Immunotherapy Combined With Yttrium-90 RadioEmbolization in the Treatment of Colorectal Cancer With Liver Metastases [iRE-C - Clinical Trial]
Phase: PHASE1
Conditions: Colorectal Cancer Metastatic, Colon Cancer, Metastatic Colorectal Cancer, Rectal Cancer, Liver Metastasis Colon Cancer, Colo-rectal Cancer, Colorectal Adenocarcinoma, Colorectal Neoplasms, Liver Metastases, Colorectal Carcinoma
Sponsor: University of Iowa

Protocol Version 07June2022 
  
MC#### 
 
 
University of Iowa Hospitals and Clinics 
Holden Comprehensive Cancer Center 
 
Immunotherapy combined with Yttrium-90 RadioEmbolization in the treatment of Colorectal 
Cancer with Liver Metastases [iRE-C – Clinical Trial] 
 
Principal Investigator: 
Chandrikha Chandrasekharan, MD  
 
University of Iowa Hospitals and Clinics 
 
200 Hawkins Drive, C21 GH 
Iowa City, IA 52242 
319-356-2425 
Co-principal investigator: 
Sandeep Laroia, MD 
IDE Sponsor [TheraSphere®]: 
Parren McNeely, M.D. 
IDE number: 
G200069 
Co-investigators: 
Daniel Berg, M.D. 
Saima Sharif, MD 
Carlos Chan, MD, PhD 
Andrew Bellizzi, MD 
Anthony Snow, MD  
Biostatistician: 
√Sarah Bell 
FDA CDER exemption: 
141,185 
Protocol amendment: 
07June2022 
Trial Supported by: 
Funding: 
Biocompatibles UK Ltd, a BTG International Group Company 
Durvalumab: 
AstraZeneca 
TheraSphere®: Biocompatibles UK Ltd, a BTG International Group Company 
 
 
 
√Study contributor(s) not responsible for patient care 

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Summary of Changes 
 
Section 
Change 
 
07 June 2022 
 Title page  
 
     Updated date 
 
3.2.16 
 
 
     Removed 3.2.16 exclusion regarding Hepatitis B, Hepatitis C and HIV 
 
 
 
 
     requirement. 
 
       3.2.5 
 
Revised exclusion criteria 3.2.5 to add “infections.” Updated exclusion to 
read as: “Co-morbid systemic illnesses, infections, or other severe 
concurrent disease which, in the judgment of the investigator, would make 
the patient inappropriate for entry into this study or interfere significantly 
with the proper assessment of safety and toxicity of the prescribed 
regimens.” 
 
4.1   
 
 
    Removed Hep B surface ag, Hep C ab, HIV 1/2, from Test Schedule.  
 
18.0  
   Pathology Considerations/Tissue Biospecimens- updated location of specimens to    
University of Iowa Tissue Procurement Core 
 
 
           
_____________________________________________________________________________________ 
 04 March 2022 
  Title page  
 
     Updated PI Name and contact information.  
 
       _________________________________________________________________________________ 
  03 April 2020 
 
Title page 
Updated date; inserted IDE number 
1.4.5 
[FDA requested edit] 
 
1.4.7 
[FDA requested edit] 
 
 
 
3.1.7 
[FDA requested edit] 
 
 
 
 
3.1.7 
[FDA requested edit] 
 
3.2.14 
[FDA requested edit] 
Removed “…last dose of…” so sentence reads, “….fixed dose 
durvalumab and the dose limiting toxicity (DLT) observation phase for 8 
weeks post Y90-RE.” 
Edited sentence to read, “The dose limiting toxicity (DLT) observation 
phase is 8 weeks post Y90-RE.” 
Changed inclusion criterion from “These include at least treatment with 
a fluoropyrimidine, oxaliplatin, and/or irinotecan-based therapy, an 
anti-VEGF therapy and, if RAS wild-type, an anti-EGFR therapy, unless 
deemed intolerant or not suitable by the treating oncologist.” to “These 
include at least treatment with a fluoropyrimidine, oxaliplatin, and/or 
irinotecan-based therapy and an anti-EGFR therapy if RAS wild-type 
(unless deemed intolerant or not suitable by the treating oncologist), 
with or without an anti-VEGF therapy.” 
Inserted inclusion criterion to specify a minimum gap of 4-weeks 
between Tc-99m-labelled mAA eligibility mapping and any anti-VEGF 
therapy; renumbered inclusion criteria accordingly. 
Reduced steroid allowance to 10 mg prednisone equivalent 
7.4.2 
Removed “up to” to clarify the DLT window is 8 weeks post Y90-RE 

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Added, “Any event resulting in a delay of cycle 2 ≥ 14 calendar days,” 
Added, “Any Grade 3 irAE…” 
Added Grade 4 neutropenia lasting > 5 days 
Added any instance of grade 4 thrombocytopenia 
Added any instance of grade 3 thrombocytopenia with accompanying 
hemorrhage 
7.4.2 
[FDA requested edits] 
 
 
 
 
 
 
 
 
 
 
Table 8.21 
[FDA requested edits] 
Added grade 3 nausea / vomiting exception 
Added grade 3 nausea / vomiting / diarrhea exception 
Added grade 4 vomiting / diarrhea exception 
Added grade 3 hypertension exception 
Added grade 3 metabolic abnormalities exception 
Added grade 3, 4, 5 electrolyte abnormality exception 
Added grade 3, 4 elevation in amylase/lipase exception 
Added grade 3 rash exceptions 
Changed Grade 3 diarrhea or colitis dose modification to permanently 
discontinue 
Added grade 2 to hyperglycemia/T1DM 
Added grades 2 & 4 to hypothyroidism 
Added grade 2 to hyperthyroidism 
Added grade 1 to dose modification for infusion related reaction 

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03 April 2020 (cont’d) 
 
 
 
Table 8.21 
[FDA requested edits] 
 
 
 
 
 
17.5.3 
[FDA requested edits] 
 
Clarified, “…and corticosteroid dose is less than or equal to prednisone 
10 mg per day (or equivalent)…” to pneumonitis grade 2 dose 
modification 
Clarified, “…and corticosteroid dose is less than or equal to prednisone 
10 mg per day (or equivalent)…” to all other non-hematologic events 
grade 3 dose modification 
Clarified, “…and corticosteroid dose is less than or equal to prednisone 
10 mg per day (or equivalent)…” to pneumonitis grade 2 dose 
modification 
Clarified mRECIST as evaluation criteria for ORR 
Clarified time point window 
Clarified response categories and evaluation criteria 
17.5.3 
Inserted text from Appendix A.9 regarding results reporting 
Footer 
Updated protocol date 
 
04 March 2020 
 
Title page 
Reformatted, updated to include IDE sponsor 
Throughout 
Clarified section numbers; formatting updated for consistency 
1.2.3 
Inserted ‘Tc-99m’ prior to MAA for clarification 
1.2.3 
Inserted further details regarding calculation of prescription activity as 
well as protective measures for lung and bowel. 
1.4.2 
Inserted information about the Tc99m MAA eligibility mapping for 
eligibility and screening. 
3.2.1 
Provided Cockcroft Gault formula 
3.2.1 
Included recommendations from FDA for total bilirubin and serum 
creatinine 
3.2.2 
Incorporated recommendations from FDA 
4.0 
Clarified footnote 18 for inclusion of the Tc99m labelled MAA 
mapping. 
7.1.2 
Inserted information from package insert on radiation dose. 
10 (overall) 
Heavy revision for compliance and consistency with FDA, IRB, and 
DSMC requirements. 
10.2.2 
Clarified that subjects will be followed for up to 2 years for radiation 
associated adverse effects; this determination will be made by an 
authorized user (NRC). 
16 (new section) 
Created section in investigational device; renumbered subsequent 
sections accordingly. 
17.3 
Updated to address concerns and queries from FDA 
17.5.3 
Defined evaluable patient 

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Table of Contents 
Summary of Changes .................................................................................................................................... 2 
Table of Contents .......................................................................................................................................... 4 
Schema .......................................................................................................................................................... 5 
1.0 
Background .................................................................................................................................... 6 
2.0 
Goals ............................................................................................................................................ 17 
3.0 
Registration Patient Eligibility ..................................................................................................... 18 
4.0 
Test Schedule ............................................................................................................................... 22 
5.0 
Stratification Factors OR Grouping Factor .................................................................................. 24 
6.0 
Enrollment Procedures ................................................................................................................. 24 
7.0 
Protocol Treatment ....................................................................................................................... 24 
8.0 
Dosage Modification Based on Adverse Events (details tabulated in appendix VIII) ................. 27 
9.0 
Ancillary Treatment/Supportive Care .......................................................................................... 29 
10.0 Adverse Event (AE) Monitoring and Reporting .......................................................................... 32 
11.0 Treatment Evaluation/Measurement of Effect ............................................................................. 37 
12.0 Descriptive Factors ....................................................................................................................... 39 
13.0 Treatment/Follow–up Decision at Evaluation of Patient ............................................................. 39 
14.0 Body Fluid Biospecimens ............................................................................................................ 40 
15.0 Drug Information.......................................................................................................................... 41 
16.0 Device Information ...................................................................................................................... 42 
17.0 Statistical Considerations and Methodology ................................................................................ 44 
18.0 Pathology Considerations/Tissue Biospecimens .......................................................................... 47 
19.0 Records and Data Collection Procedures ..................................................................................... 48 
20.0 Budget .......................................................................................................................................... 49 
21.0 References .................................................................................................................................... 50 
Appendix I: ECOG Performance Status ..................................................................................................... 53 
Appendix II: New York Heart Association Classification .......................................................................... 54 
Appendix III: EORTC QLQ-C30 ............................................................................................................... 55 
Appendix IV: RECIST 1.1, iRECIST, mRECIST ...................................................................................... 58 
IV.A. Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference ............................... 58 
IV.B. Immunotherapy in Cancer Response Evaluation Criteria in Solid Tumors (iRECIST) ............... 62 
IV.C. Modified Evaluation Criteria in Solid Tumors (mRECIST) Quick Reference ............................ 63 
Appendix V: Restrictions for blood donation and for those of childbearing age ........................................ 64 
Appendix VI: TheraSpheres Prescribing Information ................................................................................ 66 
Appendix VII: Dosing Modification and Toxicity Management Guidelines .............................................. 95 
Specific Immune-Mediated Reactions .................................................................................................... 96 

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Schema 
Prior to discussing protocol entry with the patient, call the Registration Office and discuss with 
clinical trial coordinator and/or Study PI for dose level and to ensure that a place on the protocol is 
open to the patient. 
↓ 
↓ 
↓ 
↓ 
 
↓ 
Events at any time: 
Disease Progression 
Intolerable adverse effects 
Patient refusal 
↓ 
 
 
 
 
 
 
Cycle = 14 days; *number of durvalumab doses post Y90-RE are dependent on assigned cohort level 
 
CFU 
Survival Follow-up 
Generic name: durvalumab 
Brand name(s):IMFINZI® 
Abbreviation: MEDI4746 
Availability: Investigational 
Treatment: 0-3 doses of Durvalumab* 
Treatment: 1 dose of Durvalumab + 
Y90-RE 
Treatment: 0-1 dose of Durvalumab* 
Registration 

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1.0 
Background 
1.1 
Colorectal cancer (CRC) 
Colorectal cancer (CRC) accounts for approximately 135,000 new cancers diagnosed annually in the United 
States. Despite recent advances in treatment, it still remains the third most common cause of cancer 
mortality, causing 50,000 deaths per year. (Siegel, et al, 2016; Ryerson, et al, 2016) Patients who have 
isolated liver metastases that are amenable to surgical resection may be potentially cured. However, less 
than 25% of patients present with easily resectable disease. (Khatri, et al, 2005; Morris, et al, 2010) A 
number of interventional oncologic loco-regional modalities have emerged to treat patients who are not 
surgical candidates and provide disease control. One such promising modality is radioembolization (RE), 
which consists of delivering transvascular brachytherapy to the tumor via the hepatic artery. A phase III 
trial comparing RE with chemotherapy to chemotherapy alone demonstrated an improved time to liver 
progression by approximately eight months. (Hendlisz, et al, 2010) Overall survival benefit, however, is 
lacking based on more recent randomized controlled trials, and underlying patient- and tumor-related 
factors are being explored. 
In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a number of 
cancers. They target the programmed cell death ligand-1 (PD-L1), Programmed cell death protein 1 (PD- 
1) or cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathways. These immune escape mechanisms allow 
tumors to progress by evading the body’s immune response. ICIs inhibit these pathways and activate 
lymphocytes to recognize tumor antigens, thereby enhancing tumor killing (Pardoll, et al, 2012). They have 
shown activity and efficacy in a number of malignancies including melanoma, lung cancer, renal cell 
cancer, bladder cancer, head and neck cancer, and Hodgkin lymphoma. (Topalian, et al, 2012; Brahmer, et 
al, 2012; Rosenberg, et al, 2016; Robert, et al, 2015; Ferris, et al, 2016; Gettinger, et al, 2016) 
Immunotherapy alone in patients with metastatic colorectal cancer (mCRC) had been of limited value until 
recently. The factors identified behind immunotherapies working for some cancers while not others include 
tumor related factors (mutational burden) and host related factors (immune response). In colorectal cancers, 
these tumors can be classified as microsatellite instability-high (MSI-H) with a high mutational burden 
(Lynch-syndrome like) and microsatellite stable (MSS), with a low mutational burden. The results of a 
landmark immunotherapy trial published in 2015 for the first time showed great promise for 
immunotherapies in mCRC. Of note, while seven out nine patients who were MSI-H had an objective 
response, 0 out 18 patients who were MSS had a response to anti-PD-1 blockade. (Le, et al, 2015) 
Unfortunately, MSI-H tumors constitute a very small proportion (~5%) of mCRC. Therefore, novel 
approaches are needed to make immunotherapy a viable option for MSS tumors, which constitute more 
than 95% of the tumors. Furthermore, immunotherapy is only approved for this particular patient subset 
after failure of traditional chemotherapy and not first-line. 
Increasing exposure of neo-antigens to the immune system could be one potential strategy to enhance the 
response of immunotherapy to patients with mCRC. Yttrium 90-radioembolization (Y90-RE) in 
combination with immunotherapy may result in immunotherapy working for patients with mCRC and/or 
increasing the efficacy of Y90-RE. Furthermore, the “abscopal effect” is a phenomenon in the treatment of 
cancer where localized treatment of a tumor causes an effect on the treated tumor, and tumors outside the 
localized treatment field. It has been reported in a number of different human cancers. This phenomenon 
has also been demonstrated in mouse tumor models and been shown to be mediated by immune 
mechanisms, and therefore, does not occur in immunodeficient mice. Tumor cells exposed to radiation can 
undergo an immunogenic death that exposes tumor antigens and triggers an anti-tumor immune response 
that results from an increase in maturation of antigen presenting cells. Additionally, radiation makes the 
tumor microenvironment conducive to effector T-cell recruitment and function. It induces chemokines 
involved in the recruitment of effector T cells, thereby making the tumor susceptible to T-cell attack. 
(Herrera, et al, 2017) Y90-RE in essence, provides not only local radiation therapy to the treated tumor but 
also a potential opportunity for immunotherapy to work for patients for whom immunotherapy was not an 

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option by increasing exposure to neo-antigens and altering the tumor microenvironment. Radiation in 
general has been combined with immunotherapy for a number of malignancies. Therefore, we hypothesize 
that combining immunotherapy agents with Y90-RE is feasible, safe and will improve outcomes in patients 
with mCRC with liver-predominant metastases. 
Current Y90-RE relies on the transarterial administration of several million yttrium-90 (Y90) containing 
resin or glass microspheres ranging from 20-30 microns that provide intratumoral brachytherapy through 
the emission of beta particles. It provides a unique dosimetry advantage by relying on an inherent dose 
preferential related to tumor relative hyperarteriolization and the minor parenchymal penetration of emitted 
beta particles. (Hazel, et al, 2016; Ruers, et al, 2012; Kasi, et al, 2015) In contrast to external photon or 
proton radiotherapy, Y90-RE is not only treating in field disease, but also via in situ tumor ablation 
generating both antigen exposure and changes in the tumor microenvironment (TME) from an immune 
standpoint. (den Brok, et al, 2004) Both the antigen exposure and immune related changes in TME are 
aspects that can be harnessed to generate a more robust, effective and potentially durable immune response 
against the tumor. Some of the recent small translational studies are showing that the tumor 
microenvironment from an immune perspective does undergo changes post-RE (Chew, et al, 2018). 
Panel A: from Valerie et al 2018: Immune profiles of tumour infiltrating leucocytes (TILs) isolated from Yttrium-90 
(Y90)-radioembolization (RE)-treated and treatment-naïve tumours. Valerie Chew et al. Gut doi:10.1136/gutjnl-2017- 
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Panel B: from Valerie et al 2018: Next-generation sequencing (NGS) and pathway analysis of post-Yttrium-90 
(Y90)-radioembolization (RE) and treatment-naïve (control (Ctl)) 
ICIs have shown remarkable durable efficacy in a number of cancers by harnessing the body’s immune 
system to attack the tumor. Unfortunately, in mCRC this effect is limited to a small percentage of tumors 
that are MSI-H who have failed immunotherapy. By combining ICIs with radioembolization, we could 
potentially increase the number of patients who could attain durable benefit from immunotherapy and Y90- 
RE. The safety data as well as the translational data generated from this trial would also be of value for 
other tumor types since Y90-RE is utilized for treatment of other primary and secondary liver tumors as 
well. 
1.2 
Y-90 Radioembolization (Y90-RE) 
Y-90 radioembolization (Y90-RE) is a combination of radiation therapy and in the case of glass 
microembolization to treat cancer of the liver. Radioembolization consists of the transarterial administration 
of yttrium-90 containing glass or resin microspheres as tumor brachytherapy for hepatic malignancy. 
Radioembolization safely achieves tumor biological equivalent doses that exceed both external beam 
radiotherapy by exploiting tumor hypervascularity as an inherent dose preferential and the limited 
parenchymal penetration of beta particles. (Kennedy, et al, 2014) These properties allow for ablative doses 
of radiation with minimal toxicity administered in as little as one or two outpatient sessions. (Riaz, et al, 
2011; Gates, et al, 2014) It results in a minimally invasive treatment in which the primary mechanism is 
delivery of radiation with microembolization of the vascular bed. Glass Radioembolization employs 
microspheres with the radioactive isotope yttrium-90 incorporated within the glass microsphere. Normally 
the microspheres are made by tiny glass or resin beads. Those microspheres will be placed inside the blood 

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vessels that feed a tumor. The microspheres will be delivered by catheter through the skin after X-Ray 
imaging and a contrast material in order to visualize the blood vessel. TheraSphere®, an Y90-RE owned by 
BTG International Canada will be used in this clinical trial. As per the FDA approved USPI Technitium- 
99m (Tc-99m) labeled Macroaggregated Albumin (MAA) scintigraphy will precede microsphere 
administration to ensure proper delivery of radiotherapy and minimize collateral toxicity. 
1.2.1 
Variances in Radioembolization 
Applications of radioembolization include whole liver, lobar, and segmental treatments encompassing 
surgical neoadjuvant, bridge to transplantation, definitive radiotherapy, and palliative intention. Greater 
than 50% complete pathologic response rates in hepatocellular carcinoma (HCC) and metastatic colorectal 
carcinoma (mCRC) previously treated with radioembolization in liver explants and hepatic resection 
specimens are evidence of its ablative potential. (Vouche, et al, 2014; Shah, et al, 2017; Lewandowski, et 
al, 2016) Randomized control trial data has shown palliative radioembolization to be well tolerated with 
concurrent systemic chemotherapy in mCRC. Differing safety and efficacy outcomes can be seen due to 
techniques, methodologies, institutional practices, selection of patients and products used. 
1.2.2 
Glass Radioembolization for Liver Predominant Colorectal Carcinoma 
Although the largest prospective randomized trial utilizing radioembolization for the treatment of liver 
metastatic colorectal carcinoma were performed with resin spheres, our current trial will be utilizing glass 
microspheres. The two products vary in specific activity (60 Bq vs 2500 Bq), specific gravity, and 
administration technique. Although data from a prospective randomized study utilizing glass microspheres 
for colorectal hepatic metastases (EPOCH) is yet unavailable, multicenter retrospective data demonstrates 
both safety and tumor response in utilizing glass for this indication. Results from this analysis demonstrated 
that in 531 patients, the most common clinical adverse events were fatigue (55%), abdominal pain (34%) 
and nausea (19%). Grade 3 or 4 hyperbilirubinemia occurred in 13% of patients. Median overall survival 
from first Y90-RE treatment was 10.6 months (95% CI 8.8-12.4). Performance status, tumor burden ≤25%, 
no extra-hepatic metastases, albumin >3 g/dL and having received ≤2 chemotherapeutic agents 
independently predicted better improved outcomes (Hickey, et al, 2016). These are relatively consistent 
with the published literature for resin microspheres. 
1.2.3 
Radioembolization Dosimetry 
The understanding of how to best deliver transvascular microsphere brachytherapy has slowly matured 
since its inception in the mid 1960’s to the current iteration. Dosimetry began as an empiric administration 
approximately 20 years ago which resulted in high toxicity and low efficacy. The notion of tailoring the 
dose to an individual’s anatomy led to the development of body surface area dosimetry or the BSA method. 
This has been the most widely studied method for delivering resin microspheres which have a lower specific 
gravity and activity when compared to glass microspheres. The advantages to the BSA method are mainly 
rooted in the conservative doses that rarely result in toxicity, but even less commonly achieve major 
responses. An alternative method and most used approach for glass microspheres, which are orders of 
magnitude greater in activity to resin spheres (2,500 vs 60 Bq/sphere), is the Medical Internal Radiation 
Dose or MIRD formula. This has a distinct advantage to BSA in that it factors true anatomic volumes in 
which a predetermined activity is administered which gives a generic dose. 
Unfortunately, this method does not take into consideration the tumor favoring dose preferential of vascular 
conduit therapy amongst other flow altering factors and the true microsphere deposition is not accounted 
for. The 3D evaluation of Tc-99m MAA as a temporary particle simulant prior to radioembolization has 
prompted the compartmental approach in which the general sorting of Tc-99m MAA can be converted to a 
presumed dose after treatment. While this is an improvement, the technique has traditionally assumed single 
infusion points from the main hepatic arteries and may not match the heterogeneous distribution of liver 
metastases in patients. The angiosomal approach involves segmenting the liver based on individual 
supplying arteries and performing individual volumetric and compartmental assessments to determine the 

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strength of dose to each volume based on tumor content and risk of overall hepatic dysfunction based on 
hepatic substrate and volume of treatment. If the tumor to parenchyma ratio is high, then dose escalation is 
performed given the higher chance for efficacy with less collateral damage. The converse is also true. An 
additional subset involves the compartmentalization of doses achieved through preferential deposition of 
spheres related to tumor hypervascularity. This can be prospectively approximated through the analysis of 
Tc-99m MAA deposition, which has shown to be highly predictive of normal tissue deposition but less 
predictive of tumor deposition. This can be utilized to determine the risk of normal tissue complications 
and overall guide dosimetry, typically limited by the non-target organ dose. The majority of glass 
administrations will utilize a qualitative assessment of administered activity equating to a MIRD dose that 
can be both with ablative and non-ablative intent based on the tumor to parenchyma ratio within each 
treatment angiosome. The previously mentioned retrospective analysis of glass radioembolization utilized 
for colorectal carcinoma showed a median radiation dose delivered to the liver of 120.2 Gy (range, 35–391 
Gy). 
Non-ablative doses typically range from 40-80 Gy and ablative doses may exceed 120 Gy per lobe with 
segmental administrations measuring >190 Gy. To prospectively determine dosimetry as a fixed range for 
all patients may prove challenging as oncologic intent, performance, liver substrate, tumor stage, tumor 
vascularity and arterial physiology are all variable. 
At our institutions and centers with more expertise in interventional oncology, the focus of our 
interventional oncology group is to maximize dose when possible but maintaining safety as a primary 
objective. Additionally, Y90-RE is done with as much parenchymal sparing as possible while delivering 
higher doses to the areas of maximum tumor involvement. The treatment in conjunction could potentially 
allow for not only durable local control but also systemic control by exposure of neoantigens. The more 
durable control stems from increased PD-L1 expression noted post radiation as a mechanism of evasion 
and resistance to therapy, which can be overcome by anti-PD1/PD-L1 agents. 
Target dose administrations will fall within package insert recommendations of 80 Gy to 150 Gy per lobe 
of liver in order to prevent radioembolization-induced liver disease (REILD). Required activity at the time 
of administration may be calculated as 
 
 
 
Activity Required (GBq) = 
[Desired Dose (Gy)][Target Liver Mass (kg)] 
50 
 
and the actual dose delivered to the liver is 
50[Injected Activity (GBq)][1 − F] 
Dose (Gy) = 
 
 
Affected Liver Mass (kg) 
 
, where F is the lung shunting fraction measured during the Tc-99m labelled MAA eligibility study. 
 
