Radioiodine (RAI) in Combination With Durvalumab (Medi4736) for RAI-avid, Recurrent/Metastatic Thyroid Cancers
Phase: EARLY_PHASE1
Conditions: Thyroid Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-218 A(8) 
Approval date: 15-Jan-2021 
 
 
 
 
 
MSK PROTOCOL COVER SHEET 
Radioiodine (RAI) in Combination with Durvalumab (Medi4736) for RAI-avid, 
Recurrent/Metastatic Thyroid Cancers 
Alan Ho, MD, PhD / Medicine/Head & Neck Oncology Svc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 72 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-218 A(8) 
Approval date: 15-Jan-2021 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................ 3 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 4 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ..................................................................12 
4.1 
Design ................................................................................................................................ 12 
4.2 
Intervention ...............................................................................................................................12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 13 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................. 15 
6.1 
Subject Inclusion Criteria .................................................................................................... 15 
6.2 
Subject Exclusion Criteria .................................................................................................. 17 
7.0 
RECRUITMENT PLAN .................................................................................................................... 18 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 18 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................ 19 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 26 
11.0 
TOXICITIES/SIDE EFFECTS .....................................................................................................28 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 29 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 35 
14.0 
BIOSTATISTICS ............................................................................................................... 35 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES37 
15.1 Research Participant Registration ......................................................................................... 37 
15.2 
Randomization ................................................................................................................... 37 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 37 
16.1 
Quality Assurance .............................................................................................................. 37 
16.2 
Data and Safety Monitoring .....................................................................................................37 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 38 
17.1 
Privacy ............................................................................................................................... 39 
17.2 
Serious Adverse Event (SAE) Reporting ................................................................................39 
17.2.1  ........................................................................................................................................ 40 
18.0 
INFORMED CONSENT PROCEDURES ...................................................................................45 
19.0 
REFERENCES ...................................................................................................................... 46 
20.0 
APPENDICES ................................................................................................................... 49 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-218 A(8) 
Approval date: 15-Jan-2021 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a pilot study with the primary objective to assess the safety of administering the PD-L1 
targeting agent durvalumab in combination with recombinant human thyroid stimulating hormone 
(rhTSH, Thyrogen) stimulated/prepared radioiodine (RAI; 131I) therapy in patients with RAI-avid 
(RAIA) recurrent and/or metastatic (R/M) thyroid cancer.  Secondary objectives are assessing best 
overall response (BOR) and progression-free survival (PFS).   Enrolled patients will be treated with 
durvalumab 1500 mg IV approximately every 4 weeks.  In Cycle 1/Week 3, Thyrogen 0.9 mg IM  
will be administered on two consecutive calendar days followed by 100 mCi (+/- 10 mCi) of RAI the 
next calendar day. Durvalumab will be continued approximately every 4 weeks.  Only adverse 
events occurring within 6 weeks of the first durvalumab dose will be counted as dose limiting 
toxicities (DLTs). If >1 of the first 3 patients or >2 of the first 6 patients develop a DLT related to 
durvalumab, further accrual to the study will be halted. If this threshold is not crossed, 11 patients  
in total will be accrued to the pilot study.  All adverse events will be graded according to CTCAE 
v4.0.  Tumor assessments according to RECIST v1.1 will be conducted with serial radiologic 
imaging at baseline and approximately every 2 cycles of durvalumab therapy (or every 8 weeks +/- 
1 week).  After 6 months of treatment, imaging will be obtained every 3 cycles (or every 12 weeks 
(+/- 1 week)).  Patients will remain on durvalumab treatment until there is confirmed progression of 
disease, unacceptable toxicity, withdrawal of consent, or if the study physician feels removal from 
the study is in the patient’s best interest.  One exception to these discontinuation rules: given the 
potential for delayed responses following short periods of disease progression with  
immunotherapy, subjects may continue to receive therapy beyond radiographic progression if the 
investigator concludes that the subject is tolerating study drug and continued therapy may provide 
clinical benefit.  Subjects who decide to continue to receive therapy beyond  radiographic 
progression will be asked to reconsent. Adverse events will be monitored from the time informed 
consent is signed until 90 days after the last dose of drug. 
It is mandatory that patients agree to undergo two research biopsies, which will be analyzed to 
evaluate how this experimental approach changes the genomic/transcriptomic landscape of the 
tumor and the tumor immune infiltrate (exemption from the second biopsy may be considered if 
after performance of the first biopsy it is felt that a subsequent biopsy is not reasonably safe for the 
patient).  Archival tumor tissue and serial peripheral blood collections will also be analyzed for 
potential biologic correlates of immune activation and efficacy derived from the combination 
therapy. 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective 
 
To assess the safety of administering durvalumab in combination with rhTSH-stimulated RAI 
therapy in patients with recurrent/metastatic thyroid cancer. 
 
Secondary Objectives 
 
1) To assess the best overall response to durvalumab in combination with rhTSH-stimulated RAI 
therapy in patients with recurrent/metastatic thyroid cancer. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-218 A(8) 
Approval date: 15-Jan-2021 
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2) To assess the progression-free survival of durvalumab in combination with rhTSH-stimulated 
RAI therapy in patients with recurrent/metastatic thyroid cancer. 
Exploratory Objective 
 
To explore in tumor specimens, peripheral blood collections (for peripheral blood mononuclear 
cells (PBMCs), and cell free DNA (cfDNA)) potential biologic correlates of immune response, 
impact upon the tumor biology/immune cell infiltrate, and efficacy associated with durvalumab in 
combination with rhTSH-stimulated RAI therapy. 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
Thyroid cancers and radioiodine (RAI; 131I): The majority of thyroid cancers are differentiated 
carcinomas of follicular origin (also known as “differentiated thyroid cancers” or “DTCs”) with 
papillary thyroid cancer (PTC) being the most common followed by follicular thyroid cancer (FTC) 
(use of the term “thyroid cancer” in this protocol refers specifically to follicular cell-derived thyroid 
malignancies).  Metastatic disease represents the most frequent cause of thyroid cancer-related 
death1, and radioiodine (RAI or 131I) remains a mainstay of therapy for these patients.  The capacity 
of thyroid tumors to concentrate RAI is mediated by the expression of thyroid-specific gene 
products which in the normal follicular cell function to incorporate iodine into the protein 
thyroglobulin (Tg) to produce thyroid hormone (“iodine organification”).  These genes include Tg, 
the sodium-iodide symporter (NIS; mediates iodide uptake into cells), pendrin (another iodide 
transporter), and thyroid peroxidase (TPO).  Importantly, thyroid-stimulating hormone (TSH or 
thyrotropin) engagement of the TSH receptor (TSHR) in follicular cells, and indeed also thyroid 
cancer cells, upregulates the expression of these genes to promote enhanced iodide   
concentration.  This biology is routinely exploited in standard clinical practice by prescribing thyroid 
hormone withdrawal or administering recombinant human TSH (rhTSH; thyrotropin alpha; 
ThyrogenTM   (Genzyme))2 to elevate circulating TSH for the purpose of enhancing tumoral RAI 
incorporation for diagnostic and therapeutic purposes. 
Though 131I can be particularly effective for treating small volume (< 1 cm), metastatic RAI-avid 
(RAIA; tumors with detectable RAI uptake) disease3, efficacy is significantly lower for patients with 
larger, structurally evident disease.  Sabra et. al. published a retrospective study evaluating the 
efficacy of first-line 131I therapy and reported that for these patients the rate of response with RAI 
was only 22%4.  This observation is consistent with the 10% to 24% response rates reported in 
other retrospective series for similar subsets of patients3,5-7.   Though repeated administration of 
RAI is often possible, unfortunately many patients with metastatic tumors lose the ability to trap 
iodine, leading to RAI-refractory (RAIR) disease.  This is associated with a worse prognosis (10% 
10-year survival3), and systemic therapy options being limited to tyrosine kinase inhibitors (TKIs)8,9. 
With regards to clinical terminology, the “RAI-avid” designation is often used to not only describe 
the ability of tumors to incorporate RAI, but also infers that such tumors are responsive to RAI 
therapy.  However, RAI avidity is not a binary variable, but a continuous one, and the clinical reality 
is that the degree of avidity encountered varies broadly from patient to patient, and indeed tumor to 
tumor.  Since RAI efficacy is ultimately dependent upon the capability of thyroid tumors to take up 
and retain sufficient isotope to deliver tumoricidal doses of radiation, some RAI-refractory tumors 
are still “RAI-avid” in that isotope uptake can be identified on diagnostic scans10.   In this protocol, 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-218 A(8) 
Approval date: 15-Jan-2021 
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the term “RAI-avid” (RAIA) is limited to designating tumors that retain the ability to take up and 
retain iodide, and does not communicate the degree of avidity or sensitivity to RAI treatment (“RAI- 
avid” here can include both RAI-sensitive and –refractory patients).  This RAIA patient population is 
the cohort that will be evaluated in this clinical trial. 
Targeting T cell checkpoints as a therapeutic strategy for DTCs: Immunotherapies directed at 
blocking inhibitory checkpoints to activate T cell immune responses is an effective therapeutic 
strategy for a variety of human cancers11. The efficacy of these therapies for thyroid cancer, 
however, is not known.  Targeting the programmed death protein 1 (PD-1)/PD ligand 1 (PD-L1) 
checkpoint in DTCs is of particular interest given that PD-L1 expression occurs at a high rate in 
these tumors and has been correlated to aggressive disease with poorer prognosis12-14.  Recently 
reported in abstract form were the preliminary results from a cohort of PD-L1 positive, advanced 
DTC patients treated on a phase 1b trial with the PD-1 targeting antibody pembrolizumab (Merck)15.  
Among 22 evaluable patients, two partial responses (9.1%), a 64% rate of tumor regression,       
and 36% 12-month progression-free survival (PFS) rate were observed.  While these                 
data validate that targeting immune checkpoints may have therapeutic efficacy against DTC, it also 
highlights that a better understanding of the thyroid cancer-immune system interaction is needed to 
develop rational approaches that improve upon the modest activity elicited with PD-1 targeting 
alone. 
Determinants of “foreignness” in DTCs: Tumor “foreignness”, specifically tumor presentation of 
peptides in major histocompatibility complexes (MHCs) that T cells recognize as non-self, is 
hypothesized to be essential for therapeutic efficacy with immunotherapeutic approaches targeting 
T cell checkpoints.  Clinical trial data support the hypothesis that foreignness is predominantly 
driven by the presentation of “neoantigens”, epitopes which are uniquely generated by the tumor, 
most commonly via somatic mutations16.  Published correlations between high mutational load, 
neoantigen detection, and efficacy with checkpoint blockade suggests a probabilistic process in 
which a greater somatic mutation rate enhances the likelihood of creating neoantigens to drive 
tumor response17,18, a principle convincingly demonstrated by pembrolizumab efficacy in mismatch 
repair deficient tumors19. 
However, the relevance of neoantigens in thyroid cancer remains to be investigated.  The 
mutational load for the majority of DTCs (<1 mutation per Mb) is 1-2 logs lower than in other 
malignancies, such as melanoma and lung cancers (>10 mutations per Mb), diseases for which the 
existence of neoantigens and significant benefit to PD-1 blockade has been established16,20.  While 
acknowledging that low mutational load does not exclude the possibility of neoantigen formation 
and recognizing that poorly differentiated forms of thyroid cancer are characterized by higher 
mutation rates21, we posit that foreignness in DTC may be determined in part by the expression of 
nonmutated proteins to which T cell tolerance is lost or incomplete.  The therapeutic contribution of 
T cell responses to nonmutated antigens, and the enhancement of these responses by checkpoint 
blockade, has already been demonstrated in melanoma22,23.  Along with the observed efficacy of T 
cell products directed against nonmutated peptide epitopes (e.g. NY-ESO-1), several lines of 
evidence now suggest that along with neoantigen formation, loss of immune tolerance to native 
proteins can play a critical therapeutic role in establishing foreignness.  This is a particularly 
appealing hypothesis for DTC given that the thyroid gland is one of the most immunogenic organs 
in the body, and autoimmune thyroid disease is the most common form of autoimmunity in humans 
(~5% US prevalence)19,24.  Subclinical autoimmunity has been estimated to be as high as 10-20% 
among women24.  Glandular lymphocytic infiltration in these cases have been shown to include T 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-218 A(8) 
Approval date: 15-Jan-2021 
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cell subsets that proliferate in response to native thyroid proteins25.  Development of immune- 
mediated hypothyroidism and hyperthyroidism with CTLA-4 and PD-1 targeting agents provides 
evidence that  clinically targeting T cell checkpoints may be sufficient to augment or stimulate T cell 
responses against native, immunogenic thyroid epitopes.  DTCs to a varying degree maintain the 
expression of nonmutated thyroid-specific genes, including the biochemical machinery responsible 
for mediating iodide avidity and therapeutic susceptibility to RAI.  In fact, the same genes that 
govern tumoral RAI avidity have also been shown to be immunogenic antigens relevant to thyroid 
autoimmunity (e.g. thyroglobulin (Tg), thyroid peroxidase (TPO), and thyroid stimulating hormone 
receptor (TSHR))26. 
Taken together, our central hypothesis is that in addition to putative neoantigens, nonmutated 
protein immunogens contribute to thyroid cancer foreignness, and can be upregulated/released to 
optimize antigenic T cell priming to enhance the efficacy of PD-1 pathway directed therapy. 
Rationale for combining TSH-stimulated RAI therapy with PD-1 pathway blockade: Here we 
propose using TSH-simulated RAI therapy to upregulate the expression and release of nonmutated 
proteins and putative neoantigens to amplify the therapeutic efficacy of PD-1 pathway blockade for 
the treatment of RAI-avid recurrent/metastatic thyroid cancers.  TSH stimulation globally increases 
the expression of thyroid-specific genes in DTCs.  This effect extends to those genes which 
mediate RAI avidity, a property that is routinely exploited clinically for diagnostic and therapeutic 
purposes when recombinant human TSH (rhTSH; Thyrogen (Genzyme)) is administered to  
patients in order to optimize RAI uptake in normal and malignant thyroid tissue. Consistent with 
this mechanism of action, rhTSH has been reported to boost circulating TG levels on average ~3 
fold or higher27.  Additionally, dramatic increases in TG have also been documented after RAI 
administration28-30, consistent with RAI-induced thyroiditis and tumor lysis leading to the release of 
thyroid antigens.  In this way, RAI may boost PD-1 pathway directed therapies in a manner similar 
to the “abscopal effect” described with radiation therapy, except that systemically administered RAI 
may optimize antigen release from not just one irradiated site, but multiple tumor sites, unmasking 
the full complement of neoantigens accompanying disease heterogeneity.   Hence, rhTSH- 
stimulated RAI may be an effective approach for optimizing nonmutated protein and neoantigen 
release to optimally prime the T cell response simulated by PD-1 pathway blockade, which we 
propose to achieve with the PD-L1 targeting antibody durvalumab (AstraZeneca). 
Durvalumab: Durvalumab is a human monoclonal antibody (MAb) of the immunoglobulin G1 kappa 
(IgG1κ) subclass that inhibits binding of PD-L1 to PD-1 and CD80 (B7-1). Durvalumab is 
composed of 2 identical heavy chains and 2 identical light chains, with an overall molecular weight 
of approximately 149 kDa. Durvalumab contains a triple mutation in the constant domain of the 
immunoglobulin (Ig) G1 heavy chain that reduces binding to complement protein C1q and the 
fragment crystallizable gamma (Fcγ) receptors involved in triggering effector function. 
Overview of the clinical experience with durvalumab: As of July 12th, 2018, a total of 5127 subjects 
have been enrolled and treated AstraZeneca or MedImmune-sponsored interventional studies in 
multiple tumor types, stages of diseases and lines of therapy.  Of the 5127 subjects, 2229 received 
durvalumab monotherapy, 1573 received durvalumab in combination with tremelimumab, and 1325 
received durvalumab in combination with an investigational and or an approved product. An 
estimated 8252 patients are currently enrolled in blind studies. In addition, 1637 patients have 
aprticipated in the durvalumab Early Access Programme (EAP; Study D4194C00002 for patients 
with locally advanced, unresectable non-small cell lung cancer [NSCLC] whose disease has not 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-218 A(8) 
Approval date: 15-Jan-2021 
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progressed following platinum-based chemoradiation therapy). The total post-marketing exposure 
to durvalumab to 12 July 2018 was estimated to be approximately 1854 patient-years. 
Durvalumab safety: The safety profile of durvalumab as monotherapy and combined with other 
anticancer agents was consistent with the pharmacology of the target and other agents in the 
immune checkpoint inhibitor class. Most adverse drug reactions (ADRs) seen with the immune 
checkpoint inhibitor class of agents are thought to be due to the effects of inflammatory cells on 
specific tissues and could occur in any organ system. Adverse events of special interest (AESIs) 
and immune-mediated AEs (imAEs) observed with anti PD-L1/PD-1 agents such as durvalumab 
and durvalumab in combination with tremelimumab include diarrhea/colitis, pneumonitis, 
hepatitis/hepatotoxicity,  intestinal perforation, endocrinopathies (hypo- and hyper-thyroidism, 
adrenal insufficiency, hypophysitis/hypopituitarism  and Type 1 diabetes mellitus), rash/dermatitis, 
nephritis myocarditis, myositis/polymyositis, pancreatitis and rare/less frequest imAEs including 
neuropathy/neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome. 
These events are manageable by available/established treatment guidelines as described in the 
study protocols. 
AEs reported with durvalumab monotherapy in key clinical studies are described below. 
 
