume should be kept under 1000
cGy and no single point dose in the esophagus should exceed 2700 cGy.
x
Brachial Plexus: maximal allowable point dose is 2400 cGy
x
Liver: Approx 2/3 of liver or at least 700cc < 1920c Gy 
x
Kidneys: 2/3 volume of each kidney <1060 cGy.
x
Small Bowel: <5% of bowel limited to <2000 cGy.
6.3
Follow-Up Procedures


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March 4, 2019 (Version 9.0)
18
Subsequent to Cycle 1 Day 1, patients will be followed clinically, radiographically, and 
with bloodwork. A detailed medical and physical examination will be performed at 8 
weeks and 16 weeks, 6 months, 12 months, 18 months and 24 months. A complete 
blood count (CBC) and comprehensive chemistry panel and CT scan including the 
treated site will be performed at the 8 week and 16 week follow-up and will continue at 
intervals of every 6 months until 2 years post SBRT treatment.
Tumor measurements (Recist 1.1) at 8 weeks (+/- 10 days) and 16 weeks (+/- 10
days) will be used to determine radiographic response.
6.4
Duration of Therapy
The patient will receive CBI as indicated and recommended by the treating medical 
oncologist. 
6.5
Duration of Follow-Up
It is anticipated that this study will last 5 years. Routine follow-up appointments as 
clinically indicated after 2 years will be used to capture and determine overall survival 
endpoints. 
6.6
Criteria for Patient Removal
Unacceptable adverse events grade IV or greater with an attribution of possibly
related to CBI Monotherapy, Combination CBI, or CBI combined with SBRT. 
Intercurrent illness that prevents further administration of treatment.
Extraordinary Medical Circumstance: If at any time the treating physician feels 
constraints of this protocol are detrimental to the patients’s health the patient can be 
removed from protocol therapy. 
Patient can elect to discontinue treatment at any time.
6.7
Alternatives
The study has been designed to minimize potential risks to participants. This is
primarily through designation of a dose range shown to be safe in previous SBRT
trials and careful patient monitoring. The risks of CBI are detailed in section 7 as well 
as in the manufacturer treatment guidelines.
Risks
to
confidentiality will be
minimized by having access to study records available only to the investigators with
the exception of the standard clinical records (lab values, dictations, operative notes,
etc) which are maintained through the UCSD Health System and Moores Cancer 
Center.
Standard
therapies
for
metastatic
disease
include
conventional
radiotherapy,
chemotherapy, or observation. Such treatment may or may not be applicable for
patients enrolled in this study. Regardless, patients will be expected to forgo
standard
chemotherapy or radiotherapy until there is evidence of clinical or
radiographic disease
progression. The amount
of radiation administered via
protocol therapy will be considered in determining how much additional radiation
can be given using conventional external beam fractionation.


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March 4, 2019 (Version 9.0)
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6.8
Costs
Patients and/or their insurance companies will be responsible for the cost of all
procedures and treatments under this protocol.
6.9
Compensation
Patients and/or their insurance companies will be responsible for the cost of all
procedures and treatments under this protocol.
6.10 Withdrawal from Study
The reasons for withdrawal from the study include:
x
Subject withdraws consent for follow-up.
x
Subject is lost to follow-up.
x
Study is terminated for any reason.
If participants withdraw from the study, they will be followed for survival data.
7.
CHECKPOINT BLOCKADE IMMUNOTHERAPY DRUG 
INFORMATION 
7.1
ANTI-CTLA-4 DRUG INFORMATION AND ADMINISTRATION
7.1.1 Relevant Prior Clinical Information
The results of a randomized, Phase 3 clinical trial published in 2010 showed a 
first-ever overall survival (OS) benefit for patients with previously treated stage 
III/stage IV metastatic melanoma who received ipilimumab compared with the 
controls. The patients in that trial (N=676) were randomized to receive either 
glycoprotein 100 (gp100) vaccine with Ipilimumab, gp100 alone, or Ipilimumab 
monotherapy in a 3:1:1 ratio. Patients receiving Ipilimumab monotherapy or with 
gp100 experienced a significantly longer median OS compared to those who 
received gp100 alone (approximately 10 vs. 6.4 months respectively). The risk of 
progression was reduced 19% with Ipilimumab plus gp100 and 36% with 
Ipilimumab alone compared to gp100 alone; subsequently, the FDA approved 
Ipilimumab alone in 2011. This OS advantage was observed while using a lower 
dose (3 mg/kg), than preceding studies (10 mg/kg) with a durable response 
demonstrated despite the lack of a maintenance phase.
In a Phase 1 trial testing ipilimumab in patients with stage III and IV melanoma, 
three doses were given: 0.3 mg/kg, 1 mg/kg, and 3 mg/kg. A dose-response was 
VHHQZLWKRQO\WKHPJNJGRVHDFKLHYLQJWURXJKFRQFHQWUDWLRQVRIȝJP/
Steady state was achieved by the third dose at approximately 22 ȝJP/ 2Q
average, the elimination half-life of Ipilimumab is 14.7 days. Volume of 
distribution and clearance increase with increasing body weight. The following 
mean (percent coefficient of variation) parameters have been generated through 
population pharmacokinetic analysis: terminal half-life of 15.4 days (34%); 
systemic clearance (CL) of 16.8 mL/h (38%) [17]. The volume of distribution at 
steady-state (Vss) is 7.21 L and the mean (±SD) Ipilimumab Cmin achieved at 


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
20
steady state with the 3-mg/kg regimen is 21.8
The effects of various covariates on Ipilimumab pharmacokinetics have been 
assessed in population pharmacokinetic analyses. Ipilimumab CL increases with 
increasing body weight; however, no dose adjustment of ipilimumab is required 
for body weight after administration on a milligram per kilogram basis. The 
following factors have no clinically meaningful effect on the CL of Ipilimumab: 
age (range 26 to 86 years), gender, performance status, renal impairment, mild 
hepatic impairment, prior use of systemic anticancer therapy, or baseline lactate 
dehydrogenase (LDH) levels. [84].
Renal Impairment: Creatinine clearance at baseline does not have a clinically 
important effect on Ipilimumab pharmacokinetics in patients with calculated 
creatinine clearance values of 29 mL/min or greater[84].
Hepatic Impairment: Baseline AST, total bilirubin, and ALT levels does not have 
a clinically important effect on Ipilimumab pharmacokinetics in patients with 
various degrees of hepatic impairment[84].
7.1.2 Safety Profile
Ipilimumab has been reported to cause high levels of adverse events (AEs), the 
most common of which are immune related[84]. Blockade of CTLA-4 may cause 
an increase in self-reactive T cells and autoimmunity leading to rash, vitiligo, 
diarrhea, colitis, uveitis, episcleritis, hepatitis and hypophysitis.called immune 
related adverse events (irAEs).
The results of dose escalation studies have shown that increasing dosage 
correlates with increased efficacy as well as increased severity of irAEs. Roughly 
60% of patients taking Ipilimumab experienced an irAE of any grade, with 10-
15% of those grade 3 or 4 at the 3mg/kg dose. The most commonly reported 
adverse effects at the 3 mg/kg dose are grade I and II adverse events including 
rash, pruritus and diarrhea[84]. A cases series of 11 patients found an increased 
rate of transaminitis compared to the results from the Hodi et al trial[37]. Six of 
eleven patients had >Grade 1 elevations of liver enzymes compared to only 3 
patients in the Hodi trial; four of eleven had grade 3 elevations compared to none 
in the Hodi trial[37].
irAEs can have a delayed onset and may be persistent. The reported median time 
to onset of an irAE depends on event type but ranges from 3.1 to 11 weeks. The 
median time to resolution of any grade II-IV event has been reported to be 4.9 
weeks. Diarrhea, the most common irAE in clinical trials, has a median time to 
resolution of 1-2 weeks but it may be longer than 4 weeks for a grade III or IV 
event. The standard of care for treating irAEs is systemic administration of 
corticosteroids, as the majority of irAEs caused by ipilimumab can be resolved 
with steroids alone. Additional therapies that have been published include 
immune-suppressants, hormone replacement therapy for irAEs of the endocrine 
system, and intravenous immunoglobulin for immune-mediated blood disorders.