Safety is the primary goal of our clinical trial. For patients who are deemed candidates through multi- 
disciplinary decision, this factors all the recent updates and guidelines. Variation in doses would not be a 
concern since all the patients will be treated at one institution (University of Iowa). Important aspects 
factored in this patient selection includes but is not limited to absence of shunting to bowel along the GI 
tract. Protective measures against radiation pneumonitis require a lung shunting fraction (F) <15% or 
estimated lung doses <30 Gy for a single Y90-RE administration and a cumulative total of <50 Gy from 
multiple administrations. 

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1.2.4 
Radioembolization and Immunomodulation 
In addition to promotion of immunity, radiation may exhibit certain immuno- inhibitory effects. Radiation 
upregulates transforming growth factor β and galectin-1 which have been shown to indirectly suppress T 
cell activity. (Demaria, et al, 2015) Although radioembolization does not rely on the embolic effect of 
microspheres, high particle volume treatments may reduce local blood supply. (Pellerin, et al, 2013) 
Transient lymphopenia has been previously observed in patients undergoing radioembolization which is 
usually of no clinical consequence, but this effect may interfere with immune response. (Salem, et al, 2005). 
While radiation induces tumor vascular normalization, it can also exacerbate local hypoxia via endothelial 
damage and venoocclusive associated interstitial hypertension which theoretically abates local immune 
response (Park, et al, 2012; Fan, et al, 2014). Although preclinical models support hypofractionated external 
beam therapy to maximize effective anti-tumor immune response, the equivalent dosimetry of 
brachytherapy has not been specifically studied for this purpose (Dewan, et al, 2009). Ultimately, 
understanding the precise role and balance of both potential immunostimulatory and inhibitory effects of 
radioembolization will require considerable investigation. Some of the recent studies, however, (as shown 
in panel A and B earlier) do offer proof of principle in terms of value of potentially combining immune 
checkpoint inhibitors in conjunction with Y90-RE (Chew, et al, 2018) approaches. 
1.2.5 
Hepatic Benefit of Radioembolization 
Of all radiotherapy modalities, radioembolization is unique in its ability to provide low normal tissue 
complication rates with whole organ treatment. This offers potentially more comprehensive immune 
exposure of heterogeneous tumor clones in both patients with metastatic disease and field defects while 
conceptually preventing local expansion untreated variants. (Greaves, et al, 2012; Li, et al, 2013; Zarour, et 
al, 2017) Radioembolization is also distinctive in its ability to achieve the highest reported doses of radiation 
(>2,000 Gy segmental MIRD uniform distribution, >11,000 Gy tumor uniform distribution) (Riaz, et al, 
2011) with minimal toxicity in anatomic locations that would otherwise be unamenable to other ablation 
modalities including stereotactic body radiation therapy. (Scorsetti, et al, 2014) In further contradistinction 
to external source radiation, repeat segmental brachytherapy treatments of parallel structure organs such as 
the liver are unconstrained by cumulative non-target dose. Radioembolization is also not compromised by 
physiologic movement and does not require fiducial placement. 
1.2.6 
Controversies in Radioembolization for Colorectal Carcinoma 
Although the predominant cause for morbidity and mortality in patients with metastatic colorectal 
carcinoma arises from involvement of critical organs, namely the liver and peritoneum, survival benefits 
by providing locoregional therapy have been challenging to establish. The CLOCC trial showed that for 
patients with favorable biology, there was a benefit to performing radiofrequency ablation vs chemotherapy 
alone in patients with hepatic colorectal metastases. (Ruers, et al, 2011) Translating this to 
radioembolization has not been successful. The final analysis of SIRFLOX demonstrated a progression free 
survival benefit in the liver vs chemotherapy alone, however only showed a survival benefit in patients with 
right-sided primary colon cancer. (Wasan, et al, 2017) Of note, this was not the primary outcome of this 
study. 
Dosimetry in radioembolization presents a formidable challenge given both the nonuniformity of methods 
and the variability of administration inherent to vascular brachytherapy. Given that most patients who 
undergo either resection or locoregional therapy for hepatic metastases are at high risk for non-target disease 
progression, either due to limitations in staging or tumor biology assessment, there is a formidable challenge 
in delineating at which point cytoreduction conveys benefit to patients. In general, the concept of response 
depth, or a low hepatic tumor state, appears to be a reasonable objective at face value, particularly if 
achieved while maintaining a high quality of life. 
Unfortunately, factors that ultimately contribute to patient demise in colorectal cancer are a concatenation 
of deficits that are unique to tumor genotype, subject performance and physiologic reserve, and 

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permutations of iatrogenic intervention. In the actual trial, one critique was the lack of continuation of what 
would be considered standard of care therapy including use of anti-VEGF agents and/or anti-EGFR agents 
as well as Regorafenib and/or TAS-102. Systemic therapy was less likely to be continued and outcomes 
based on tumor based genetic testing were not presented. As to which patients can truly benefit from such 
an approach is still debatable and not established. There are patients with mCRC who may benefit from a 
personalized approach of utilizing Y90-RE in combination with immunotherapy as is being proposed on 
this clinical trial. 
1.3 
Durvalumab 
Durvalumab, commercial name IMFINZI®, a PD-L1 inhibitor owned by AstraZeneca, received accelerated 
approval from FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma. 
It comes as 500mg/10mL or 120mg/2.4mL solution in a single-dose vial, and will be further diluted prior 
to intravenous infusion. 
1.4 
Clinical Trial 
1.4.1 
Clinical Data to Date 
This clinical trial will be the first trial combining Y90-RE and durvalumab and therefore no previous clinical 
data of this combination is available. 
A similar trial which employs the Y90-RE and PD-1 inhibitor nivolumab is currently in the stage of 
recruiting/ongoing on clinicaltrials.gov website, but not open yet to the best of our knowledge 
(NCT03307603). There are other trials employing other checkpoint inhibitors that are showing that they 
are in development as well (details not available). 
1.4.2 
Dose Rationale 
For each subject, the starting dose of Y90-RE will be personalized based on the lobe and number of 
metastatic lesions. The actual dose will comply with the FDA-approved prescribing information 
(Appendix). Each subject will receive a fixed dose of 750mg of durvalumab with at least 2 weeks between 
doses depending on the dose level assigned to. This will coincide with the Tc99m labelled MAA eligibility 
mapping and treatment with Y90-RE and every 2 weeks visits with labs post Y90-RE, which is the preferred 
standard practice at most institutions. As noted in the study schema, there is margin for a few days before 
or after the planned 2-week cycle to accommodate scheduling issues. The timing and frequency of 
durvalumab varies on the dose level. Please discuss with the principal investigator and study clinical trial 
coordinator to know which dose level the patient is assigned to. From a safety perspective since we need to 
know about the shunting to other organs prior to the Y90-RE, the mapping can be done during the screening 
or even prior to considerations for this study if already performed within 12 months of intended Y90-RE, 
it would not need to be repeated unless as per interventional radiology. 
Note: The dosing of Y90-RE, dose and administration will be as per FDA approved USPI. Goal is to deliver 
an ablative radiation dose to the targeted region and trigger a release of neo-antigens in order to augment 
immunotherapy; all the while minimalizing collateral damage by sparing normal liver parenchyma. As 
noted in the protocol, there are numerous dosing methods in place for Durvalumab. 
1.4.3 
Rationale for Combination of Y90-RE and Durvalumab 
While surgery remains the conventional definitive treatment for metastatic liver cancer, many patients are 
unamenable at presentation and most will ultimately sustain disease recurrence. (Vigano, et al, 2013; 
Cucchetti, et al, 2009) The inherent limitations of traditional staging with serologic, imaging, and histologic 
assessment lack the sensitivity to detect microscopic disease in its entirety outside of the treatment field. 
Theoretically, extirpation of metastatic disease may remove tumor antigens that, if properly exploited, could 
potentially generate signal for comprehensive immune mediated disease control. For patients with 
surgically unmanageable disease, locoregional treatments that maximize antigenic exposure may produce 

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immunologic responses that could provide a powerful adjunct to therapy while maintaining quality of life 
with a minimally invasive, outpatient, procedure. 
Sustained immune tumoricidal responses require complex environmental interactions of antigen 
recognition and presentation, T cell activation, T cell relevance in the setting of continuous tumor genetic 
variation, and circumvention of tumor suppression mechanisms. The locoregional modalities which have 
shown particular promise in preserving tumor antigen allowing for host activation include cryoablation, 
irreversible electroporation, ischemic therapies such as embolization, and vascular micro-brachytherapy 
achieved via transarterial radioembolization. A large body of literature has been already generated to 
support ionizing radiation as an immunologic adjuvant to many of these requirements. (Kang, et al, 2016) 
Localized radiation therapy holds great promise as an immunologic antitumor adjuvant. Radioembolization 
has a wide range of exclusive properties that warrant exploration to determine how best to incorporate it 
within the radiotherapeutic inventory. Given an increasing knowledge base and experience with 
radioembolization, and the current enthusiasm for immunotherapy-based oncology, currently recruiting 
clinical trials will hopefully materialize the promise of their synergism. 
The clinical benefit of using Y90-RE in combination with durvalumab is yet to be known since 
immunotherapy has not, to date, significantly benefited patients with mCRC. However, addition of Y90- 
RE may improve the antigen exposure to immunotherapy and further improve the outcome of the treatment. 
Furthermore, both Y90-RE and durvalumab will be used at the dose recommended by the manufacturer in 
which the doses are well established. Given the absence of any significant untoward side effects, major 
safety issue is not expected and there is potential benefit. Concurrent translational and correlative data 
would significantly improve insights on how to help improve immunotherapy as an option for patients with 
mCRC. 
1.4.5 
Rationale for Durvalumab Dose Escalation 
The trial, for each subject, will consist of a screening period, a treatment and observation phase. The 
treatment phase is approximately 2 months with Y90-RE in combination with fixed dose durvalumab and 
the dose limiting toxicity (DLT) observation phase for 8 weeks post Y90-RE. The rationale for the 
proposed dosing schema is keeping in mind the timing of toxicities that are typically seen post Y90-RE. 
Most patients have elevation of their liver enzymes the first 1-2 weeks. Therefore, with the dosing 
escalation, we did not include the added dose at week 2 for the first dose escalation (see dose level table – 
section 7.41 and Table 1 section 1.23 below). Patients get fixed dosing of immunotherapy, which is the case 
for all immunotherapy-based studies. Depending on the dose level, patients can get a maximum of 2 doses 
before and 3 doses post Y90-RE. As noted in Table 1 (section 1.23 below), while dose level 1 and dose 
level -1 have the same number of durvalumab administrations, they are different since dose level 1 get 2 
doses pre-Y90-RE (‘priming doses of immunotherapy before Y90-RE) while dose level -1 only get 2 doses 
post-Y90-RE. 
1.4.6 
Study Design 
This clinical trial will be conducted as a single-center, open-label, Phase I trial to evaluate the feasibility 
and safety of Y90-RE in combination with a fixed dose of durvalumab in subjects with liver-predominant, 
mCRC. It can be offered in the refractory setting and/or more so integrated into the current standard 
systemic chemotherapy ± biologics, by focusing on enhancing the effect of Y90-RE with immunotherapy. 
Therefore, there is the option for patients with significant liver-predominant disease burden that are 
considered candidates for Y90-RE to temporarily discontinue their current chemotherapy in order to 
participate within this trial. Subjects will be approached for screening at outpatient clinic visit appointments 
and interested qualified subjects will be consented and offered participation in this trial. Once consent has 
been obtained, for eligible subjects, baseline values will be established, and subjects will begin treatment 
and be followed-up for the next three months. The washout period to begin treatment (cycle 1 day 1) for 

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this clinical trial will be at least 2 weeks after prior chemotherapy or biologic. Screening can begin prior. 
The goal is to keep the duration on the clinical trial minimal. 
The trial, for each subject, will consist of a screening period, a treatment and observation phase. The 
treatment phase is approximately 2 months post-Y90-RE in combination with fixed dose durvalumab. The 
DLT observation phase will be for 8 weeks post dose of Y90-RE. 
The trial will be performed in 18 subjects with mCRC with liver metastasis and the safety of 
immunotherapy (durvalumab) with Y90-RE will be investigated in an accelerated titration design. This 
would allow a maximum tolerated dose with the minimum number of subjects. At any point as noted below 
if there is a DLT, the study design defaults to a standard 3+3 design. Assuming a 10% loss of subjects after 
enrollment, the dose escalation design will require at least 9 evaluable subjects to establish the highest dose 
level as the maximum tolerated dose (MTD). If less than 18 subjects are administrated in the dose escalation, 
the rest of subjects will be administrated the MTD in the expansion cohort. Sample size of maximum of 
18 was based on an accelerated titration design and on the correlative studies including pre- and post-
biopsies. The primary goal of this study is to establish safety and with a secondary goal of looking at 
biomarkers and other immune signals as noted. 
This study will utilize an accelerated titration design. The dose levels to which patients will be assigned in 
sequential cohorts are listed in the table 1. 
Table 1. Dose escalation cohort of durvalumab* 
 
Immunotherapy (Durvalumab) Administrations 
Pre-Y90 doses 
Y90-Radio-embolization 
Post-Y90 doses 
Number of 
Administration of 
Durvalumab 
Dose level 
Week-2 
Week0 
Week2 
Week4 
Week6 
-2 
X 
1 
-1 
X 
X 
2 
1 (start)** 
X 
X 
2 
2 
X 
X 
X 
3 
3 
X 
X 
X 
X 
4 
4 
X 
X 
X 
X 
X 
5 
 
* Please note: As noted above, the rationale for the proposed dosing schema is keeping in mind the timing 
of toxicities that are typically seen post Y90-RE. Most patients have elevation of their liver enzymes the first 
1-2 weeks. Therefore, with the dosing escalation, we did not include the added dose at week 2 for the first 
dose escalation (dose level 2). Patients get fixed dosing of immunotherapy, which is the case for all 
immunotherapy-based studies. Depending on the dose level, patients can get a maximum of 2 doses before 
and 3 doses post Y90-RE (dose level 4). 
**While dose level 1 and dose level -1 have the same number of durvalumab administrations, they are 
different since dose level 1 get 2 doses pre-Y90-RE (‘priming doses of immunotherapy before Y90-RE) while 
dose level -1 only get 2 doses post-Y90-RE. 

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A single patient will be treated per dose level until the first DLT is recorded. Once the first DLT is recorded, 
two additional patients are treated at the same dose level and the trial reverts to a standard 3+3 design. At 
which time, decisions on when and how to dose escalate are described below. 
 
Number of patients with DLT 
at a given dose level 
Decision Rule 
0 out of 3 
Enter 3 patients at the next higher dose level 
1 out of 3 
Enter up to 3 additional patients at the same dose level. 
• 
If 0 of these 3 patients experience DLT, proceed to the next dose 
level. 
• 
If 1 or more of these 3 patients experience DLT, then dose 
escalation is stopped, and this dose is declared the maximally 
administered dose. Three (3) additional patients will be entered 
at the next lowest dose level if only 3 patients were treated 
previously at that dose. 
≥2 out of 3 
Dose escalation will be stopped. This dose level will be declared the 
maximally administered dose. Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients were treated 
previously at that dose. 
 
Up to 6 patients will be treated at each dose level. The MTD will be defined as the highest dose level for 
which at most 1 out of 6 patients experience a DLT. If DLT meets the stopping boundaries set by the above 
dose algorithm at dose level 1 (for example, more than 1 out of 3 or more than 1 out of 6 patients), the next 
cohort of 3 patients will be entered at the dose level of -1. If dose level -1 meets the stopping boundaries, 
the next cohort of 3 patients will be entered at dose level -2. 
If an MTD is determined, an expansion cohort using the RP2D will be carried out in additional patients for 
a maximum of 18 patients. If an MTD is not determined, the expansion cohort will utilize the dosing scheme 
from cohort 4. 
After the end of treatment visit (EoT) subjects (if applicable) are to resume the previously discontinued 
chemotherapy until all cycles have been administered or treatment is discontinued as per regular standard 
of care or secondary resection if deemed a candidate. The decision to resume the previously discontinued 
chemotherapy is to be done at investigators discretion. As the patients will commence a different treatment 
regime, no active follow-up will be done as part of this study other than progression free survival and overall 
survival. 
The clinical trial will be conducted at one site, the Holden Comprehensive Cancer Center, University of 
Iowa. 
1.4.7 
Number of Subjects 
This clinical trial will recruit 18 subjects. The estimated recruitment rate is at least one subject every 1-2 
months, in which a minimum of 12-18 subjects will be enrolled over a period of 18-24 months. The number 
of subjects in the dose escalation will depend on the number of dose levels needed to determine the MTD 
or confirm the current dosing for durvalumab can be used in combination with Y90-RE. The dose limiting 
toxicity (DLT) observation phase is 8 weeks post Y90-RE. 
In the expansion cohort, the remaining subjects (from the total 18 subjects) will be treated at the MTD dose 
of the combination of Y90-RE and durvalumab. Since all patients received immunotherapy and Y90-RE, 
they would be included in the evaluation of efficacy objectives and correlative components of the study. 

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1.4.8 
Duration of Participation 
The total duration of the trial for each subject will be approximately three months (from the first subject 
first visit to first subject last observation). The entire trial from the first subject enrollment to the last subject 
visit (end of treatment visit) will last 24 months. For the purpose of data analysis, the trial will start with 
first subject signing informed consent and will end when the last subject performed the last clinical follow 
up visit, under the standard protocol. After the last clinical follow up visit, planned time needed for final 
report/publication following last subject last visit is six months. 
1.3 
Correlative Research 
• 
Immune Correlates (Pre- and Post- immunotherapy and Y90-RE) 
• 
Tumor Correlates (Pre- and Post- immunotherapy and Y90-RE) 
 
The specifics and timing of sample collection are detailed in the schedule of testing/companion laboratory 
manual for this clinical trial. Both in-house research/clinical as well as commercially available platforms 
would be utilized to accomplish the goals listed. 
Broadly speaking as noted, the main goal would be study 2 main 
correlates (pre- and post- Y90-RE and immunotherapy) from a) an 
immune perspective and b) tumor perspective. As noted in detail 
in the schedule of testing and companion laboratory manual, there 
are additional serial collections from a blood testing perspective 
to allow for assessment of blood-based immune markers as well 
as tumor based liquid biopsies (circulating tumor DNA testing – 
ctDNA testing). 
1.3.1 
Immune correlates: 
Analysis of immune cells by flow cytometry: Analysis of immune 
cell populations via flow cytometry will allow for more 
quantitative and in-depth profiling of immune cells. In addition, 
these experiments will be done at the University of Iowa at the 
time of sample collection. 
Immune  cell  analysis  of  peripheral  blood  and  tumor  tissue: 
Frequencies of innate (monocytes, macrophages, neutrophils, 
dendritic cells, NK cells) and adaptive (CD4+ T cells, CD8+ T 
cells, NKT cells, B cells) immune cells present in the peripheral 
blood or tumors of patients will be determined via flow cytometry. 
In addition, we will examine expression of inhibitory markers on 
T cells including, but not limited to, PD-1, CTLA-4, TIM3 and LAG3. For peripheral blood samples we 
will compare frequencies of immune cell populations at the several serial time points as denoted in the 
table. Tumor infiltrating cells in tumor tissue samples will be compared at two time points for the tissue as 
denoted in the schedule of testing/companion laboratory manual. 
Serum cytokine and chemokine analysis: Use of a Multiplex assay will allow us to examine multiple 
cytokine and chemokine targets at multiple time points with use of minimal serum sample. These again 
would be done at the University of Iowa at the time of sample collection. Serum will be collected from 
peripheral blood of patients at 8 different time points as denoted in the table. A bead based multiplex assay 
will be used to quantitatively measure levels of 27 different cytokines and chemokines at various time 
points. This analysis will be done at the University of Iowa. 
From a tumor microenvironment perspective, would evaluate for immune related changes including PD-L1 
and PD-1 expression and tumor-infiltrating lymphocytes. 
Immune Correlates 
Tissue: Pre- and Post 
Immunotherapy + Y90RE 
Blood/Serum: Pre- and Post 
Immunotherapy + Y90RE 
Tumor Correlates 
Tissue: Pre- and Post 
Immunotherapy + Y90RE 
Blood/Plasma: Pre- and Post 
Immunotherapy + Y90RE 
(criculating tumor DNA 
(ctDNA) - Liquid Biopsies) 

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1.3.2 
Tumor correlates: 
We will have 2 timepoints of tumor evaluation in terms of tissue i.e. pre- and post-immunotherapy and 
Y90-RE. Additionally, a unique and strong aspect of this study is the use of liquid biopsies 
(ctDNA/circulating tumor DNA testing) at multiple serial timepoints. 
• 
We will measure the variant allele fraction (%) and the spectrum of mutations through next 
generation sequencing based platforms. 
• 
Tumor mutation burden would also be estimated and studied. 
• 
On tissue whole exome sequencing would be performed pre- and post-immunotherapy and Y90-RE. 
• 
Gain and/or loss of clones and sub-clones would be studied serially on liquid biopsies. 
 