Study CD-ON-durvalumab-1108: The safety profile of durvalumab monotherapy in the 694 subjects 
with advanced solid tumors treated at 10 mg/kg Q2W in Study CD-ON-durvalumab-1108 has been 
broadly consistent with that of the overall 1,279 subjects who have rec eived durvalumab 
monotherapy (not including subjects treated with blinded investigational product) across the clinical 
development program. The majority of treatment-related AEs were manageable with dose delays, 
symptomatic treatment, and in the case of events suspected to have an immune basis, the use of 
established treatment guidelines for immune-mediated toxicity. As of 07 May2015,  among the 
694 subjects treated with durvalumab 10 mg/kg Q2W in Study CD-ON-durvalumab-1108, a total of 
378 subjects (54.5%) experienced a treatment-related AE, with the most frequent (occurring in ≥ 
5% of subjects) being fatigue (17.7%), nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%), 
pruritus (6.3%), rash (6.1%), and vomiting (5.0%). A majority of the treatment-related AEs were 
Grade 1 or Grade 2 in severity with ≥ Grade 3 events occurring in 65 subjects (9.4%). Treatment- 
related ≥ Grade 3 events reported in 3 or more subjects (≥ 0.4%) were fatigue (12 subjects, 1.7%); 
increased aspartate aminotransferase (AST; 7 subjects, 1.0%); increased gamma- 
glutamyltransferase (GGT; 6 subjects, 0.9%); increased alanine aminotransferase (ALT; 5 
subjects, 0.7%); and colitis, vomiting, decreased appetite, and hyponatremia (3 subjects, 0.4% 
each). Six subjects had treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, 
increased AST, dyspnea, neutropenia, colitis, diarrhea, and pneumonitis) and 1 subject had a 
treatment-related Grade 5 event (pneumonia). Treatment-related serious adverse events (SAEs) 
that occurred in ≥ 2 subjects were colitis and pneumonitis (3 subjects each). AEs that resulted in 
permanent discontinuation of durvalumab were considered as treatment related in 18 subjects 
(2.6%), with colitis being the most frequent treatment-related AE resulting in discontinuation 
(3 subjects). A majority of the treatment-related AEs resulting in discontinuation of durvalumab 
were ≥ Grade 3 in severity and resolved with or without sequelae. 
Study D4191C00003/ATLANTIC:  The safety profile of durvalumab monotherapy in Study CD-ON- 
durvalumab-1108 is generally consistent with that of Study D4191C00003/ATLANTIC  in subjects 
with locally advanced or metastatic non-small-cell lung cancer (NSCLC) treated with durvalumab 
10 mg/kg Q2W. As of 05May2015, 264 of 303 subjects (87.1%) reported any AE in Study 

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IRB Number: 17-218 A(8) 
Approval date: 15-Jan-2021 
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D4191C00003/ATLANTIC.  Overall, events reported in ≥ 10% of subjects were dyspnea (18.8%), 
fatigue (17.8%), decreased appetite (17.5%), cough (14.2%), pyrexia (12.2%), asthenia (11.9%), 
and nausea (11.2%). Nearly two-thirds of the subjects experienced AEs that were Grade 1 or 2 in 
severity and manageable by general treatment guidelines as described in the current durvalumab 
study protocols. Grade 3 or higher AEs were reported in 107 of 303 subjects (35.3%). A total of 
128 subjects (42.2%) reported AEs that were considered by the investigator as related to 
investigational product. Treatment-related AEs (all grades) reported in ≥ 2% of subjects were 
decreased appetite (6.6%); fatigue (5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); 
diarrhea, hyperthyroidism, hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight 
decreased (2.3%); and vomiting (2.0%). Treatment-related Grade 3 AEs reported in ≥ 2 subjects 
were pneumonitis (3 subjects) and increased GGT (2 subjects). There was no treatment-related 
Grade 4 or 5 AEs. Ninety-four of 303 subjects (31.0%) reported any SAE. SAEs that occurred in 
≥ 1.0% of subjects were dyspnea (6.6%); pleural effusion, general physical health deterioration 
(2.3% each); pneumonia (2.0%); hemoptysis, pulmonary embolism (1.3% each); and pneumonitis, 
respiratory failure, disease progression (1.0% each). Nine subjects had an SAE considered by the 
investigator as related to durvalumab. Each treatment-related SAE occurred in 1 subject each with 
the exception of pneumonitis, which occurred in 3 subjects. Fifteen of 303 subjects (5.0%) have 
died due to an AE (pneumonia [3 subjects]; general physical health deterioration, disease 
progression, hemoptysis, dyspnea [2 subjects each]; pulmonary sepsis, respiratory distres s, 
cardiopulmonary arrest [verbatim term (VT)], hepatic failure, and sepsis [1 subject each]). None of 
these events was considered related to durvalumab. Twenty-three of 303 subjects (7.6%) 
permanently discontinued durvalumab treatment due to AEs. Events that led to discontinuation of 
durvalumab in ≥ 2 subjects were dyspnea, general physical health deterioration, and pneumonia. 
Treatment-related AEs that led to discontinuation were increased ALT and increased hepatic 
enzyme, which occurred in 1 subject each. 
Safety data have been pooled for 3 durvalumab monotherapy studies (CD-ON-MEDI4736-1108 
[n=970], ATLANTIC [n=444] and PACIFIC [n=475]) for patients who received a durvalumab dose 
of 10 mg/kg Q2W; a total of 1889 patients are included in this validated pooled data set. 
• 
Overall, AEs reported in ≥15% of patients were fatigue, cough, decreased appetite 
dyspnoea, nausea, constipation, diarrhoea and pyrexia; AEs considered by the investigator 
as related to durvalumab in ≥5% of patients were fatigue, diarrhoea, hypothyroidism, 
nausea, pruritus, decreased appetite and rash. 
• 
A total of 45.2% patients reported AEs of Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 3 or higher: Grade 3, 4 and 5 (fatal) events were reported in 42.1%, 6.7% 
and 5.3% patients, respectively; Grade 3, 4 and 5 (fatal) events considered related to 
durvalumab were reported in 9.4%, 0.7% and 0.6% patients, respectively. 
• 
Grade 3 or 4 events occurring in ≥2% of patients were anaemia, dyspnoea, hyponatraemia, 
gamma-glutamyltransferase (GGT) increased, pneumonia, fatigue, aspartate 
aminotransferase (AST) increased and back pain; Grade 3 or 4 events considered related 
to durvalumab occurring in ≥0.5% patients were fatigue, AST increased, GGT increased, 
pneumonitis, alanine aminotransferase (ALT) increased and diarrhoea. 
• 
The most common Grade 5 events were general physical health deterioration (0.8% 
patients), respiratory failure (0.5% patients) and sepsis (0.4% patients) The only Grade 5 
event considered related to durvalumab occurring in ≥2 patients was pneumonitis. 
• 
A total of 9.4% patients discontinued from study treatment due to an AE. The most common 
events leading to treatment discontinuation were pneumonitis, pneumonia, dyspnoea, 
general physical health deterioration and radiation pneumonitis. 

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• 
A total of 5.7% patients had serious AEs (SAEs) that were considered by the investigator as 
related to durvalumab. 
• 
A total of 56.3% patients experienced an AESI. The most common grouped term AESI was 
diarrhoea (17.4% patients; of whom 0.7% had events of Grade ≥3). Other common AESIs 
(>10%; grouped term) were dermatitis (15.8% patients; of whom 0.2% had events of Grade 
≥3); rash (15.0% patients; of whom 0.6% had events of Grade ≥3); select hepatic events 
(12.0% patients; of whom 4.6% had events of Grade ≥3); and hypothyroidism (10.9% 
patients; of whom 0.1% had events of Grade ≥3). 
PACIFIC: Overall durvalumab monotherapy (10 mg/kg Q2W) was well-tolerated and had a 
manageable safety profile relative to the standard of care (SoC) in this placebo-controlled study 
where durvalumab or placebo was given to patients following concurrent chemoradiation to the 
chest for stage IIIA/IIIB  unresectable NSCLC. Generally, the type, incidence, and severity of AEs 
were comparable between the durvalumab and placebo treatment groups. Where not comparable, 
the type, incidence, and severity of events were consistent with the established durvalumab safety 
profile to date (safety monotherapy pool). The exception to this was for events of 
pneumonitis/radiation pneumonitis, for which, as expected in this patient population, there was a 
high background incidence. However, despite a numerical increase in these events for patients 
receiving durvalumab over those receiving placebo, most of these events were low grade. 
Clinically important CTCAE Grade 3 or 4 events were infrequent and balanced between the 2 
treatment groups. The data incidences for this study are provided in the format of durvalumab vs 
placebo arms respectively. 
 
• 
AEs experienced during the study with an incidence of >15% were cough (35.4% vs 
25.2%); fatigue (23.8% vs 20.5%); dyspnoea (22.3% vs 23.9%); radiation pneumonitis 
(20.2% vs 15.4%); and diarrhoea (18.3% vs 18.8%). Combined events of pneumonitis or 
radiation pneumonitis occurred in 33.9% vs 24.8% of patients. 
• 
CTCAE Grade 3 or 4 AEs were reported in 32.0% vs 27.8% of patients. CTCAE Grade 3 
pneumonitis or radiation pneumonitis occurred in 3.4% vs 2.6% of patients and there were 
no Grade 4 events. 
• 
SAEs were reported in 28.6% vs 22.6% of patients. 
• 
AEs with an outcome of death were comparable between treatment groups (4.4% vs 6.0%). 
The only AEs with an outcome of death experienced by >1 patient in the durvalumab arm 
were pneumonitis and cardiac. Fatal events of pneumonitis or radiation pneumonitis were 
balanced between the 2 treatment groups. 
• 
A total of 15.4% vs 9.8% of patients had an AE that led to permanent discontinuation of 
treatment. AEs leading to discontinuation reported in ≥2 patients were pneumonitis (4.8% 
vs 2.6%), radiation pneumonitis (1.3% vs 1.3%) and pneumonia (1.1% vs 1.3%). 
• 
A total of 66.1% vs 48.7% of patients experienced an AESI. AESIs, grouped terms, with an 
overall incidence >15% were dermatitis or rash (32.6% vs 17.9%) and diarrhea (18.3% vs 
19.2%). A total of 8.2% vs 3.8% of patients experienced CTCAE Grade 3 or 4 AESIs. 
AESIs with an outcome of death occurred in 4 patients (0.8%) treated with durvalumab (all 
pneumonitis events) and 4 patients (1.7%) treated with placebo (3 patients [1.3%] with 
pneumonitis and 1 patient [0.4%] with eosinophilic myocarditis). 
• 
Consistent with the immune-mediated mechanism of action for durvalumab, there was a 
higher incidence of imAEs for patients receiving durvalumab (24.2% vs 8.1% of patients). 
ImAEs of CTCAE Grade 3 or 4 were reported for 3.4% vs 2.6% of patients. 
Durvalumab efficacy: 
Clinical activity has been observed across numerous monotherapy and combination therapy 
studies for which efficacy data are available. 

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Study CD-ON-durvalumab-1108: The ORR per BICR was 21.8% (95% CI: 15.4, 29.3) and 6.4% 
(95% CI: 2.6, 12.8) in PD-L1 high and low/negative patients, respectively. Median OS was 12.4 
months (95% CI: 9.3, 15.2). HNSCC: ORR per BICR was 16.7% (95% CI: 3.6, 41.1) and 2.9% 
(95% CI: 0.1, 14.9) in PD-L1 high and low/negative patients, respectively. Median OS was 8.4 
months (95% CI: 5.7, 12.3). UC: ORR was 27.7% (95% CI: 19.3, 37.5) in the PD-L1 high subgroup 
compared to 5.9% (95% CI: 1.9, 13.2) in the PD-L1 low/negative subgroup. The median OS was 
10.5 months (95% CI: 6.9, 15.7). HCC: ORR per RECIST v1.1 was 10% (95% CI: 2.8, 23.7). The 
median OS was 13.2 months (95% CI: 6.3, 23.0). 
 
Study D4190C00007 (MDS): In the 40 patients with MDS treated in Study D4190C00007, the best 
overall responses were mCR in 13 patients (32.5%). The median PFS was 32.0 weeks (95% CI: 
10.4, 49.6) and median OS was 51.1 weeks (95% CI: 34.0, 71.4). 
 
PACIFIC (NSCLC): The median PFS by BICR was significantly longer with durvalumab treatment 
(16.8 months [95% CI: 13.0, 18.1]) compared with placebo (5.6 months [95% CI: 4.6, 7.8]); hazard 
ratio 0.52; 98.9% CI: 0.39, 0.70; p<0.0001. The median OS was not reached for the durvalumab 
arm and was 28.7 months for the placebo arm; stratified hazard ratio for death, 0.68; 99.73% CI: 
0.47, 0.997; p=0.0025). The 24 month OS rate was 66.3% with durvalumab vs 55.6% with placebo. 
 