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
21
Ipilimumab has been attributed to the death of 14 patients in the Hodi et al trial, 7 
of those due to immune related adverse events[37]. A boxed warning regarding 
the risk of enterocolitis, hepatitis, dermatitis, neuropathies, and endocrinopathies 
is included with ipilimumab. A Risk Evaluation and Mitigation Strategy (REMS) 
program for ipilimumab is mandated by the FDA to ensure that the benefits of 
ipilimumab outweigh the risk of these severe irAEs.
7.1.3 Ipilimumab Dosing
Ipilimumab will be dosed and scheduled according to FDA approved labels or per 
institutional guidelines at discretion of treating medical oncologist. For additional 
details regarding drug storage, preparation, and administration please refer to 
Ipilimumab package insert[84].
7.1.4 Treatment of Ipilimumab Related Infusion Reactions
Infusion reactions should be graded according to CTCAE Version 4.0 Allergic 
reaction/hypersensitivity criteria. Severe infusion reactions require the immediate 
interruption of ipilimumab therapy and permanent discontinuation from further 
treatment. Appropriate medical therapy including epinephrine, corticosteroids, 
intravenous antihistamines, bronchodilators, and oxygen should be available for use 
in the treatment of such reactions. Subjects should be carefully observed until the 
complete resolution of all signs and symptoms. In each case of an infusion reaction, 
the investigator should institute treatment measures according to the best available 
medical practice.
7.2
ANTI-PD-1/ ANTI-PD-L1 DRUG INFORMATION AND ADMINISTRATION
7.2.1 Relevant Prior Clinical Information
Nivolumab (Opdivo) is a fully human monoclonal immunoglobulin (Ig) G4 antibody 
that binds to the programmed death-1 (PD-1) cell surface membrane receptor, a 
negative regulatory molecule expressed by activated T and B lymphocytes[85].
Inhibition of the interaction between PD-1 and its ligands promotes immune 
responses and antigen-specific T cell responses to both foreign antigens as well as 
self antigens. PD-1 receptor blockade by Nivolumab is an FDA approved approach 
for immunotherapy of advanced metastatic melanoma, lung cancer, and renal cell 
carcinoma[85]. Nivolumab received FDA approval on March 4th 2015 for treatment 
of advanced squamous NSCLC that has progressed after treatment with platinum-
based chemotherapy. In the phase II clinical trial CheckMate-063, tumors shrank in 
15% of patients who took Opdivo, and 26% had stable disease. Additionally the 
phase III CheckMate-017 trial in which NSCLC patients received either docetaxel 
chemotherapy or Opdivo was stopped early after it became evident that nivolumab 
outperformed docetaxel.
Pembrolizumab (Keytruda) is a human programmed death receptor-1 (PD-1)-
blocking antibody and is an FDA approved approach for immunotherapy of advanced 


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
22
metastatic melanoma and lung cancer[86]. Pembrolizumab  received FDA approval 
on Oct 2nd, 2015 for advanced (metastatic) non-small cell lung cancer (NSCLC) 
whose disease has progressed after other treatments and with tumors that express PD-
L1. The accelerated FDA approval was based on a multicenter, open-label multi-
cohort, activity-estimating study (KEYNOTE-001), which evaluated Pembrolizumab
in a cohort of 280 patients with metastatic NSCLC that had progressed following 
platinum-containing chemotherapy and any evidence of PD-L1 expression by a 
clinical trial immunohistochemistry assay. In the KEYNOTE-001 trial Keytruda 
resulted in an overall response rate of 41% (n=25/61) in patients who had PD-L1 
positive tumors (Tumor proSRUWLRQVFRUH
Atezolizumab (Tecentriq) is a fully humanized, engineered monoclonal antibody of 
IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1). It has 
multiple FDA approved indications. 
Avelumab (Bavencio) is a fully human monoclonal antibody targeting the protein 
programmed death-ligand 1 (PD-L1). It was FDA approved in March 2017 for 
Merkel-cell carcinoma.
'XUYDOXPDE ,PILQ]L LV D KXPDQ LPPXQRJOREXOLQ * NDSSD ,J*ț PRQRFORQDO
antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1). It has 
multiple FDA approved indications.
7.2.2 Safety Profiles
7.2.2.1 Nivolumab
Patients have received nivolumab at doses of 0.1, 0.3, 1, 3, 10, or 20 
mg/kg intravenously every 2 weeks with no maximal tolerated dose 
identified[85]. The incidence, severity and relationship of AEs are 
generally similar across dose levels and tumor types. Nivolumab related 
AEs of any grade occur in approximately 75% of subjects[85]. The most 
frequently reported AEs are fatigue (54.9%), decreased appetite (35.0%), 
diarrhea (34.3%), nausea (30.1%), and cough (29.4%). Most treatment-
related AEs are low grade. Treatment-related high grade (Grade 3-4) AEs 
have been reported in approximately. 17.0% of subjects. The most 
common treatment-related high grade AEs are fatigue (2.3%) and 
diarrhea (1%). Drug-related SAEs have been reported to occur in 
approximately in 11% of subjects. Select AE categories include: GI AEs, 
pulmonary AEs, renal AEs, hepatic AEs, skin AEs, and endocrinopathies. 
Patients who receive 10 mg/kg have had a numerically greater frequency 
of high-grade select AEs including the subcategories of endocrinopathies, 
GI, pulmonary, and infusion reaction.  High grade events have been 
reported to resolve following the treatment guidelines for the treatment of 
pulmonary events, GI events, hepatic events, renal events, and endocrine 
events, respectively. Treatment-related AEs leading to discontinuation 
have been reported in 10.5%, the most frequent of these were 
pneumonitis (2.6%) and colitis (1.0%)[85].