Details of the tissue and immune based collection including specimen and handling requirements outlined 
in details in schedule of testing/companion laboratory manual for this clinical trial. 
Of note, if enough tissue is available and lesions are safe/amenable to biopsy, feasibility of developing 
patient derived organoids, xenografts and cell-lines at the time of pre- and post-treatment biopsies will be 
evaluated. 
Additional Correlates: 
 
• 
For patients where we have stool and swab samples available, we would run panel-based 
microbiome profile inhouse with Dr. Ashutosh Mangalam’s lab. Initially the specimens would be 
biobanked. 
• 
Where tissue is sufficient, would assess the feasibility of developing a cell line and/or organoid 
for drug testing. However, the tissue correlates outlined earlier take priority first. 
 
2.0 
Goals 
2.1 
Primary Goal 
2.1.1 
To assess the feasibility and safety of Y90-RE combined with immunotherapy durvalumab 
to treat liver-predominant mCRC. 
2.2 
Secondary Goals* 
2.2.1 
To report treatment related adverse events in patients treated with the combination 
treatment of Y90-RE and durvalumab as assessed by Common Toxicity Criteria for 
Adverse Events (CTCAE) version 5.0 
2.2.2 
To determine the Recommended Phase II dose (RP2D) of durvalumab in combination 
with Y90-RE to treat liver-predominant mCRC. 
2.2.3 
To determine the efficacy of combination treatment of Y90-RE and durvalumab in patients 
with liver-predominant mCRC measured by overall response rate (ORR) (complete 
response (CR) + partial response (PR)) post-Y90-RE and immunotherapy. 
2.2.4 
To determine the efficacy of combination treatment of Y90-RE and durvalumab in patients 
with liver-predominant mCRC measured by the disease control rate (DCR) 
(CR+PR+stable disease (SD)) at 2 months post-Y90-RE treatment. 
2.2.5 
To determine the efficacy of the regimen in the treated liver metastases (liver-specific 
progression free survival (Liver-PFS) in the lesions in the Y90-RE field). 
2.2.6 
To determine the efficacy of the regimen in the patient as a whole (PFS); including both 
Y90-RE field and outside the Y90-RE field. 

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2.2.7 
To determine the efficacy of combination treatment of Y90-RE and durvalumab in subject 
with liver-predominant mCRC as measured by overall survival (OS) at 1-year and 2-year. 
2.2.8 
To determine duration of response (DOR) in the Y90-RE field and outside of Y90-RE field 
* Given Y90-RE to the liver and use of immunotherapy, all response assessments by 
modified RECIST (mRECIST) as well as immune RECIST (iRECIST). In all instances, 
the landmark time is the initiation of immunotherapy. 
2.3 
Correlative Research 
2.3.1 
To assess the changes in immune infiltration (TISSUE: tumor-infiltrating lymphocytes – 
TILs (CD-3, CD-8), PD-L1 and PD-1 expression, pre- and post-Y90-RE and 
immunotherapy). 
2.3.2 
To analyze serial changes in immune cells (BLOOD) pre- and post-Y90-RE and 
immunotherapy 
2.3.3 
To determine changes in the expression profile and in levels of circulating tumor DNA 
(ctDNA) in blood pre- and post- treatment. 
2.3.4 
To evaluate mutation burden by whole-exome sequencing pre- and post-treatment 
(TISSUE) 
2.3.5 
To evaluate concomitant expression profile changes through RNA-Seq pre- and post- 
treatment (TISSUE) 
2.3.6 
To evaluate the feasibility of developing patient derived organoids, xenografts and/or cell- 
lines at the time of pre- and post-treatment biopsies 
2.3.7 
Correlation of outcomes based on subtypes of mCRC (sidedness, mutational/molecular 
subtypes) 
2.3.8 
To report on any abscopal effects seen in terms of responses outside the Y90-RE field. 
 
3.0 
Registration Patient Eligibility 
Prior to discussing protocol entry with the patient, call the GI clinical trial coordinator or PI for dose level 
and to ensure that a place on the protocol is open to the patient. 
3.1 
Inclusion Criteria 
3.1.1 
Age ≥18 years 
3.1.2 
Histological or cytological confirmation of colorectal cancer with metastasis to the liver. 
Mismatch repair or microsatellite instability status of the tumor needs to be known. Tumors 
need to be mismatch repair proficient (for mismatch repair deficient tumors 
immunotherapy is already approved). 
3.1.3 
Patient must have at least 1 liver lesion measurable as defined in Section 11.0. 
3.1.4 
Must have liver metastases and be appropriate for treatment with Y90-RE therapy as 
determined by the treating medical oncologist and interventional radiologist/oncologist, 
and nuclear medicine physician(s). 
NOTE: the goal of therapy is safety and parenchymal sparing. Typically, since the treatment is 
personalized, the goal is to have at least 30% liver parenchymal sparing post treatment. 
3.1.5 
Must have a metastatic focus amendable to biopsy. It is permissible to use same or 
alternative lesion for biopsy for assessment for tumor response and changes in 
microenvironment (mandatory pre- and post-Y90-RE biopsy). 
3.1.6 
At least 2 but no more than 3 lines of therapy allowed in metastatic setting. These include 
at least treatment with a fluoropyrimidine, oxaliplatin, and/or irinotecan-based 

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therapy and an anti-EGFR therapy if RAS wild-type (unless deemed intolerant or not 
suitable by the treating oncologist), with or without an anti-VEGF therapy. 
NOTE: adjuvant and/or maintenance chemotherapy does not count as an additional line of 
therapy. (Patients with more than 3 lines of therapy are at risk for liver disease from prior 
systemic therapies and would not be reasonable candidates for Y90-RE). 
3.1.7 
At least a 4-week gap between anti-VEGF therapy and the IR Tc-99m labelled MAA 
eligibility mapping 
3.1.8 
ECOG Performance Status (PS) 0 or 1 (Appendix I). 
3.1.9 
Negative serum pregnancy test done ≤7 days prior to registration, for persons of 
childbearing potential only. 
3.1.10 Females of childbearing potential (FOCBP), must use appropriate method(s) of contraception. 
FOCBP are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, 
bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months 
with no menses without an alternative medical cause). Additionally, FOCBP must agree to 
follow instructions for method(s) of contraception for the duration of treatment with 
durvalumab plus 5 half-lives of durvalumab (13 weeks) plus 30 days (duration of ovulatory 
cycle) for a total of 17 weeks post-treatment completion (details in appendix). 
3.1.11 Men who are sexually active with FOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with durvalumab plus 5 half-lives of 
durvalumab plus 90 days (duration of sperm turnover) for a total of 25 weeks post- 
treatment completion (details in appendix). 
3.1.12 Provide written informed consent. 
3.1.13 Ability to complete questionnaire(s) by themselves or with assistance. 
3.1.14 Willingness to provide mandatory blood specimens for correlative research (see Section 
14.0). 
3.1.15 Willingness to provide mandatory tissue specimens for correlative research (see Section 
17.0). NOTE: If tissue is deemed inaccessible, patient cannot participate in study. 
3.1.16 Willingness to return to enrolling institution for follow-up (during the Active Monitoring 
Phase of the study). 
3.1.17 Must have a life expectancy of at least 6 months. 
3.2 
Exclusion Criteria 
3.2.1 
Any of the following laboratory abnormalities: 
• 
Hemoglobin <9.0 g/dL 
• 
Absolute neutrophil count (ANC) <1500/mm3 
• 
Platelet count <100,000/mm3 
• 
Total bilirubin >1.5 x ULN or > 2.0 mg/dL, whichever is lowest (exception for patients 
with Gilbert Syndrome, who cannot have a total bilirubin > 3.0 mg/dL) 
• 
Alanine aminotransferase (ALT) and Aspartate transaminase (AST) >2.5 x ULN 
• 
Serum creatinine > 1.5 x ULN or 2.0 mg/dL, whichever is lowest. 
OR 
• 
Calculated creatinine clearance <30 ml/min using the Cockcroft-Gault formula 
below: 

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*NOTE: These can be repeated if outside of range to determine eligibility. Growth 
factor support not allow. Transfusion support for low hemoglobin allowed up 
to 5 days prior to start of treatment. 
3.2.2 
Patients with any of the following contraindications to TheraSphere treatment: 
• 
Shunting to the bowel along the gastrointestinal tract 
• 
Lung shunting of ≥ 15% 
• 
Estimated dose to lungs ≥ 30 Gy in a single administration 
• 
Cumulative estimated dose to lungs ≥ 50 Gy for multiple administrations 
• 
Liver size ≤ 1.5L 
3.2.3 
Prior radiation therapy unless reviewed by the IDE sponsor and approved. This is on a 
case-by-case basis. Radiation plans should be provided for review. 
3.2.4 
Persons who are actively breastfeeding a child and unwilling to discontinue. 
3.2.5 
Co-morbid systemic illnesses, infections, or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into this study 
or interfere significantly with the proper assessment of safety and toxicity of the prescribed 
regimens. 
3.2.6 
Untreated central nervous system (CNS) metastatic disease (including spinal cord and 
leptomeningeal disease). NOTE: Patients with previously treated CNS metastases that are 
radiographically and neurologically stable for ≥ 6 weeks are permitted. 
3.2.7 
Uncontrolled intercurrent illness including, but not limited to, autoimmune disease, 
ongoing or active infection, or psychiatric illness/social situations that would limit 
compliance with study requirements. Please note: with respect to autoimmune disease, 
patients with history of severe autoimmune disease or active autoimmune disease within 
two years of study entry or have a medical condition that requires systemic 
immunosuppression are excluded from the study. 
3.2.8 
Received any other investigational agent incorporating chemotherapy and/or biologics 
within 14 days prior to first dose of durvalumab which would be considered as a treatment 
for the primary neoplasm. For patients on active treatment, last treatment and 1st dose of 
Durvalumab should be at least ≥ 14 days. EXCEPTION: Other forms of concurrent 
observational studies are permitted. 
3.2.9 
Other active malignancy ≤3 years prior to registration. EXCEPTIONS: Non-melanoma 
skin cancer, lentigo maligna- in-situ, or carcinoma-in-situ of the cervix. Also, prior 
malignancy already treated with curative intent and with no known active disease present 
would be considered eligible. 
3.2.10 History of unstable cardiac disease defined as one of the following: 
• 
Congestive heart failure > class II New York Heart Association (NYHA). 
(Appendix II) 
• 
Unstable angina (angina symptoms at rest) or new onset angina (began ≤ 3 
months prior to registration) 
• 
Myocardial infarction ≤ 3 months 
• 
Uncontrolled cardiac ventricular arrhythmias. EXCEPTION: Subjects that 
are stable on anti-arrhythmic therapy are eligible. 
Cockcroft-Gault Equation: 
Creatinine clearance for males = 
(140 – age) (weight in kg) 
(72) (serum creatinine in mg/dL) 
Creatinine clearance for females = 
(140 – age) (weight in kg) (0.85) 
(72) (serum creatinine in mg/dL) 

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3.2.11 Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment within 
14 days of first dose of durvalumab. NOTE: Subjects can be screened during washout 
period. 
3.2.12 History of severe allergic reactions (i.e. Grade 4 allergy, anaphylactic reaction from which 
the subject did not recover ≤ 6 hours of initiation of supportive care) 
3.2.13 Failure to recover from toxicities from prior anti-cancer therapy, defined as having not 
resolved to National Cancer Institute (NCI) CTCAE version 5.0 Grade ≤ 1. 
EXCEPTIONS: Alopecia and laboratory values listed per the exclusion criteria. Also 
subjects with irreversible toxicity that is not reasonably expected to be exacerbated by any 
investigational products (i.e. hearing loss) will be permitted. 
3.2.14 Use of steroids. EXCEPTIONS: Systemic glucocorticoids will be permitted as long as it 
is ≤10 mg of prednisone equivalent. Topical steroids, such as bronchodilators and local 
steroid injections are also permitted if clinically required. 
3.2.15 Patients with renal failure currently requiring dialysis of any kind. 
3.2.16 Patients weighing <30kg will be excluded from enrollment 
3.2.17 History of allogenic organ transplantation 

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4.0 
Test Schedule 
4.1 
Test schedule for metastatic CRC 
Screening 
Active Monitoring Phase 
Tests and procedures 
Reg 
Cycle 1 
Cycle 2 
(2nd dose of 
Durva + 
Y90-RE)* 
Cycle 3 
Cycle 4 
Cycle 5 
End of 
treatment 
visit12 
Clinical 
Follow-up13 
(every 3 
months) 
Window 
21 days 
±5 days 
±5 days 
±5 days 
±5 days 
±5 days 
±5 days 
History and exam3, 
Wt5, BP, HR, ECOG PS 
X 
Exam, Wt5, BP, HR, 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
review 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
IR Consult 
X 
Pregnancy test1 
X 
X 
X 
X 
X 
Hematology group 
CBC w/ 5-part 
differential 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistries21 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid Function Test 
TSH, free T4, amylase, 
lipase, Vitamin D 
X 
X 
X 
X 
X 
Creatinine clearance 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
PT, PTT, INR 
X 
X 
Cholesterol, 
triglycerides 
X 
IR Tc-99m labelled MAA 
eligibility mapping 
X18 
Tumor measurement2 
X 
X 
X 
ECG6 
X 
X 
X 
X 
Urinalysis7 
X 
X 
X 
X 
X 
X 
X 
X 
Administer durvalumab8,R 
X16,17,18,19 
X9,16,17,18,19 
X19 
X17,18,19 
X17,18,19 
Administer Y90-RE 
X 
Patient Questionnaire 
Booklets4 (Appendix III) 
X 
X 
X 
X 
X 
X 
Mandatory Research 
Specimens (see companion 
Lab Manual)10,R 
X 
X14,15,16,17 
X14,15,16,17 
X17 
X15,16,17 
X15,16,17 
X 
Mandatory Research 
Tissue specimens (see 
companion Lab Manual) 
11,R 
X (Pre- 
treatment) 
18 
X (Post- 
treatment) 
19, 20 
 
Cycle = 14 days 

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1. For women of childbearing potential only. Serum pregnancy test. Must be done ≤7 days prior to 
registration. 
2. A scan is required at baseline prior to the first dose of durvalumab. The scan does not need to be 
repeated as long as it is ≤ 28 days prior to registration. Preferably we would recommend a CT of the 
chest and pelvis; and an MRI of the abdomen for assessment of liver metastases. If an MRI cannot be 
performed, a CT chest, abdomen, and pelvis would be acceptable. Please use same imaging 
throughout the study. 
3. History and exam include prior surgery, cancer-related and other treatment and known positivity for 
Hepatitis B surface antigen, Hepatitis C virus antibodies, and Human Immunodeficiency Virus 
antibodies 1 /-2. 
4. Patient questionnaire booklets must be used; copies are not acceptable for this submission 
5. Body weight to be measured within 72 hours prior to durvalumab administration. 
6. Single 12-lead ECG after 5 min rest in supine position. 
7. Gross (dipstick) urine examination: Leukocytes, nitrite, pH, protein, glucose, ketone, urobilinogen, 
bilirubin, blood (hemoglobin and erythrocytes). If abnormalities are detected by dipstick, then a 
microscopic sediment test should also be performed. If a UTI is suspected, it can be treated. 
8. Durvalumab administration over 60 minutes. Following infusion, subjects must be observed for 30 
minutes post infusion for potential infusion related reactions. The number of doses administered is per 
dose level for each patient cohort. 
9. The 2nd durvalumab dose can be done ≤ 5 days prior to Y90-RE or same day as long as it is before the 
Y90-RE. 
10. Blood biomarkers will be collected in the morning of visit. Kits are required. 
11. Tissue specimens must be collected the following timepoints: pre-treatment [screening/prior to cycle 
1 of Durvalumab (fresh as well as archived if available)], and post-treatment. Kits are required 
(banking, clinical as well as real-time send out). 
12. Visit will occur 8 weeks after Y90-RE. 
13. Clinical follow-up visits will be performed at least every 3 months (or as per standard physician 
practice) for 2 years. 
14. Cohort 1- Durvalumab given at cycle 1 and cycle 2 only 
15. Cohort 2- Durvalumab given at cycle 1, 2, and 4 
16. Dose escalation cohort- Durvalumab given cycle 1, 2, 4 and 5 
17. Dose expansion cohort- Durvalumab given cycle 1, 2, 3, 4, and 5 
18. As long as the lesion is amenable to a biopsy and is done, the biopsy can be done on the Tc-99m 
labelled MAA eligibility mapping day to save patient a visit. Has to be prior to anti-PD1 therapy 
though. From a safety perspective since we need to know about the shunting to other organs prior to 
the Y90-RE, the mapping can be done during the screening or even prior to considerations for this 
study if already performed within 12 months of intended Y90-RE, it would not need to be repeated 
unless as per interventional radiology. Biopsy still needs to be done as noted. 
19. If there is complete response of the lesion in the field of Y90-RE, tissue biopsy of the field would still 
be done to assess for the immune changes and an alternative tumor lesion can be biopsied for testing 
of the tumor itself. 
20. At the time of progression, patient would be approached for a tissue biopsy and research blood 
sampling similar to the end of treatment visit. 
21. Creatinine, ALP, ALT, AST, total bili, direct bilirubin, AlkPhos, GGT, total protein, uric acid, BUN, Na, K, Ca, 
Cl, LDH, CPK, inorganic phosphate, CEA, CA-19-9, ESR, CRP 
* 2 research blood drawn (pre-post Y90 RE on the day of procedure). Timing not important. 
R 
Research funded (see Section 19.0) 

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4.2 
Survival Follow-up 
Survival Follow-up 
q. 3 months 
until PD 
At PD 
After PD 
q. 3 months 
Death 
New Primary 
Survival Follow-up 
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
 
5.0 
Stratification Factors OR Grouping Factor 
None. 
 
6.0 
Enrollment Procedures 
6.1 
Call the GI clinical research coordinator/PI for slot reservation. 
6.2 
Correlative research is mandatory in this trial and the subject will automatically be 
registered to this component (see Sections 3.19d, 3.19e 14.0, 17.31, 17.32, and 17.34). 
Please contact PI if there are any questions or concerns or exceptions. 
6.3 
Documentation of IRB approval must be on file before an investigator may enroll any 
patients. 
6.4 
Prior to enrollment, verify the following: 
• 
IRB approval 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
6.5 
Treatment cannot begin prior to screening and must begin ≤ 21 days after screening. 
6.6 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.7 
All required baseline symptoms (see Section 10.3) must be documented and graded. 
6.8 
Treatment on this protocol must commence at University of Iowa Holden Comprehensive 
Cancer Center institution under the supervision of a medical oncologist. 
6.9 
Case has been discussed or an interventional oncologist has seen the patient and confirms 
the patient is a suitable candidate for this study. 
6.10 
Study drug is available on site. 
6.11 
Blood draw kit is available on site. 
 
7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
Use actual weight or estimated dry weight if fluid retention. Quality Control and Definitions of 
Deviations will be done according to the guidelines in Appendix IV 
7.1.1 
Treatment medication table 
Agent 
Dose Level 
Route 
ReRx 
Durvalumab 
750 mg 
IV 
q2w* 
Cycle= 14 days 
Note: All cycles will be based on durvalumab given once at least two weeks apart. The number of 
durvalumab doses are dependent on the cohort assigned during dose escalation. 

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*Refer to table 1 section 1.23 to see the number and timing of durvalumab immunotherapy 
administrations. 
7.1.2 
Treatment table for Y-90 Radioembolization (Y90-RE) 
Agent 
ReRx 
TheraSpheres™ 
Per Table 1 section 7.4.1 
Cycle= 14 days 
Note: Y90-RE is administered 2 weeks post first durvalumab dose administration with cycle 2 of 
Durvalumab. The immunotherapy dose is prior to the Y90-RE. The immunotherapy does not have 
to be the same day as long as it is prior to Y90-RE. 
Note: The Y90-RE dose and administration will be as per the FDA approved USPI for each patient. 
Goal is to deliver an ablative radiation dose to the targeted region and trigger a release of neo- 
antigens in order to augment immunotherapy; all the while minimalizing collateral damage by 
sparing normal liver parenchyma. Per package insert, recommended Y90-RE dose is 80 Gy to 150 
Gy per lobe of liver; this is intended to prevent radioembolization-induced liver disease (REILD). 
Upper limit for dose administration is also determined by the lungs, which may receive an estimated 
dose of no more than 30 Gy from a single administration nor a cumulative total of 50 Gy from 
multiple administrations. 
As noted in the protocol, there are numerous dosing methods in place for Durvalumab. 
7.2 
Return to consenting institution 
For this protocol, the patient must return to the consenting institution for evaluation at least every 
14 days during treatment and every 90 days during clinical follow-up (Active Monitoring Phase). 
7.3 
Treatment by local medical doctor (LMD) 
Treatment by a local medical doctor (LMD) is not allowed. 
7.4 
Phase I – determination of Maximum Tolerated Dose (MTD) 
7.4.1 
Dose Escalation 
 
Dose level 
Immunotherapy (Durvalumab) Administrations 
Number of Durvalumab 
Administrations (total) 
Prior to Y90-RE 
Y-90 
Radioembolization 
(Y90-RE) 
Post Y90-RE 
Week -2 
Week 0 
Week2 
Week 4 
Week 6 
-2 
X 
1 
-1 
X 
X 
2 
1 (start) 
X 
X 
2 
2 
X 
X 
X 
3 
3 
X 
X 
X 
X 
4 
4 
X 
X 
X 
X 
X 
5 
7.4.1.1 Treatment by a local medical doctor is not allowed. All patients to be treated at University 
of Iowa. 
7.4.1.2 Investigators are to contact the Study Chair as soon as any dose-limiting toxicity (DLT) 
occurs. 