HAW K: In patients with PD-L1 high (≥25% TC) HNSCC. ORR (per BICR) was 16.2% (95% CI: 
9.90, 24.41). The median PFS was 2.1 months (95% CI: 1.9, 3.7). The median OS was 7.1 months 
(95% CI: 4.9, 9.9); the OS rate at 12 months was 33.6% (95% CI: 24.8, 42.7). 
 
Study D4190C00006 (NSCLC): In the dose expansion Cohort A (treatment-naive NSCLC selected 
by PD-L1 status), the ORR was 15.6% (7/45; 95% CI: 6.5, 29.5). ORRs were 16.7% (3/18; 95% CI: 
3.6, 41.4) and 12.0% (3/25; 95% CI: 2.5, 31.2) in the PD L1 high and PD-L1 low/negative groups, 
respectively. Median OS was not reached, with an OS rate at 6 months of 83.6%. In the dose 
expansion Cohort B co-administration group (immunotherapy-naïve, 1L or 2L patients with 
NSCLC), no objective responses were observed per investigator assessment. A best overall 
response of SD was observed for 9 of the 19 patients (DCR 47.4%; 95% CI: 24.4, 71.1). In the 
dose expansion Cohort B sequential administration group (2L patients with non squamous 
NSCLC), the ORR per BICR was 18.8% (40/213; 95% CI: 13.8, 24.7); ORRs were 35.1% (20/57; 
95% CI: 22.9, 48.9) and 11.8% (16/136; 95% CI: 6.9, 18.4) in the PD-L1 high and PD-L1 
low/negative subgroups, respectively. Median PFS per BICR was 3.5, 7.1 and 3.3 months in the 
total, PD-L1 high and PD-L1 low/negative groups, respectively. The median OS was 15.4 months; 
the OS rate at 12 months was 53.8% and higher in the PD-L1 high (71.6%) vs the PD-L1 
low/negative (47.3%) subgroup. In Cohort C (immunotherapy-pretreated, 2L to 4L patients with 
NSCLC), the ORR by investigator assessment was 5.1% (4/78; 95% CI: 1.4, 12.6); ORRs were 
7.7% (2/26; 95% CI: 0.9, 25.1) and 2.9% (1/34; 95% CI: 0.1, 15.3) in the PD-L1 high and PD-L1 
low/negative subgroups, respectively. Median PFS was 1.8, 1.7 and 1.7 months in the total, PD-L1 
high and PD-L1 low/negative groups, respectively. The median OS was 8.4 months; the OS rate at 
12 months was 34.1% and was similar in the PD-L1 high (31.5%) vs the PD-L1 low/negative 
(29.8%) subgroup. 
 
Study D4190C00022: ORR was 17.5% (95% CI: 7.3, 32.8). The median TTR was 8 weeks (range, 
7.6 to 24 weeks). The DCR (defined as any CR + PR + SD >16 weeks) was 57.5% (95% CI: 40.9, 
73.0). 
 
Durvalumab fixed dosing: A population PK model was developed for durvalumab using 
monotherapy data from a Study 1108 and ATLANTIC  across dose levels and tumor types (Model 
1; n= 1324, doses ranging from 0.1 mg/kg to 10 mg/kg Q2W or 15 mh/kg Q3W or 20 mg/kg Q4W ). 

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Population PK analysis indicated only minor impact of body weight (WT) on PK of durvalumab 
(coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W or 20 mg/kg Q4W) and fixed 
dosing (750 mg Q2W or 1500 mg Q4W) of durvalumab was evaluated by comparing predicted 
steady state PK concentrations (5th, median and 95th  percentiles) using the population PK model. A 
fixed dose of 750 mg Q2W was selected to approximate 10 mg/kg Q2W and a fixed dose of 1500 
mg Q4W was selected to approximate 20 mg/kg Q4W (based on median body WT of ~75 kg). A 
total of 1000 patients were simulated using body WT distribution of 40–120 kg. Simulation results 
demonstrate that body WT-based and fixed dosing regimens yield similar median steady state PK 
concentrations with slightly less overall between-subject variability with fixed dosing regimen. 
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors. Given expectation of similar pharmacokinetic exposure and variability, we considered 
it feasible to switch to fixed dosing regimens. Based on average body WT of 75 kg, a fixed dose of 
750 mg Q2W durvalumab (equivalent to 10 mg/kg Q2W), 1500 mg Q4W durvalumab (equivalent to 
20 mg/kg Q4W) is included in the current study. Fixed dosing of durvalumab is recommended only 
for subjects with > 30kg body weight due to endotoxin exposure. Patients with a body weight less 
than or equal to 30 kg should be dosed using a weight-based dosing schedule (Appendix 2). 
Study overview: The objective of this pilot clinical trial is to assess the safety of administering the 
PD-L1 targeting agent durvalumab in combination with rhTSH-stimulated RAI in RAIA, recurrent 
and/or metastatic thyroid cancer patients.  Secondary and exploratory objectives will be to collect 
preliminary efficacy data as well as explore potential biologic correlates in sampled tumors and 
peripheral blood to clinical efficacy with the combination.  Since RAI is being administered for the 
primary purpose of augmenting the immunotherapeutic response, patients with at least one RAI- 
avid tumor of any degree will be eligible, including patients who are clinically designated either 
“RAI-sensitive” or “RAI-refractory.” 

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4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a pilot study with the primary objective to assess the safety of administering the PD-L1 
targeting agent durvalumab in combination with recombinant human thyroid stimulating hormone 
(rhTSH, Thyrogen) stimulated/prepared radioiodine (RAI; 131I) therapy in patients with RAI-avid 
(RAIA) recurrent and/or metastatic (R/M) thyroid cancer.  If >1 of the first 3 patients or >2 of the  
first 6 patients develop a DLT related to durvalumab, further accrual to the study will be halted. If 
this threshold is not crossed, 11 patients in total will be accrued to the pilot study. All adverse 
events will be graded according to CTCAE v4.00.  Secondary objectives are assessing best overall 
response (BOR) and progression-free survival (PFS) RECIST v1.1 criteria. 
4.3 
Intervention 
 
Enrolled patients will be treated with durvalumab 1500 mg IV approximately every 4 weeks. In 
Cycle 1/Week 3, Thyrogen 0.9 mg IM will be administered on two consecutive calendar days 
followed by 100 mCi (+/- 10 mCi) of RAI the next calendar day. Durvalumab will be continued 
approximately every 4 weeks. Only adverse events occurring within 6 weeks of the first 
durvalumab dose will be counted as dose limiting toxicities (DLTs).  Tumor assessments according 
to RECIST v1.1 criteria will be conducted with serial radiologic imaging at baseline and 
approximately every 2 cycles of durvalumab therapy (or every 8 weeks +/- 1 week).  After 6 months 
of treatment, imaging will be obtained every 3 cycles (or every 12 weeks (+/- 1 week)).  Patients  
will remain on durvalumab treatment until there is confirmed progression of disease, unacceptable 
toxicity, withdrawal of consent, or if the study physician feels removal from the study is in the 
patient’s best interest.  One exception to these discontinuation rules: given the potential for 
delayed responses following short periods of disease progression with immunotherapy, subjects 
may continue to receive therapy beyond radiographic progression if the investigator concludes that 
the subject is tolerating study drug and continued therapy may provide clinical benefit.  Adverse 
events will be monitored from the time informed consent is signed until 90 days after the last dose 
of drug.  It is mandatory that patients agree to undergo two research biopsies, which will be 
analyzed to evaluate how this experimental approach changes the genomic/transcriptomic 
landscape of the tumor and the tumor immune infiltrate (exemption from the second biopsy may be 
considered if after performance of the first biopsy it is felt that a subsequent biopsy is not 
reasonably safe for the patient).  Archival tumor tissue and serial peripheral blood collections will 
also be analyzed for potential biologic correlates of immune activation and efficacy derived from 
the combination therapy. 

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5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.2 Durvalumab 
The Investigational  Products Supply section of AstraZeneca/MedImmune  will supply durvalumab to 
the investigator as a 500-mg vial solution for infusion after dilution.  Durvalumab is an IND agent 
that is not FDA-approved for any indication. 
 
Formulation/packaging/storage 
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) polysorbate 80; it has a pH of 6.0. The nominal fill 
volume is 10 mL.  Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must 
not be frozen. Durvalumab must be used within the individually assigned expiry date on the label. 
Durvalumab Doses and treatment regimens 
Durvalumab will be administered 1500 mg IV approximately every 4 weeks.  Two weeks after the 
first dose and prior to the second dose of durvalumab, Thyrogen and RAI will be administered. 
Durvalumab will be continued approximately every 4 weeks.  Patients will remain on durvalumab 
until there is confirmed progression of disease, unacceptable toxicity, withdrawal of consent, or if 
the study physician feels removal from the study is in the patient’s best interest.  One exception to 
these discontinuation rules: given the potential for delayed responses following short periods of 
disease progression with immunotherapy, subjects may continue to receive therapy beyond 
radiographic progression if the investigator concludes that the subject is tolerating study drug and 
continued therapy may provide clinical benefit. 
Study drug preparation 
For patients weighing ≥ 30 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg 
Q4W) (based on an average body WT of 75 kg) should be prepared. For subjects <30 kg body 
weight, dose is determined using body mass, calculating the stock volume of durvalumab to 
achieve the accurate dose according to Appendix 2. 
 
Preparation of durvalumab doses for administration with an IV bag 
 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique. 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) 
 
• 
4 hours at room temperature 
 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration. 

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No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been 
observed. Dose of 1500 mg durvalumab for patients >30 kg will be administered using an IV bag 
containing 0.9% (w/v) saline with a final durvalumab concentration ranging from 1 to 20 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. 
Remove a volume of IV solution from the IV bag equal to the calculated volume of durvalumab to be 
added to the IV bag prior to addition of durvalumab. Next, the volume of durvalumab (i.e., 15.0 mL 
for 750 mgor 30.0 mL for 1500 mgof durvalumab) is added to the IV bag suchthat final concentration 
is within 1 to 20 mg/mL (IV bag volumes 100 to 1000 mL). Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag. 
Patient weight at baseline should be used for dosing calculations in patients ≤30 kg unless there is 
a ≥10% change in weight. Dosing day weight can be used for dosing calculations instead of baseline 
weight per institutional standard. 
For patients <30kg, calculate the dose volume of durvalumab and number of vials needed for the 
subject to achieve the accurate dose according to Appendix 2. 
 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled infusion 
via an infusion pump into a peripheral or central vein. Following preparation of durvalumab, the entire 
contents of the IV bag should be administered as an IV infusion over approximately 60 minutes (±5 
minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 minutes is considered a deviation. 
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline) equal to the priming volume 
of the infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document if the 
line was not flushed. 
Standard infusion time is 1 hour. However, if there are interruptions during infusion, the total allowed 
time should not exceed 8 hours at room temperature. The table below summarizes time allowances 
and temperatures. 
Durvalumab hold and infusion times 
 
Maximum time from needle 
puncture to start of administration 
4 hours at room temperature, 
24 hours at 2°C to 8°C 
Maximum time for IV bag infusion, 
including interruptions 
8 hours at room temperature 
 
 
In the event that either preparation time or infusion time exceeds the time limits outlined above, a 
new dose must be prepared from new vials.  Durvalumab does not contain preservatives, and any 
unused portion must be discarded. 
Monitoring of dose administration 
Subjects will be monitored before, during and after the infusion with assessment of vital signs at the 
times specified in the Schedule of Assessment. Subjects are monitored (pulse rate, blood pressure) 

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approximately every 30 minutes during the infusion period (including times where infusion rate is 
slowed or temporarily stopped). 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug maybe decreased 
by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial 
rate until completion of the infusion. For subjects with a ≤Grade 2 infusion-related reaction, 
subsequent infusions may be administered at 50% of the initial rate. Acetaminophen and/or an 
antihistamine (e.g., diphenhydramine) or equivalent medications per institutional standard may be 
administered at the discretion of the investigator.  If the infusion-related reaction is Grade 3 or higher 
in severity, study drug will be discontinued. The standard infusion time is one hour, however if there 
are interruptions during infusion, the total allowed time from infusion start to completion of infusion 
should not exceed 4 hours at room temperature, with maximum total time at room temperature not 
exceeding 4 hours (otherwise requires new infusion preparation). 
As with any antibody, allergic reactions to dose administration are possible. 
 
5.2 Thyrotropin alpha (Thyrogen; Genzyme) 
Thyrogen will be given as 0.9 mg IM daily injections administered for two consecutive days prior to 
RAI. The Thyrogen will be administed in clinic. 
5.3 131I (RAI; sodium iodide; I-131) 
100 mCi (+/- 10 mCi) of 131I will be administered a day after Thyrogen injections have been 
administered for two consecutive calendar days.  This is a low, empiric 131I activity recommended 
for the treatment of loco-regional or metastatic RAIA thyroid cancer, even in patient populations at 
increased risk of 131I therapy (elderly, patients with renal insufficiency)31.  131I has a half-life of 8 
days and relatively high principal photon energy of 364 keV accompanied by beta particle 
emissions.  It is administered orally in the form of capsules or liquid.  Pregnancy and breastfeeding 
are contraindications to radioiodine treatment.  A beta-HCG pregnancy test must be performed up 
to 2 days prior to the administration of 131I (for woman of child-bearing potential).  131I is an FDA- 
approved agent for the treatment of thyroid cancer.  The 131I will be administed in clinic. 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
The protocol will enroll patients with RAI-avid recurrent/metastatic thyroid cancer. 
 
6.2 
Subject Inclusion Criteria 
 
• Patients must have histologically or cytologically confirmed thyroid carcinoma of follicular origin 
(including papillary, follicular, hurthle cell or poorly differentiated subtypes and their respective 
variants). 
 
• Diagnosis of recurrent and/or metastatic thyroid cancer. 
 
• At least one RAI-avid lesion identified on the most recent radioiodine scan (a diagnostic, post- 
therapy, or post-ablation scan) OR at least one lesion on the most recent FDG PET scan with 
an SUVmax of 10 or less. (Both RAI-sensitive and RAI-refractory patients are eligible if at least 
one tumor with RAI avidity of any degree can be identified within one of these parameters.) 

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• Patients must have measurable disease, defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and 
short axis for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with CT 
scan, MRI, or calipers by clinical exam.  See Section 12 for the evaluation of measurable 
disease.  Tumors in previously irradiated fields may be considered measureable if there is 
evidence of tumor progression after radiation treatment. 
 
• ECOG Performance Status (PS) 0 or 1.  (or Karnofsky ≥60%) 
 
• Age > 18 years at time of study entry 
 
• Adequate normal organ and marrow function as defined below: 
 
− Hemoglobin ≥ 9.0 g/dL 
 
− Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) 
− Platelet count ≥ 100 x 109/L (>100,000 per mm3) 
− Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  (This will not apply to 
subjects with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia  that is 
predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be 
allowed only in consultation with their physician.) 
− AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases 
are present, in which case it must be ≤ 5x ULN 
− Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) 
or by 24-hour urine collection for determination of creatinine clearance: 
 
Males: 
Creatinine CL (mL/min) 
= 
W eight (kg) x (140 – Age) 
. 
72 x serum creatinine (mg/dL) 
Females: 
Creatinine CL (mL/min) 
= 
W eight (kg) x (140 – Age) 
x  0.85 
72 x serum creatinine (mg/dL) 
 
• Female subjects must either be of non-reproductive potential (i.e., post-menopausal by history: 
≥60 years old and no menses for 1 year without an alternative medical cause; OR history of 
hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or 
must have a negative serum pregnancy test upon study entry. 
 