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
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7.2.2.2   Pembrolizumab
The most common adverse reactions with Pembrolizumab include 
fatigue, pruritus, rash, constipation, diarrhea, nausea, and decreased 
appetite (Reported in >20% of patients) [86]. Pneumonitis has been 
reported to occur in approximately 2.9% of melanoma patients, including 
Grade 2 or 3 cases in 1.9% and 0.2% of patients, respectively [86]. The 
median time to development of pneumonitis was 5 months (range 0.3 
weeks-9.9 months). The median duration was 4.9 months (range1 week-
14.4 months). Five of eight patients with Grade 2 and one patient with 
Grade 3 pneumonitis required initial treatment with high-dose systemic 
corticosteroids  followed by a corticosteroid taper. The median initial 
dose of high-dose corticosteroid treatment was 63.4 mg/day of 
prednisone or equivalent with a median duration of treatment of 3 days 
(range 1-34) followed by a corticosteroid taper. Pneumonitis led to 
discontinuation of Pembrolizumab in 3 (0.7%) patients. Pneumonitis 
completely resolved in seven of the nine patients with Grade 2-3
pneumonitis[86]. Colitis has been reported to occur in approximately 1% 
of patients, including Grade 2 or 3 cases in 0.2% and 0.5% of patients, 
respectively. The median time to onset of colitis was 6.5 months (range 
2.3-9.8). The median duration was 2.6 months (range 0.6 weeks-3.6
months). All three patients with Grade 2 or 3 colitis were treated with 
high-dose corticosteroids with a median initial dose of 70 mg/day of 
prednisone or equivalent; the median duration of initial treatment was 7 
days (range 4-41), followed by a corticosteroid taper. Hepatitis (including 
autoimmune hepatitis) has been reported to occur in approximately 0.5% 
of patients, including  Grade 4 in 0.2% of patients. The time to onset was 
22 days for the case of Grade 4 hepatitis which lasted 1.1 months. 
Hypophysitis has been reported to occur in approximately 0.5% of
patients including Grade 2 and Grade 4 at at 0.2% each in patients. The 
time to onset was 1.7 months for the patient with Grade 4 hypophysitis 
and 1.3 months for the patient with Grade 2 hypophysitis. Hypophysitis 
may require permanent hormone replacement therapy. Nephritis has been 
reported to occur in approximately 0.7% of patients, including Grade 2 
autoimmune nephritis (0.2%), and Grade 3 and Grade 4 interstitial 
nephritis with renal failure (0.5%). All patients fully recovered renal
function with treatment with high-dose corticosteroids  followed by a 
corticosteroid taper. Hyperthyroidism has been reported to occur in 
approximately 1.2% of patients, including Grade 2 or Grade 3 cases at 
0.5% and 0.2% respectively. The median time to onset was 1.5 months 
(range 0.5-2.1). The median duration was 2.8 months (range 0.9 to 6.1). 
The following clinically significant, immune-mediated adverse reactions 
have been reported to occur in less than 1% of patients treated with 
Pembrolizumab: exfoliative dermatitis, uveitis, arthritis, myositis, 
pancreatitis, hemolytic anemia, partial seizures arising in a patient with 
inflammatory 
foci in brain parenchyma, adrenal insufficiency, 


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
24
myasthenic syndrome, optic neuritis, and rhabdomyolysis.
7.2.3 Nivolumab Dosing
Nivolumab will be dosed and scheduled according to FDA approved labels or per 
institutional guidelines at discretion of treating medical oncologist. For additional 
details regarding drug storage, preparation, and administration please refer to 
Nivolumab package insert[85]
7.2.4 Nivolumab combined with Ipilimumab Dosing
Nivolumab combined with Ipilimumab will be dosed and scheduled according to 
FDA approved labels or per institutional guidelines at discretion of treating medical 
oncologist.
For additional details regarding drug storage, preparation, and 
combination administration please refer to Nivolumab package insert[85]
7.2.5 Pembrolizumab Dosing:
Pembrolizumab will be dosed and scheduled according to FDA approved labels or per 
institutional guidelines at discretion of treating medical oncologist
For additional 
details regarding drug storage, preparation, and combination administration please 
refer to Pembrolizumab package insert[86].
7.2.6 Atezolizumab Dosing
Atezolizumab will be dosed and scheduled according to FDA approved labels or per 
institutional guidelines at discretion of treating medical oncologist. For additional 
details regarding drug storage, preparation, and administration please refer to 
Atezolizumab package insert [87]
7.2.7 Avelumab Dosing
Avelumab will be dosed and scheduled according to FDA approved labels or per 
institutional guidelines at discretion of treating medical oncologist. For additional 
details regarding drug storage, preparation, and administration please refer to 
Avelumab package insert [88]
7.2.8 Durvalumab Dosing
Durvalumab will be dosed and scheduled according to FDA approved labels or per 
institutional guidelines at discretion of treating medical oncologist. For additional 
details regarding drug storage, preparation, and administration please refer to 
Durvalumab package insert [89]
7.2.9 Treatment of anti-PD-1/PD-L1 Related Infusion Reactions
Infusion reactions should be graded according to CTCAE Version 4.0 Allergic 
reaction/hypersensitivity criteria. Severe infusion reactions require the immediate 
interruption of anti-PD-1/PD-L1 therapy and permanent discontinuation from further 
treatment. Appropriate medical therapy including epinephrine, corticosteroids, 
intravenous antihistamines, bronchodilators, and oxygen should be available for use 
in the treatment of such reactions. Subjects should be carefully observed until the 