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7.4.2 
Definitions of Dose Limiting Toxicities (DLT) 
A DLT will be defined as any Grade 3 or higher treatment-related toxicity that occurs during the 
DLT observation phase (8 weeks post Y90-RE), including: 
• 
Any event resulting in a delay of cycle 2 by ≥ 14 calendar days 
• 
Any Grade 4 immune related adverse event (irAE) 
• 
Any Grade 3 immune related AE (irAE) that does not resolve to ≤ Grade 1 or to baseline with 
immunosuppressive therapy within 3 weeks 
• 
Any Grade 3 colitis 
• 
Any Grade 3 noninfectious pneumonitis irrespective of duration 
• 
Grade 4 neutrophil count decreased lasting longer than 5 calendar days 
• 
Grade 4 platelet count decreased 
• 
Grade 3 platelet count decreased with hemorrhage 
• 
Any ≥ Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 7 days of the initiation 
of maximal supportive care 
• 
Any other Grade 3 irAE (excluding colitis or pneumonitis), that does not downgrade to Grade 
2 within 7 days after onset of the event despite optimal medical management including systemic 
corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 days 
• 
Liver transaminase elevation > 8 × ULN 
• 
Total bilirubin > 5 × ULN 
• 
AST or ALT > 5-8 × ULN with concurrent increase in total bilirubin > 2 × ULN without evidence 
of cholestasis or alternative explanations, e.g., viral hepatitis, disease progression in the liver, etc. 
(Hy’s Law). Exception: If it is present at cycle 3 but resolves at cycle 4 it is not a DLT. 
• 
Any ≥ grade 3 non-hematologic toxicity, except: 
- 
Grade 3 nausea or vomiting that lasts < 48 hours and resolves to ≤ Grade 1 either 
spontaneously or with conventional medical intervention 
- 
Grade 3 nausea, vomiting, and diarrhea lasting < 72 hours in the absence of maximal 
medical therapy 
- 
Grade 4 vomiting and diarrhea lasting < 72 hours in the absence of maximal medical 
therapy 
- 
Grade 3 hypertension in the absence of maximal medical therapy 
- 
Grade 3 metabolic abnormalities (e.g. hypokalemia, hypomagnesemia, hypocalcemia, 
hypophosphatemia) that recover to ≤ Grade 1 within 48 hours 
- 
≥ Grade 3 electrolyte abnormality lasting < 72 hours, is not clinically complicated, and 
resolves spontaneously or responds to conventional medical intervention. 
- 
Grade 3 or 4 elevation in serum amylase and/or lipase that are not associated with clinical 
or radiographic evidence of pancreatitis. 
- 
Grade 3 rash < 5 calendar days 
- 
Grade 3 rash that resolves to ≤ Grade 1 within 3 weeks 
- 
Grade 3 fatigue lasting ≤ 7 days 
- 
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the subject is asymptomatic 

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- 
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., inflammatory 
reaction at sites of metastatic disease, lymph nodes) 
- 
Concurrent vitiligo or alopecia of any AE grade 
- 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management 
- 
Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 7 days. Grade 3 or Grade 4 febrile neutropenia will be 
a DLT regardless of duration or reversibility 
 
8.0 
Dosage Modification Based on Adverse Events (details tabulated in appendix VIII) 
Strictly follow the modifications in this table for the first two cycles, until individual treatment tolerance 
can be ascertained. Thereafter, these modifications should be regarded as guidelines to produce mild-to- 
moderate, but not debilitating, side effects. 
8.1 
Treatment schedule modifications in patients based on adverse events 
Patients will be evaluated by the study team prior to each dose of durvalumab for an adverse event 
check. Determination will be made if the adverse event is treatment-related (possible, probable or 
definite), i.e. a toxicity (see Section 10; Adverse event monitoring and reporting). If any adverse 
event has occurred, then the treatment schedule will be modified as in Section 8.2. 
8.2 
Treatment schedule modifications for durvalumab 
Adverse events (both non-serious and serious) associated with durvalumab exposure may represent 
an immunologic etiology. These adverse events may occur shortly after the first dose or several 
months after the last dose of treatment. Durvalumab must be withheld for drug-related toxicities 
and severe or life-threatening AEs per Table 8.21 below. See Section 9.0 for supportive care 
guidelines, including use of corticosteroids. 
 
Table 8.21 Dose Modification Guidelines for Drug-Related Adverse Events for Durvalumab 
CTCAE 
System/Organ/Class 
Adverse Event 
Grade 
Action 
Gastrointestinal disorders 
Diarrhea or Colitis 
2 
Hold all protocol treatment until Grade 0-1. If 
AE does not resolve to Grade 0-1 within 2 
weeks, then permanently discontinue all 
protocol treatment 
3, 4 
Permanently discontinue all protocol 
treatment 
Investigations 
Alanine aminotransferase 
increased, Aspartate 
aminotransferase 
increased, and blood 
bilirubin increased 
2 
Hold all protocol treatment until Grade 0-1. If 
AE does not resolve to Grade 0-1 within 2 
weeks, then permanently discontinue all 
protocol treatment 
3-4 
Permanently discontinue all protocol 
treatment 
Metabolism and nutrition 
disorders 
Glucose intolerance (Type 
1 diabetes mellitus [if new 
onset]) or Hyperglycemia 
T1DM or 
2-4 
Hold all protocol treatment until clinically and 
metabolically stable. 

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Table 8.21 Dose Modification Guidelines for Drug-Related Adverse Events for Durvalumab 
CTCAE 
System/Organ/Class 
Adverse Event 
Grade 
Action 
Endocrine disorders 
Endocrine disorders- 
Other, specify: 
Hypophysitis 
2-4 
Hold all protocol treatment until Grade 0-1. 
If AE does not resolve to Grade 0-1 within 
2 weeks, then permanently discontinue all 
protocol treatment 
Hypothyroidism 
2-4 
Therapy with durvalumab can be continued 
while thyroid replacement therapy is instituted 
Hyperthyroidism 
2-3 
Hold all protocol treatment until Grade 
0-1. If AE does not resolve to Grade 0- 
1 within 2 weeks, then permanently 
discontinue all protocol treatment 
4 
Permanently discontinue all protocol 
treatment 
General disorders and 
administration site 
conditions 
Infusion related reaction 
1, 2 
Follow infusion related reaction treatment 
guidelines (Table 9.21). Hold all protocol 
treatment until Grade 0-1. If AE does not 
resolve to Grade 0-1 within 2 weeks, then 
permanently discontinue all protocol treatment 
3, 4 
Follow infusion related reaction treatment 
guidelines (Table 9.21). Permanently 
discontinue all protocol treatment 
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis 
2 
Hold all protocol treatment until Grade 0-1 and
corticosteroid dose is less than or equal to 
prednisone 10 mg per day (or equivalent). 
If AE does not resolve to Grade 0-1 within 
2 weeks, then permanently discontinue all 
protocol treatment 
3-4 
Permanently discontinue all protocol 
treatment 
Renal and urinary 
disorders 
2 
Hold all protocol treatment until Grade 0-1 
and corticosteroid dose is less than or equal to 
prednisone 10 mg per day (or equivalent). 
If AE does not resolve to Grade 0-1 within 2 
weeks, then permanently discontinue all 
protocol treatment 
3-4 
Permanently discontinue all protocol 
treatment 
All Other Non-hematologic Events 
3 
Hold all protocol treatment until Grade 0-1 
and corticosteroid dose is less than or equal to 
prednisone 10 mg per day (or equivalent). 
If AE does not resolve to Grade 0-1 within 2 
weeks, then permanently discontinue all 
protocol treatment 
4 
Permanently discontinue all protocol 
treatment 

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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
Patients should receive full supportive care while on this study. This includes blood product 
support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 
conditions. All blood products and concomitant medications such as antidiarrheals, analgesics, 
and/or antiemetics received from the first day of study treatment administration until 30 days after 
the final dose will be recorded in the medical records. 
9.2 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. The use of growth factors should follow published 
guidelines of the Journal of Clinical Oncology, Volume 33, No 28 (October 1), 2015: pp. 3199- 
3212 (WBC growth factors) AND Journal of Clinical Oncology, Volume 28, No 33 (November 
20), 2010: pp. 4955-5010 (darbepoetin/epoetin). 
9.21 
Neutropenia 
Prophylactic use of colony-stimulating factors including Granulocyte Colony-Stimulating Factor 
(G-CSF), PEGylated G-CSF or Granulocyte Macrophage Colony-Stimulating Factor GM-CSF is 
not allowed in this study. Therapeutic use of G-CSF is allowed in patients with Grade 3-4 febrile 
neutropenia. 
9.22 
Anemia 
Transfusions and/or erythropoietin may be utilized as clinically indicated for the treatment of 
anemia but should be clearly noted as concurrent medications. 
9.23 
Thrombocytopenia 
Transfusion of platelets may be used if clinically indicated. ITP should be ruled out before initiation 
of platelet transfusion. 
9.3 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
9.4 
Diarrhea 
Diarrhea could be managed conservatively with loperamide. The recommended dose of loperamide 
is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free (maximum 16 mg/day). 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: hydration, 
octreotide, and antidiarrheals. 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or severe 
neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients with severe 
diarrhea or any diarrhea associated with severe nausea or vomiting should be hospitalized for 
intravenous hydration and correction of electrolyte imbalances. 
9.5 
Immunotherapy-related toxicities 
Patients should be thoroughly evaluated, and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an irAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune related. 
All toxicities will be graded according to NCI CTCAE, Version 5. 

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Patients should be monitored for signs and symptoms of immunotherapy-related toxicities, which 
include but are not limited to the following: 
9.5.1 
Pneumonitis 
• 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
• 
For Grade 3-4 events, immediately treat with intravenous steroids. Administer additional 
anti-inflammatory measures, as needed. 
• 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
9.5.2 
Diarrhea/colitis 
Patients should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus). 
All patients who experience diarrhea/colitis should be advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via 
IV infusion. 
• 
For Grade 2 or higher diarrhea, consider GI consultation and endoscopy to confirm or rule 
out colitis. 
• 
For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
• 
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose oral 
steroids. 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 

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9.5.3 
Type 1 Diabetes Mellitus 
if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated 
with ketosis (ketonuria) or metabolic acidosis (DKA) 
For T1DM or Grade 3-4 Hyperglycemia: 
• 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3- 
4 hyperglycemia associated with metabolic acidosis or ketonuria. 
• 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide. 
9.5.4 
Hypophysitis 
• 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
• 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
9.5.5 
Hyperthyroidism or hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
• 
Grade 2 hyperthyroidism events: non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
• 
Grade 3-4 hyperthyroidism treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
• 
Grade 2 – 4 hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyronine, is indicated per standard of care. 
9.5.6 
Hepatic 
• 
For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly). 
• 
Treat with IV or oral corticosteroids 
• 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
• 
When symptoms improve to Grade 1 or less, a steroid taper should be started and continued 
over no less than 4 weeks. 
9.5.7 
Renal failure or nephritis 
• 
For Grade 2 events, treat with corticosteroids. 
• 
For Grade 3-4 events, treat with systemic corticosteroids. 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 

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9.5.8 
Rash 
• 
Grade 2: Treat symptomatically with topical steroid cream, as well as antihistamines (i.e., 
loratadine, diphenhydramine, etc.). For patients that do not respond, consider starting 
steroids at 0.5 mg/kg prednisone or equivalent. 
• 
Grade 3: As above for grade 2 and Start steroids at 1 mg/kg prednisone or equivalent. 
• 
If any signs of Steven Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TENS), 
immediately hospitalize patient and treat with high dose IV steroids (1-gram 
methylprednisolone) and consult dermatology. 
9.5.9 
Management of Infusion Reactions: 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. 
Table 9.21 below shows treatment guidelines for subjects who experience an infusion reaction associated 
with administration of durvalumab. 
Table 9.21 Infusion reaction treatment guidelines as per standard care are included in the appendix. 
 
10.0 Adverse Event (AE) Monitoring and Reporting 
This study is monitored by internal oversight specialists at the University of Iowa. The Data and Safety 
Monitoring Plan of the Holden Comprehensive Cancer Center provides standard operating procedures to 
monitor all investigator-initiated trials at UIHC by the Data and Safety Monitoring Committee (DSMC). A 
copy of the detailed data and safety monitoring plan for this study is on file with the Data and Safety 
Monitoring Committee of the Holden Comprehensive Cancer Center and the IRB of record; an abbreviated 
copy is provided (Appendix). 
This study has been assigned as a risk level 4 as it utilizes an investigator sponsored IDE [P. McNeely, MD, 
sponsor]. 
10.1 
Definitions 
10.1.1 Adverse Event [durvalumab] 
Any untoward medical occurrence or undesirable event experienced in a subject of a clinical 
investigation that associated with the use of a drug in humans, whether or not considered drug 
related. Note: this term is for study drug and not the study device 
10.1.2 Suspected Adverse Reaction [durvalumab] 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse event. 
For the purposes of safety reporting, "reasonable possibility" means there is evidence to suggest a 
causal relationship between the drug and the adverse event. Suspected adverse reaction implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. [21CFR§312.32(a)] 
10.1.3 Unexpected adverse event or unexpected suspected adverse reaction [durvalumab] 
An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as amended. 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the investigator brochure listed only cerebral vascular accidents. 
"Unexpected," as used in this definition, also refers to adverse events or suspected adverse reactions 

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that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug but are not specifically mentioned as occurring 
with the particular drug under investigation. [21CFR§312.32(a)] 
10.1.4 Serious Adverse Event [durvalumab] 
Per 21CFR§312.32, an adverse event is considered serious if, in the view of the investigator, the 
adverse event results in any of the following outcomes: 
• 
Death, 
• 
A life-threatening adverse event, 
• 
An inpatient hospitalization or a prolongation of existing hospitalization, 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, 
• 
A congenital anomaly/birth defect, or, 
• 
An important medical event that may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the other outcomes listed in this definition 
10.1.5 Serious Adverse Reaction [durvalumab] 
A serious adverse event for which there is a reasonable possibility that the drug caused the serious 
adverse event. 
10.1.5 Adverse effect [90Y TheraSpheres] 
Any adverse medical occurrence that may or may not be related to the investigational device 
10.1.6 Unanticipated Adverse Device Effect (UADE) [90Y TheraSpheres] 
Any serious adverse effect on health or safety or any life-threatening problem or death caused by, 
or associated with, a device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects [21CFR§812.3(s)] 
10.1.7 Attribution to durvalumab or 90Y-TheraSpheres 
When assessing whether an adverse event (AE) is related to durvalumab or an adverse effect is 
related to 90Y-TheraSpheres, the following attribution categories are utilized: 
• 
Definite - The AE is clearly related to the agent(s)/procedure. 
• 
Probable - The AE is likely related to the agent(s)/procedure. 
• 
Possible - The AE may be related to the agent(s)/procedure. 
• 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
• 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.2 
Determination of Reporting Requirements 
Toxicity will be graded according to NCI’s Common Toxicity Criteria (CTCAE v5). The principal 
investigator will have final responsibility for determining the attribution of toxicity as it is related 
to durvalumab. The IDE sponsor will have final responsibility for determining the attribution of 
toxicity as it is related to 90Y-TheraSpheres. 
The clinical research team is responsible for collecting and recording the research data. As these 
results are collected, all toxicities and adverse events will be identified and reported to the principal 
investigator (PI). The principal investigator (PI) will determine final relationship of the event to the 
investigational product (ascorbate): 

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• 
Grade 1 and 2 events do not require attributions assigned. 
• 
Grade 3 and higher adverse events require attribution assigned to durvalumab and 90Y 
TheraSpheres. 
• 
All serious adverse events, regardless of severity, require attribution assigned to 
durvalumab and 90Y TheraSpheres. 
• 
All dose limiting toxicities, regardless of severity, require attribution assigned to 
durvalumab and 90Y TheraSpheres. 
10.2.1 Exemption from reporting requirements 
The following hospitalizations are exempted from reporting because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
• 
Hospitalizations for respite care 
• 
Planned hospitalizations required by the protocol 
• 
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
• 
Hospitalization for elective procedures unrelated to the current disease and/or treatment on 
this trial 
• 
Hospitalization for administration of study drug or insertion of access for administration of 
study drug 
• 
Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place before study entry 
10.2.2 Reporting window 
The adverse event collection window is from the first treatment (durvalumab or TheraSphere) 
through 30 days after the final administration (durvalumab or TheraSphere). Medical records and 
study records will be reviewed for up to 2 years post-embolization for radiation-induced adverse 
events. These will be assessed by the IDE-sponsor or delegate and captured in the electronic data 
capture system. 
10.3 
Institutional Review Board reporting requirements 
10.3.1 Serious adverse drug reactions 
In a subject enrolled by a UI investigator, any adverse events meeting criteria of both serious and 
attributed (possible, probable, or definite) occurring to the study agent must be reported within 10 
business days to the University of Iowa Institutional Review Board. Both expected and unexpected 
SAE must be reported. Thus: 
• 
Serious adverse events only 
• 
Attributable to durvalumab (i.e., drug related) 
• 
Report to the IRB via HawkIRB within 10 business days of event 

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10.3.2 Serious adverse device effects 
In a subject enrolled by a UI investigator, any adverse device effect meeting criteria of both serious 
and associated (possible, probable, definite) to the use of the study device must be reported within 
10 business days to the University of Iowa Institutional Review Board. Both anticipated and 
unanticipated device effects must be reported. Thus: 
• 
Serious adverse device effects only 
• 
Attributable to 90Y-Theraspheres (i.e., device related) 
• 
Report to the IRB via HawkIRB within 10 business days of effect 
10.4. 
FDA reporting requirements [90Y TheraSphere IDE, P. McNeely, sponsor] 
10.4.1 Unanticipated adverse device effects 
Adverse device effects meeting criteria of serious, unanticipated, and associated (possible, 
probable, or definite) to 90Y-Theraspheres must be reported by the sponsor or the sponsor’s 
appointed designee to the FDA within 10 working days of the sponsor’s initial receipt of 
information: 
• 
Causing serious adverse effect on health or safety or any life-threatening problem or death. 
• 
Unanticipated adverse effects only: the effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or 
application (including a supplementary plan or application) 
• 
Associated with 90Y TheraSpheres with a causal relationship as described 
To help the sponsor meet these reporting requirements, all unanticipated adverse device effects 
must be reported to the IDE sponsor within 1 business day. This coincides with SAE reporting 
requirements for the DSMC. 
10.4.2 Unanticipated serious problems 
The IDE sponsor will report any unanticipated serious problem associated with a device that relates 
to the rights, safety, or welfare of subjects within 10 working days of the sponsor’s initial receipt 
of information. To help the sponsor meet these reporting requirements, all unanticipated problems 
must be reported to the IDE sponsor within 1 business day. 
10.5. 
The Holden Comprehensive Cancer Center’s Data and Safety Monitoring 
Committee [NCI] 
Interventional treatment trials involving investigational agents or devices with a risk of death* 
(>5% or grade 4 – 5 SAE >5%), e.g. all investigator-initiated INDs, most Phase I/II trials, gene 
therapy, gene manipulation or viral vector systems high-risk clinical procedures if performed solely 
for research purposes. The use of a new chemical or drug for which there is limited or no available 
safety data in humans. 
An independent study monitor and/or the DSMC Chair (or designee), will review study data 
(provided by the PI/available in OnCore) and communicate with the PI at least biannually. A copy 
of this communication will be forwarded to the DSMC and PRMC Chairs. 
Additional reporting requirements: 
• 
A scanned copy of the completed eligibility checklist, with screening information and PI 
signature, will be attached in OnCore for ongoing review by DSMC staff. 

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• 
Serious adverse events will be entered directly into an OnCore SAE report by the research 
team. OnCore will send an automatic notification to the DSMC Chair/acting Chair and staff 
for review. 
• 
The DSMC utilizes a risk-based monitoring approach. The trial's research records will be 
monitored at minimum twice per year. Monitoring may be done more frequently depending 
on the protocol, risks to subjects, reported serious/adverse events, patient population and 
accrual rate. Records for a minimum of 25% of subjects will be monitored for the entire 
study. 
Monitoring will involve the following: 
• 
review eligibility of patients accrued to the study, 
• 
check for the presence of a signed informed consent, 
• 
determine compliance with protocol’s study plan, 
• 
determine whether SAEs are being appropriately reported to internal and external 
regulatory agencies, 
• 
compare accuracy of data in the research record with the primary source documents, 
• 
review investigational drug processing and documentation, 
• 
assess cumulative AE/SAE reports for trends and compare to study stopping rules. 
10.5.1 Routine Adverse Event Reporting Requirements 
An adverse event (AE) is defined in the CTEP, NCI Guidelines [2005] as “any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom or disease temporally 
associated with the use of a medical treatment or procedure (attribution of unrelated, unlikely, 
possible, probably or definite).” Routine adverse events occurring in study subjects are captured in 
OnCore, the clinical trials management system, for review and assessment by the P.I. and IDE 
sponsor as well as the DSMC. 
10.5.2 Routine Adverse Device Effect Reporting Requirements 
An adverse effect is defined by FDA as “Any adverse medical occurrence that may or may not be 
related to the investigational device.” All adverse effects occurring in study subjects will be 
captured in OnCore, the clinical trials management system, for review and assessment by the P.I. 
and IDE sponsor as well as the DSMC. 
10.5.3 Serious Adverse Events 
Any experience or condition meeting the definition of a serious adverse event (SAE; 21CFR312.32) 
occurring in a study subject from the first day of study treatment and typically continue through the 
30-day follow-up period after treatment is discontinued will be captured. Investigators must report 
to the DSMC any SAE, regardless of attribution to study drug. SAEs must be reported via an 
OnCore SAE Report ≤ 1 business day of learning of the event. 
10.5.4 Unanticipated Device Effects 
Any experience or condition meeting the definition of an unanticipated adverse device effect 
(UADE) in a study subject (SAE; 21CFR812.3(s)), from the first day of study treatment and 
typically continue through the 30-day follow-up period after treatment is discontinued will be 
captured. Investigators must report to the DSMC any unanticipated adverse device effect via an 
OnCore SAE Report ≤ 1 business day of learning of the effect. 