• Subject is willing and able to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations including follow up. 
 
• Patients must agree to undergo two research biopsies of (a) malignant lesion(s). Biopsies do not 
need to be done if the investigator or person performing the biopsy judges there is no tumor 
accessible for biopsy, the only accessible tumor must be used for RECIST measurement, or the 
biopsy poses too great a risk to the patient.  .  If the patient has only one RECIST measureable 
target lesion for response assessment, research biopsies must not be performed on that target 
lesion. 
 
• Availability of archival tumor tissue from the thyroid cancer primary or metastasis (a tissue block 
or a minimum of 30 unstained slides would be required.  Patients with less archival tissue 
available may still be eligible for the study after discussion with the MSK Principal Investigator.) 

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6.3 
Subject Exclusion Criteria 
• 
131I  therapy < 6 months prior to initiation of therapy on this protocol. A diagnostic study using < 
10 mCi of 131I  is not considered 131I therapy.  Any previous treatment with a PD1 or PD-L1 
inhibitor, including durvalumab. 
 
• History of pneumonitis. 
 
• External beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol.. 
 
• Chemotherapy, immunotherapy, targeted therapy, monoclonal antibodies, tumor embolization, 
or other investigational agent within 28 days prior to the first dose of study drug. 
 
• Current or prior use of immunosuppressive medication within 28 days before the first dose of 
durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic 
corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an 
equivalent  corticosteroid. 
 
• Any unresolved toxicity CTCAE grade > 2 from previous anti-cancer therapy.  Exceptions 
include hearing loss, peripheral neuropathy, and alopecia. 
 
• Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous 
immunotherapy agent, or any unresolved irAE >Grade 1. 
 
• Active or prior documented autoimmune disease within the past 2 years. NOTE: Subjects with a 
history of autoimmune thyroid disease are not excluded.   Subjects with vitiligo or psoriasis not 
requiring systemic treatment (within the past 2 years) are not excluded. 
 
• Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative 
colitis). 
 
• History of primary immunodeficiency. 
 
• History of allogeneic organ transplant. 
 
• History of hypersensitivity to durvalumab or any excipient. 
 
• History of hypersensitivity to thyrotropin alpha (Thyrogen). 
 
• Patients unable to follow a low iodine diet or requiring medication with high content in iodide 
(amiodarone). 
 
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, acute or 
chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric 
illness/social situations that would limit compliance with study requirements or compromise the 
ability of the subject to give written informed consent. 

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• Known history of active tuberculosis 
 
• Symptomatic brain metasteses, leptomeningeal carcinomatosis, or spinal cord compression 
(treated metastatic brain, leptomeningeal carcinomatosis, or spinal cord compression are 
allowed). Note: Patients must be off steroids used for brain metasteses, leptomeningeal 
carcinomatosis, or spinal cord compression. 
 
• Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of 
receiving durvalumab. 
 
• Female subjects who are pregnant, breast-feeding or male or female patients of reproductive 
potential who are not employing an effective method of birth control. 
 
• Any condition that, in the opinion of the investigator, would interfere with evaluation of study 
treatment or interpretation of patient safety or study results 
 
• Subjects with uncontrolled seizures. 
 
7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or research team.  Patient recruitment most likely will occur in the medical 
oncology and endocrinology clinics of the Head and Neck Disease management team. If the 
investigator is a member of the treatment team, s/he will screen their patient’s medical records for 
suitable research study participants and discuss the study and their potential for enrolling in the 
research study. Potential subjects contacted by their treating physician will be referred to the 
investigator/research staff of the study.  Investigators will discuss the study and review/sign the 
informed consent documents with the patient. 
During the initial conversation between the investigator/researc h staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. The investigator/research staff may also review portions of their medical 
records in order to further assess eligibility. They will use the information provided by the patient 
and/or medical record to confirm that the patient is eligible and to contact the patient regarding 
study enrollment. If the patient turns out to be ineligible for the research study, the research staff 
will destroy all information collected on the patient during the initial conversation and medical 
records review. 
8.1 
PRETREATMENT EVALUATION 
 
W ithin 4 weeks of starting on study, the following tests/evaluations need to be done: 
• Signing the Informed Consent Form. 
• History and Physical Examination. 
• Vital signs (pulse, blood pressure), including weight. 
• Performance Status (Eastern Cooperative Oncology Group (ECOG) or Karnofsky Performance 
Status (KPS)) designation. 
• Electrocardiogram (ECG or EKG) in triplicate. 
• Radiology studies (CT(s) without contrast and/or MRI(s)) for disease assessment). 
• Recording concurrent medications. 

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• Confirm availability of archival tumor tissue (if tissue is not already available at MSK, physical 
receipt of tissue is not required for study enrollment or initiation). 
• Research tumor biopsy: The research biopsy will be performed any time prior to Week 1 Day 1 
(can completed > 4 weeks before starting on study).  Radiologic guidance (CT, MRI or 
ultrasound guided) approaches and obtaining multiple cores to ensure sufficient biopsy material 
(at least 3 cores preferred) are allowed as long as it is considered safe for the patient (image- 
guided biopsies will be performed by a radiology physician with the appropriate expertise). 
• Research blood draw: Any time prior to start of study, approximately 10 mL of blood, preferably 
in a lavender top tube (with EDTA). 
• Hematology tests (see Section 10). 
• Clinical chemistry tests (see Section 10). 
• Urinalysis (see Section 10). 
• Pregnancy test in women of child-bearing potential (serum or urine beta-hCG within 7 days of 
starting the study). 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 Concomitant  Medications 
 
The following medications are considered exclusionary during the study. 
 
1. Any investigational anticancer therapy. 
 
2. Any concurrent chemotherapy, radiotherapy (except  palliative radiotherapy), immunotherapy, 
biologic or hormonal therapy for cancer treatment, other than TSH suppressive therapy and/or 
bisphosphonates and/or denosumab. 
 
3. Immunosuppressive medications including, but not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and TNF-α 
blockers. Use of immunosuppressive medications for the management of investigational product- 
related AEs or in subjects with contrast allergies is acceptable. In addition, use of inhaled and 
intranasal corticosteroids is permitted. A temporary period of steroids will be allowed for different 
indications, at the discretion of the principal investigator (e.g., chronic obstructive pulmonary 
disease, radiation, nausea, etc). 
 
4. Live attenuated vaccines within 30 days of durvalumab dosing (i.e., 30 days prior to the first dose, 
during treatment with durvalumab and for 30 days post discontinuation of durvalumab). 
Inactivated vaccines, such as the injectable influenza vaccine, are permitted. 

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Contraception 
 
Females of childbearing potential who are sexually active with a nonsterilised male partner must use 
at least 1 highly effective method of contraception (Table 1) from the time of screening, and must 
agree to continue using such precautions at least 90 days following the last infusion of durvalumab 
and avoid pregnancy for 9 months after RAI (131I) administration; 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. 
 
1. Females of childbearing potential 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). 
 
2. Subjects must use 2 acceptable methods of effective contraception as described in Table 1. 
 
3. Nonsterilised males who are sexually active with a female partner of childbearing potential must 
use 2 acceptable methods of effective contraception (see Table 1) from Day 1 and for 90 days 
after receipt of the final dose of investigational product. Males should avoid impregnating females 
partners for 9 months after RAI (131I). 
 
Table 1: Highly Effectivea Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• Male condom plus spermacide 
• Copper T intrauterine device 
• Levonorgesterel-releasing 
intrauterine system (eg, Mirena®)b 
• Etonogestrel implants: e.g. Implanon or 
Norplan 
• Intravaginal  device: e.g. ethinylestradiol 
and etonogestrel 
• Medroxyprogesterone  injection: e.g. 
Depo-Provera 
• Normal and low dose combined oral 
contraceptive pill 
• Norelgestromin/ethinylestradiol 
transdermal system 
• Cerazette (desogestrel) 
a   Highly effective (i.e. failure rate of <1% per year) 
b   This is also considered a hormonal method 
 
Blood donation 
Subjects should not donate blood while participating in this study for at least 90 days following the 
last infusion of durvalumab and a minimum 12 months after administration of RAI. 
 
9.3 Schedule of Events 
 
• Patients will initiate treatment with durvalumab on Week 1, Day 1.  The required evaluations and 
laboratory tests (detailed in Section 10) can be performed up to 7 days prior to initiation of 
treatment.  It is unnecessary to repeat laboratory tests if the screening assessments of the same 
tests were performed within 7 days prior to first dose of therapy.  Durvalumab 1500 mg IV 

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approximately every 4 weeks will be administered (adjustment to the dose may be necessary for 
patients weighing <30 kg). All other Week 1 evaluations (detailed in Section 10) may be 
performed up to 3 days prior to initiation of study treatment. 
 
• In Cycle 1/Week 3, Thyrogen 0.9 mg IM will be administered on two consecutive calendar days 
followed by 100 mCi (+/- 10 mCi) RAI the next calendar day (these agents will be administered 
in clinic). The laboratory tests detailed in Section 10 are to be drawn prior to the first Thyrogen 
injection. 
 
• Research tumor biopsy: If after performance of the first research biopsy the investigator judges 
that it is safe to proceed with a second research biopsy, it is preferred that the procedure be 
performed during Cycle 2, Week 3 or 4 (though alternate timing for this second biopsy during 
Cycle 2 or later is allowed per investigator discretion or for safety reasons related to RAI 
administration).  Biopsy of the same tumor that was sampled previously is preferred, but not 
required.  Radiologic guidance (CT, MRI or ultrasound guided) approaches and obtaining 
multiple cores to ensure sufficient biopsy material (at least 3 cores preferred) are allowed as 
long as it is considered safe for the patient (image-guided biopsies will be performed by a 
radiology physician with the appropriate expertise). 
 
• DLT monitoring and evaluations (including research blood collections) are to be conducted 
according to the schedule detailed in Section 10.  Guidelines for holding durvalumab will be 
performed as outlined in Section 11 and Appendix 1. 
 
9.4 Definition of Dose-Limiting Toxicity (DLTs) 
 
The period of DLT monitoring will be 6 weeks beginning from the first durvalumab dose 
administered.  Patients who are removed from the study for reasons other than DLT prior to the 
administration of the first Thyrogen injection will be replaced with another subject.  Patients who do 
not complete the 6 week period of monitoring beginning from the first durvalumab dose for reasons 
other than DLT will also be replaced.  Grading of DLTs will follow the guidelines provided in the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
 
If >1 of the first 3 patients or >2 of the first 6 patients develop a DLT related to durvalumab, further 
accrual to the study will be halted. If this threshold is not crossed, 11 patients in total will be 
accrued to the pilot study. 
 
With the exception of specific AEs discussed below, a DLT will be defined as any Grade 3 or 
higher toxicity that occurs during the DLT evaluation period felt to be possibly, probably, or 
definitely related to durvalumab.  For > Grade 3 adverse events that occur in patients during the 
DLT monitoring period, investigators must use their discretion to decide if the adverse event is a 
DLT (e.g., alkaline phosphatase elevation in the context of known progression of hepatic and/or 
bone metastases might be attributed to progression of disease per investigator discretion). 
 
Any AE requiring discontinuation of durvalumb will also be considered a DLT.  Durvalumab-related 
AEs that occur during the 6-week DLT evaluation period and delay the administration of the 
second durvalumab dose and/or Thyrogen/RAI therapy by more than two weeks will also be 
considered DLTs. 

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Toxicity that is clearly and directly related to the primary disease or to another etiology is excluded 
from this DLT definition. 
 
The following will be DLTs: 
• Any Grade 4 immune related Adverse Event (irAE) 
• Any ≥ Grade 3 colitis 
• Any ≥ Grade 3 noninfectious pneumonitis 
• Any ≥ Grade 3 nephritis or renal dysfunction (elevated serum creatinine) 
• Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation of 
maximal supportive care 
• Any Grade 3 irAE (excluding colitis, pneumonitis, thyroiditis, or nephritis) that does not downgrade 
to Grade 2 within 3 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 > 8x ULN or total bilirubin > 5x ULN 
• Any ≥ Grade 3 non-irAE, except for the exclusions listed below 
 
The DLT definition excludes the following conditions: 
• Grade 3 fatigue lasting ≤ 7 days 
• Any grade hypothyroidism or elevation of TSH 
• Grade 3 endocrine disorder (pituitary, thyroid, and/or adrenal insufficiency) that is managed with 
or without systemic corticosteroid therapy and/or hormone replacement therapy and the subject 
is asymptomatic 
• Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., inflammatory reaction 
at sites of metastatic disease, lymph nodes, etc) 
• 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 3 days. Grade 3 or Grade 4 febrile neutropenia will be a DLT regardless of 
duration or reversibility 
• Grade 3 or 4 lymphopenia 
• Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that requires 
medical intervention, and improves by at least 1 grade within 3 days 
• Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or symptoms 
and are reversed with appropriate maximal medical intervention within 3 days 
 
The following toxicities are excluded from the definition of DLT if observed within 30 days of RAI 
administration: 
• Grade 3 low white blood cell count 
• Grade 3 or 4 neutropenia 
• Grade 3 thrombocytopenia 
 
Regarding immunosuppression, the laboratory parameter for DLT determination will be absolute 
neutrophil count (not total white blood cell count). 
9.5 Correlative Studies 

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Tumor Analysis: (These studies will be conducted in collaboration with Drs. Timothy Chan, Luc 
Morris, and James Fagin.) 
 
Exploratory objective:  To investigate potential tumor predictors/correlates of benefit to durvalumab 
plus rhTSH-stimulated/prepared RAI therapy. 
 
Rationale: We hypothesize that interfering with the PD-1/PD-L1 axis in thyroid cancers can result in 
the loss of tolerance to immunogenic thyroid antigens, which can be augmented by rhTSH 
stimulated RAI therapy.   Other predictors of benefit to immunotherapeutic approaches delineated 
in other settings include PD-L1 expression, tumor mutation burden, and neoantigen load.  To 
evaluate the potential correlation of these tumor features with the efficacy of durvalumab plus 
rhTSH-prepared RAI, we will perform whole exome and transcriptome analysis in fresh research 
biopsies and/or archival tissues. 
 