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
25
complete resolution of all signs and symptoms. In each case of an infusion reaction, 
the investigator should institute treatment measures according to the best available 
medical practice.
8
DOSING DELAYS/DOSE MODIFICATIONS AND 
DISCONTINUATION CRITERION 
8.1) Dose Delay Criterion for CBI or CBI combined with SBRT
Dose delay criteria specified below apply for all checkpoint blockade immunotherapies or 
any combination of checkpoint blockade immunotherapies with SBRT (regardless of 
whether or not the event is attributed to CBI, SBRT or both)
CBI and SBRT administration should be delayed for the following:
$Q\*UDGHQRQ-skin, drug-related adverse event, with the following exceptions:
í *UDGH  GUXJ-related fatigue or laboratory abnormalities do not require a 
treatment delay
• Any Grade 3 skin, drug-related adverse event
• Any Grade 3 drug-related laboratory abnormality, with the following exceptions for
asymptomatic amylase or lipase, AST, ALT, or total bilirubin:
í*UDGHDP\ODVHRUOLSDVHDEQRUPDOLWLHVWKDWDUHQRWDVVRFLDWHGZLWKV\PSWRPV
or clinical manifestations of pancreatitis do not require a dose delay. 
í,IDVXEMHFWKDVDEDVHOLQH$67$/7RUWRWDOELOLUXELQWKDWLVZLWKLQQRUPDO
limits, delay dosing for drug-UHODWHG*UDGHWR[LFLW\
í ,I D VXEMHFW KDV EDVHOLQH $67 $/7 RU WRWDO ELOLUXELQ ZLWKLQ WKH *UDGH 
toxicity range, delay dosing for drug-UHODWHG*UDGHWR[LFLW\
• Any adverse event, laboratory abnormality, or concurrent illness which, in the judgment 
of the investigator, warrants delaying the dose of study medication.
8.2) Discontinuation Criterion for CBI or CBI combined with SBRT:
Discontinuation criteria apply for all drug-related adverse events attributed to checkpoint 
blockade immunotherapies or any combination of checkpoint blockade immunotherapies 
with SBRT (regardless of whether or not the event is attributed to CBI, SBRT or both)
Treatment should be permanently discontinued for the following:
x
Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment 
period OR requires systemic treatment.
x
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory 
abnormalities, uveitis, pneumonitis, 
bronchospasm, diarrhea, colitis, neurologic toxicity, hypersensitivity reactions, and 
infusion reactions:
o
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic toxicity, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation


C BI a n d S B R T
Pr ot oc ol PI:  A n dre w S hara bi,  M. D., P h. D
Marc h 4, 2 0 1 9 ( Versi o n 9. 0)
2 6
o
Gra de  3  dr u g-rel ate d  l a b orat or y  a b n or malities  d o  n ot  re q uire  treat me nt  
disc o nti n uati o n e x ce pt: 
Gra de 3 dr u g-rel ate d t hr o m b oc yt o p e nia > 7 d a ys or 
ass ociate d wit h blee di n g re q uires disc o nti n uati o n
A n y dr u g-r elate d li ver f u ncti o n test ( L F T) a b n or m alit y t hat meets t he f oll o wi n g
criteria r e q uire disc o nti n uati o n:
o
A S T or A L T > 8 x U L N
o
T otal bilir u bi n > 5 x U L N
o
C o nc urre nt A S T or A L T > 3 x U L N a n d t otal bilir u bi n > 2 x U L N
o
A n y Gra d e 4 dr u g-r elate d a d vers e e v e nt or l a b orat or y a b n or malit y, e x ce pt f or 
t he f oll o wi n g e v e nts w hi c h d o n ot re q uire disc o nti n uati o n:
Gra de 4 a m ylas e or li pase a b n or malitie s t hat are n ot ass ociate d wit h 
s y m pt o ms  or  cli nical  ma nifestati o ns,  or  ra di o gra p hi c  si g ns  of  
pa ncreatitis. 
Is olat e d  Gra de  4  electr ol yte  i m bala nces/a b n or malities  t hat  are  n ot  
ass ociate d
 wit h
 cli nical
 se q u elae
 a n d
 are
 c orrecte d
 wit h
 
s u p ple me ntati o n/a p pr o priate  ma na ge me nt  wit hi n  7 2  h o urs  of  t h eir  
o nset.
If a s u bject disc o nti n ues c o m bi nati o n C BI treat me nt f or e x a m ple wit h ni v ol u ma b 
+ i pili m u ma b d ue t o a dr u g-relat e d a d verse e v e nt pri or t o c o m pleti n g f o ur d oses 
of t he c o m bi nati o n t hera p y, t h e s u bject ma y c o nti n ue treat me nt wit h ni v ol u ma b 
3 m g/ k g e ver y 2 w ee ks as l o n g as t h e A E lea di n g t o disc o nti n uati o n was clearl y 
attri b ute d t o i pili m u ma b a n d n ot ni v ol u ma b. I n s uc h circ u msta nces, t he s u bject 
ma y re-start ni v ol u ma b t hera p y w he n t h e s u bject f ull y rec o vers fr o m t h e dr u g-
relate d a d v erse e ve nt t hat le d t o disc o nti n uati o n.
8. 3) D ose M o dificati o n f or S B R T:
D ose m o dificati o ns t o S B R T d ue t o safet y or t o xicit y c o ncer ns will be perf or me d b y t he 
treati n g ra diati o n o nc ol o gist as cli nicall y i n dicate d. T his i ncl u des d ose re d ucti o n bel o w 
9. 5 G y x 3 fracti o ns i n or der t o meet t olera nces liste d a b o ve f or critical n or mal str uct ures 
w he n dee me d necessar y b y t he treati n g ra diati o n o nc ol o gist. T he mi ni m u m d ose of S B R T 
deli vere d will be 6 G y x 3 fracti o ns. 
9
C O R R E L A TI V E / S P E CI A L S T U DI E S  
9. 1) Bl o o d S a m ple Tr a ns p ort, Pr ocessi n g, a n d St or a ge.
9. 1. 1  
A p eri p h er al  bl o o d  dr a w  ( 8 0 c c  m a xi m u m  f or  a d ult s  a n d  2 0  c c  
m a x i  m u  m  f o r  partici pa nts  < 1 8  years  ol d  or  t h ose  u n der  a  s pecific  wei g ht  
criteria)  will be o btai ne d b y ve ni p u nct ure i n B D Vac utai ner ® C P T ™ ( Fra n kli n 
La kes, NJ) t u bes or a n a p pr o priate s u bstit ute cell pre parati o n t u be at baseli ne pri or 
t o treat me nt, pri or t o c ycle # 2 of C BI, a n d at 2 m o nt h p ost- S B R T f oll o w- u p visit.
9. 1. 2 
T he st u d y c o or di nat or or researc h staff fr o m t he la b orat or y of Dr. A n dre w S hara bi 
will tra ns p ort t he s peci me n t o t he la b orat or y of A n dre w B. S hara bi, M. D., P h D f or 
st ora ge a n d pr ocessi n g. Sa m ples  will be st ore d i n defi nitel y.
9. 1. 3 
Bl o o d f or ser u m s h o ul d be c ollecte d i n sta n dar d 1 0 ml re d t o p p ol y pr o p yle ne t u bes 
a n d all o we d t o cl ot f or 3 0  mi n utes at r o o m  te m perat ure i n a vertical p ositi o n.  T he 