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10.5.5 Dose limiting Toxicities 
Any adverse event meeting the criterion of a dose limiting toxicity will be reported via an OnCore 
SAE Report ≤ 1 business day of learning of the event or from determining the event met DLT 
criteria. 
10.6 
Principal Investigator Reporting Requirements 
As per 21CFR812.50, the principal investigator shall prepare and submit the following complete, 
accurate, and timely reports to the IDE Sponsor of 90Y TheraSpheres (P. McNeely, MD): 
• 
Withdrawal of IRB approval. An investigator shall report to the sponsor, within 5 
working days, a withdrawal of approval by the reviewing IRB of the investigator's part of 
an investigation. 
• 
Annual Progress Report. An annual progress reports on the investigation to the sponsor, 
the monitor, and the reviewing IRB at regular intervals, but in no event less often than 
yearly. 
• 
Deviations from the investigational plan. An investigator shall notify the sponsor and the 
reviewing IRB (see §56.108(a) (3) and (4)) of any deviation from the investigational plan 
to protect the life or physical well-being of a subject in an emergency. Such notice shall be 
given as soon as possible, but in no event later than 5 working days after the emergency 
occurred. Except in such an emergency, prior approval by the sponsor is required for 
changes in or deviations from a plan, and if these changes or deviations may affect the 
scientific soundness of the plan or the rights, safety, or welfare of human subjects, FDA and 
IRB in accordance with §812.35(a) also is required. 
• 
Informed consent. If an investigator uses a device without obtaining informed consent, 
the investigator shall report such use to the sponsor and the reviewing IRB within 5 
working days after the use occurs. 
• 
Final report. An investigator shall, within 3 months after termination or completion of the 
investigation or the investigator's part of the investigation, submit a final report to the 
sponsor and the reviewing IRB. 
• 
Other. An investigator shall, upon request by a reviewing IRB or FDA, provide accurate, 
complete, and current information about any aspect of the investigation. 
 
11.0 Treatment Evaluation/Measurement of Effect 
Various measurement options exist that are being done in patients with liver cancer and liver 
metastases and immunotherapy that are of value to consider. These include: 
• 
RECIST 1.1 
• 
iRECIST 
• 
mRECIST 
11.1 
Treatment evaluation using mRECIST as well as iRECIST Guidelines 
The first scan prior to treatment initiation will be performed; the next scan will be then performed 
at the end of treatment visit. It will then continue every 8-12 weeks per physician discretion until 
disease progression is confirmed or withdrawn of consent. (See Section 4.0). 
Disease progression for this protocol is defined as meeting the mRECIST as well as iRECIST 
criteria detailed in appendix VI. 

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11.2 
Definitions of measurable and non-measurable disease 
11.21 Target Lesion Response mRECIST 
• 
Complete Response - Disappearance of any intratumoral arterial enhancement in all target 
lesions. 
• 
Partial Response - At least a 30% decrease in the sum of the diameters of viable 
(enhancement in the arterial phase) target lesions, taking as reference the baseline sum of 
the diameters of target lesions. 
• 
Progressive Disease – An increase of at least 20% in the sum of the diameters of viable 
(enhancing) target lesions, taking as reference the smallest sum of the diameters of viable 
(enhancing) target lesions recorded since treatment started. 
• 
Stable Disease – Any cases that do not qualify for either partial response or progressive 
disease. 
11.22 Nontarget Lesion Response 
• 
Complete Response - Disappearance of intratumoral arterial enhancement in nontarget 
lesions. 
• 
Incomplete Response/Stable Disease - Persistence of intratumoral arterial enhancement 
in 1 or more nontarget lesions. 
• 
Progressive Disease – Appearance of 1 or more new lesions and/or unequivocal 
progression of existing nontarget lesions. 
Special recommendations for assessment of tumor response in nontarget lesions in patients with 
HCC and cirrhosis can be made regarding the following: 
• 
Portal vein thrombosis: Malignant portal vein thrombosis should be considered a 
nonmeasurable lesion due to the difficulty in performing consistent measurements of the 
malignant thrombus during the course of treatment. 
• 
Porta hepatis lymph node: Lymph nodes detected at the porta hepatis can be considered 
as malignant if the lymph node short axis is at least 20 mm. 
• 
Pleural effusion and ascites: Cytopathologic confirmation of the neoplastic nature of any 
effusion (particularly ascites) that appears or worsens during treatment is required when 
the measurable tumor has met criteria for response or stable disease. 
11.23 Appearance of New Lesions 
In the assessment of tumor progression, the following concepts have been adopted by mRECIST 
for HCC: 
• 
A newly detected hepatic nodule will be classified as HCC, and therefore will be declared 
as evidence of progression, when its longest diameter is at least 1 cm and the nodule shows 
the typical vascular pattern of HCC on dynamic imaging (i.e., hypervascularization in the 
arterial phase with washout in the portal venous or late venous phase). 
• 
Liver lesions larger than 1 cm that do not show a typical vascular pattern can be diagnosed 
as HCC by evidence of at least 1-cm-interval growth in subsequent scans. The date of 
progression is defined as the time a new lesion was first detected by imaging techniques, 
even if strict criteria were fulfilled only on subsequent radiologic testing. 

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11.24 Overall Response Assessment 
In mRECIST for HCC, identical to conventional RECIST v1.1, overall subject response is a result 
of the combined assessment of both intra- and extrahepatic target lesions, non-target lesions, and 
new lesions. 
 
12.0 Descriptive Factors 
Baseline characteristics pertaining to the patient as well as the tumor would be reported. With 
respect to the patient, this would include but not limited to age, sex, the performance status, lines 
of prior therapy and types of previous therapies received. We would also report on 
pharmacogenomics assessed on each patient. With respect to the tumor, we would obtain 
information including but not limited to mutational status (RAS/RAF), mismatch repair status (or 
microsatellite instability), tumor mutation burden (based on NGS assay), RNA-seq and PD-L1/PD- 
1 expression. 
 
13.0 Treatment/Follow–up Decision at Evaluation of Patient 
Reason Off Treatment (from the Off-Treatment Form) 
Go to CFU, SFU, or end 
folder rollout 
1 = Treatment (Intervention) Completed Per Protocol Criteria 
CFU 
2 = Patient Withdrawal/Refusal After Beginning Protocol Therapy 
(Intervention) 
CFU/SFU/No follow-up 
3 = Adverse Events/Side Effects/Complications 
CFU 
4 = Disease Progression, Relapse During Active Treatment (Intervention) 
SFU 
5 = Alternative Therapy 
SFU/No follow-up 
6 = Patient Off-Treatment (Intervention) For Other Complicating Disease 
SFU 
7 = Death On Study 
No follow-up 
8 = Other 
SFU/SFU/No follow-up 
10 = Disease Progression Before Active Treatment (Intervention) 
No follow-up 
24 = Patient Withdrawal/Refusal Prior To Beginning Protocol Therapy 
(Intervention) 
No follow-up 
13.1 
Continuation of treatment 
Patients who are CR, PR, or SD will continue treatment per protocol. 
13.2 
Progressive disease (PD) 
Patients who develop PD while receiving therapy will go to the survival follow-up phase. 
13.3 
Off protocol treatment 
Patients who go off protocol treatment for reasons other than PD will go to the event-monitoring 
phase per Section 4.0. 
13.4 
Observation 
If the patient has achieved CR, PR, or SD, the patient will be observed at 3 months, every 3 months 
for 1 year, and then every 3 months for up to 5 years from time of registration. 
13.5 
Duration of therapy for CR 
Patients who achieve a CR will receive a maximum total of cycles for assigned cohort. After 
completion of cycles, they should be observed (see 13.4 above) every 3 months for 2 years or until 
PD and then they will go to survival follow-up. 
13.6 
Duration of therapy for PR or SD 
Patients who are in PR or SD will continue on therapy for a maximum total of cycles for assigned 
cohort. After completion of cycles, they should be observed (see 13.4 above) every 3 months for 2 

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years or until PD and then they will go to survival follow-up (see 13.5 above). Subsequent treatment 
is at the discretion of their attending physician 
13.7 
Non-CNS PD 
Patients who develop non-CNS PD at any time should go to event monitoring. These patients 
should be treated with alternative chemotherapy if their clinical status is good enough to allow 
further therapy. 
13.8 
Unevaluable patients 
If a patient fails to complete the first cycle of treatment, prior to administration of Y-90, for reasons 
other than toxicity, the patient will be regarded as unevaluable and will be replaced. 
13.9 
Ineligible 
A patient is deemed ineligible if after enrollment, it is determined that at the time of screening, the 
patient did not satisfy each and every eligibility criterion for study entry. If the patient received 
treatment, the patient may continue treatment at the discretion of the physician as long as there are 
not safety concerns. The patient will continue in the Active Monitoring/Treatment phase of the 
study, as per section 4.0 of the protocol. 
If the patient never received treatment, on-study material must be submitted. Survival Follow-up 
will be required per Section 4.0 of the protocol. 
13.10 Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in cycle 1 of 
the initial therapy are severely violated that evaluability for primary end point is questionable. If 
the patient received treatment, the patient may continue treatment at the discretion of the physician 
as long as there are not safety concerns. The patient will continue in the Active 
Monitoring/Treatment phase of the study, as per section 4.0 of the protocol. 
13.11 Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before any study 
treatment is given. On-study material and the End of Active Treatment/Cancel Notification Form 
must be submitted. No further data submission is necessary. 
OR 
For intent to treat trials, use this wording (consult stats) A patient is deemed a cancel if he/she is 
removed from the study for any reason before any study treatment is given. On-study material and 
the End of Active Treatment/Cancel Notification Form must be submitted. The patient will go 
directly to the survival follow-up of the study, and survival follow-up will be required per Section 
4.0 of the protocol. 
 
14.0 Body Fluid Biospecimens 
Please 
refer 
to 
the 
companion 
laboratory 
companion 
manual 
for 
details 
on 
collection/processing/kits. 

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15.0 Drug Information 
IND Exempt. See prescribing information for full information. 
15.1 
Durvalumab (MEDI4736, IMFINZI™): 
15.1.1 Background: Durvalumab is a human immunoglobulin (Ig) G1 kappa (IgG1κ) 
monoclonal antibody (mAb) that blocks the interaction of programmed cell death ligand 1 
(PD-L1) (but not programmed cell death ligand-2) with programmed cell death 1 (PD-1) 
on T-lymphocyte (T-cells) and cluster of differentiation (CD)80 (B7.1) on immune cells 
(IC) and is engineered to reduce antibody-dependent cell-mediated cytotoxicity (ADCC). 
15.1.2 Formulation: Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for 
infusion after dilution. The solution contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume 
(w/v) polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL. The nominal fill volume 
is 10.0 mL. Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must 
not be frozen. Drug product should be kept in original packaging until use to prevent 
prolonged light exposure 
15.1.3 Preparation and storage: Withdraw desired volume from vial and dilute in either 0.9% 
sodium chloride or 5% Dextrose in Water to a final concentration of 1 to 15 mg/mL. Total 
time from needle puncture of the durvalumab vial to the start of administration should not 
exceed 24 hours at 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature. Infusion 
solution must be allowed to equilibrate to room temperature prior to commencement of 
administration. 
15.1.4 Administration: Durvalumab is delivered through an IV administration set with a 0.2- or 
0.22-micron filter. The standard infusion time is 1 hour. Do not co-administer other drugs 
through the same infusion line. Flush the IV line with a volume of IV diluent equal to the 
priming volume of the infusion set used after the contents of the IV bag are fully 
administered. 
15.1.5 Pharmacokinetic information: 
• 
Volume of Distribution: The mean volume of distribution at steady state was 5.6 
liters 
• 
Half-life  elimination: 
The mean terminal half-life at steady state was 
approximately 18 days. 
• 
Excretion: Mean steady state clearance was 8.2 mL/hr. 
15.16 Potential Drug Interactions: Durvalumab is an immunoglobulin; therefore, no formal 
pharmacokinetic drug-drug interaction studies have been conducted. 
15.17 Known potential toxicities: 
• 
Very common, > 10%: Fatigue, cough, decreased appetite, dyspnea, nausea, constipation, 
diarrhea, pyrexia, back pain, anemia, vomiting, pruritus, arthralgia, headache, asthenia, 
peripheral edema, rash. 
• 
Common, 1% - 10%: Abdominal pain, hypothyroidism, insomnia, urinary tract infection, 
myalgia, dizziness, AST and ALT increased, musculoskeletal pain, upper respiratory tract 
infection, pneumonia, weight decreased, pain in extremity, hyponatremia, productive 
cough, dehydration, hyperthyroidism, musculoskeletal chest pain, radiation pneumonitis, 
hypokalemia, GGT increased, blood alkaline phosphatase increased. 
• 
Rare, <1% (Limited to important or life-threatening): Pulmonary embolism, 
respiratory failure, COPD, hemoptysis, atrial fibrillation, pericardial effusion. 

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15.18 Procurement: Durvalumab will be provided free of charge to study participants from 
AstraZeneca. 
15.2 
Nursing Guidelines 
15.2.1 Anti PD-L1 side effects vary greatly from those of traditional chemotherapy and can vary 
in severity from mild to life threatening. Instruct patients to report any side effects to the 
study team immediately. Side effects may be immediate or delayed up to months after 
discontinuation of therapy. Most side effects are reversible with prompt intervention of 
corticosteroids. 
15.2.2 Diarrhea can be common and can be very severe, leading to colonic perforation. Instruct 
patients to report ANY increase in the number of stools and/or change in baseline, blood 
in the stool, abdominal pain to the study team immediately. 
15.2.3 Rash/pruritis/dermatitis is seen. Patients should report any rash to the study team. Treat per 
section 8.0 and monitor for effectiveness. 
15.2.4 Monitor LFT’s closely as elevations in these levels could indicate early onset autoimmune 
hepatitis. Patients should also be instructed to report any jaundice, or right upper quadrant 
pain to the study team immediately. 
15.2.5 Pneumonitis can be seen and may be mild (only seen on imaging) to severe. Patients should 
be instructed to report any SOB, dyspnea, cough, chest pain, etc. to the study team 
immediately. Patients reporting these symptoms should have a pulse ox checked and 
consider immediate imaging per the treating MD. 
15.2.6 Endocrinopathies (including hypopituitarism, hypothyroidism, hypophysitis, and adrenal 
insufficiency) are a concern given the mechanism of action of this agent. Patients may 
present only with the vague sense of fatigue and “not feeling well”. Additional symptoms 
may be that of nausea, sweating and decreased activity tolerance. Instruct patients to report 
these signs or symptoms immediately and obtain appropriate labs as ordered by MD. 
15.2.7 Pancreatitis is possible with anti PD-L1 therapy based on mechanism of action. Instruct 
patients to report abdominal pain, nausea and vomiting to the study team. 
15.2.8 Patients who are started on steroid therapy for any side effects of anti PD-L1 toxicity should 
be instructed to take the steroids as ordered, and not to discontinue abruptly as symptoms 
may return and be severe. Patients may be on steroid therapy for weeks. Instruct patients 
to report any increase or change in side effects with any dosage decrease as patients may 
need a slower taper. 
 
16.0 Device Information 
This medical device is utilized under an investigator-sponsored Investigational Device Exemption (IDE), 
P. McNeely, M.D. IDE Sponsor. The use and prescription of TheraSpheres is not under the HDE approval. 
16.1 
TheraSpheres [Yttrium-90 Glass Microspheres) 
16.1.1. Background: TheraSpheres is indicated only for radiation treatment or as a neoadjuvant to 
surgery or transplantation in patients with unresectable carcinoma (HCC) who can have 
placement of appropriately positioned hepatic arterial catheters and is approved for this 
indication under Humanitarian Device Exemption H980006. 
16.1.2. Regulatory Status. Use of this device is limited to the subjects meeting explicit protocol 
criteria under the investigational device exemption (IDE XXXXXX, McNeely sponsor- 
investigator). 
16.1.3. Labeling. The investigational device and/or package will have a label stating it is for 
investigational use only and limited by Federal law to investigational use, as well as all 
other required contents per 21CFR§812.5(a) 

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16.1.4 Records. Shipment, disposition, and destruction of the device must be documented by 
research personnel authorized per the delegation log. Accountability and receipt records 
documenting the device life-cycle must be used per 21CFR§812.40. 
16.1.5 Prescription. Individuals authorized to prescribe must be an authorized user (10CFR§35) 
and have been delegated the authority from the IDE sponsor. 
16.1.6 Administration. TheraSpheres will be planned and administered per the approved package 
insert as well as following currently recommended guidelines: Sangro et al (2017), Lau et 
al (2012), Venkatanarsimha et al (2017), as well as the EANM procedure guideline for 
intra-arterial radioactive compounds (Giammarille et al 2011). Per package insert, targeted 
administrations will fall within recommended values of 80 Gy to 150 Gy per lobe of liver 
in order to preventing radioembolization induced liver disease (REILD). Required activity 
at the time of administration and actual dose delivered to the liver may be respectively 
calculated as 
 
Activity Required (GBq) = 
[Desired Dose (Gy)][Target Liver Mass (kg)] 
50 
 
 
Dose (Gy) = 50[Injected Activity (GBq)][1 − F] 
Affected Liver Mass (kg) 
 
, where F is the lung shunting fraction measured during the Tc-99m labelled MAA 
eligibility mapping. Additional eligibility criteria will include the absence of shunting to 
bowel along the GI tract as well as a lung shunting fraction (F) <15% or estimated lung 
doses <30 Gy for a single Y90-RE administration and a cumulative total of <50 Gy from 
multiple administrations. As noted earlier, from a safety perspective since we need to know 
about the shunting to other organs prior to the Y90-RE, the mapping can be done during 
the screening or even prior to considerations for this study if already performed within 12 
months of intended Y90-RE, it would not need to be repeated unless as per interventional 
radiology. 
16.1.7 Drug interactions. External beam radiation is known to interact with immunotherapy, 
often resulting in heightened immune responses. (Wang et al, 2018, PMID 29556198). 
16.1.8 Radiation observation window. Due to the long-term side effects of radiation therapy, it 
is recommended subjects be followed for a minimum of 2 years post-radiation. 
16.1.9 Procurement. Investigational device will be ordered by the IDE sponsor or delegate. Upon 
receipt, it will be labelled as per 21CFR§812.5(a) and secured. Subject will be billed for 
the research device as allowed under 42CFR§405 Subpart B upon approval by the 
appropriate CMS contractor. 

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17.0 Statistical Considerations and Methodology 
17.1 
Study Design 
This is a single arm phase I study designed to determine the maximally tolerated dose (MTD) and 
toxicity profile of Yttrium-90 radioembolization combined with immunotherapy in the treatment 
of liver-predominant, metastatic colorectal cancer using the accelerated titration design. 
Once the MTD is reached, if total accrual is less than 18, additional patients will be enrolled in an 
expansion cohort to reach full accrual of 18 patients. 
17.2 
MTD Definition and Determination 
For this protocol, the patient must return to clinic for evaluation at least every 14 days +/- 5 days. 
Patients will be treated and observed for a minimum of 8 weeks post-Y90-RE before new patients 
are treated. Doses will not be escalated in any individual patient. 
MTD Definition: The MTD will be defined as the highest dose level for which at most 1 out of 6 
patients experience a dose-limiting toxicity (DLT). A total of 6 patients treated at the MTD will be 
sufficient to identify common toxicities at the MTD. For instance, those toxicities with an incidence 
of at least 25% will be observed with a probability of at least 82% (1-(1-0.25)6). 
Refer to Section 7.42 for definition of dose-limiting toxicity (DLT). 
MTD Determination: 
This study will utilize an accelerated titration design. The dose levels to which patients will be 
assigned in sequential cohorts are listed in the table below. 
 
 
Immunotherapy (Durvalumab) Administrations 
Pre-Y90 doses 
Y90-Radio-embolization 
Post-Y90 doses 
Number of Administration of Durvalumab 
Dose level 
Week 
-2 
Week 0 
Week 
2 
Week 4 
Week 6 
-2 
X 
1 
-1 
X 
X 
2 
1 (start) 
X 
X 
2 
2 
X 
X 
X 
3 
3 
X 
X 
X 
X 
4 
4 
X 
X 
X 
X 
X 
5 
 
In the first phase, a single patient will be treated per dose level until the first DLT is recorded. Once 
the first DLT is recorded, two additional patients are treated at the same dose level and the trial 
reverts to a standard 3+3 design in the second phase. At which time, decisions on when and how to 
dose escalate are described below. 
 
 
Number of patients with DLT 
at a given dose level 
Decision Rule 
0 out of 3 
Enter 3 patients at the next higher dose level 
1 out of 3 
Enter up to 3 additional patients at the same dose level. 
• 
If 0 of these 3 patients experience DLT, proceed to the next dose 
level. 
• 
If 1 or more of these 3 patients experience DLT, then dose 

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escalation is stopped, and this dose is declared the maximally 
administered dose. Three (3) additional patients will be entered 
at the next lowest dose level if only 3 patients were treated 
previously at that dose. 
≥2 out of 3 
Dose escalation will be stopped. This dose level will be declared the 
maximally administered dose. Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients were treated 
previously at that dose. 
 