Of particular importance is the lack of data addressing how immune checkpoint inhibition and RAI 
therapy impacts the dynamics of the thyroid cancer immune microenvironment and genomic 
landscape.  For the latter, immunotherapy induced changes to the tumor genome could provide 
insights into the “immunoediting” induced by therapy and potentially identify epitopes of particular 
significance for efficacy.  The only approach that will provide new insight into these biologic 
processes is the analysis of serial research biopsies performed during therapy.  On this study, 
biopsies will be performed pre-treatment and after durvalumab/RAI in Cycle 2.  These tissues will 
be analyzed with next-generation sequencing of DNA and RNA.  For cases in which sufficient 
tissue is collected, the immune microenvironment may be characterized by cytometric techniques, 
including flow cytometry or mass cytometry (CyTOF; MIBI).   Protein based approaches, including 
IHC (e.g. for PD-L1, PD-L2 status), will also be employed.  We hypothesize that durvalumab and 
RAI will increase tumoral immune infiltration characterized by enhanced markers of T cell activation 
(increased granzyme/perforin expression, enrichment of the IFN-gamma signaling pathway, 
decreased Treg/CD8+ ratio).  Beyond characterizing the tumor-associated T cell infiltrate, therapy 
induced changes of other immune cell popoulations will be examined (e.g. macrophages, NK cells, 
B-cells).  Additionally,  how durvalumab/RAI impacts the status of other immune checkpoint 
molecules (e.g. LAG-3, CTLA-4, TIM-3) may provide insights into putative mechanisms of 
resistance to this therapeutic approach.  Such studies will be essential for rationally developing 
future immunotherapy based therapeutic approaches for advanced thyroid cancer patients. 
 
Approach: The research biopsy samples will be divided for fixation and flash freezing at the 
discretion of the Principle Investigator.  These samples will be used to evaluate the genomic and 
transcriptomic landscape of the tumors.  Archival tissues may also be used if of sufficient quantity 
and quality. 
DNA and RNA will be extracted from frozen samples and/or paraffin tissue. The research 
peripheral blood sample collected on the study will be used as a control, matched normal sample 
(microdissection of normal tissue in the tumor samples may also be used for this purpose). 
DNA will be submitted for next generation sequencing, possibly whole exome or whole genome 
sequencing.  The specific assay that will be employed to analyze for genomic alterations will be 
dependent upon the technology available at the time of analysis. Comparisons of DNA between 
tumor and normal tissue (from the research blood draw) will be performed as appropriate, thus 
generating germline sequence data.  There is no intention to analyze the germline data beyond 

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Page 24 of 72 
 
 
 
 
utilizing it as a normal control for the tumor tissue analysis, and generally germline data will not be 
communicated to the patient. 
This data will be used to quantitate mutation load and identify 
candidate neoantigens. 
 
Extracted RNA will be analyzed with RNAseq technology, or alternative assays, depending on 
technical limitations and assay availability.   RNAseq data will be used to define a set of expressed 
neoepitopes and explore gene expression signatures that may correlate with response.  RNAseq 
data analysis may include: 
 
• Quantification of the following: 1) Markers of the MAPK pathway transcriptional output (e.g. 
Etv1, Etv4, Etv5, Spry2, Spry4, Dusp6); 2) Genes required for thyroid hormone biosynthesis 
(e.g. Nkx2.1, Pax8, Foxe1, Tg, Tpo, TshR, Nis, Pendrin, Dio2); 3) PD-L1 expression (PD-L1 
expression will also be analyzed by IHC). 
• Analysis to characterize tumor (a) immune cell infiltration and (b) immunologic gene signatures. 
 
For patients in whom two serial research biopsies are obtained, evolution of the mutation, 
neoantigen, and gene expression landscape in pre- and post-treatment samples will be analyzed  
to gain insights into immunoediting that may occur and infer what epitopes may be critical for 
efficacy.  RNAseq data will also be used to explore changes in the expression of nonmutated 
thyroid gene expression (e.g. TG, THSR, TPO, etc…) with therapy for the same purpose.  The 
same data can be analyzed to evaluate how immune cell tumoral infiltration and immunologic gene 
signatures may change with therapy. 
 
Frozen tissues from the research biopsy may be evaluated for relevant protein targets by Western 
blot or other proteomic assays that may be available at time of analysis. 
Fixed archival and/or research biopsy tissues may also be evaluated by immunohistochemistry to 
assess changes in tumor immune infiltrates and tumor/immune cell protein expression (e.g. PD-L1 
status). For patients in whom sufficient fresh tissue can be collected in the research biopsies, the 
tumor immune cell infiltrate (or tumor infiltrating lymphocytes (“TILs”) may be extracted and 
characterized by cytometric techniques, including flow cytometry or mass cytometry (CyTOF). 
Note regarding next generation sequencing analysis performed on this protocol: In the course of 
this research it is possible that some patients whose tumors are analyzed through investigational 
“next-generation” profiling in a research (non-CLIA) environment will be found to have somatic or 
germline mutations in genes that are known to be associated with an increased risk of cancer or 
other diseases. It will be stated in the consent that the participants will not receive any specific 
results from research tests. The consent will tell participants that if they wish to have genetic 
testing done for personal reasons than they should make an appointment with the MSK Clinical 
Genetics Service. 
If in the course of this research a research finding is obtained that, in the opinion of the 
investigator, may be critical to the preventive care of the participant or their family, the investigator 
can communicate that finding to the IRB Genomic Advisory Panel (GAP). The finding will be 
reviewed by the GAP to determine whether the incidental finding should be discussed with the 
participant. For MSK, in the event that the GAP determines that the finding should be discussed 
with the participant, and the participant has consented to be re-contacted, then the 

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treating/consenting physician shall be contacted by the panel and asked to refer the participant to 
the Clinical Genetics Service for further discussion of the research finding. 
The following information must be provided to GAP for review: 
 
• Participant Name/MRN # 
• Type of Biospecimen (tissue, blood, saliva) 
• Incidental Finding 
• Collection Protocol # 
• Contact: ocrgapirb@mskcc.org 
 
Peripheral Blood Analysis: 
 
Exploratory Objective #1: To investigate changes in peripheral blood populations that occur with 
durvalumab and rhTSH-prepared RAI. 
Rationale: We hypothesize that disruption of the PD-1/PD-L1 axis with durvalumab in combination 
with rhTSH-prepared RAI therapy will alter peripheral blood immune populations.  Additionally,  T 
cell receptor repertoire may be analyzed. 
Approach: (These studies will be conducted in collaboration with the MSK immune monitoring core 
facility.)  At the time points indicated in Section 10, peripheral blood samples will be collected: 4 
CPT tubes (BD, 8-ml capacity, total blood volume collected ~32 ml for PBMC purification for flow 
cytometric analysis) and 1 PAXgene tube (BD order #762165 or equivalent) (for purification of 
RNA/DNA for TCR analysis). Changes to these methods may be adapted depending upon the 
most recent, generally accepted protocols.  Flow cytometry will be used to evaluate changes in T 
cell subsets at different time points.   Alternative approaches to this analysis may be pursued 
depending upon the availability of new technologies, platforms, or approaches .  Specifically, 
assays investigating the immunogenicity of tumoral antigens in ex vivo assays utilizing these 
collected PBMCs may be of value and will be performed to identify potential neoantigens or self 
antigens that are critical for mediating therapeutic efficacy. 
Exploratory Objective #2: To investigate changes in cell free DNA (cfDNA) that occur with 
durvalumab and rhTSH-prepared RAI. 
Rationale: We hypothesize that rhTSH-prepared RAI therapy will enhance expression and release 
of thyroid-specific antigens/neoantigens  critical for augmenting immunotherapeutic responses to 
PD-L1 targeting with durvalumab.  Here, we propose using tumor cfDNA as a surrogate marker of 
tumor lysis and antigen release. 
Approach: (These studies will be conducted in collaboration with the MSK Departement of 
Laboratory Medicine, MSK cfDNA extraction facility, and Kravis Center for Molecular Oncology 
(CMO).)  At the time points indicated in Section 10, peripheral blood samples will be collected. 
Whole blood will be collected in 10-ml Cell-Free DNA BCT tubes (STRECK) and centrifuged in two 
steps to separate plasma from cells.  Cell-free plasma will then be aliquoted and frozen at minus 
80°C until ready to extract.  Extraction of cfDNA will be performed using a fully automated QIAGEN 
platform, QIAsymphony SP, and QIAsymphony DSP Virus/Pathogen Midi Kit (catalog #937055). 
This is a bead-based custom protocol, optimized to work with 3 ml of plasma as starting material. 
The extraction process includes lysis, binding, wash and elution steps. The final product is a 60 µl 

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elution of cfDNA with an average size ~170-200 bp.  Quality and quantity of cfDNA will be 
evaluated with automated electrophoresis using either TapeStation with High Sensitivity D1000 
ScreenTape and Reagents (Agilent Technologies) or Fragment Analyzer with High Sensitivity 
genomic DNA Analysis Kit (Advanced Analytical). 
The resulting cfDNA can then be further analyzed to detect and quantify amounts of tumor driver 
oncogenes (BRAF mutations, RAS mutations, etc…) or other gene mutations if appropriate.   These 
cfDNA results will be analyzed in an exploratory/descriptive manner. 
10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
Pre-Studyf 
Cycle 1 
Week 1t 
Cycle 1 
Week 3 
Cycle 2+ 
Week 1u 
Off Studyl 
Durvalumaba 
X 
X 
Adherenceto low iodine diet 
Xh 
Thyrogen 
Xi 
100 mCi (+/- 10 mCi) 131I (RAI) 
Xi 
Concurrent meds 
X 
X 
X 
X 
X 
Physical exam 
X 
Xg 
X 
X 
X 
Vital signs (pulse, blood pressure) 
X 
Xg 
X 
X 
X 
Weight 
X 
Xg 
X 
X 
X 
Perf ormance status 
X 
Xg 
X 
X 
X 
EKGs 
X 
X 
Hematology testsb 
X 
Xg 
Xj 
X 
X 
Clinical chemistry testsb 
X 
Xg 
Xj 
X 
X 
Urinalysisb 
X 
Xg 
X 
TSH, TG, and antibody serologies 
for TG, TPO, TSHRr 
X 
Xr 
X 
X 
Beta-HCG (serumor urine) 
Xc 
Xk 
Research peripheral blood 
collectiono 
X 
X 
Xp 
Xp 
DLT Monitoringd 
X ----------------------------------------------- X 
Adverse eventevaluation 
X -------------------------------------------------------------------------------- X 
(Monitored for 90 days follow ing the last dose of durvalumab.) 
Radiologic evaluation (CT(s) and/or 
MRI(s)) for tumor measurementse 
NO IODINATED CONTRAST IS 
ALLOWED PRIOR TO RAI 
 
ADMINISTRATION 
X 
CT and/or MRI w ill be performed every 8 w eeks (+/- 1 w eek) (or 
approximately every 2 cycles). After 6 months, scans will be 
performed every 12 w eeks (+/- 1 w eek)(or approximately every 3 
cycles). Objective responses should be confirmed w ith a second 
assessment performed at least 4 w eeks later. Iodinated contrast 
may be used after RAI has been administered. 
Research blood drawm 
X 
Research tumor biopsyn 
X 
Xn 
Archival tissue collectionq 
X 
a: 
1500 mg IV durvalumab w ill be administered during w eek 1 of every cycle. Dose adjustment is required for patients 
w eighing <30 kg as detailed in Appendix 2. Patients w ill remain on durvalumab treatment until there is confirmed 
progression of disease, unacceptable toxicity, withdrawal of consent, or if the study physician feels removal fromthe 
study is in the patient’s best interest. One exception to these discontinuation rules: given the potential for delayed 
responses following short periods of disease progression with immunotherapy, subjects may continue to receive 
therapy beyond radiographic progression if the investigator concludes that the subject is tolerating study drug and 
continued therapy may provide clinical benefit. If a dose of durvalumab is missed or held for unforeseen scheduling 
conflicts (e.g. extreme w eather related issues, etc…), medical issues unrelated to study drug toxicities, or patient’s 
personal conflicts (e.g. personal travel, holidays, etc…), durvalumab may be restarted at the investigator’s 
discretion. The w eek that durvalumab dose is restarted w ill be considered Week 1; subsequent 
treatments/evaluations may then be scheduled accordingly. 
b: 
For components of the hematology tests, see Table 1 below . For components of the clinical chemistry test, see 
Table 2 below . For components of the urinalysis, see Table 3 below . 
c: 
Serum or urine Beta-hcg (for women of childbearing potential): for pre-study evaluation, this should be obtained 
w ithin 7 days of starting the study. 
d: 
The DLT monitoring period w ill be 6 w eeks beginning fromthe f irst durvalumab dose. 
e: 
The treating physician may reschedule radiology scans due to treatment delays at his or her discretion. If the 
patient has CT and/or MRI scans completed early for any reason (i.e. suspicion of disease progression), the next 
set of scans may be ordered in 8 w eeks (+/- 1 w eek) fromthat assessment (or in 12 w eeks (+/- 1 w eek) for patients 
w ho are on treatment for more than 6 months). 
f: 
All Pre-Study evaluations must be done w ithin 4 w eeks prior to the start of durvalumab unless otherw ise specified. 

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g: 
These Week 1 evaluations may be performed up to 7 days prior to starting treatment. It is unnecessary to repeat 
these laboratory tests if the screening assessments of the same tests w ere performed within 7 days prior to the f irst 
dose of therapy. 
h: 
Patients should start a low iodine diet for 5 days prior to the f irst Thyrogen injection, and maintain the diet through 1 
day after RAI is given. 
i: 
0.9 mg Thyrogen w ill be administered intramuscularly in 2 consecutive calendar days. RAIis administered the 
calendar day after the second Thyrogen injection. Perf ormance of a post-RAI w hole body scan will be done as per 
standard of care per investigator discretion. The administration of these agents and evaluations w ill be performed in 
clinic. If modification of durvalumabdose schedule is required prior to RAI therapy, a delay in the schedule 
of Thyrogen and RAI administrationis allowedas long as it is given prior to the seconddurvalumab dose. 
j: 
These laboratory tests preferably will be performed prior to the f irst Thyrogen injection (not required). 
k: 
Serum or urine beta-hcg (for women of childbearing potential) is to be completed w ithin 2 days prior to 
administration of RAI. 
l: 
Off-study evaluation w ill be performed w ithin 30 days of the patient’s last dose of durvalumab. 
m:   The research blood sample can be obtained any time (for germline DNA). 
n: 
Radiologic guidance (CT, MRI or ultrasound guided) approaches and obtaining multiple cores to ensure sufficient 
biopsy material (at least 3 cores preferred) are allow ed as long as it is considered safe for the patient (image-guided 
biopsies w ill be performed by a radiology physician w ith the appropriate expertise). The f irst research biopsy will be 
performed any time prior to Week 1 Day 1; the second research biopsy will preferably be conducted during Cycle 2, 
Week 3 or 4 (though alternate timing during Cycle 2 or later is allow ed per investigator discretion or for safety 
reasons related to RAI administration). 
o: 
Peripheral blood samples w ill be collected for peripheral T cell analysis as w ell as cf DNA analysis. For peripheral T 
cells, blood w ill be collected in 4 CPT tubes (BD, 8-ml capacity, total blood volume collected~32 ml for PBMC 
purification for f low cytometric analysis) and 1 PAXgene tube (BD order #762165 or equivalent) (for purification of 
RNA/DNA for TCR analysis). For cf DNA analysis, blood w ill be collected in 10-ml Cell-Free DNA BCT tubes 
(STRECK).  These blood samples (peripheral T cells and cf DNA) w ill be collected Cycle 1/Week 1 (prior to 
durvalumab). In Cycle 1/Week 3 or 4, only the cf DNA sample w ill be draw n at various time points: on the day of f irst 
Thyrogen injection (but prior to Thyrogen injection) and on the day of RAI administration (but prior to RAI ingestion) . 
p: 
Research blood collection (for peripheral T cell analysis and cf DNA analysis) after Cycle 1 w ill be conducted on 
Week 1 of Cycles 2, 3, and 4 (preferably prior to durvalumab administration, if possible), as w ell as Off Study. Cycle 
2 cf DNA collection does not have to be performed if it the Principle Investigator decides that it is redundant given  
the cf DNA collections performed for footnote o. 
q: 
Confirm availability of archival tumor tissue (if tissue is not already available at MSK, physical receipt of tissue is not 
required for study enrollment or initiation). 
r: 
TSH, thyroglobulin (TG), and antibody serologies for TG, thyroperoxidase (TPO), and TSH receptor (TSHR) w ill be 
draw n Cycle 1/Week 1 (prior to durvalumab). In Cycle 1/Week 3, TSH and TG w ill be draw n at various time points: 
on the day of f irst Thyrogen injection (but prior to Thyrogen injection) and on the day of RAI administration (but prior 
to RAI ingestion). Subsequently, TSH and TG w ill be draw n on Week 1 of every cycle. Additionally, antibody 
serologies for TG, TPO, TSHR w ill be required to be draw n on Week 1 of every even numbered cycle, up to and 
including Cycle 6. 
s. 
EKG w ill be performed in triplicate. Repeat the EKG in Cycle 1 (Week 3)(only 1 EKG required at that time point). 
t. 
If Cycle 1 Week 1 labs fall below screening requirements, the patient can start treatment at the discretion of the 
treating investigator if safety is not compromised. 
u. 
Week 1 evaluations/tests and research collections during Cycles 2 and beyond may be performed up to 3 days prior 
to the patient being treated. 
 