C BI a n d S B R T
Pr ot oc ol PI:  A n dre w S hara bi,  M. D., P h. D
Marc h 4, 2 0 1 9 ( Versi o n 9. 0)
2 7
sa m ples s h o ul d be se parate d i n a ce ntrif uge f or 3 0 mi n utes at 3 5 0 0 r p m.  Wit h o ut 
dela y, 1. 5 ml ser u m ali q u ots s h o ul d be pi pette d i nt o a 2. 0 ml s na p ca p cr y o vials.  
After re m o vi n g t he ser u m, t he re d t o p t u be will be discar de d a n d eac h cr y o vial will 
be la ble d wit h t he date a n d patie nt case I D t o pr otect patie nt pri vac y. C yr o vials will 
be  fr oze n i m me diatel y at  - 7 0° C  i n  a  de dicate d  freezer  i n  t he  la b orat or y of  Dr.  
A n dre w S hara bi. If a - 7 0° C freezer is n ot a vaila ble ser u m sa m ples ma y be st ore d at -
2 0° C..
9. 1. 4 
Bl o o d f or plas ma s h o ul d be c ollecte d i n sta n dar d 1 0 ml He pari n c oate d t u bes.  T he 
sa m ples s h o ul d be i m me diatel y se parate d i n a ce ntrif u ge f or 1 0 mi n utes at 1 5 0 0 +/-
1 5 0 g ( = 1 5 0 0 R C F). Wit h o ut dela y, tra nsfer t he res ulti n g s u per nata nt plas ma t o a 
fres h 1 5 ml c o nical ce ntrif u ge t u be.  After re m o vi n g t he plas ma, use t he sa me 
tra nsfer pi pet t o caref ull y as pirate t he e x p ose d W B C la yer ( b uff y c oat) i n a v ol u me 
of 1 ml or less.  As pirate sl o wl y, usi n g a circ ular m oti o n, t o p ull all t he visi ble 
b uff y c oat material i nt o t he pi pet. E x pel t he b uff y c oat i nt o o ne cr y o vial.  Discar d 
t he la ve n der t o p t u bes a n d t he tra nsfer pi pet ti p.  La bel eac h b uff y c oat cr y o vial 
wit h t he wit h t he date a n d patie nt case I D t o pr otect patie nt pri vac y. R u n t he 1 5 ml 
c o nical  ce ntrif u ge  t u be  c o nt ai ni n g  t he  s u per nata nt  plas ma  i n  a  ce ntrif u ge  f or  a  
sec o n d ti me f or 1 0 mi n utes at 1 5 0 0 +/- 1 5 0 g ( = 1 5 0 0 R C F).  Wit h o ut dela y a n d 
usi n g a fres h tra nsfer pi pet ti p, 1. 5 ml plas ma ali q u ots of t he res ulti n g s u per nata nt 
s h o ul d be pi pette d i nt o a 2. 0 ml s na p ca p cr y o vials.  Lea ve a resi d ual v ol u me of 
a b o ut 0. 3 ml ( ~ 7 m m) o n t he b ott o m of t he 1 5 ml c o nical ce ntrif u ge t u be t o a v oi d 
cell ular  c o nta mi nati o n.  C yr o vials  will  be  fr oze n i m me diatel y  at  - 7 0° C  i n  a  
de dicate d freezer i n t he la b orat or y of Dr. A n dre w S hara bi. If a - 7 0° C freezer is n ot 
a vaila ble ser u m sa m ples ma y be st ore d at - 2 0° C.
9. 2)  Assess me nt of I m m u ne Re p o nses
9. 2. 9  
M u lti para metic  Fl o w  c yt o meter y  will  be  use d  t o  a nal yze  I m m u ne  s u bset  
pr o p orti o ns ( % C D 4 + T-cells, % C D 8 + T-cells, % T re g T-cells, % M yel oi d Deri ve d 
S u p press or  Cells,  % Nat ural  Killer  cells,  etc.)  will  be  deter mi ne d  b y  fl o w  
c yt o metr y  a nal ysis  perf or me d  i n  t he  U C S D  M o ores  Ca ncer  Ce nter  Fl o w  
C yt o metr y C ore.
9. 2. 1 0 T-cell Rece pt or  Re pert oire  a nal ysis  will  be  perf or me d  o n  Baseli ne  a n d  p ost-
treat me nt P B M C.  D N A will be e xtracte d a n d assesse d f or q ualit y c o ntr ol utilizi n g 
sta n dar d ma n ufact urer D N A e xtracti o n kits a n d per ma n ufact urer i nstr ucti o ns (i.e. 
D Neas y,  Qia ge n,  N. V.)  a n d  per  sta n dar d  s pectr o p h ot o metric  2 6 0 n m/ 2 8 0 n m  
met h o ds.  E xtracte d D N A fr o m eac h sa m ple will be a nal yze d f or T-cell a n d B-cell 
rece pt or  m utati o ns  b y  ne xt  ge nerati o n  se q ue nci n g  o n  t he  A da pti ve  
Bi otec h n ol o gies  I m m u n ose q  platf or m.   T his  w or k  will  be  o uts o urce d  a n d  
perf or me d i n c olla b orati o n wit h A da pti ve Bi otec h n ol o gies ( Seattle, W A).
9. 2. 1 1 Se q ue nci n g  A nal ysis.  D N A  will  be  e xtr acte d  a n d  assesse d  f or  q ualit y  c o ntr ol  
utilizi n g  sta n dar d  ma n ufact urer  D N A  e xtracti o n  kits  a n d  per  ma n ufact urer  
i nstr ucti o ns  (i.e.  D Neas y,  Qia ge n,  N. V.)  a n d  per  sta n dar d  s pectr o p h ot o metric  
2 6 0 n m/ 2 8 0 n m met h o ds.  E xtracte d D N A fr o m eac h sa m ple will be a nal yze d f or 
o verall m utati o n b ur de n, i n di vi d ual ge ne m utati o ns, a n d i n di vi d ual ge ne f usi o ns 
o n t he Ill u mi na Hi Se q Ne xt Ge nerati o n Se q ue nci n g platf or m.
9. 2. 1 2 Ser u m mar kers a n d c yt o ki ne of i nterest (i.e. I F N-
, T G F- , I L- 1 0, I L- 4, I L- 5, I L-


C BI a n d S B R T
Pr ot oc ol PI:  A n dre w S hara bi,  M. D., P h. D
Marc h 4, 2 0 1 9 ( Versi o n 9. 0)
2 8
1 3, I F N-
)  will be a nal yze d will be selecte d base d o n assa y met h o d ol o g y 
o pti mizati o n a n d vali dati o n testi n g. 
9. 2. 1 3  A d diti o nal e x pl orat or y a nal ysis of t he relati o ns hi p bet wee n circ ulati n g free t u m or 
D N A/ R N A, micr o- R N A, a n d ot her n o vel pl atf or ms will be p urs ue d as res o urces 
a n d s peci me n a vaila bilit y per mit.