Up to 6 patients will be treated at each dose level. If DLT meets the stopping boundaries set by the 
above dose algorithm at dose level 1 (for example, more than 1 out of 3 or more than 1 out of 6 
patients), the next cohort of 3 patients will be entered at the dose level of -1. If dose level -1 meets 
the stopping boundaries, the next cohort of 3 patients will be entered at dose level -2. 
17.3 
Sample Size 
This phase I study is expected to require 9 evaluable patients to establish the highest dose level as 
the MTD. We do not expect serious adverse events or DLTs based on experience of treating patients 
with Y90-RE. Experience with immunotherapy as well has been reassuring from a safety 
perspective. Anecdotally, we have had some patients who were on immunotherapy for HCC, which 
got FDA approved in October 2017 who got Y90-RE with no untoward side effects and good 
responses. Given the clinical experience and data that is available so far, we do not expect to reach 
the maximum accrual dictated by budget restrictions during the MTD determination portion of the 
study. Once the MTD is determined, additional patients will be accrued in an expansion cohort in 
order to reach full accrual of 18 patients between Phase I and the expansion cohort. 
The primary objective of the expansion cohort is to evaluate whether Y90-RE in combination with 
durvalumab confers an immune response (mechanism of action) irrespective of dose level as 
estimated by the change in frequency of immune cells pre- and post-treatment. A sample size of 18 
patients will allow the sample mean for the pairwise difference to be estimated with a 95% 
confidence interval half-width of 0.5 SD. 
The overarching goal of the expansion cohort is to gain preliminary evidence as to whether Y90- 
RE in combination with durvalumab confers an immune response, the hypothesized mechanism of 
action. Immune response will be assessed by estimating the mean change in the frequencies of 
immune cells from pre-treatment to post-treatment. More specifically, each patient’s immune cell 
frequencies at pre-treatment will be subtracted from the post-treatment value to obtain the pairwise 
difference for a patient. Immune cell analysis will include, but is not limited to, the frequencies of 
innate (monocytes, macrophages, neutrophils, dendritic cells, NK cells) and adaptive (CD4+ T 
cells, CD8+ T cells, NKT cells, B cells) immune cells. A change is immune cell frequencies after 
treatment is anticipated, but the expected average change for each type of immune cell is not known, 
thus the purpose of the expansion cohort. No formal hypotheses are being tested, rather the change 
in immune profile along with other data obtained (e.g. changes in circulating tumor DNA, tumor 
response to treatment, etc.) will be collectively evaluated and used to inform a subsequent Phase II 
trial. From previously done similar studies, a 25% change is taken to represent a biologically 
meaningful downregulation of some of the key negative players (e.g. Tregs) and upregulation of 
positive players (e.g. PD-L1) expression, which will be taken into consideration when evaluating 
the immune profile. 
17.4 
Accrual and Study Duration 
Given previous data for the similar studies and our clinical volume, it is expected that the annual 
accrual rate will be 12 patients. With that being said, we expect full accrual to be reached within 
18 months if not sooner. 

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17.5 
Analysis Plans 
All the relevant results pertaining to toxicity, MTD, response, timed endpoints and laboratory 
correlates will be examined in an exploratory and hypothesis-generating fashion. The small sample 
size and the heterogeneous patient population associated with phase I studies restricts the 
generalizability of the results. Any notable statistical result should only be viewed as an impetus 
for further study in Phase II trials rather than a definitive finding in and of itself. 
17.5.1 Adverse Events Profile 
The number and severity of all adverse events (overall, by dose-level, and by tumor group) 
will be tabulated and summarized in this patient population. The Grade 3+ adverse events 
will also be described and summarized in a similar fashion. This will provide an indication 
of the level of tolerance for this treatment combination in this patient group. 
17.5.2 Toxicity Profile 
The term toxicity is defined as adverse events that are classified as either possibly, 
probably, or definitely related to study treatment. Non-hematologic toxicities will be 
evaluated via the ordinal CTC standard toxicity grading. Hematologic toxicity measures of 
thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous 
variables as the outcome measures (primarily nadir) as well as categorization via CTC 
standard toxicity grading. 
Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site 
will be explored and summarized. Frequency distributions, graphical techniques and other 
descriptive measures will form the basis of these analyses. 
Please note for the response/efficacy evaluation, it will be mRECIST as well as iRECIST 
that will be reported. A confirmatory scan can be done 4 weeks post completion of therapy 
if there are clinical concerns. 
17.5.3 Overall Response Rate 
Overall response rate is defined as the proportion of evaluable patients that have achieved 
a complete response or partial response using mRECIST evaluation criteria. ORR will be 
evaluated at 2 months post-Y90RE treatment (± 5 business days). 
ORR will be analyzed descriptively as a point estimate with a 95% confidence interval. 
Results will be reported consistent with RECIST v1.1 (Appendix A.9). 
An “evaluable subject” for the purpose of evaluation of the combinatorial therapy is one 
who receives both Y90-radioembolization and at least 1 dose of durvalumab. 
Subjects who do not receive Y90-RE or received only a single incomplete dose of 
immunotherapy (i.e., allergic reaction), are considered non-evaluable for assessment of 
efficacy. These subjects would be replaced for the proposed sample size of 18. 
All subjects 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 subject will be assigned one of the following categories: 1) complete response 
(mRECIST), 2) partial response (mRECIST), 3) stable disease (mRECIST), 4) progressive 
disease (mRECIST), 5) early death from malignant disease, 6) early death from toxicity, 
7) early death because of other cause, or 9) unknown (not assessable, insufficient data). 
Category 4 (protocol specific definition): includes clinical progression as determined by 
the principal investigator and confirmed by the independent data and safety monitoring 
committee (DSMC). 

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Category 5 (protocol specific definition): death from malignant disease as determined by 
the principal investigator and confirmed by the independent data and safety monitoring 
committee (DSMC). 
Category 6 (protocol specific definition): death from toxicity as determined by the 
principal investigator and confirmed by the independent data and safety monitoring 
committee (DSMC). 
Category 7 (protocol specific definition): includes death not meeting categories 5 or 6, or 
death defined as not otherwise specified. 
Category 9 (protocol specific definition): includes subjects who did not receive 
radioembolization, or who did not receive at least 1 complete infusion of durvalumab, or 
who did not undergo follow-up imaging (other than for clinical progression, toxicity, or 
death), or subjects who are lost to follow-up. 
17.5.4 Disease Control Rate 
Disease control rate is defined as the proportion of evaluable patients that have achieved a 
complete response, partial response, or stable disease by a specified time point. DCR will 
be evaluated at 2 months post-Y90RE treatment. DCR will be analyzed descriptively as a 
point estimate with a 95% confidence interval. 
17.5.5 Overall Survival 
Overall survival is defined as the time from randomization to death of any cause. Patients 
that are still alive at the time of analysis will be censored at the date they were last known 
to be alive. OS will be analyzed descriptively as a point estimate for the median with a 95% 
confidence interval using the Kaplan-Meier method. 
17.5.6 Laboratory Correlates 
Baseline tumor markers including CEA and CA-19-9 will be assessed and then at 
subsequent study visits. Complete differential would be obtained to assess and report 
neutrophil to lymphocyte ratio. Markers of inflammation ESR, CRP and vitamin D levels 
to be assessed at baseline and the subsequent visits. 
17.6 
Inclusion of Women and Minorities 
This study will be available to all eligible patients regardless of race, gender, or ethnic group. 
There is no information currently available regarding differential agent effects of either regimen in 
subsets defined by gender, race, or ethnicity, and there is no reason to expect such differences exist. 
Therefore, although the planned analyses will, as always, look for differences in treatment effect 
based on gender and racial groupings, the samples sizes are not increased in order to provide 
additional power for such subset analyses. 
 
18.0 Pathology Considerations/Tissue Biospecimens 
DNA and RNA extraction will be performed at University of Iowa. DNA and RNA sequencing will 
be performed at TEMPUS. The biopsies (both clinical and research) will be performed at University 
of Iowa. Detailed instructions in the companion laboratory manual. 
Tissue Samples are held at the University of Iowa Tissue Procurement Core.  
 Contact: 
Kristen Coleman, PhD 
Tissue Procurement Core 
380 MRC 
501 Newton Road 
Iowa City, Iowa 52242 
 

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19.0 Records and Data Collection Procedures 
19.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission Schedule. 
19.2 
Survival Follow-up 
See Section 4. 
19.3 
CRF completion 
Data  will be collected through HCCC’s Clinical Trial Management System (OnCore). See 
Appendix V. A. 

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19.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, registration 
number, and protocol number. Patient’s name must be removed. 
19.5 
Supporting documentation 
This study requires supporting documentation for diagnosis and progression prior to study entry as 
well as for evidence of response to study therapy and progression after study therapy. These 
documents should be submitted within 14 days of registration. 
19.6 
Labeling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, registration 
number, and protocol number. Patient’s name must be removed. 
 
20.0 Budget 
20.1 
Costs charged to patient: routine clinical care 
20.2 
Tests to be research funded: 
Research testing on blood and tissue specimens 
20.3 
Other budget concerns: 
BTG International Canada, Inc. will provide University of Iowa with funding to support 
the costs of running this study. 
AstraZeneca Pharmaceuticals will provide study drug durvalumab for use in this study 

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21.0 References 
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Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and Activity of Anti-PD-L1 Antibody in Patients with 
Advanced Cancer. The New England Journal of Medicine, 2012; 366:2455-65. 
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3. 
Chang Q, Ornatsky OI, Siddiqui I, Loboda A, Baranov VI, Hedley DW. Imaging Mass Cytometry. 
Cytometry Part A, 2017; 91:160-69. 
4. 
Chang Q, Ornatsky OI, Siddiqui I, Straus R, Baranov VI, Hedley DW. Biodistribution of Cisplatin 
Revealed by Imaging Mass Cytometry Identifies Extensive Collagen Binding in Tumor and Normal 
Tissues. Scientific Reports, 2016; 6:36641. 
5. 
Chew V, Lee YH, Pan L, et al. Immune Activation Underlies a Sustained Clinical Response to Yttrium-90 
Radioembolisation in Hepatocellular Carcinoma. Gut, 2018 Feb 13; doi: 10.1136/gutjnl-2017-315485. 
6. 
Cucchetti A, Piscaglia F, Caturelli E, et al. Comparison of Recurrence of Hepatocellular Carcinoma After 
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7. 
Demaria S, Golden EB, Formenti SC. Role of Local Radiation Therapy in Cancer Immunotherapy. JAMA 
Oncology, 2015; 1(9):1325. 
8. 
den Brok MH, Stutmuller RP, van der Voort R, et al. In Situ Tumor Ablation Creates an Antigen Source for 
the Generation of Antitumor Immunity. Cancer Res, 2004; 64:4024-9. 
9. 
Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated But Not Single-Dose Radiotherapy Induces 
an Immune-Mediated Abscopal Effect When Combined with Anti-CTLA-4 Antibody. Clin Cancr Res, 
2009; 15(17):5379-88. 
10. 
Fan CQ, Crawford JM.Sinusoidal Obstruction Syndrome (Hepatic Veno-Occlusive Disease). J Clin Exp 
Hepatol, 2014; 4(4):332-46. 
11. 
Ferris RL, Blumenschein G, Jr., Fayette J, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the 
Head and Neck. The England Journal of Medicine, 2016; 375:1856-67. 
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13. 
Gettinger S, Rizvi NA, Chow LQ, et al. Nivolumab Monotherapy for First Line Treatment of Advanced 
Non-Small Cell Lung Cancer. Journal of Clinical Oncology, 2016; 34:2980-7. 
14. 
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of Tumor Tissues with Subcellular Resolution by Mass Cytometry. Nat Methods, 2014; 11(4):417-22. 
15. 
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16. 
Hazel Gav, Heinemann V, Sharma NK, et al. SIRFLOX: Randomized Phase II Trial Comparing First-Line 
mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus 
Selective Internal Radiation Therapy in Patients with Metastatic Colorectal Cancer. Journal of Clinical 
Oncology, 2016; 34:1723-31. 
17. 
Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III Trial Comparing Protracted Intravenous 
Fluorouracil Infusion Alone or with Yttrium-90 Resin Microspheres Radioembolization for Liver-Limited 
Metastatic Colorectal Cancer Refractory to Standard Chemotherapy. Journal of Clinical Oncology: Official 
Journal of the American Society of Clinical Oncology, 2010; 28:3687-94. 
18. 
Herrera FG, Bourhis J, Coukos G. Radiotherapy Combination Opportunities Leveraging Immunity for the 
Next Oncology Practice. CA Cancer J Clin, 2017; 67:65-85. 
19. 
Hickey R, Lewandowski RJ, Prudhomme T, et al. Y90 Radioembolization of Colorectal Hepatic 
Metastases Using Glass Microspheres: Safety and Survival Outcomes from a 531- Patient Multicenter 
Study. J Nucl Med, 2016; 57(5): 665-71. 
20. 
Kang J, Demaria S, Formenti S. Current Clinical Trials Testing the Combination of Immunotherapy with 
Radiotherapy. J Immunother Cancer, 2016; 4(1):51. 
21. 
Kasi PM, Hubbard JM, Grothey A. Selection of Biologics for Patients with Metastatic Colorectal Cancer: 
the Role of Predictive Markers. Expert Review of Gastroenterology & Hepatology, 2015; 9:273-6. 
22. 
Kennedy A. Radioembolization of Hepatic Tumors. J Gastrointest Oncol, 2014; 5(3):178-189. 
23. 
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Metastases: Is There a Limit? Journal of Clinical Oncology, 2005; 23:8490-9. 
24. 
Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. The New 
England Journal of Medicine, 2015; 372:2509-20. 

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25. 
Lewandowski RJ, Donahue L, Chokechanachaisakul A, et al. Y90 Radiation Lobectomy: Outcomes 
Following Surgical Resection in Patients with Hepatic Tumors and Small Future Liver Remnant Volumes. 
J Surg Oncol, 2016; 114(1):99-105. 
26. 
Li S, Mao M. Next Generation Sequencing Reveals Genetic Landscape of Hepatocellular Carcinomas. 
Cancer Lett., 2013; 340(2): 247-53. 
27. 
Morris EJ, Forman D, Thomas JD, et al. Surgical Management and Outcomes of Colorectal Cancer Liver 
Metastases. The British Journal of Surgery, 2010; 97:1110-8. 
28. 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol, 1982; 5:649-55. 
29. 
Pardoll DM. The Blockade of Immune Checkpoints in Cancer Immunotherapy. Nature Reviews Cancer, 
2012; 12:252-64. 
30. 
Park HJ, Griffin RJ, Hui S, Levitt SH, Song CW. Radiation-Induced Vascular Damage in Tumors: 
Implications of Vascular Damage in Ablative Hypofractionated Radiotherapy (SBRT and SRS). Radiat 
Res, 2012; 177(3): 311-27. 
31. 
Pellerin O, Lin M, Bhagat N, Shao W, Geschwind J-F. Can C-Arm Cone-Beam CT Detect a Micro 
Embolic Effect After TheraSphere Radioembolization of Neuroendocrine and Carcinoid Liver Metastasis? 
Cancer Biother Radiopharm, 2013; 28(6): 459-65. 
32. 
Riaz A, Gates VL, Atassi B, et al. Radiation Segmentectomy: A Novel Approach to Increase Safety and 
Efficacy of Radioembolization. Int J Radiat Oncology Biol Phys, 2011; 79(1):163-71. 
33. 
Robert C, Schachter J, Long GV, et al. Pembrolizumab Versus Ipilimumab in Advanced Melanoma. The 
New England Journal of Medicine, 2015; 372:2521-32. 
34. 
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in Patients with Locally Advanced and 
Metastatic Urothelial Carcinoma Who Have Progressed Following Treatment with Platinum-Based 
Chemotherapy: A Single-Arm, Multicentre, Phase 2 Trial. Lancet (London, England), 2016; 387:1909-20. 
35. 
Ruers T, Punt C, Van Coevorden F, et al. Radiofrequency Ablation Combined with Systemic Treatment 
Versus Systemic Treatment Alone in Patients with Non-Resectable Colorectal Liver Metastases: A 
Randomized EORTC Intergroup Phase II Study (EORTC 40004). Annals of Oncology, 2012; 23:2619-26. 
36. 
Ruers T, Punt C, Van Coevorden F, et al. Final Results of the EORTC Intergroup Randomized Study 40004 
(CLOCC) Evaluating the Benefit of Radiofrequency Ablation (RFA) Combined with Chemotherapy for 
Unresectable Colorectal Liver Metastases (CRC LM). Ann Surg Oncol, 2011; 18:S6. 
37. 
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2012, Featuring the Increasing Incidence of Liver Cancer. Cancer 2016; 122:1312-37. 
38. 
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of Y90 Microspheres (Therasphere): Safety, Tumor Response, and Survival. J Vasc Interv Radiol, 2005; 
16(12): 1627-39. 
39. 
Schuffler PJ, Schapiro D, Giesen C, Wang HA, Bodenmiller B, Buhmann JM. Automatic Single Cell 
Segmentation on Highly Multiplexed Tissue Images. Cytometry Part A, 2015; 87:936-42. 
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Shah JL, Zendejas-Ruiz IR, Thornton LM, et al. Neoadjuvant Transarterial Radation Lobectomy for 
Colorectal Hepatic Metastases: A Small Cohort Analysis on Safety, Efficacy, and Radiopathologic 
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42. 
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45. 
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2017 Dec;72(12):1002-1013. 

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Appendix I: ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649- 
655, 1982. 
 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
From http://www.ecog.org/general/perf_stat.html 

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Appendix II: New York Heart Association Classification 
 
Clinical Evaluation of Functional Capacity of Patients 
with Heart Disease in Relation to Ordinary Physical Activity 
 
Class 
Cardiac Symptoms 
Limitations 
Need for 
Additional Rest * 
Physical Ability 
To Work** 
I 
None 
None 
None 
Full Time 
II 
Only Mild 
Slight 
Usually only slight 
or occasional 
Usually Full Time 
III 
Defined, with less than 
ordinary activity 
Marked 
Usually moderate 
Usually Part Time 
IV 
May be present event 
at rest and any activity 
increases discomfort 
Extreme 
Marked 
Unable to work 
* To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
** At accustomed occupation or usual tasks. 
 
Reference: Bruce, R. A.: Mod. Concepts Cardiovasc. Dis. 25:321, 1956. (Modified from New 
York Heart Association, 1953). 

Y 9 0 -R E / D ur val u ma b  
5 6  
 
Pr ot oc ol Versi o n 0 7J u ne 2 0 2 2  
 
A p pe n di x III: E O R T C Q L Q -C 3 0  
 
P A TI E N T I N F O R M A TI O N S H E E T 
P atie nt C o m plete d B o o klet 
( B aseli ne) 
 
 
Y o u h a ve bee n gi ve n a b o o klet t o c o m plete f or t his st u d y. T his b o o klet c o nt ai ns s o me q uesti o ns 
a b o ut y o ur ‘ q u alit y -of -life’ as a p atie nt recei vi n g tre at me nt f or c a ncer. Y o ur a ns wers will hel p us 
t o better u n derst a n d h o w t he tre at me nt y o u are recei vi n g is affecti n g t he w a y y o u feel. 
 
1.  Y o u are bei n g as ke d t o c o m plete a q uesti o n naire b o o klet f or t his st u d y. T his b o o klet m ust  be 
c o m plete d o n t he da y y o u e nr oll i n t he  st u d y. 
 
i. C ycle 1 - 5 Pre-treat me nt 
ii. E n d  of treat me nt visit. ( 8 wee ks after Y 9 0 - R E treat me nt) 
 
2.  T his b o o klet c o ntai ns t he f oll o wi n g  q uesti o n naires:  
 Q ualit y of life ( E O R T C Q L Q -C 3 0)  
3.  Directi o ns o n h o w t o c o m plete eac h set of q uesti o ns are writte n o n t he t o p of eac h  set. 
 
4.  It is ver y i m p orta nt t hat y o u ret ur n t he b o o klets t o us, w het her y o u fi nis h t he st u d y or  n ot.  
 
5.  Y o u will be gi ve n t he n urse’s or st u d y c o or di nat or’s na me a n d tele p h o ne n u m ber. Y o u ca n call 
a n yti me wit h a n y c o ncer ns or  q uesti o ns.  
 
6.  After c o m pleti n g t his b o o klet, please ret ur n it t o y o ur n urse or  p h ysicia n.  
 
T h a n k y o u f or t a ki n g t he ti me t o hel p us.  

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EORTC QLQ - C30 
 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling 
the number that best applies to you. There are no "right" or "wrong" answers. The information that you provide 
will remain strictly confidential. 
 
1. Do you have any trouble doing strenuous activities, 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. Do you have any trouble taking a short walk outside 
of the house? 
1 
2 
3 
4 
4. Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
6. Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
7. Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. Were you short of breath? 
1 
2 
3 
4 
9. Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
16. Have you been constipated? 
1 
2 
3 
4 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 

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19. Did pain interfere with your daily activities? 
 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that best applies to you. 
 
29. How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
Very poor 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
Very poor 
Excellent 

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Appendix IV: RECIST 1.1, iRECIST, mRECIST 
 
IV.A. Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference 
A.1 
Eligibility 
• 
Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint. 
• 
Measurable disease - the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
• 
Measurable lesions - lesions that can be accurately measured in at least one dimension 
with longest diameter ≥20 mm using conventional techniques or ≥10 mm with spiral CT 
scan. 
• 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 
mm with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic lesions, and also abdominal masses that are not 
confirmed and followed by imaging techniques; and. 
• 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
• 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. 
• 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
A.2 
Methods of Measurement 
• 
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI 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. Head and neck tumors and those of extremities usually require 
specific protocols. 
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable. 
• 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) 
should not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid 
nodules. US might also be useful to confirm the complete disappearance of superficial 
lesions usually assessed by clinical examination. 
• 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet 
been fully and widely validated. Their uses in this specific context require sophisticated 
equipment and a high level of expertise that may only be available in some centers. 
Therefore, the utilization of such techniques for objective tumor response should be 
restricted to validation purposes in specialized centers. However, such techniques can be 
useful in confirming complete pathological response when biopsies are obtained. 

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• 
Tumor markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared. 
• 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., 
after treatment to differentiate between residual benign lesions and residual malignant 
lesions in tumor types such as germ cell tumors). 
A.3 
Baseline documentation of “Target” and “Non-Target” lesions 
• 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline. 
• 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). 
• 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor. 
• 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up. 
A.4 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, taking as reference 
the baseline sum LD 
At least a 20% increase in the sum of the LD of target lesions, taking as reference 
Progressive Disease (PD): 
the smallest sum LD recorded since the treatment started or the appearance of 
one or more new lesions 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum LD since the treatment started 
 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor marker 
level 
Incomplete Response / Stable 
Disease (SD): 
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. Although a clear progression of “non target” 
lesions only is exceptional, in such circumstances, the opinion of the 
treating physician should prevail and the progression status should be 
confirmed later on by the review panel (or study chair). 
A.5 
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 PD the smallest measurements recorded since the 
treatment started). In general, the patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria 

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Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
• 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having “symptomatic deterioration”. Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
• 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 
A.6 
Confirmation 
• 
The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed. In cases where confirmation of response is not feasible, it should 
be made clear when reporting the outcome of such studies that the responses are not 
confirmed. 
• 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met. Longer intervals as determined by the study protocol may also be 
appropriate. 
• 
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the 
study protocol 
A.7 
Duration of overall response 
• 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever status is recorded first) until the first date that recurrence or PD 
is objectively documented, taking as reference for PD the smallest measurements recorded 
since the treatment started. 
• 
Duration of stable disease 
• 
SD is measured from the start of the treatment until the criteria for disease progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
• 
The clinical relevance of the duration of SD varies for different tumor types and grades. 
Therefore, it is highly recommended that the protocol specify the minimal time interval 
required between two measurements for determination of SD. This time interval should 
take into account the expected clinical benefit that such a status may bring to the population 
under study. 
A.8 
Response review 
• 
For trials where the response rate is the primary endpoint it is strongly recommended that 
all responses be reviewed by an expert(s) independent of the study at the study’s 
completion. Simultaneous review of the patients’ files and radiological images is the best 
approach. 