 
NOTE: Timing/scheduling of the administration of Thyrogen, RAI, and subsequent durvalumab 
doses beyond the first one, as well as the requisite evaluations listed in the calendar, may be 
rescheduled at different days due to delays related to durvalumab toxicity, holiday schedules, 
patients’ personal commitments or conflicts. 

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Table 1. Hematology Laboratory Tests 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
Mean corpuscular hemoglobin 
Total white cell count 
Mean corpuscular hemoglobin  concentration 
 
 
 
Table 2. Clinical chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline  phosphatase 
Alanine  aminotransferase 
Lipase 
Amylase 
Magnesium 
Aspartate  aminotransferase 
Potassium 
Bicarbonate 
Sodium 
Calcium 
Total bilirubina 
Chloride 
Total protein 
Creatinine 
Urea or blood urea nitrogen, depending on local practice 
a   If Total bilirubin is ≥2xULN (and no evidence  of Gilbert’s syndrome) then fractionate into direct and indirect 
bilirubin. 
 
Table 3. Urinalysis Testsa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 
a   Microscopy should be used as appropriate  to investigate  white blood cells and use the high power field for 
red blood cells. 
 
 
 
 
 
 
 
11.1 TOXICITIES/SIDE EFFECTS 

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For adverse events (AEs) that are considered related to administration of durvalumab, the 
following may be applied: 
• Following the first dose of durvalumab, subsequent administration of durvalumab can be 
modified based on toxicities observed (see Appendix 1).  Dose reductions are not permitted. 
• Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required). 
• If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of durvalumab along with appropriate continuing supportive care 
according to guidelines outlined in Appendix 1. 
• If modification of durvalumab treatment is required prior to the administration of RAI, delay in 
giving Thyrogen and RAI therapy prior to the second dose of durvalumab is allowed if the 
patient remains on study. 
• In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued. 
• Cycle 2 and 3 doses of durvalumab will not be held for hematologic cytopenias (leukopenia, 
anemia, neutropenia, thrombocytopenia), which can occur following RAI therapy. 
• Re-starting of durvalumab administration after holding therapy for toxicity can be done at the 
investigator’s discretion as long as criteria in Appendix 1 are fulfilled.  The week that 
durvalumab is re-started will then considered to be Week 1.  Subsequent treatments and 
evaluations can then be scheduled accordingly. 
 
Based on the mechanism of action of durvalumab leading to T-cell activation and proliferation, 
there is the possibility of observing immune related Adverse Events (irAEs) during the conduct of 
this study.  Potential irAEs include immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies. Subjects should be monitored for signs and symptoms of irAEs.  In the absence 
of an alternate etiology (e.g., infection or PD) signs or symptoms of enterocolitis, dermatitis, 
hepatitis, and endocrinopathy should be considered to be immune-related. 
Dose modification recommendations and toxicity management guidelines for immune- 
mediated reactions, for infusion-related reactions, and for non-immune-mediated reactions 
related to durvalumab are detailed in Appendix 1.  In addition, management guidelines for 
adverse events of special interest (AESIs) are detailed in Appendix 1. All toxicities will be 
graded according to NCI CTCAE v4.0. 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Please refer to Section 10 regarding the timing of tumor measurement assessments. 
 
Documentation (radiologic) must be provided for patients removed from study for progressive 
disease (not necessary if removed based on criteria for clinical progression). 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 
1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (uni dimensional 

Memorial Sloan Kettering Cancer Center 
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measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
12.1 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area are not considered 
measurable unless there has been demonstrated progression in the lesion. 
Malignant  lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
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), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements.  It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 

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presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
12.2 
Methods for Evaluation of Measurable Disease 
 
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. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable. 
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines  to prescribe 
specific MRI pulse sequence parameters for all scanners, body parts, and diseases. 
Ideally, the same type of scanner should be used and the image acquisition protocol should 
be followed as closely as possible to prior scans. Body scans should be performed with 
breath-hold scanning techniques, if possible. 
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement.  Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure at 
CT, MRI may be used instead of CT in selected instances. 

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Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation 
is not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  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.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008]. In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression 
criteria which are to be integrated with objective tumor assessment for use in first-line trials 
in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable  
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm. (Note:  the appearance of one or more new 
lesions is also considered progressions). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. 

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12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non- 
pathological in size (<10 mm short axis). Note:  If tumor 
markers are initially above the upper normal limit, they 
must normalize for a patient to be considered in complete 
clinical response. 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or 
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. 
Unequivocal progression should not normally trump target 
lesion status.  It must be representative of overall disease 
status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
12.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best  Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non- 
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non- 
CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non- 
CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 

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Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
 See RECIST 1.1 manuscript for further details on what is evidence  of a new 
lesion. 
** 
Only for non-randomized  trials with response as primary  endpoint. 
***  In exceptional circumstances, unequivocal  progression in non-target  lesions 
may be accepted as disease progression. 
Note: 
Patients with a global  deterioration  of health  status requiring 
discontinuation of treatment without objective evidence  of disease 
progression at that time should be reported as “symptomatic 
deterioration.”   Every  effort  should be made to document the objective 
progression even  after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target  Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal  PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’  is preferred  over ‘stable disease’ for non-target  disease since 
SD is increasingly used as an endpoint  for assessment of efficacy in some trials so 
to assign this category when no lesions can be measured is not advised 
 
 
12.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 

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13.1 
CRITERIAFOR REMOVAL FROM STUDY 
 
• Disease progression. 
 
• Development of unacceptable toxicity. 
 
• Participants can be removed from the study at any time if the study doctor feels that it is in their 
best interest to do so. 
• Patients may withdraw consent from the study at any time. 
 
Treatment Beyond Progression 
 
Given the potential for delayed responses following short periods of disease progression with 
immunotherapy, subjects may continue to receive therapy beyond radiographic progression if the 
investigator concludes that the subject is tolerating study drug and continued therapy may provide 
clinical benefit. 
If treatment is continued beyond initial evidence of radiographic progression, study therapy should 
be discontinued if further evidence of progression is subsequently observed, defined as an 
additional 10% or greater increase in tumor burden (by RECIST v1.1 criteria) from time of initial 
progression (including all target lesions and new measureable lesions). 
14.0 
BIOSTATISTICS 
 
The primary objective of this pilot study will be to assess the safety of administering durvalumab in 
combination with Thyrogen-stimulated RAI therapy in patients with recurrent/metastatic thyroid 
cancer. The period of dose limiting toxicity (DLT) monitoring will be 6 weeks beginning from the 
first durvalumab dose.  Definitions for DLT are in Section 9.3.  Subjects who are removed from the 
study for reasons other than DLT prior to the administration of the first Thyrogen injection will be 
replaced with another subject.  Patients who do not complete the 6 week period of monitoring 
beginning from the first durvalumab dose for reasons other than DLT will also be replaced.  If >1 of 
the first 3 patients, or >2 of the first 6 patients, develop DLT related to durvalumab, further accrual 
to the study will be halted. If this rule is not met, we plan to accrue 11 patients in total to this pilot 
study (see table below).  All toxicities will be graded according to CTCAE v4.0. 
 
 
Number of 
DLTs to stop 
in first 3 
patients 
Number of 
DLTs to stop 
in first 6 
patients 
Number of 
DLTs to stop 
in all 11 
patients 
Acceptable 
toxicity rate 
(H0) 
Unacceptable 
toxicity rate 
(H1) 
Type I error 
rate 
Power 
>1 
>2 
>2 
0.10 
0.35 
0.101184466 0.80748277 
 
Secondary objectives will be determining the best overall response rate (BOR; CRs plus PRs per 
RECIST v1.1 criteria) and progression-free survival (estimated using Kaplan-Meier methodology with 
time origin at the start of the treatment; PFS). For PFS, patients will be followed until progression of 
disease or death, whichever come first. Patients who continue treatment beyond initial investigator- 
assessed, RECIST 1.1-defined progression, and are subsequently removed from study within the 

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next radiographic  assessment for  progression, will be considered to have  investigator-assessed 
progressive disease at the time of the initial progression event. 
Exploratory objectives: 
 
Mutation burden, neoantigen landscape, and immunoediting analysis: While the low DTC mutation 
burden implies a low likelihood of neoantigen formation, neoantigen analysis has never been 
conducted for DTC.  Whole-exome sequencing data will be analyzed using the neoepitope 
bioinformatics pipeline developed by Dr. Chan’s group. Mutation calling is performed by analyzing 
FASTQ files with four mutation callers and filtering by allelic frequency, call quality and other empiric 
measures. Mutations are validated with an orthogonal next-gen sequencing panel. Candidate 
neoantigens are identified based on peptide sequences and predicted binding to patient-specific 
MHC Class I alleles. RNAseq data will be used to define a set of expressed neoepitopes and 
explore gene expression signatures that may correlate with response.  Evolution of the mutation, 
neoantigen, and gene expression landscape in pre- and post-treatment samples will be analyzed to 
gain insights into immunoediting that may occur and infer what epitopes may be critical for efficacy. 
RNAseq data will also be used to explore changes in the expression of nonmutated thyroid gene 
expression (TG, THSR, TPO, etc…) with therapy for the same purpose. Biostatistical analysis: 
Categorical pre- and post-treatment measures will be summarized by 2-by-2 tables; continuous pre- 
and post-treatment measures will be summarized by mean and standard deviation of the change as 
well as graphical method. 
Immune cell infiltrate and immunologic gene signature analysis:  Tumor RNAseq data will be used to 
analyze changes in (a) immune cell infiltration and (b) immunologic gene signatures with therapy. 
First, we will estimate the relative infiltration levels of individual immune cell populations in tumor 
samples using two computational approaches. The first was developed by Yasin Senbabaoglu and 
Chris Sander at MSK which uses single set enrichment analysis (ssGSEA) to determine the 
abundance of T cell and other immune cell populations in the tumor microenvironment32. A related 
but alternative approach uses support vector regression to model cellular populations based on a 
reference expression matrix33. These techniques provide efficient and accurate alternatives to flow 
cytometry sorting. In addition, RNAseq data permits quantification of related immunologic gene 
expression signatures such as IFN  signaling, granzyme B, and antigen presenting machinery 
genes. 
Intratumor heterogeneity analysis: Recently we have developed a technique to characterize the 
intratumor genetic heterogeneity of tumors based on sequencing data32. Using copy number and 
mutational data, our computational pipeline infers subclonal populations in tumors.  Here, we 
propose to characterize the evolution of tumors under the selective pressure of rhTSH-stimulated 
RAI and durvalumab treatment, and examine subclonal expansions that are associated with an 
immune escape phenotype, by comparing the subclonal architecture of pre- and post-treatment 
samples. 
PBMCs: In addition to the research biopsies, peripheral blood samples will be collected serially for 
flow cytometry to evaluate changes in T cell subsets at different time points of therapy. 
Biostatistical analysis: Proportions of T cell subsets will be summarized at each time point and 
plotted to reveal any trend. 
cfDNA: Collected cfDNA will be analyzed to detect and quantify total cfDNA and the amounts of 
tumor driver oncogenes (BRAF mutations, RAS mutations, etc…) or other gene mutations present 

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as appropriate.  Biostatistical analysis: Changes in these parameters that occur with therapy will be 
analyzed by graphical method. 
Accrual to the trial is anticipated to be approximately 1 patient per month. 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain informed 
consent, by following procedures defined in section entitled Informed Consent Procedures. During 
the registration process registering individuals will be required to complete a protocol specific 
Eligibility Checklist. The individual signing the Eligibility Checklist is confirming whether or not the 
participant is eligible to enroll in the study. Study staff are responsible for ensuring that all 
institutional requirements necessary to enroll a participant to the study have been completed. See 
related Clinical Research Policy and Procedure #401 (Protocol Participant Registration). 
15.3 
Randomization 
 
Not applicable. 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinating the activities of the protocol 
study team. 
 
The data collected for this study will be entered into a secure database. Source documentation will 
be available to support the computerized patient record. 
 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action. 
 
 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new policies 
set forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data and 
Safety Monitoring of Clinical Trials” which can be found at:  
http://www.cancer.gov/clinicaltrials/conducting/dsm -guidelines /page1.  The DSM Plans at MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
 
https://one.mskcc.org/sites/pub/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20  
Monitoring%20Plans.pdf 

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There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical 
research QA) and departmental procedures for quality control, plus there are two institutional 
committees that are responsible for monitoring the activities of our clinical trials programs. The 
committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and 
the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the Center’s 
Research Council and Institutional  Review Board. 
 
 
During the protocol development and review process, each protocol is assessed for the level of risk 
and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and the monitoring 
procedures will be established at the time of protocol activation 
17.1 PROTECTION OF HUMAN SUBJECTS 
 
Inclusion of Children in Research 
 
This protocol/project does not include children because the number of children is limited and 
because the majority is already accessed by a nationwide pediatric cancer research network. This 
statement is based on exclusion 4b of the NIH Policy and Guidelines on the Inclusion of Children 
as Participants in Research Involving  Human Subjects. 
 
Risks, Benefits, Toxicities/side effects 
 
Potential risks to human subjects include drug related toxicity, placement of IV catheters, 
phlebotomy, and possible psychological discomfort from the stresses associated with obtaining 
imaging studies (e.g., CT scan, PET scan). All efforts will be made to avoid any complication by 
completely reviewing patients’ symptoms, providing appropriate management, and monitoring 
blood tests. 
 