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
29
10 STUDY CALENDAR 
Parameter
Pre-
TX
CBI
Cycle#1
SBRT
3 Fx
CBI
Cycle #2
CBI
Cycle#3+
Post 
C1D1
8 weeks 
@
Post 
C1D1
16 weeks 
@
Post 
C1D1
6mo @
Post 
C1D1
12mo @
Post 
C1D1
18mo @
Post C1D1
24mo @
Informed
Consent
X
Demographics
X
Med HX &
Medication
Rev
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
Standard of 
Care Labs
X
X
X
X
X
X
X
X
X
X
Research Blood
Draw
X*
X*
X
*
Imaging 
Assessment
X
X
X
X
X
X
AE Evaluation
X
X
X
X
X
X
X
X
X
X
~ SBRT: to be administered in three fractions.
* indicates optional
@ +/- 10 days


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
29
11
MEASUREMENT OF EFFECT 
        11.1     Antitumor Effect-Solid Tumors
For the purposes of this study, patients should be re-evaluated for response 8
weeks after the initial treatment, 16 weeks after treatment, and at 6 month 
intervals thereafter. 
Response and progression will be evaluated in this study using the new
international criteria proposed by the Response Evaluation Criteria in Solid
Tumors (RECIST 1.1) Committee (30). Changes in only the largest diameter
(unidimensional measurement) of
the tumor lesions are used in the RECIST
criteria.
The RECIST read at 16 weeks will be used to determine the objective response rate
for the primary endpoint of this study.  
11.2
Definitions
Evaluable Population: will consist of all patients who have received at least 1
cycle of CBI with or without SBRT. 
Safety Population: Will consist of all subjects who were enrolled and have
received at least 1 cycle of CBI with or without SBRT. This will be used to
assess the clinical safety and tolerability of the study.
Evaluable
for
Objective Response:
Patients who
have
measurable disease
present at baseline and have received at least 1 cycle of CBI , and have had their
disease re- evaluated will be considered evaluable for response. These patients will
have their response classified according to the definitions stated below.
11.3 Disease Parameters
Measurable
Disease: Measurable lesions
are
defined as
those
that can
be
accurately measured in at least one dimension (longest diameter to be recorded)
as >0.5 cm with diagnostic techniques (CT, PET/CT (all are optional), or MRI).
All tumor measurements must be recorded in centimeters.
Non-Measurable Disease: All other lesions (or sites of disease), including small
lesions (longest diameter <0.5 cm with diagnostic techniques), are considered
non-measurable
disease.
Bone
lesions,
leptomeningeal
disease,
ascites,
pleural/pericardial effusions,
lymphangitis,
inflammatory breast
disease, and
cystic lesions are all non-measurable. 
Target Lesions: Target lesion in this study will be considered metastatic sites up to a 
maximum of 3 lesions per patient. They should be recorded and measured at 
baseline. Target lesions should be equal to or larger than 1.0 cm in the smallest 


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
30
cross-sectional diameter on CT or MRI and/or any lesion that shows increase 
metabolic uptake on PET/CT scans. 
Non-Target Lesions: Non-Target lesion in this study will be considered metastatic 
sites up to a maximum of 10 lesions per patient. They should be recorded and 
measured at baseline. Non-target lesions should be equal to or larger than 0.5 cm in 
the smallest cross-sectional diameter on CT or MRI and/or any lesion that shows 
increase metabolic uptake on PET/CT scans. Importantly, a sum of the longest 
diameter (LD) for all non-target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD of the non-target lesions will be used as 
reference by which to characterize the objective tumor response.
11.4 Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation. All baseline
evaluations
should be
performed as
closely as
possible
to the
beginning of
treatment and never more than 6 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to
characterize each identified and reported lesion at baseline and during follow-up.
Imaging-based evaluation is preferred to evaluation by clinical examination when
both methods have been used to assess the antitumor effect of a treatment.
Conventional CT, PET/CT (all are optional), and MRI These techniques should be
performed with cuts of 10 mm or less in slice thickness contiguously. Spiral CT
should be performed using a 5 mm contiguous reconstruction algorithm. This applies
to tumors of the chest, abdomen, and pelvis.
11.5 Response Criteria (via RECIST 1.1)
11.5.1 Evaluation of Target Lesions
Complete Response (CR):
Disappearance of all targeted and Non-Targeted lesions
Objective Response (OR):
At least a 30% decrease in the sum of the 
longest
diameter (LD) of targeted and Non-targeted lesions,
taking as reference the baseline sum LD
Progressive Disease (PD):
At least a 20% increase in the sum of the LD of 
Targeted or Non- Targeted lesions, taking as reference
the smallest sum LD recorded since the treatment
started or the appearance of one or more new lesions
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor
sufficient
increase to qualify for PD, taking as reference the


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
31
smallest sum LD since the treatment started
11.5.2 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the
treatment
until
disease
progression/recurrence
(taking
as
reference
for
progressive disease the smallest measurements recorded since the treatment
started). Best overall response will be based on the overall response of the Non-
targeted lesions.
11.5.3 Duration of Response
Response will be defined as evidence of CR, PR, or stable disease. The
duration of response will be measured from the start of treatment until the
criteria for progression are met.
Duration of CR or PR: The duration of CR or PR will be recorded from
the time measurement criteria are met for CR or PR (whichever is first
recorded) until the first date that current or progressive disease is objectively
documented (taking as
reference
for
progressive
disease
the
smallest
measurements recorded since the treatment started).
Duration of Stable Disease: Stable disease is measured from the start of the
treatment and must be at least 6 months in duration or until the criteria for
progression are met, taking as reference the smallest measurements recorded
since the treatment started.
11.5.4 Clinical Response Parameters
Time to Local Progression (TTLP) is defined as the elapsed time from the start
of treatment to the date of documented local progression or death, whichever
happens earliest.
Progression-Free Survival (PFS) is defined is the time from starting treatment
to the time of first documented tumor progression or death due to any
cause, whichever
occurs first. Death is considered as an event here. For
subjects whose disease does not progress or who do not die, PFS will be
censored at the time of the last visit.
Time to Progression (TTP) is defined as the time from starting treatment to
the time of first documented tumor progression. Subjects who do not progress
will be censored at the time of the last contact. In addition, death from any
cause will also be censored.
Overall Survival (OS) is defined as the time from starting treatment until death
due to any cause. For subjects who do not die, time to death will be censored
at the time of last contact.