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A.9 
Reporting of results 
• 
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 9) unknown (not assessable, 
insufficient data). 
• 
All of the patients who met the eligibility criteria should be included in the main analysis 
of the response rate. Patients in response categories 4-9 should be considered as failing to 
respond to treatment (disease progression). Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate. Precise 
definitions for categories 4-9 will be protocol specific. 
• 
All conclusions should be based on all eligible patients. 
• 
Subanalyses 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 
subanalyses 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 95% confidence intervals should be provided. 

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IV.B. Immunotherapy in cancer Response Evaluation Criteria in Solid Tumors 
(iRECIST) Quick Reference 
 
 

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IV.C. Modified Evaluation Criteria in Solid Tumors (mRECIST) Quick Reference 
 
 
 

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Appendix V: Restrictions for blood donation and for those of childbearing age 
 
The following restrictions apply while the patient is receiving study treatment and for the specified times 
before and after: 
Female patient of child-bearing potential 
Female patients of childbearing potential who are not abstinent and intend to be sexually active 
with a non-sterilized male partner must use at least 1 highly effective method of contraception from 
the time of screening throughout the total duration of the drug treatment and the drug washout 
period (90 days after the last dose of durvalumab monotherapy). Non-sterilized male partners of a 
female patient of childbearing potential must use male condom plus spermicide throughout this 
period. Cessation of birth control after this point should be discussed with a responsible physician. 
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
birth control. Female patients should also refrain from breastfeeding throughout this period. 
Male patients with a female partner of childbearing potential 
Non-sterilized male patients who are not abstinent and intend to be sexually active with a female 
partner of childbearing potential must use a male condom plus spermicide from the time of 
screening throughout the total duration of the drug treatment and the drug washout period (90 days 
after the last dose of durvalumab monotherapy). However, periodic abstinence, the rhythm method, 
and the withdrawal method are not acceptable methods of contraception. Male patients should 
refrain from sperm donation throughout this period. 
Female partners (of childbearing potential) of male patients must also use a highly effective method 
of contraception throughout this period. 
N.B Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. 
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without 
an alternative medical cause. The following age-specific requirements apply: 
Women <50 years of age would be considered post-menopausal if they have been amenorrhoeic 
for 12 months or more following cessation of exogenous hormonal treatments and if they have 
luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the 
institution. 
Women ≥50 years of age would be considered post-menopausal if they have been amenorrhoeic 
for 12 months or more following cessation of all exogenous hormonal treatments, had radiation- 
induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last 
menses >1 year ago. 
Highly effective methods of contraception, defined as one that results in a low failure rate (ie, less 
than 1% per year) when used consistently and correctly are herein described. Note that some 
contraception methods are not considered highly effective (e.g. male or female condom with or 
without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper 
containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition 
of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered 
highly effective]; and triphasic combined oral contraceptive pills). 
Highly effective methods 
Copper T intrauterine device 
Levonorgestrel-releasing intrauterine system (e.g., Mirena®)a 
Implants: Etonogestrel-releasing implants: e.g. Implanon® or Norplant® 
Intravaginal: Ethinylestradiol/etonogestrel-releasing intravaginal devices: e.g. NuvaRing® 
Injection: Medroxyprogesterone injection: e.g. Depo-Provera® 
Combined Pill: Normal and low dose combined oral contraceptive pill 
Patch: Norelgestromin/ethinylestradiol-releasing transdermal system: e.g. Ortho Evra® 

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Minipillc: Progesterone based oral contraceptive pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based 
Blood donation 
Patients should not donate blood while participating in this study of Durvalumab with Y90-RE for 
at least 90 days following the last infusion of durvalumab. 

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Appendix VI: TheraSpheres Prescribing Information 
 

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Appendix VII: Dosing Modification and Toxicity Management Guidelines 
 
Immune-Mediated, Infusion-Related, and Non-Immune–Mediated Reactions 
 
 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen 
will be made to manage potential immune-related AEs based on 
severity of treatment-emergent toxicities graded per CTCAE v5.0. 
In addition to the criteria for permanent discontinuation of study 
drug/study regimen based on CTC grade/severity (below), 
permanently discontinue study drug/study regimen for the 
following conditions: 
- Inability to reduce corticosteroid to a dose of ≤10 mg of 
prednisone per day (or equivalent) within 12 weeks after last 
dose of study drug/study regimen 
- Recurrence of a previously experienced Grade 3 treatment- 
related AE following resumption of dosing 
Grade 1: 
No dose modification 
Grade 2: 
- Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1. 
- If toxicity worsens, then treat as Grade 3 or Grade 4. 
- Study drug/study regimen can be resumed once event stabilizes 
to Grade ≤1 after completion of steroid taper. 
- Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study 
drug/study regimen on the following conditions: 
• 
The event stabilizes and is controlled. 
• 
The patient is clinically stable as per Investigator or 
treating physician’s clinical judgement. 
• 
Doses of prednisone are at ≤10 mg/day or equivalent. 
Grade 3: 
- Depending on the individual toxicity, study drug/study regimen 
may be permanently discontinued. Please refer to guidelines 
below. 
Grade 4: 
- Permanently discontinue study drug/study regimen. 
Note: For asymptomatic amylase or lipase levels of >2X ULN, 
hold study drug/study regimen, and if complete work up shows no 
evidence of pancreatitis, study drug/study regimen may be 
continued or resumed. 
Note: Study drug/study regimen should be permanently 
discontinued in Grade 3 events with high likelihood for morbidity 
and/or mortality – e.g., myocarditis, or other similar events even if 
they are not currently noted in the guidelines. Similarly, consider 
whether study drug/study regimen should be permanently 
discontinued in Grade 2 events with high likelihood for morbidity 
and/or mortality – e.g., myocarditis, or other similar events even if 
they are not currently noted in the guidelines – when they do not 
rapidly improve to Grade <1 upon treatment with systemic 
steroids and following full taper 
Note: There are some exceptions to permanent discontinuation of 
study drug for Grade 4 events (i.e., hyperthyroidism, 
hypothyroidism, Type 1 diabetes mellitus and also liver function 
tests as noted earlier in the protocol). 
It is recommended that management of immune-mediated adverse 
events (imAEs) follows the guidelines presented in this table: 
- It is possible that events with an inflammatory or immune 
mediated mechanism could occur in nearly all organs, some of 
them not noted specifically in these guidelines. 
- Whether specific immune-mediated events (and/or laboratory 
indicators of such events) are noted in these guidelines or not, 
patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, concomitant 
medications, and infections) to a possible immune-mediated 
event. In the absence of a clear alternative etiology, all such 
events should be managed as if they were immune related. 
General recommendations follow. 
- Symptomatic and topical therapy should be considered for low- 
grade (Grade 1 or 2, unless otherwise specified) events. 
- For persistent (>3 to 5 days) low-grade (Grade 2) or severe 
(Grade ≥3) events, promptly start prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
- Some events with high likelihood for morbidity and/or 
mortality – e.g., myocarditis, or other similar events even if 
they are not currently noted in the guidelines – should progress 
rapidly to high dose IV corticosteroids (methylprednisolone at 
2 to 4 mg/kg/day) even if the event is Grade 2, and if clinical 
suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the study physician, 
and promptly pursue specialist consultation. 
- If symptoms recur or worsen during corticosteroid tapering 
(28 days of taper), increase the corticosteroid dose (prednisone 
dose [e.g., up to 2 to 4 mg/kg/day PO or IV equivalent]) until 
stabilization or improvement of symptoms, then resume 
corticosteroid tapering at a slower rate (>28 days of taper). 
- More potent immunosuppressives such as TNF inhibitors 
(e.g., infliximab) (also refer to the individual sections of the 
imAEs for specific type of immunosuppressive) should be 
considered for events not responding to systemic steroids. 
Progression to use of more potent immunosuppressives should 
proceed more rapidly in events with high likelihood for 
morbidity and/or mortality – e.g., myocarditis, or other similar 
events even if they are not currently noted in the guidelines – 
when these events are not responding to systemic steroids. 
- With long-term steroid and other immunosuppressive use, 
consider need for Pneumocystis jirovecii pneumonia (PJP, 
formerly known as Pneumocystis carinii pneumonia) 
prophylaxis, gastrointestinal protection, and glucose 
monitoring. 
- Discontinuation of study drug/study regimen is not mandated 
for Grade 3/Grade 4 inflammatory reactions attributed to local 
tumor response (e.g., inflammatory reaction at sites of 
metastatic disease and lymph nodes). Continuation of study 
drug/study regimen in this situation should be based upon a 
benefit-risk analysis for that patient. 

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Specific Immune-Mediated Reactions 
 
Severity (CTCAE v 5.0) 
Dose Modifications 
Toxicity Management 
 
Any 
General Guidance 
- Monitor patients for signs and symptoms of pneumonitis or ILD (new onset or 
worsening shortness of breath or cough). Patients should be evaluated with imaging 
and pulmonary function tests, including other diagnostic procedures as described 
below. 
- Initial work-up may include clinical evaluation, monitoring of oxygenation via pulse 
oximetry (resting and exertion), laboratory work-up, and high- resolution CT scan. 
 
Grade 1 
No dose modifications required. However, consider holding - Monitor and closely follow up in 2 to 4 days for clinical symptoms, pulse oximetry 
(asymptomatic, clinical, 
radiographic, or diagnostic 
observations only; intervention not 
indicated) 
 
Grade 2 
(symptomatic; medical intervention 
indicated; limiting instrumental 
ADL) 
study drug/study regimen dose as clinically appropriate and 
during diagnostic work-up for other etiologies. 
 
 
 
- Hold study drug/study regimen dose until resolution to 
Grade ≤1. 
- If toxicity worsens, then treat as Grade 3 or Grade 4. 
- If toxicity improves to Grade ≤1, then the decision to 
reinitiate study drug/study regimen will be based upon 
treating physician’s clinical judgment and after 
completion of steroid taper. 
(resting and exertion), and laboratory work-up and then as clinically indicated. 
- Consider Pulmonary and Infectious disease consult. 
 
 
- Monitor symptoms daily and consider hospitalization. 
- Promptly start systemic steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent). 
- Reimage as clinically indicated. 
- If no improvement within 3 to 5 days, additional workup should be considered and 
prompt treatment with IV methylprednisolone 2 to 4 mg/kg/day started 
- If still no improvement within 3 to 5 days despite IV methylprednisolone at 2 to 
4 mg/kg/day, promptly start immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is important to rule out sepsis 
and refer to infliximab label for general guidance before using infliximab. 
- Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, or anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B recommendation])a 
- Consider pulmonary and infectious disease consult. 
- Consider, as necessary, discussing with study physician. 
Grade 3 or 4 
Grade 3: severe symptoms; limiting 
self-care ADL; oxygen indicated 
Grade 4: life-threatening respiratory 
compromise; urgent intervention 
indicated [e.g., tracheostomy or 
intubation] 
Permanently discontinue study drug/study regimen. 
- Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or equivalent. 
- Obtain Pulmonary and Infectious disease consult; consider, as necessary, discussing 
with study physician. 
- Hospitalize the patient. 
- Supportive care (e.g., oxygen). 
- If no improvement within 3 to 5 days, additional workup should be considered and 
prompt treatment with additional immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks’ dose) started. Caution: rule out sepsis and 
refer to infliximab label for general guidance before using infliximab. 
Pneumonitis/Interstitial Lung Disease (ILD) 

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Severity (CTCAE v 5.0) 
Dose Modifications 
Toxicity Management 
 
- Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and, in particular, anti-PJP treatment (refer to 
current NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
Any Grade 
General Guidance 
- Monitor for symptoms that may be related to diarrhea/enterocolitis (abdominal pain, 
cramping, or changes in bowel habits such as increased frequency over baseline or 
blood in stool) or related to bowel perforation (such as sepsis, peritoneal signs, and 
ileus). 
- Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., 
disease progression, other medications, or infections), including testing for 
clostridium difficile toxin, etc. 
- Steroids should be considered in the absence of clear alternative etiology, even for 
low-grade events, in order to prevent potential progression to higher grade event. 
- Use analgesics carefully; they can mask symptoms of perforation and peritonitis. 
Grade 1 
Diarrhea: stool frequency of <4 over 
baseline per day 
Colitis: asymptomatic; clinical or 
diagnostic observations only; 
intervention not indicated 
No dose modifications. 
- Monitor closely for worsening symptoms. 
- Consider symptomatic treatment, including hydration, electrolyte replacement, 
dietary changes (e.g., American Dietetic Association colitis diet), and loperamide. 
Use probiotics as per treating physician’s clinical judgment. 
Grade 2 
Diarrhea: stool frequency of 4 to 6 
over baseline per day; limiting 
instrumental ADL 
Colitis: abdominal pain; mucus or 
blood in stool) 
Hold study drug/study regimen until resolution to Grade ≤1 
- If toxicity worsens, then treat as Grade 3 or Grade 4. 
- If toxicity improves to Grade ≤1, then study drug/study 
regimen can be resumed after completion of steroid 
taper. 
- Consider symptomatic treatment, including hydration, electrolyte replacement, 
dietary changes (e.g., American Dietetic Association colitis diet), and loperamide 
and/or budesonide. 
- Promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
- If event is not responsive within 3 to 5 days or worsens despite prednisone at 1 to 2 
mg/kg/day PO or IV equivalent, GI consult should be obtained for consideration of 
further workup, such as imaging and/or colonoscopy, to confirm colitis and rule out 
perforation, and prompt treatment with IV methylprednisolone 2 to 4 mg/kg/day 
started. 
- If still no improvement within 3 to 5 days despite 2 to 4 mg/kg IV 
methylprednisolone, promptly start immunosuppressives such as infliximab at 5 
mg/kg once every 2 weeksa. Caution: it is important to rule out bowel perforation 
and refer to infliximab label for general guidance before using infliximab. 
- Consider, as necessary, discussing with study physician if no resolution to Grade ≤1 
in 3 to 4 days. 
- Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a 
Diarrhea / Colitis 

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Grade 3 or 4 
Grade 3 diarrhea: stool frequency of 
≥7 over baseline per day; limiting 
self-care ADL 
Grade 4 diarrhea: life threatening 
consequences) 
Grade 3 colitis: severe abdominal 
pain, fever; ileus; peritoneal signs 
Grade 4 colitis: life-threatening 
consequences, urgent intervention 
indicated 
Grade 3 
Permanently discontinue study drug/study regimen for 
Grade 3 if toxicity does not improve to Grade ≤1 within 14 
days; study drug/study regimen can be resumed after 
completion of steroid taper. 
Grade 4 
Permanently discontinue study drug/study regimen. 
- Promptly initiate empiric IV methylprednisolone 2 to 4 mg/kg/day or equivalent. 
- Monitor stool frequency and volume and maintain hydration. 
- Urgent GI consult and imaging and/or colonoscopy as appropriate. 
- If still no improvement within 3 to 5 days of IV methylprednisolone 2 to 4 mg/kg/day 
or equivalent, promptly start further immunosuppressives (e.g., infliximab at 5 mg/kg 
once every 2 weeks). Caution: Ensure GI consult to rule out bowel perforation and 
refer to infliximab label for general guidance before using infliximab. 
- Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 
Any elevation in AST, ALT or 
TBIL (i..e, > ULN) 
General Guidance 
- Monitor and evaluate liver function test: AST, ALT, ALP, and TB. 
- Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, 
concomitant medications). 
 
Grade 1 AST, ALT, or TBIL 
AST or ALT > ULN x 3 ULN 
and/or 
TBIL > ULN – 1.5 x ULN 
Grade 2 AST, ALT, or TBIL 
AST or ALT >3.0 – 5 ×ULN 
and/or 
TBIL >1.5 – 3× ULN 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST or ALT >5.0×ULN 
and/or 
- No dose modifications. 
- If it worsens, then treat as described for elevations in the 
row below. 
 
- Hold study drug/study regimen dose until resolution to 
AST or ALT ≤3.0×ULN and/or TB ≤1.5×ULN. 
- If toxicity worsens, then treat as described for elevations 
in the row below. 
- If toxicity improves to AST or ALT ≤3.0×ULN and/or 
TB ≤1.5×ULN, or baseline, resume study drug/study 
regimen after completion of steroid taper. 
 
 
 
 
 
 
 
 
 
 
For elevations in transaminases ≤8 × ULN or elevations in 
TBIL ≤5 × ULN: 
Continue LFT monitoring per protocol. 
 
 
 
 
- Regular and frequent checking of LFTs (e.g., every 1 to 2 days) until elevations of 
these are improving or resolved. 
- If no resolution to AST or ALT ≤3.0×ULN and/or TB ≤1.5×ULN in 1 to 2 days, 
consider, as necessary, discussing with study physician. 
- If event is persistent (>3 to 5 days) or worsens, promptly start prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
- If still no improvement within 3 to 5 days despite 1 to 2 mg/kg/day of prednisone PO 
or IV equivalent, consider additional work up and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
- If still no improvement within 3 to 5 days despite 2 to 4 mg/kg/day of IV 
methylprednisolone, promptly start immunosuppressives (i.e., mycophenolate 
mofetil).a Disyycuss with study physician if mycophenolate mofetil is not available. 
Infliximab should NOT be used. 
- Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a 
- Promptly initiate empiric IV methylprednisolone at 1 to 4 mg/kg/day or equivalent. 
- If still no improvement within 3 to 5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, promptly start treatment with 
Hepatitis (elevated LFTs) Infliximab should not be used for management of immune-related hepatitis 

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TBIL >3.0×ULN 
- Hold study drug/study regimen dose until resolution to 
AST or ALT ≤3.0×ULN and/or TB ≤1.5×ULN, or 
baseline 
- Resume study drug/study regimen if elevations 
downgrade to AST or ALT ≤3.0×ULN and/or TB 
≤1.5×ULN, or baseline within 14 days and after 
completion of steroid taper. 
- Permanently discontinue study drug/study regimen if the 
elevations do not downgrade to AST or ALT ≤3.0×ULN 
and/or TB ≤1.5×ULN or baseline within 14 days. 
For elevations in transaminases >8 × ULN or elevations in 
bilirubin >5 × ULN, permanently discontinue study 
drug/study regimen. 
Permanently discontinue study drug/study regimen for any 
case meeting Hy’s law criteria (AST and/or ALT >3×ULN 
+ bilirubin >2×ULN without initial findings of cholestasis 
(i.e., elevated alkaline phosphatase) and in the absence of 
any alternative cause.b Note that this does not apply to the 
week 2 (cycle 3) post Y90-RE when this is usually seen and 
subsides in the upcoming weeks (cycle 4). Also for those 
with Gilbert’s syndrome, would need to rely on AST/ALT 
rather than total bilirubin. 
immunosuppressive therapy (i.e., mycophenolate mofetil). Discuss with study 
physician if mycophenolate is not available. Infliximab should NOT be used. 
- Perform hepatology consult, abdominal workup, and imaging as appropriate. 
- Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 
 
 
Any Grade 
General Guidance 
- Consult with nephrologist. 
- Monitor for signs and symptoms that may be related to changes in renal function 
(e.g., routine urinalysis, elevated serum BUN and creatinine, decreased creatinine 
clearance, electrolyte imbalance, decrease in urine output, or proteinuria). 
- Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., 
disease progression or infections). 
- Steroids should be considered in the absence of clear alternative etiology even for 
low-grade events (Grade 2), in order to prevent potential progression to higher grade 
event. 
Grade 1 
(serum creatinine > ULN to 1.5 × 
ULN) 
No dose modifications. 
Monitor serum creatinine weekly and any accompanying symptoms. 
- If creatinine returns to baseline, resume its regular monitoring per study protocol. 
- If creatinine worsens, depending on the severity, treat as Grade 2, 3, or 4. 
- Consider symptomatic treatment, including hydration, electrolyte replacement, and 
diuretics. 
- If baseline serum creatinine is elevated above normal, and there is a rise to > 1 to 1.5 
× baseline, consider following recommendations in this row. 
 
 
Nephritis or renal dysfunction (elevated serum creatinine) 

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Grade 2 
(serum creatinine >1.5 to 3.0 × 
baseline; >1.5 to 3.0 × ULN) 
- Hold study drug/study regimen until resolution to Grade 
≤1 or baseline. 
- If toxicity worsens, then treat as Grade 3 or 4. 
- Consider symptomatic treatment, including hydration, electrolyte replacement, and 
diuretics. 
- Carefully monitor serum creatinine every 2 to 3 days and as clinically warranted. 
- If toxicity improves to Grade ≤1 or baseline, then resume - Consult nephrologist and consider renal biopsy if clinically indicated. 
study drug/study regimen after completion of steroid 
taper. 
- If event is persistent (>3 to 5 days) or worsens, promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
- If event is not responsive within 3 to 5 days or worsens despite prednisone at 1 to 2 
mg/kg/day PO or IV equivalent, additional workup should be considered and prompt 
treatment with IV methylprednisolone at 2 to 4 mg/kg/day started. 
- Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a 
- When event returns to baseline, resume study drug/study regimen and routine serum 
creatinine monitoring per study protocol. 
 
Grade 3 or 4 
Grade 3: serum creatinine 
>3.0 × baseline; >3.0 to 6.0 × ULN; 
Grade 4: serum creatinine >6.0 × 
ULN 
Permanently discontinue study drug/study regimen. 
- Carefully monitor serum creatinine on daily basis. 
- Consult nephrologist and consider renal biopsy if clinically indicated. 
- Promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
- If event is not responsive within 3 to 5 days or worsens despite prednisone at 1 to 2 
mg/kg/day PO or IV equivalent, additional workup should be considered and prompt 
treatment with IV methylprednisolone 2 to 4 mg/kg/day started. 
- Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 
Any Grade 
(refer to NCI CTCAE v 5.0 for 
definition of severity/grade 
depending on type of skin rash) 
General Guidance 
- Monitor for signs and symptoms of dermatitis (rash and pruritus). 
- IF THERE IS ANY BULLOUS FORMATION, THE STUDY PHYSICIAN 
SHOULD BE CONTACTED AND STUDY DRUG DISCONTINUED. 
 