If an adverse medical event occurs, the patient will first contact the primary oncologist or the 
Principal Investigator. At nights and on weekends, there is an oncology physician on call at all 
times. Patients may either call or come directly to the urgent care center at Memorial Hospital (or to 
their local emergency room) to be seen. Patients suffering serious adverse reactions must be 
carefully followed and all follow-up information also recorded. 
 
Alternatives/options 
 
Participation in this trial is voluntary. Depending on the specific details of the situation, patient 
options without being in a study might include: 
 
• Other palliative chemotherapy off study. 
• Participation in a different clinical trial 
• Best supportive care  
Financial Costs/Burdens 
The patient will be responsible for all costs related to treatment and complications of treatment. 
Costs to the patient (third party insurer) will include hospitalizations, routine blood tests and 
diagnostic studies, office visits, baseline EKG, Thyrogen, RAI (131I) and doctor’s fees. Patients will 

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not be charged the cost of analysis for the research correlates. The patient also will not be 
charged for the subsequent research analysis of these specimens.  Durvalumab is provided by 
AstraZeneca and therefore is not billable to research participants. 
17.2 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information pursuant to 
a completed and signed Research Authorization form. The use and disclosure of protected health 
information will be limited to the individuals described in the Research Authorization form. A 
Research Authorization form must be completed by the Principal Investigator and approved by the 
IRB and Privacy Board (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or 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 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant starts investigational treatment/intervention. 
SAE reporting is required for 30-days after the participant’s last investigational treatment or 
intervention. Any events that occur after the 30-day period and that are at least possibly related to 
protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention and is 
related to a screening test or a procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must eb submitted in PIMS. If an SAE requires submission to the HRPP office per IRB 
SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be sent to the IRB within 
5 calendar days of the event. All other SAEs must be submitted within 30 calendar days of the 
event. 
 
The report should contain the following information: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 

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• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
 
For IND/IDE protocols: 
The SAE report should be completed as per above instructions. If appropriate, the report will the 
forwarded to the FDA by the IND office. 
 
 
17.2.1 SAE reporting for Sponsor 
 
All SAEs will be reported, whether or not considered causally related to the investigational product, 
or to the study procedure(s). The reporting period for SAEs is the period immediately following the 
time that written informed consent is obtained through 90 days after the last dose of durvalumab or 
until the initiation of alternative anticancer therapy.  The investigator is responsible for informing the 
Ethics Committee and/or the Regulatory Authority of the SAE as per local requirements 
The sponsor must inform the FDA, via a MedWatch/AdEERs form, of any serious or unexpected 
adverse events that occur in accordance with the reporting obligations of 21 CFR 312.32, and will 
concurrently forward all such reports to AstraZeneca.  A copy of the MedWatch/AdEERs report 
must be faxed to AstraZeneca at the time the event is reported to the FDA.  It is the responsibility 
of the sponsor to compile all necessary information and ensure that the FDA receives a report 
according to the FDA reporting requirement timelines and to ensure that these reports are also 
submitted to AstraZeneca at the same time. 
* A cover page should accompany the MedWatch/AdEERs form indicating the following: 
 
• 
“Notification from an Investigator Sponsored Study” 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number (ESR-15-11685) 
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of events in 
relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s  
designated mailbox: 
AEMailboxClinicalTrialTCS@astrazeneca.com 

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If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA. 
Serious adverse events that do not require expedited reporting to the FDA still need to be reported 
to AstraZeneca preferably using the MedDRA coding language for serious adverse events.  This 
information should be reported on a monthly basis and under no circumstance less frequently than 
quarterly. 
17.2.2 Definition of adverse events of special interest (AESI) 
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational  Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product. 
 
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. These 
AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-related adverse event (irAE) is defined as an adverse event that 
is associated with drug exposure and is consistent with an immune-mediated mechanism of action 
and where there is no clear alternate aetiology. Serologic, immunologic, and histologic (biopsy) 
data, as appropriate, should be used to support an irAE diagnosis. Appropriate efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE. 
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician. 
 
AESIs observed with durvalumab include: 
• Pneumonitis 
• Hepatic events (ALT/AST increases / hepatitis / hepatotoxicity) 
• Colitis/diarrhea 
• Intestinal  perforation 
• Endocrinopathies (i.e. events of hyper- and hypothyroidism, adrenal insufficiency, hypophysitis, 
hypopituitarism, and Type 1 diabetes mellitus) 
• Nephritis 
• Rash/dermatitis 
• Myocarditis 
• Myositis/polymyositis 
• Pancreatic events (or labs suggestive of pancreatitis - increased serum lipase, increased serum 
amylase) 
• Rare or less frequenst AESIs and imAEs (i.e. pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, hemaetological, rheumatological events, vasculitis, non-infectious 
meningitis, and non-infectious encephalitis) 

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• Infusion related/hypersensitivity  reactions (includes cytokine release syndrome, and immune- 
complex disease) 
• Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis) 
• Renal events 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab Investigator Brochure. 
Pneumonitis 
Adverse events of pneumonitis are of interest for AstraZeneca/Medimmune, as pneumonitis has 
been reported with anti-PD-1 MAbs (Topalian et al, NEJM 2012). Initial work-up should include 
high-resolution CT scan, ruling out infection, and pulse oximetry. Pulmonary consultation is highly 
recommended. 
 
Guidelines for the management of subjects with immune-mediated events including pneumonitis 
are outlined in Appendix 1. 
 
Hypersensitivity Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-PD-L1 
and anti-PD-1 therapy. As with the administration of any foreign protein and/or other biologic 
agents, reactions following the infusion of MAbs can be caused by various mechanisms, including 
acute anaphylactic (immunoglobulin E-mediated) and anaphylactoid reactions against the MAb, 
and serum sickness. Acute allergic reactions may occur, may be severe, and may result in death. 
Acute allergic reactions may include hypotension, dyspnea, cyanosis, respiratory failure, urticaria, 
pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, 
headache, hypertension, myalgia, vomiting and unresponsiveness. 
 
Guidelines for management of subjects with hypersensitivity (including anaphylactic reaction) and 
infusion-related reactions are outlined in Appendix 1. 
 
Hepatic function abnormalities (hepatotoxicity) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies.  Inflammatory hepatitis has been reported in 3% to 9% of subjects treated with 
anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The clinical manifestations of ipilimumab- 
treated subjects included general weakness, fatigue, nausea and/or mild fever and increased liver 
function tests such as AST, ALT, alkaline phosphatase, and/or total bilirubin. 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN and 
concurrent increase in total bilirubin to be greater than 2 × ULN. Concurrent findings are those that 
derive from a single blood draw or from separate blood draws taken within 8 days of each other. 
Follow-up investigations and inquiries will be initiated promptly by the investigational site to 
determine whether the findings are reproducible and/or whether there is objective evidence that 
clearly supports causation by a disease (e.g., cholelithiasis and bile duct obstruction with distended 
gallbladder) or an agent other than the investigational product. Guidelines for management of 
subjects with hepatic function abnormality are outlined in Appendix I. 

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Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN may need to be 
reported as SAEs. These cases should be reported as SAEs if, after evaluation they meet the 
criteria for a Hy’s Law case or if any of the individual liver test parameters fulfill any of the SAE 
criteria. 
 
Gastrointestinal disorders 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when tremelimumab is 
used as monotherapy.  In rare cases, colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome if not properly managed.  Guidelines on management of 
diarrhea and colitis in patients receiving durvalumab are provided in Appendix 1. 
 
Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism.  Guidelines for the management of patients with immune-mediated endocrine 
events are provided in Appendix 1.  Hypothyroidism on this study will not be considered an AESI. 
 
Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation.   Guidelines for the management of patients with immune-mediated pancreatic disorders 
are provided in Appendix 1. 
 
Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis.  Guidelines for the management of patients 
with immune-mediated neurotoxic events are provided in Appendix 1. 
 
Nephritis 
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, proteinuria, etc) 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, infections etc.) 
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. 
Guidelines for 
the management of patients with immune-mediated neurotoxic events are provided in Appendix 1. 

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Criteria for Hy’s Law (FDA Guidance 2009) 
 
• The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or greater 
elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug or placebo 
• Among trial subjects showing such aminotransferase elevations, often with aminotransferases 
much greater than 3 x ULN, one or more also show elevation of serum total bilirubin to >2 x ULN, 
without initial findings of cholestasis (elevated serum alkaline phosphatase) 
No other reason can be found to explain the combination of increased aminotransferases and 
total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury. 
 
 
Other events requiring reporting 
Overdose 
An overdose is defined as a subject receiving a dose of durvalumab in excess of that specified in 
the Investigator’s Brochure, unless otherwise specified in this protocol. 
 
Any overdose of a study subject with durvalumab, with or without associated AEs/SAEs, is required 
to be reported within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune  Patient Safety or designee using the designated Safety e-mailbox (see 
Section 10.3.2 for contact information). If the overdose results in an AE, the AE must also be 
recorded as an AE (see Section 10.3). Overdose does not automatically make an AE serious, but if 
the consequences of the overdose are serious, for example death or hospitalization, the event is 
serious and must be recorded and reported as an SAE (see Section 17.2). There is currently no 
specific treatment in the event of an overdose of durvalumab. 
 
The investigator will use clinical judgment to treat any overdose. 
 
Hepatic function abnormality 
Hepatic function abnormality (as defined in Section 17.2.2) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” within 
24 hours of knowledge of the event to the sponsor and AstraZeneca/MedImmune Patient Safety 
using the designated Safety e-mailbox (see Section 10.3.2 for contact information), unless a 
definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that 
is unrelated to investigational product has been confirmed. 
 
• If the definitive underlying diagnosis for the abnormality has been established and is unrelated to 
investigational product, the decision to continue dosing of the study subject will be based on the 
clinical judgment of the investigator. 
 
• If no definitive underlying diagnosis for the abnormality is established, dosing of the study subject 
must be interrupted immediately. Follow-up investigations and inquiries must be initiated by the 
investigational site without delay. 

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Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune. 
 
Pregnancy 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may 
have interfered with the effectiveness of a contraceptive medication. Congenital abnormalities or 
birth defects and spontaneous miscarriages should be reported and handled as SAEs. Elective 
abortions without complications should not be handled as AEs. The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital 
abnormality) should be followed up and documented even if the patient was discontinued from the 
study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, ie, immediately, but no later 
than 24 hours of when he or she becomes aware of it. 
 
The designated AstraZeneca representative will work with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 to 5 calendar days 
for SAEs and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
 
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 90 days 
after the last dose of durvalumab monotherapy. 
Pregnancy of the patient’s  partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
should, if possible, be followed up and documented. 
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the patient’s partner. Therefore, the local study team should 
adopt the generic ICF template in line with local procedures and submit it to the relevant Ethics 
Committees (ECs)/Institutional Review Boards (IRBs) prior to use. 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from the 
study at any time. All participants must sign an IRB/PB-approved consent form indicating their 
consent to participate. This consent form meets the requirements of the Code of Federal 

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Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form will 
include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic 
studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.0 
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20.1 
APPENDICES 
 
Appendix 1: Dosing Modification and Toxicity Management Guidelines  for Immune-mediated, 
Infusion-Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
Appendix 2: Durvalumab Dose Calculations 

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APPENDIX 1: Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion-Related, and Non Immune-mediated  Reactions related to Durvalumab Monotherapy 
 
 
Appendix 1 
 Dosing  Modification  and Toxicity  Management  Guidelines  for 
Immune-mediated,  Infusion-Related,  and Non Immune-mediated 
Reactions  for Durvalumab  Monotherapy 1 November  2017 
Version 
General Considerations 
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 NCI CTCAE 
v4.03. 
In addition to the criteria for permanent discontinuation of study 
drug/study regimen based on CTC grade/severity (table 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: 
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 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. 
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., myo-carditis, 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, 

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Appendix 1 
 Dosing  Modification  and Toxicity  Management  Guidelines  for 
Immune-mediated,  Infusion-Related,  and Non Immune-mediated 
Reactions  for Durvalumab  Monotherapy 1 November  2017 
Version 
 
 
General Considerations 
 
Dose Modifications 
Toxicity Management 
Note: For Grade ≥3 asymptomatic amylase or lipase levels, 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). 
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. 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated 
adverse event; IV intravenous; NCI National Cancer Institute; PO By mouth. 
 
 
Pediatric Considerations 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity is the same for pediatric 
patients as it is for adult patients, as well as to permanently 
discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤ a dose equivalent to that required for 
corticosteroid replacement therapy within 12 weeks after last 
dose of study drug/study regimen 
− 
All recommendations for specialist consultation should occur 
with a pediatric specialist in the specialty recommended. 
− The recommendations for dosing of steroids (i.e., mg/kg/day) 
and for IV IG and plasmapheresis that are provided for adult 
patients should also be used for pediatric patients. 
− 
The infliximab 5 mg/kg IV dose recommended for adults is 
the same as recommended for pediatric patients ≥ 6 years old. 
For dosing in children younger than 6 years old, consult with 
a pediatric specialist. 
− 
For pediatric dosing of mycophenolate mofetil, consult with a 
pediatric specialist. 
− 
With long-term steroid and other immunosuppressive use, 
consider need for PJP prophylaxis, gastrointestinal protection, 
and glucose monitoring. 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
For Any Grade: 
− 
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 
(asymptomatic, 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated) 
No dose modifications 
required. However, consider 
holding study drug/study 
regimen dose as clinically 
appropriate and during 
diagnostic work-up for other 
etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 4 
days for clinical symptoms, pulse oximetry 
(resting and exertion), and laboratory work- 
up and then as clinically indicated. 
− 
Consider Pulmonary and Infectious disease 
consult. 
Grade 2 
(symptomatic; 
medical 
intervention 
indicated; limiting 
instrumental ADL) 
Hold study drug/study regimen 
dose until Grade 2 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. 
For Grade 2 (mild to moderate new symptoms): 
− 
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. 

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− 
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. 
For Grade 3 or 4 (severe or new symptoms, 
new/worsening hypoxia, life-threatening): 
− 
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. 
− 
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 
Diarrhea/Colitis 
Any Grade 
General Guidance 
For Any Grade: 
− 
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  
No dose modifications. 
For Grade 1: 
− 
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. 

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diagnostic observations only) 
Grade 2 
(Diarrhea: stool 
frequency of 4 to 6 
over baseline per 
day) (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. 
−
−
−
−
Grade 3 or 4 
(Grade 3 diarrhea: 
stool frequency of 
≥7 over baseline 
per day; 
Grade 4 diarrhea: 
life threatening 
consequences) 
(Grade 3 colitis: 
severe abdominal 
pain, change in 
bowel habits, medi- 
cal intervention 
indi-cated, 
peritoneal signs; 
Grade 4 colitis: 
life-threatening 
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. 
−
−
−

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consequences, 
urgent intervention 
indicated) 
infections [Category 2B 
recommendation]).a 
 
 
Hepatitis 
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any Grade 
General Guidance 
For Any Grade: 
− 
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 or ALT 
>ULN and 
≤3.0×ULN and/or 
TB > ULN and 
≤1.5×ULN) 
 
Grade 2 
(AST or 
ALT >3.0×ULN 
and ≤5.0×ULN 
and/or 
TB >1.5×ULN and 
≤3.0×ULN) 
• 
No dose modifications. 
• 
If it worsens, then treat as 
Grade 2 event. 
 