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
32
Locoregional Control (LRC) is defined as the time from starting treatment until
local and/or regional relapse is documented
11.5.5 Response Review
All responses will be reviewed by the study co-investigator radiologist.
12
ADVERSE EVENT REPORTING REQUIREMENTS 
12.1      General
Adverse event collection and reporting is a routine part of every clinical trial. This
study will use the descriptions and grading scales found in the NCI Common
Terminology Criteria for Adverse Events version 4.0 (CTCAE v 4.0) that is available
at http://ctep.cancer.gov/reporting//ctc.html.
Information on all Grade 3 or greater adverse events, whether reported by the
participant, directly observed, or detected by physical examination, laboratory test
or other means, will be collected, recorded, followed and reported as described in the 
following sections. In addition, grade 1 and 2 adverse events treated with concomitant 
medicine/procedure or deemed to be of clinical significance by a study investigator will 
be collected, recorded, followed and reported as described in the following sections.
Participants should be instructed to report any serious post-study event(s) that
might
reasonably be related to participation in this study. The investigator should
notify the IRB and any other applicable regulatory agency of any unanticipated
death or adverse event occurring after a participant has discontinued or terminated
study participation that may reasonably be related to the study.
12.2
Definitions
12.2.1
Adverse Event (AE)
An adverse event 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 adverse events only
if they induce clinical signs or symptoms or require treatment or further diagnostic
tests.
For this Phase II study only Grade 3 or higher adverse events, or grade 1 and 2 
adverse events treated with concomitant medicine/procedure,  or grade 1 and 2 
adverse events deemed to be of clinical significance by a study investigator will be 
collected.


CBI and SBRT
Protocol PI: Andrew Sharabi, M.D.,Ph.D
March 4, 2019 (Version 9.0)
33
12.2.2
Serious adverse event (SAE)
A serious adverse event is an undesirable sign, symptom, or medical condition
which:
x
is fatal or life-threatening;
x
requires or prolongs inpatient hospitalization;
x
results in persistent or significant disability/incapacity;
x
constitutes a congenital anomaly or birth defect; or
x
jeopardizes the participant and requires medical or surgical intervention to 
prevent one of the outcomes listed above.
Events not considered to be serious adverse events are hospitalizations for:
x
routine treatment or monitoring of the studied indication, not associated with
any deterioration in condition, or for elective procedures
x
elective or pre-planned treatment for a pre-existing condition that did not worsen
x
emergency outpatient  treatment for an event not fulfilling the serious
criteria outlined above and not resulting in inpatient admission
x
respite care
12.2.3
Expectedness
x
Expected: Expected adverse events are those that have been previously
identified as resulting from administration of the agent. For the purposes of
this study, an adverse event is considered expected when it appears in the
current adverse event list, the Investigator’s Brochure, the package insert or is
included in the informed consent document as a potential risk.
x
Unexpected: An adverse event is considered unexpected when it varies in
nature, intensity or frequency from information provided in the current adverse
event list, the Investigator’s Brochure, the package insert or when it is not
included in the informed consent document as a potential risk
12.2.4
Attribution
Attribution is the relationship between an adverse event or serious adverse event
and the study treatment. Attribution will be assigned as follows:
x
Definite – The AE is clearly related to the study treatment.
x
Probable – The AE is likely related to the study treatment.
x
Possible – The AE may be related to the study treatment.
x
Unlikely - The AE is doubtfully related to the study treatment.
x
Unrelated - The AE is clearly NOT related to the study treatment.
12.3 Potential Adverse Events
Signs and symptoms of disease progression are not considered AEs. The development
of a new cancer should be regarded as an AE. New cancers are those that are
not
the primary
reason for administration of
study
treatment and have been


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March 4, 2019 (Version 9.0)
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identified after inclusion of the patient into the clinical study.
Because patients are receiving standard treatments, which are not part of this study,
their treating physician will be counseling them on the risk of their treatments,
including the risk of surgery, radiation therapy, and/or chemotherapy, whichever is
appropriate for the type and the stage of their cancer. The procedures related to the
study are phlebotomy, PET imaging (all are optional), SBRT, and CBI administration.
Phlebotomy can cause pain, bleeding, and rare needle site infection. PET imaging
results in low dose radiation exposure (see Investigator’s Brochure for details of
dosimetry), which has an extremely small risk of causing a secondary cancer.
12.4 Stereotactic Body Radiation Treatment
It is difficult at this time to predict with confidence the complication rate from the
proposed SBRT; however, it is reasonable to extrapolate from the current experience
and reported literature with SBRT. One significant toxicity is radiation pneumonitis,
which can be manifested as fever, increased excertional dypsnea, pleuritic chest pain,
and peritumoral infiltrate on chest imaging. It generally occurs between 1 to 3
months of completion of radiotherapy. The risk of grade 2-4 radiation pneumonitis is
aproximately
10-15% in patients treated with standard fractionated large field
radiotherapy and higher in patients treated with combined chemoradiotherapy. It is
highly dependent on the volume of the lung treated to high dose and the mean
lung dose. At this point, the incidence of RT pneumonitis from SBRT combined 
with immunotherapy for small pulmonary tumors is unknown. However, if the
treated tumor volume is kept  65 cc, the risk should be <10-15% with the proposed
dose level.
Other toxicities commonly associated with such treatment includes colitis, diarrhea, 
hypophysitis, rash, arthritis, fatigue, nausea, vomiting, anorexia, and weight loss. Some
of these symptoms can also be due to tumor progression. Clinical and radiographic
assessments will be performed as indicated to identify all adverse effects, ascertain
their etiology, and provide the most appropriate palliative measures. Complications
orther than radiation pneumonitis, if any, will be graded according to the Common
Toxicity Criteria, National Cancer Institute, version 4.0.
12.5 Reporting Procedures
12.5.1
General
Adverse events will be recorded at each visit. If an adverse event requiring
medical attention occurs between visits, this will be recorded as well. The
variables to be recorded for each adverse event include, but are not limited to,
onset, resolution, intensity, action taken, outcome, causality rating and whether it
constitutes an SAE or
not. The intensity of the adverse event should be
captured using CTCAE criteria, version 4.0, when possible.


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Pregnancy in itself is not reported as an AE unless there is a suspicion that an
investigational
product
may have
interfered
with
the
effectiveness
of a
contraceptive medication.
All adverse events will be captured on the appropriate study-specific case
report forms (CRFs).
12.5.2
Institutional Review Board
All adverse events and serious adverse events will be reported to the IRB per
current institutional standards. If an adverse event requires modification of
the informed consent, these modifications will be provided to the IRB with
the report of the adverse event. If an adverse event requires modification to
the study protocol, these modifications will be provided to the IRB as soon as
is possible.
13
DATA AND SAFETY MONITORING PLAN 
Data and safety monitoring oversight will be conducted by the UCSD Moores 
Cancer Center Safety Monitoring Committee at the University of California at San 
Diego. All reportable anticipated and unanticipated protocol events/problems and 
amendments that are submitted to the IRB will also be reviewed by the Safety 
Monitoring Committee Chair (or designee) and QA manager.
14
REGULATORY CONSIDERATIONS 
14.1 Protocol Review and Amendments
Information regarding study conduct and progress will be reported to the
Institutional Review Board (IRB) per the current institutional standards.
Any changes to the protocol will be made in the form of an amendment and
must be approved by the IRB prior to implementation.
14.2 Informed Consent
The investigator (or his/her designee) will explain to each subject the nature of the
study, its purpose, the procedures involved, the expected duration, the potential
risks and benefits involved and any discomfort it may entail. Each subject will
be informed that participation in the study is voluntary, that she may withdraw
from the study at any time, and that withdrawal of consent will not affect her
subsequent medical treatment or relationship with the treating physician(s) or
institution. The informed consent will be given by means of a standard written
statement, written in non-technical language, which will be IRB approved. The