 
Grade 1 
No dose modifications. 
- Consider symptomatic treatment, including oral antipruritics (e.g., diphenhydramine 
or hydroxyzine) and topical therapy (e.g., urea cream). 
Grade 2 
- For persistent (>1 to 2 weeks) Grade 2 events, hold 
scheduled study drug/study regimen until resolution to 
Grade ≤1 or baseline. 
- If toxicity worsens, then treat as Grade 3. 
- Obtain dermatology consult. 
- Consider symptomatic treatment, including oral antipruritics (e.g., diphenhydramine 
or hydroxyzine) and topical therapy (e.g., urea cream). 
- Consider moderate-strength topical steroid. 
- If toxicity improves to Grade ≤1 or baseline, then resume - If no improvement of rash/skin lesions occurs within 3 to 5 days or is worsening 
Rash (excluding bullous skin formations) 

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drug/study regimen after completion of steroid taper. 
despite symptomatic treatment and/or use of moderate strength topical steroid, 
 
 

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consider, as necessary, discussing with study physician and promptly start systemic 
steroids such as prednisone 1 to 2 mg/kg/day PO or IV equivalent. If > 30% body 
surface area is involved, consider initiation of systemic steroids sooner. 
- Consider skin biopsy if the event is persistent for >1 to 2 weeks or recurs. 
Grade 3 or 4 
For Grade 3: 
- Hold study drug/study regimen until resolution to Grade 
≤1 or baseline. 
- Consult dermatology. 
- Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or equivalent. 
- Consider hospitalization. 
- 
If temporarily holding the study drug/study regimen does - Monitor extent of rash [Rule of Nines]. 
not provide improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, then permanently 
discontinue study drug/study regimen. 
For Grade 4 (or life-threatening): 
- Permanently discontinue study drug/study regimen. 
- Consider skin biopsy (preferably more than 1) as clinically feasible. 
- Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a 
- Consider, as necessary, discussing with study physician. 
 
 
Any Grade 
(depending on the type of 
endocrinopathy, refer to NCI CTCAE 
v5.0 for defining the CTC 
grade/severity) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 1 
including those with asymptomatic 
TSH elevation 
General Guidance 
- Consider consulting an endocrinologist for endocrine events. 
- Consider, as necessary, discussing with study physician. 
- Monitor patients for signs and symptoms of endocrinopathies. Non-specific 
symptoms include headache, fatigue, behavior changes, changed mental status, 
vertigo, abdominal pain, unusual bowel habits, polydipsia, polyuria, hypotension, and 
weakness. 
- Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., 
disease progression including brain metastases, or infections). 
- Depending on the suspected endocrinopathy, monitor and evaluate thyroid function 
tests: TSH, free T3 and free T4 and other relevant endocrine and related labs (e.g., 
blood glucose and ketone levels, HgA1c). 
- For modest asymptomatic elevations in serum amylase and lipase, corticosteroid 
treatment is not indicated as long as there are no other signs or symptoms of 
pancreatic inflammation. 
- If a patient experiences an AE that is thought to be possibly of autoimmune nature 
(e.g., thyroiditis, pancreatitis, hypophysitis, or diabetes insipidus), the investigator 
should send a blood sample for appropriate autoimmune antibody testing. 
 
No dose modifications. 
- Monitor patient with appropriate endocrine function tests. 
- For suspected hypophysitis/hypopituitarism, consider consultation of an 
endocrinologist to guide assessment of early-morning ACTH, cortisol, TSH and free 
T4; also consider gonadotropins, sex hormones, and prolactin levels, as well as 
Endocrinopathy 
hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus, hypophysitis, hypopituitarism, and adrenal insufficiency; exocrine event of amylase/lipase increased included in this section 

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cosyntropin stimulation test (though it may not be useful in diagnosing early 
secondary adrenal insufficiency). 
- If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out of range in 2 subsequent 
measurements, include free T4 at subsequent cycles as clinically indicated and 
consider consultation of an endocrinologist. 
Grade 2 
Including those with symptomatic 
endorcinopathy 
- For Grade 2 endocrinopathy other than hypothyroidism 
and Type 1 diabetes mellitus, hold study drug/study 
regimen dose until patient is clinically stable. 
- If toxicity worsens, then treat as Grade 3 or Grade 4. 
- Study drug/study regimen can be resumed once event 
stabilizes and after completion of steroid taper. 
- Patients with endocrinopathies who may require 
- Consult endocrinologist to guide evaluation of endocrine function and, as indicated 
by suspected endocrinopathy and as clinically indicated, consider pituitary scan. 
- For all patients with abnormal endocrine work up, except those with isolated 
hypothyroidism or Type 1 DM, and as guided by an endocrinologist, consider short 
term- corticosteroids (e.g., 1 to 2 mg/kg/day methylprednisolone or IV equivalent) 
and prompt initiation of treatment with relevant hormone replacement (e.g., 
hydrocortisone, sex hormones). 
prolonged or continued steroid replacement (e.g., adrenal - Isolated hypothyroidism may be treated with replacement therapy, without study 
insufficiency) can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is controlled. 
2. 
The patient is clinically stable as per investigator or 
treating physician’s clinical judgement. 
3. 
Doses of prednisone are ≤10 mg/day or equivalent. 
 
 
 
 
Grade 3 or 4 
- For Grade 3 or 4 endocrinopathy other than 
hypothyroidism and Type 1 diabetes mellitus, hold study 
drug/study regimen dose until endocrinopathy 
symptom(s) are controlled. 
- Study drug/study regimen can be resumed once event 
stabilizes and after completion of steroid taper. 
- Patients with endocrinopathies who may require 
drug/study regimen interruption, and without corticosteroids. 
- Isolated Type 1 diabetes mellitus (DM) may be treated with appropriate diabetic 
therapy, without study drug/study regimen interruption, and without corticosteroids. 
- Once patients on steroids are improving, gradually taper immunosuppressive steroids 
(as appropriate and with guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a 
- For patients with normal endocrine workup (laboratory assessment or MRI scans), 
repeat laboratory assessments/MRI as clinically indicated. 
- Consult endocrinologist to guide evaluation of endocrine function and, as indicated 
by suspected endocrinopathy and as clinically indicated, consider pituitary scan. 
Hospitalization recommended. 
- For all patients with abnormal endocrine work up, except those with isolated 
hypothyroidism or Type 1 DM, and as guided by an endocrinologist, promptly initiate 
empiric IV methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as relevant 
hormone replacement (e.g., hydrocortisone, sex hormones). 
prolonged or continued steroid replacement (e.g., adrenal - For adrenal crisis, severe dehydration, hypotension, or shock, immediately initiate IV 
insufficiency) can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is controlled. 
2. 
The patient is clinically stable as per investigator or 
treating physician’s clinical judgement. 
3. 
Doses of prednisone are ≤10 mg/day or equivalent. 
corticosteroids with mineralocorticoid activity. 
- Isolated hypothyroidism may be treated with replacement therapy, without study 
drug/study regimen interruption, and without corticosteroids. 
- Isolated Type 1 diabetes mellitus may be treated with appropriate diabetic therapy, 
without study drug/study regimen interruption, and without corticosteroids. 
Once patients on steroids are improving, gradually taper immunosuppressive steroids (as 
appropriate and with guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN 
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Grade ≤1. 
Severity (CTCAE v 5.0) 
Dose Modifications 
Toxicity Management 
 
 
Any Grade 
(depending on the type of 
neurotoxicity, refer to NCI CTCAE 
v5.0 for defining the CTC 
grade/severity) 
General Guidance 
- Patients should be evaluated to rule out any alternative etiology (e.g., disease 
progression, infections, metabolic syndromes, or medications). 
- Monitor patient for general symptoms (headache, nausea, vertigo, behavior change, 
or weakness). 
- Consider appropriate diagnostic testing (e.g., electromyogram and nerve conduction 
investigations). 
- Perform symptomatic treatment with neurological consult as appropriate. 
 
 
Grade 1 
No dose modifications. 
- See “Any Grade” recommendations above. 
- Treat mild signs/symptoms as Grade 1 (e.g. loss of deep tendon reflexes or 
paresthesia) 
Grade 2 
- For acute motor neuropathies or neurotoxicity, hold 
study drug/study regimen dose until resolution to Grade 
≤1. 
- For sensory neuropathy/neuropathic pain, consider 
- Consider, as necessary, discussing with the study physician. 
- Obtain neurology consult. 
- Sensory neuropathy/neuropathic pain may be managed by appropriate medications 
(e.g., gabapentin or duloxetine). 
holding study drug/study regimen dose until resolution to - Promptly start systemic steroids prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
- If toxicity worsens, then treat as Grade 3 or 4. 
- Study drug/study regimen can be resumed once event 
improves to Grade ≤1 and after completion of steroid 
taper. 
Grade 3 or 4 
For Grade 3: 
- Hold study drug/study regimen dose until resolution to 
Grade ≤1. 
- Permanently discontinue study drug/study regimen if 
Grade 3 imAE does not resolve to Grade ≤1 within 30 
days. 
For Grade 4: 
- Permanently discontinue study drug/study regimen. 
- 
- If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day prednisone PO or IV 
equivalent, consider additional workup and promptly treat with additional 
immunosuppressive therapy (e.g., IV IG). 
 
 
- Consider, as necessary, discussing with study physician. 
- Obtain neurology consult. 
- Consider hospitalization. 
- Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or equivalent. 
- If no improvement within 3 to 5 days despite IV corticosteroids, consider additional 
workup and promptly treat with additional immunosuppressants (e.g., IV IG). 
- Once stable, gradually taper steroids over ≥28 days. 
 
 
Any Grade 
General Guidance 
- The prompt diagnosis of immune-mediated peripheral neuromotor syndromes is 
important, since certain patients may unpredictably experience acute 
decompensations that can result in substantial morbidity or in the worst case, death. 
Special care should be taken for certain sentinel symptoms that may predict a more 
Neurotoxicity 
(to include but not be limited to limbic encephalitis and autonomic neuropathy, excluding Myasthenia Gravis and Guillain-Barre) 
Peripheral neuromotor syndromes (such as Guillain-Barre and myasthenia gravis) 

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severe outcome, such as prominent dysphagia, rapidly progressive weakness, and 
signs of respiratory insufficiency or autonomic instability. 
- Patients should be evaluated to rule out any alternative etiology (e.g., disease 
progression, infections, metabolic syndromes or medications). It should be noted that 
the diagnosis of immune-mediated peripheral neuromotor syndromes can be 
particularly challenging in patients with underlying cancer, due to the multiple 
potential confounding effects of cancer (and its treatments) throughout the neuraxis. 
Given the importance of prompt and accurate diagnosis, it is essential to have a low 
threshold to obtain a neurological consult. 
- Neurophysiologic diagnostic testing (e.g., electromyogram and nerve conduction 
investigations, and “repetitive stimulation” if myasthenia is suspected) are routinely 
indicated upon suspicion of such conditions and may be best facilitated by means of a 
neurology consultation. 
- It is important to consider that the use of steroids as the primary treatment of 
Guillain-Barre is not typically considered effective. Patients requiring treatment 
should be started with IV IG and followed by plasmapheresis if not responsive to IV 
IG. 
Grade 1 
No dose modifications. 
- Consider, as necessary, discussing with the study physician. 
- Care should be taken to monitor patients for sentinel symptoms of a potential 
decompensation as described above. 
- Obtain a neurology consult. 
Grade 2 
- Hold study drug/study regimen dose until resolution to 
Grade ≤1. 
- Permanently discontinue study drug/study regimen if it 
does not resolve to Grade ≤1 within 30 days or if there 
are signs of respiratory insufficiency or autonomic 
instability. 
- Consider, as necessary, discussing with the study physician. 
- Care should be taken to monitor patients for sentinel symptoms of a potential 
decompensation as described above. 
- Obtain a neurology consult 
- Sensory neuropathy/neuropathic pain may be managed by appropriate medications 
(e.g., gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
- Steroids may be successfully used to treat myasthenia gravis. It is important to 
consider that steroid therapy (especially with high doses) may result in transient 
worsening of myasthenia and should typically be administered in a monitored setting 
under supervision of a consulting neurologist. 
- Patients unable to tolerate steroids may be candidates for treatment with 
plasmapheresis or IV IG. Such decisions are best made in consultation with a 
neurologist, taking into account the unique needs of each patient. 
- If myasthenia gravis-like neurotoxicity is present, consider starting AChE inhibitor 
therapy in addition to steroids. Such therapy, if successful, can also serve to reinforce 
the diagnosis. 
GUILLAIN-BARRE: 
- It is important to consider here that the use of steroids as the primary treatment of 
Guillain-Barre is not typically considered effective. 

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- Patients requiring treatment should be started with IV IG and followed by 
plasmapheresis if not responsive to IV IG. 
Grade 3 or 4 
For Grade 3: 
- Hold study drug/study regimen dose until resolution to 
Grade ≤1. 
- Permanently discontinue study drug/study regimen if 
Grade 3 imAE does not resolve to Grade ≤1 within 30 
days or if there are signs of respiratory insufficiency or 
autonomic instability. 
For Grade 4: 
Permanently discontinue study drug/study regimen. 
- Consider, as necessary, discussing with study physician. 
- Recommend hospitalization. 
- Monitor symptoms and obtain neurological consult. 
MYASTHENIA GRAVIS: 
- Steroids may be successfully used to treat myasthenia gravis. They should typically 
be administered in a monitored setting under supervision of a consulting neurologist. 
- Patients unable to tolerate steroids may be candidates for treatment with 
plasmapheresis or IV IG. 
- If myasthenia gravis-like neurotoxicity present, consider starting AChE inhibitor 
therapy in addition to steroids. Such therapy, if successful, can also serve to reinforce 
the diagnosis. 
GUILLAIN-BARRE: 
- It is important to consider here that the use of steroids as the primary treatment of 
Guillain-Barre is not typically considered effective. 
- Patients requiring treatment should be started with IV IG and followed by 
plasmapheresis if not responsive to IV IG. 
 
 
Any Grade 
General Guidance 
Discontinue drug permanently if biopsy-proven immune- 
mediated myocarditis. 
- The prompt diagnosis of immune-mediated myocarditis is important, particularly in 
patients with baseline cardiopulmonary disease and reduced cardiac function. 
- Consider, as necessary, discussing with the study physician. 
- Monitor patients for signs and symptoms of myocarditis (new onset or worsening 
chest pain, arrhythmia, shortness of breath, peripheral edema). As some symptoms 
can overlap with lung toxicities, simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary embolism, congestive heart failure, 
malignant pericardial effusion). A Cardiology consultation should be obtained early, 
with prompt assessment of whether and when to complete a cardiac biopsy, including 
any other diagnostic procedures. 
- Initial work-up should include clinical evaluation, BNP, cardiac enzymes, ECG, 
echocardiogram (ECHO), monitoring of oxygenation via pulse oximetry (resting and 
exertion), and additional laboratory work-up as indicated. Spiral CT or cardiac MRI 
can complement ECHO to assess wall motion abnormalities when needed. 
- Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., 
disease progression, other medications, or infections) 
 
Grade 1 
(asymptomatic or mild symptoms*; 
clinical or diagnostic observations 
only; intervention not indicated) 
No dose modifications required unless clinical suspicion is 
high, in which case hold study drug/study regimen dose 
during diagnostic work-up for other etiologies. If study 
- Monitor and closely follow up in 2 to 4 days for clinical symptoms, BNP, cardiac 
enzymes, ECG, ECHO, pulse oximetry (resting and exertion), and laboratory work- 
up as clinically indicated. 
- Consider using steroids if clinical suspicion is high. 
Myocarditis 

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*Treat myocarditis with mild 
symptoms as Grade 2. 
Grade 2, 3 or 4 
(Grade 2: Symptoms with moderate 
activity or exertion) 
(Grade 3: Severe with symptoms at 
rest or with minimal activity or 
exertion; intervention indicated; new 
onset of symptoms*) 
(Grade 4: Life-threatening 
consequences; urgent intervention 
indicated (e.g., continuous IV therapy 
or mechanical hemodynamic 
support)) 
* Consider “new onset of symptoms” 
as referring to patients with prior 
episode of myocarditis. 
drug/study regimen is held, resume after complete 
resolution to Grade 0. 
- If Grade 2 -- Hold study drug/study regimen dose until 
resolution to Grade 0. If toxicity rapidly improves to 
Grade 0, then the decision to reinitiate study drug/study 
regimen will be based upon treating physician’s clinical 
judgment and after completion of steroid taper. If 
toxicity does not rapidly improve, permanently. 
discontinue study drug/study regimen. 
- If Grade 3-4, permanently discontinue study drug/study 
regimen. 
 
 
- Monitor symptoms daily, hospitalize. 
- Promptly start IV methylprednisolone 2 to 4 mg/kg/day or equivalent after 
Cardiology consultation has determined whether and when to complete diagnostic 
procedures including a cardiac biopsy. 
- Supportive care (e.g., oxygen). 
- If no improvement within 3 to 5 days despite IV methylprednisolone at 2 to 
4 mg/kg/day, promptly start immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is important to rule out sepsis 
and refer to infliximab label for general guidance before using infliximab. 
- Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, or anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 
 
 
Any Grade 
General Guidance 
- Monitor patients for signs and symptoms of poly/myositis. Typically, muscle 
weakness/pain occurs in proximal muscles including upper arms, thighs, shoulders, 
hips, neck and back, but rarely affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing can occur and progress rapidly. 
Increased general feelings of tiredness and fatigue may occur, and there can be new- 
onset falling, difficulty getting up from a fall, and trouble climbing stairs, standing up 
from a seated position, and/or reaching up. 
- If poly/myositis is suspected, a Neurology consultation should be obtained early, with 
prompt guidance on diagnostic procedures. Myocarditis may co-occur with 
poly/myositis; refer to guidance under Myocarditis. Given breathing complications, 
refer to guidance under Pneumonitis/ILD. 
Given possibility of an existent (but previously unknown) autoimmune disorder, 
consider Rheumatology consultation. 
- Consider, as necessary, discussing with the study physician. 
- Initial work-up should include clinical evaluation, creatine kinase, aldolase, LDH, 
BUN/creatinine, erythrocyte sedimentation rate or C-reactive protein level, urine 
myoglobin, and additional laboratory work-up as indicated, including a number of 
possible rheumatological/antibody tests (i.e., consider whether a rheumatologist 
consultation is indicated and could guide need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or signal- 
recognition particle antibodies). Confirmatory testing may include electromyography, 
nerve conduction studies, MRI of the muscles, and/or a muscle biopsy. Consider 
Barium swallow for evaluation of dysphagia or dysphonia. 
Myositis/Polymyositis (“Poly/myositis”) 

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Severity (CTCAE v 5.0) 
Dose Modifications 
Toxicity Management 
 
- Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., 
disease progression, other medications, or infections). 
Grade 1 
(mild pain) 
No dose modifications. 
- Monitor and closely follow up in 2 to 4 days for clinical symptoms and initiate 
evaluation as clinically indicated. 
- Consider Neurology consult. 
- Consider, as necessary, discussing with the study physician. 
Grade 2 
(moderate pain associated with 
weakness; pain limiting instrumental 
activities of daily living [ADLs]) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 3 or 4 
(Grade 3: pain associated with severe 
weakness; limiting self-care ADLs 
 
Grade 4: life-threatening 
consequences; urgent intervention 
indicated) 
- Hold study drug/study regimen dose until resolution to 
Grade ≤1. 
- Permanently discontinue study drug/study regimen if it 
does not resolve to Grade ≤1 within 30 days or if there 
are signs of respiratory insufficiency. 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Grade 3: 
- Hold study drug/study regimen dose until resolution to 
Grade ≤1. 
- Permanently discontinue study drug/study regimen if 
Grade 3 imAE does not resolve to Grade ≤1 within 30 
days or if there are signs of respiratory insufficiency. 
 
For Grade 4: 
- Permanently discontinue study drug/study regimen. 
- Monitor symptoms daily and consider hospitalization. 
- Obtain Neurology consult, and initiate evaluation. 
- Consider, as necessary, discussing with the study physician. 
- If clinical course is rapidly progressive (particularly if difficulty breathing and/or 
trouble swallowing), promptly start IV methylprednisolone 2 to 4 mg/kg/day systemic 
steroids along with receiving input from Neurology consultant 
- If clinical course is not rapidly progressive, start systemic steroids (e.g., prednisone 1 
to 2 mg/kg/day PO or IV equivalent); if no improvement within 3 to 5 days, continue 
additional work up and start treatment with IV methylprednisolone 2 to 4 mg/kg/day 
- If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is no improvement 
within 3 to 5 days, consider start of immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is important to rule 
out sepsis and refer to infliximab label for general guidance before using infliximab. 
- Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, or anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a 
- Monitor symptoms closely; recommend hospitalization. 
- Obtain Neurology consult, and complete full evaluation. 
- Consider, as necessary, discussing with the study physician. 
- Promptly start IV methylprednisolone 2 to 4 mg/kg/day systemic steroids along with 
receiving input from Neurology consultant. 
- If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is no improvement 
within 3 to 5 days, consider start of immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is important to rule 
out sepsis and refer to infliximab label for general guidance before using infliximab. 
- Consider whether patient may require IV IG, plasmapheresis. 
- Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, or anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 

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AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; BUN 
Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated adverse event; IG 
Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI Magnetic resonance imaging; NCI  National Cancer Institute; 
NCCN National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO By mouth; T3 Triiodothyronine; 
T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 

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Appendix VII Continued: Infusion-Related Reactions 
 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
 
 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the discretion of investigator. 
− 
Monitor patients for signs and symptoms of infusion-related 
reactions (e.g., fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (e.g., generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia). 
 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event. 
 
For Grade 2: 
The infusion rate of study drug/study regimen may be decreased 
50% or temporarily interrupted until resolution of the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
− 
Consider premedication per institutional standard prior to 
subsequent doses. 
− 
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per institutional 
standards (e.g., IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid). 
 
 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute. 

Y90-RE RE/Durvalumab 
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Severity Grade of the Event 
(NCI CTCAE version 5.0) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
 
 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
Grade 3 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration. Otherwise, discontinue study drug/study 
regimen. 
Grade 4 
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.). 
 
Treat accordingly, as per institutional standard. 
Treat accordingly, as per institutional standard. 
 
 
 
 
Treat accordingly, as per institutional standard. 
 
 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.