 
 
 
 
• 
Hold study drug/study 
regimen dose until Grade 2 
resolution to Grade ≤1. 
• 
If toxicity worsens, then 
treat as Grade 3 or Grade 
4. 
• 
If toxicity improves to 
Grade ≤1 or baseline, 
resume study drug/study 
regimen after completion 
of steroid taper. 
For Grade 1: 
− 
Continue LFT monitoring per protocol. 
 
 
 
 
 
 
For Grade 2: 
− 
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 Grade ≤1 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 Discuss with study physician if 
mycophenolate mofetil is not available. 
Infliximabshould 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 
 
 
Grade 3 or 4 
(Grade 3: AST or 
ALT >5.0×ULN 
and ≤20.0×ULN 
and/or 
TB >3.0×ULN and 
≤10.0×ULN) 
For Grade 3: 
For elevations in transaminases 
≤8 × ULN, or elevations in 
bilirubin ≤5 × ULN: 
• Hold study drug/study 
regimen dose until 
resolution to Grade ≤1 or 
baseline 
For Grade 3 or 4: 
− 
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 
immunosuppressive therapy (i.e., 
 
 
PLEASE SEE 
shaded area 
immediately 
below this 
section to find 
guidance for 
management of 
“Hepatitis 
(elevated LFTS)” 
in HCC patients 

Memorial Sloan Kettering Cancer Center 
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(Grade 4: AST or 
ALT >20×ULN 
and/or 
TB >10×ULN) 
• Resume study drug/study 
regimen if elevations 
downgrade to Grade ≤1 or 
baseline within 14 days 
and after completion of 
steroid taper. 
• Permanently discontinue 
study drug/study regimen 
if the elevations do not 
downgrade to Grade ≤1 or 
baseline within 14 days 
For elevations in transaminases 
>8 × ULN or elevations in 
bilirubin >5 × ULN, 
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 P04) and 
in the absence of any 
alternative cause.b 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
mycophenolate mofetil). Discuss with study 
physician if mycophenolate is not available. 
Infliximabshould 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 
Hepatitis 
(elevated LFTs) 
Infliximab  should not be 
used for management of 
immune-related hepatitis. 
THIS shaded area 
is guidance only 
for management 
of “Hepatitis 
(elevated LFTs)” 
in HCC patients 
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver function test: 
AST, ALT, ALP, and TB. 
− 
Evaluate for alternative etiologies (e.g., 
viral hepatitis, disease progression, 
concomitant medications, worsening of 
liver cirrhosis [e.g., portal vein 
thrombosis]). 
− 
For HBV+ patients: evaluate quantitative 
HBV viral load, quantitative HBsAg, or 
HBeAg 
− 
For HCV+ patients: evaluate quantitative 
HCV viral load 
− 
Consider consulting hepatologist/Infectious 
disease specialist regarding 
change/implementation in/of antiviral 
medications for any patient with an elevated 
HBV viral load >2000 IU/ml 
− 
Consider consulting hepatologist/Infectious 
disease specialist regarding 
change/implementation in/of antiviral HCV 
medications if HCV viral load increased by 
≥2-fold 

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of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation 
− 
For HCV+ with HBcAB+: Evaluate for 
both HBV and HCV as above 
• 
No dose modifications. 
Grade 1 
• 
If ALT/AST elevations 
(Isolated AST or 
represents significant 
ALT >ULN and 
worsening based on 
≤5.0×ULN, 
investigator assessment, 
whether normal or 
then treat as Grade 2 event. 
elevated at 
For all grades, see instructions 
baseline) 
 at bottom of shaded area if 
transaminase rise is not 
isolated but (at any time) 
occurs in setting of either 
increasing bilirubin or signs 
of DILI/liver decompensation 
Grade 2 
• 
Hold study drug/study 
For Grade 2: 
(Isolated AST or 
regimen dose until Grade 2 
− 
Regular and frequent checking of LFTs 
ALT >5.0×ULN 
resolution to Grade ≤1 or 
 
(e.g., every 1 to 3 days) until elevations of 
these are improving or resolved. 
and ≤8.0×ULN, if 
baseline. 
− 
Recommend consult hepatologist; consider 
normal at baseline)    • 
If toxicity worsens, then 
 
abdominal ultrasound, including Doppler 
treat as Grade 3 or Grade 
assessment of liver perfusion. 
4. 
− 
Consider, as necessary, discussing with 
(Isolated AST or 
If toxicity improves to Grade 
 
study physician. 
ALT >2.0×baseline 
≤1 or baseline, resume study 
− 
If event is persistent (>3 to 5 days) or 
and ≤12.5×ULN, if 
drug/study regimen after 
worsens, and investigator suspects toxicity 
to be immune-mediated AE, recommend to 
elevated >ULN at 
completion of steroid taper. 
start prednisone 1 to 2 mg/kg/day PO or IV 
baseline) 
 
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 
workup and 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, consider additional 
abdominal workup (including liver biopsy) 
and imaging (i.e., liver ultrasound), and 
consider starting immunosuppressives (i.e., 
mycophenolate mofetil).a  Discuss with 
study physician if mycophenolate mofetil is 
not available.  Infliximabshould NOT be 
used. 
Grade 3 
•    Hold study drug/study 
For Grade 3: 
regimen dose until 
(Isolated AST or 
resolution to Grade ≤1 or 
− 
Regular and frequent checking of LFTs 
ALT >8.0×ULN 
baseline 
 
(e.g., every 1-2 days) until elevations of 
these are improving or resolved. 
and ≤20.0×ULN, if 
•    Resume study drug/study 
− 
Consult hepatologist (unless investigator is 
regimen if elevations 
normal at baseline) 
downgrade to Grade ≤1 or 
hepatologist); obtain abdominal ultrasound, 
baseline within 14 days 
including Doppler assessment of liver 
f
i
d
id
li
bi

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(Isolated AST or 
ALT >12.5×ULN 
and ≤20.0×ULN, if 
elevated >ULN at 
baseline) 
and after completion of 
steroid taper. 
• Permanently discontinue 
study drug/study regimen 
if the elevations do not 
downgrade to Grade ≤1 or 
baseline within 14 days 
Permanently discontinue study 
drug/study regimen for any 
case meeting Hy’s law criteria, 
in the absence of any 
alternative cause.b 
− 
Consider, as necessary, discussing with 
study physician. 
− 
If investigator suspects toxicity to be 
immune-mediated, promptly initiate 
empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days 
despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, 
obtain liver biopsy (if it has not been done 
already) and promptly start treatment with 
immunosuppressive therapy 
(mycophenolate mofetil). Discuss with 
study physician if mycophenolate is not 
available. Infliximabshould NOT be 
used. 
− 
Once the patient is improving, gradually 
taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN 
guidelines for treatment of cancer-related 
infections [Category 2B 
recommendation]).a 
Grade 4 
(Isolated AST or 
ALT >20×ULN, 
whether normal or 
elevated at 
baseline) 
Permanently discontinue study 
drug/study regimen. 
For Grade 4: 
Same as above 
(except would recommend obtaining liver biopsy 
early) 
If transaminase rise is not isolatedbut (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal 
at baseline; or 2×baseline, if >ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR): 
- 
Manage dosing for Grade 1 transaminase rise as instructedfor Grade 2 transaminase rise 
- 
Manage dosing for Grade 2 transaminase rise as instructedfor Grade 3 transaminase rise 
- 
Grade 3-4: Permanently discontinue study drug/study regimen 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
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. 

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Grade 1 
(Serum creatinine 
> 1 to 1.5 × 
baseline; > ULN to 
1.5 × ULN) 
No dose modifications. 
For Grade 1: 
− 
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. 
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. 
• 
If toxicity improves to 
Grade ≤1 or baseline, then 
resume study drug/study 
regimen after completion 
of steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including 
hydration, electrolyte replacement, and 
diuretics. 
− 
Carefully monitor serum creatinine every 2 
to 3 days and as clinically warranted. 
− 
Consult nephrologist and consider renal 
biopsy if clinically indicated. 
− 
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. 
For Grade 3 or 4: 
− 
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 
p rop hy lact ic ant ibiot ics, ant ifungals, and  

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anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related 
infections [Category 2B 
recommendation]).a 
Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI 
CTCAE v 4.03 for 
definition of 
severity/grade 
depending on type 
of skin rash) 
General Guidance 
For Any Grade: 
− 
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. 
For Grade 1: 
− 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. 
• 
If toxicity improves to 
Grade ≤1 or baseline, 
then resume 
drug/studyregimen 
after completion of 
steroid taper. 
For Grade 2: 
− 
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 no improvement of rash/skin lesions 
occurs within 3 to 5 days or is worsening 
despite symptomatic treatment and/or use of 
moderate strength topical steroid,    
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. 
− 
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. 
If temporarily holding the 
study drug/study regimen does 
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: 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
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 

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Permanently discontinue study 
drug/study regimen. 
− 
Consider, as necessary, discussing with 
study physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
hypothyroidism, Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
Any Grade 
(depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE v4.03 for 
defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
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. 
Grade 1 
No dose modifications. 
For Grade 1 (including those with asymptomatic 
TSH elevation): 
− 
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 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. 

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Grade 2 
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 prolonged or 
continued steroid replacement 
(e.g., adrenal 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. 
For Grade 2 (including those with symptomatic 
endocrinopathy): 
− 
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). 
− 
Isolated hypothyroidism may be treated 
with replacement therapy, without study 
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. 
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 prolonged or 
continued steroid replacement 
(e.g., adrenal insufficiency) can 
be retreated with study 
For Grade 3 or 4: 
− 
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). 
− 
For adrenal crisis, severe dehydration, 
hypotension, or shock, immediately initiate 
IV corticosteroids with mineralocorticoid 
activity. 
− 
Isolated hypothyroidism may be treated 
with replacement therapy, without study 
drug/study regimen interruption, and 
without corticosteroids. 

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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. 
− 
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 guidelines  for treatment of 
cancer-related infections [Category 2B 
recommendation]).a 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain- 
Barre) 
Any Grade 
(depending on the 
type of 
neurotoxicity, refer 
to NCI CTCAE 
v4.03 for defining 
the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
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. 
For Grade 1: 
− 
See “Any Grade” recommendations above. 
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 holding study 
drug/study regimen dose until 
resolution to Grade ≤1. 
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. 
For Grade 2: 
− 
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). 
− 
Promptly start systemic steroids prednisone 
1 to 2 mg/kg/day  PO or IV equivalent. 
− 
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). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen 
dose until resolution to Grade 
≤1. 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing with 
study physician. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 

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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. 
− 
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. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
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 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. 
For Grade 1: 
− 
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. 

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− 
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. 
For Grade 2: 
− 
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: 
o 
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. 
o 
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. 
o 
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: 
o 
It is important to consider here 
that the use of steroids as the 
primary treatment of Guillain- 
Barre is not typically considered 
effective. 
o 
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 
For Grade 3 or 4 (severe or life-threatening 
events): 
− 
Consider, as necessary, discussing with 
study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain neurological 
consult. 
MYASTHENIA GRAVIS: 
o Steroids may be successfully used 
to treat myasthenia gravis. They 

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insufficiency or autonomic 
instability. 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
should typically be administered 
in a monitored setting under 
supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate 
steroids may be candidates for 
treatment with plasmapheresis or 
IV IG. 
o 
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: 
o 
It is important to consider here 
that the use of steroids as the 
primary treatment of Guillain- 
Barre is not typically considered 
effective. 
o 
Patients requiring treatment 
should be started with IV IG and 
followed by plasmapheresis if not 
responsive to IV IG. 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently 
if biopsy-proven immune- 
mediated myocarditis. 
For Any Grade: 
− 
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 
No dose modifications required 
unless clinical susp icion is  
For Grade 1 (no definitive findings): 

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(asymptomatic 
with laboratory 
(e.g., BNP) or 
cardiac imaging 
abnormalities) 
high, in which case hold study 
drug/study regimen dose 
during diagnostic work-up for 
other etiologies. If study 
drug/study regimen is held, 
resume after complete 
resolution to Grade 0. 
- 
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. 
Grade 2, 3 or 4 
(Grade 2: 
Symptoms with 
mild to moderate 
activity or 
exertion) 
(Grade 3: Severe 
with symptoms at 
rest or with 
minimal activity or 
exertion; 
intervention 
indicated) 
(Grade 4: Life- 
threatening 
consequences; 
urgent 
intervention 
indicated (e.g., 
continuous IV 
therapy or 
mechanical 
hemodynamic 
support)) 
-  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. 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IVmethylprednisolone 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 
Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
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. 

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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. 
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. 
For Grade 1: 
− 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]) 
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 2: 
− 
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 wit h receiving inp ut 
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 

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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 
Grade 3 or 4 
(pain associated 
with severe 
weakness; 
limiting self-care 
ADLs) 
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. 
For Grade 3 or 4 (severe or life-threatening 
events): 
− 
Monitor symptoms closely; recommend 
hospitalization. 
− 
Obtain Neurology consult, and complete 
full evaluation. 
− 
Consider, as necessary, discussing with the 
study physician. 
− 
Promptly start IVmethylprednisolone 2 to 
4 mg/kg/day systemic steroids along wit h 
receiving inp ut 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. 
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-stimulatinghormone; ULN Upper limit of normal. 

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Infusion-Related Reactions 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
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. 

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Non–Immune-Mediated Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
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 clinicallysignificant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/studyregimen until resolution 
to ≤Grade 1 or baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/studyregimen 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 studydrug/studyregimen 
administration. Otherwise, discontinue study 
drug/studyregimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
Discontinue studydrug/studyregimen (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. 
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. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-218 A(8) 
Approval date: 15-Jan-2021 
Page 72 of 72 
 
 
 
 
Appendix 2: Durvalumab Dose Calculations 
 
Durvalumab Dosing 
 
The durvalumab dosing should be done depending on subject weight (if subject is < 30kg)): 
 
1. Cohort dose: X mg/kg 
 
2. Subject weight: Y kg 
 
3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 
 
4. Dose to be added into infusion bag: 
Dose (mL) = XY mg / 50 (mg/mL) 
where 50 mg/mL is durvalumab nominal concentration 
 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL). Dose 
adjustments for each cycle only needed for greater than 10% change in weight. 
 
5. The theoretical number of vials required for dose preparation is the next greatest whole number of vials 
from the following formula: 
Number of vials = Dose (mL) / 10 (mL/vial) 
 
 
Example: 
 
1. Cohort dose: 10 mg/kg 
 
2. Subject weight: 30 kg 
 
3. Dose for subject: 300 mg = 10 (mg/kg) × 30 (kg) 
 
4. Dose to be added into infusion bag: 
 
Dose (mL) = 300 mg / 50 (mg/mL) = 6.0 mL 
 
5. The theoretical number of vials required for dose preparation: 
Number of vials = 6.0 (mL) / 10.0 (mL/vial) = 1 vials