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March 4, 2019 (Version 9.0)
36
subject should read and consider the statement before signing and dating it, and
will be given a copy of the document. No subject will enter the study or have
study-specific procedures done before his/her informed consent has been obtained.
In accordance with the Health Information Portability and Accountability Act
(HIPAA), the written informed consent document (or a separate document
to be given in conjunction with the consent document) will include a subject
authorization
to
release
medical
information
to
the
study
sponsor
and
supporting
agencies
and/or
allow
these
bodies, a regulatory authority, or
Institutional Review Board access to subjects’ medical information that includes
all hospital records relevant to the study, including subjects’ medical history.
14.3 Ethics and GCP
This study will be carried out in compliance with the protocol and Good Clinical
Practice, as described in:
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996.
2. US 21 Code of Federal Regulations dealing with clinical studies (including
parts 50 and 56 concerning informed consent and IRB regulations).
3. Declaration
of
Helsinki,
concerning
medical
research
in
humans
(Recommendations
Guiding Physicians in Biomedical Research Involving 
Human Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong
Kong 1989, Somerset West 1996).
The investigators agree to adhere to the instructions and procedures described in
it and thereby to adhere to the principles of Good Clinical Practice that it conforms
to.
15
STATISTICAL CONSIDERATIONS 
15.1 Endpoints
15.1.1 Primary Objectives
To determine whether SBRT combined with concurrent CBI improves the 
objective response rate compared to CBI alone in patients with metastatic 
disease.
15.1.2 Secondary Objectives
o
To assess the safety and toxicity of CBI used concurrently with SBRT 
delivered in the population enrolled using grading with CTCAE v. 4.0
o
To assess progression free survival and overall survival in patients after 
completion of SBRT in combination with CBI. Progression-free survival
will be measured from time of enrollment to date of disease progression
or death. Patients who are lost to follow-up will be
censored for
determination of progression-free survival on the date of their last
evaluation. Overall survival is defined as time from enrollment to death


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March 4, 2019 (Version 9.0)
37
due to any cause.
o
To assess the rates of stable disease great than or equal to 6 months  during 
and after SBRT in combination with CBI compared to CBI alone
o
To determine whether SBRT combined with concurrent CBI results 
improvements in anti-tumor immune responses compared to CBI alone
15.2 Sample Size/Accrual Rate
The primary endpoint will be objective response rate at 16 weeks. The treatment
regimen would be considered of insufficient activity for further study in this
population if the 16 week objective response is 10% less than historical controls. 
The objective response rate to CBI monotherapy depends on disease type and is 
reported to be approximately 40% in melanoma and 20-25% in NSCLC. Dual agent 
checkpoint blockade has recently been shown to have a response rate of 61% in 
Metastatic melanoma. In order to detect a cumulative relative 33% increase in 
objective response rate [i.e. from 61% to 81% (for dual agent), 40% to 53% for 
single agent in melanoma, and 25% to 33% in NSCLC] with a one tailed p value 
<0.05% with 80% power incorporating the respective frequencies of tumor types this 
would require 146 patients total. 
15.3 Safety Run-In Phase
There is no significant published experience with SBRT used concurrently with
CBI in this study population. Therefore, to ensure that the combination is safe, the
first six patients will be treated and observed for toxicity for 30 days after
radiation before continuing with further accrual. 6 patients will be enrolled at the
proposed dose of CBI and SBRT. If  3 toxicity events occur in the first 6
patients within 30 days of therapy, we proceed with additional accrual with this
regimen to complete a total of 146 patients. If  4 toxicity events occur among
the first 6 patients, we will suspend the study pending data review.
Toxicity Event: JUDGH 3 adverse event (CTCAE v 4.0) with an attribution of
possible, probable, or definite.
15.4
Early Stopping Guidelines:
This study will monitor site-specific grade 4/5 toxicity. If it becomes evident
that the proportion of grade 4/5 toxicity at specific sites convincingly exceeds
30%, the study will be halted for a safety consultation. Specifically, we will
apply a Bayesian toxicity
monitoring rule that suspends the enrollment if the
posterior probability of toxicity being larger than 30% threshold is 75% or higher.
15.5 Analysis of Primary Objectives
The primary efficacy analysis will be the objective response rate of SBRT combined 
with concurrent CBI compared to CBI alone in patients with metastatic disease. 
Objective response is defined as at least
a
30% decrease
in
the sum of
the 
longest diameter (LD) of Non-Targeted lesion/lesions, taking as reference the


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March 4, 2019 (Version 9.0)
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baseline sum LD. The analysis population includes all registered subjects who have
received the three fractions of SBRT.
15.6 Analysis of Secondary Objectives
o
For safety analysis, adverse events will be summarized by type and grade.
o
To determine whether SBRT combined with concurrent CBI results in statistically 
significant improvements in anti-tumor immune responses compared to CBI alone 
we will perform immunologic assays quantifying lymphocyte specificity and 
activation, including Immune cell Sequencing, ProtoArrays, Immunoassays, and
multiparametric flow cytometry.
o
Hazard rate estimates and 95% confidence intervals as well as Kaplan-Meier
(KM) estimates will be used to summarize survival (OS), progression free
survival (PFS), time to locoregional progression (TTLP) and time to distant
progression (TTDP), duration of response functions over time, and stable disease 
(SD). The median OS, PFS, TTLP, TTDP, and SD will be reported.
15.7 Evaluation of Toxicity
All patients will be evaluable for toxicity from the time of their first treatment of CBI.
15.8 Evaluation of Response
All patients included in the study must be assessed for response to treatment, even if
there are major protocol treatment deviations or if they are ineligible. Each patient
will be assigned one of the following categories: 1) complete response, 2) partial
response, 3) stable disease, 4) progressive disease, 5) early death from malignant
disease, 6) early death from toxicity, 7) early death because of other cause, or 8)
unknown (not assessable, insufficient data).
All of the patients who met the eligibility criteria (with the possible exception of
those who received no study medication) should be included in the main analysis of
the response rate. Patients in response categories 4-8 should be considered to have a
treatment failure (disease progression).
All conclusions should be based on all eligible patients. Sub-analyses may then be
performed on the basis of a subset of patients, excluding those for whom major
protocol deviations have been identified (e.g., early death due to other reasons, early
discontinuation of treatment, major protocol violations, etc.). However, these sub-
analyses may not serve as the basis for drawing conclusions concerning treatment
efficacy, and the reasons for excluding patients from the analysis should be clearly
reported. The reason for performing subset analyses would be to generate hypotheses
for future prospective clinical trials.


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November 20, 2016
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