Durvalumab (MEDI4736), Tremelimumab and Palliative Hypofractionated Image Guided Radiation Therapy (HIGRT) in Patients With Recurrent/Metastatic Squamous Cell Carcinomas of the Head and Neck Previously Treated With Immune Checkpoint Inhibitors
Phase: PHASE1
Conditions: Metastatic Head and Neck Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma
Sponsor: University of Washington

9881 
 
Investigational Drug  
Substance(s) 
Durvalumab (MEDI4736) 
and tremelimumab 
Palliative hypofractionated 
radiation therapy 
Study Number 
ESR-16-1185 
Version Number 
1.7 
Date 
February 21, 2020 
Durvalumab (MEDI4736), Tremelimumab and Palliative Hypofractionated 
Image 
Guided 
Radiation 
Therapy 
(HIGRT) 
in 
patients 
with 
recurrent/metastatic squamous cell carcinomas of the head and neck previously 
treated with immune checkpoint inhibitors 
Sponsor:  University of Washington 
 
 
 
 
 
Date Received 3/6/20
FHCRC IRB Approval  
03 10 2020 
Document Released Date

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
2 
 
 
Principal Investigators 
Cristina P. Rodriguez, MD (Medical Oncology) 
Associate Professor 
University of Washington 
Ph: 206 288 2048 
Fax: 206 288 7543 
Email: rodrigcr@uw.edu 
 
Upendra Parvathaneni, MD (Radiation Oncology) 
Associate Professor 
University of Washington 
       Email: Upendra@uw.edu 
 
Subinvestigators: 
Renato Martins, MD 
Keith Eaton, MD, PhD 
Laura Chow, MD 
Christina Baik, MD 
Bernardo Goulart, MD 
Rafael Santana-Davila, MD 
Sylvia Lee, MD 
 
Statistician: 
Qian (Vicky) Wu, PhD. 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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PROTOCOL SYNOPSIS 
Clinical Protocol ESR 16 11857 
Study Title:  Durvalumab (MEDI4736), Tremelimumab and Palliative Hypofractionated Image 
guided Radiation Therapy (HIGRT) in patients with recurrent/metastatic squamous cell 
carcinomas of the head and neck previously treated with immune checkpoint inhibitors 
 
Protocol Number:  9881 (ESR 16 11857) 
 
Clinical Phase: I/II 
 
Study Duration: 48 months 
 
Investigational Product(s) and Reference Therapy: 
Durvalumab will be supplied in glass vials containing 500 mg of liquid solution at a 
concentration of 50 mg/mL for intravenous (IV) administration after dilution. 
 
Tremelimumab will be supplied in glass vials containing 400 mg or 25mg of liquid solution at 
a concentration of 20 mg/mL for intravenous (IV) administration after dilution.  
Research Hypothesis: 
Durvalumab, tremelimumab and hypofractionated palliative radiation therapy in combination is 
safe and well tolerated in patients with recurrent metastatic squamous cell carcinomas of the 
head and neck. 
Objectives: 
Primary Objective: 
Demonstrate that durvalumab, tremelimumab and hypofractionated palliative radiation therapy 
is safe and well tolerated in patients with recurrent metastatic squamous cell carcinomas of the 
head and neck. 
 
Secondary Objective(s): 
1. Evaluate the objective response rate 
2. Determine overall and progression free survival 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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Exploratory Objective(s): 
Collect tumor and blood for correlative studies 
 
Study Design: 
This is a single arm, open label, prospective study evaluating the safety and clinical efficacy of 
the combination of durvalumab, tremelimumab and hypofractionated palliative radiation 
therapy (using either hypofractionated image guided radiotherapy (HIGRT) or Stereotactic 
ablative Body Radiation Therapy (SBRT)) in patients who have previously received 
immunotherapy agents. 
All patients enrolled will receive: 
1. Durvalumab 1500 mg IV Q4W x 13 doses  
2. Tremelimumab 75mg IV Q4W x 4 doses  
3. Hypofractionated palliative radiation therapy using either (HIGRT) or (SBRT) to a 
total dose of 24Gy given in 3 fractions every other day over 1 week to lung, bone, lymph 
node, soft tissue metastases or mediastinal lesions. Radiotherapy is to be initiated 2 weeks 
after the first dose of durvalumab and tremelimumab.  
Number of Centers: 1 
Number of Subjects: 
A maximum of 20 subjects will be enrolled. 
 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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Study Population: 
The study aims to enroll patients with recurrent metastatic squamous cell carcinomas of the head and 
neck, who have received a prior immune checkpoint inhibitor, and who have a target lesion (either 
local/regional or distant metastatic site involving the lung and/or mediastinum and/or bone and/or soft 
tissue lesions and/or lymph nodes , that requires local control for palliation, as determined by a 
multidisciplinary team. 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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Inclusion Criteria: 
1. 
Histologically proven recurrent/metastatic squamous cell carcinoma arising from a 
previous head and neck primary site, and located within the head and neck region, lung 
mediastinum bone, , soft tissue, lymph nodes, and who are not candidates for curative 
intent therapy. 
 
2. 
Be ≥18 years old at the time of signing informed consent and have an actual body 
weight > 40kg. 
 
3. 
Demonstrated disease progression during, or after discontinuation, of the most recent 
line of systemic therapy. 
 
4. 
Have received any number lines of prior systemic therapy (including systemic therapy 
in the curative intent setting, and including a platinum containing regimen). 
 
5.        Have received an anti-PD1 or anti PDL1 monoclonal antibody. 
 
6.         Have a target lesion/s deemed suitable by the treating physicians for hypofractionated 
radiation therapy (HIGRT or SBRT) with the intent of palliation or prevention of 
symptoms. This lesion must be: a) 1-3 non overlapping sites in the head and neck 
region OR b) metastatic lesions outside the H&N region in the lung mediastinum, soft 
tissue metastases, lymph nodes or bone (a minimum of 1 and a maximum 5 lesions 
will be irradiated), provided there is no significant overlap between the lesions.  
Patients should have RECIST 1.1 criteria measurable disease in addition to the lesion/s 
treated with radiation. If the site/s of radiation were previously radiated to high dose 
RT (>50Gy), there should be >6 month time interval between the last dose of radiation 
and the start of radiation.  
 
7. 
Have the ability to tolerate required radiotherapy procedures(eg: lie flat and hold 
position for treatment) as determined by the treating physician 
 
8. 
Be willing and able to provide written informed consent for the trial and comply with 
the study visit requirements 
 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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9. 
Have measurable disease based on RECIST 1.1. (in addition to the lesion/s that will be 
treated with hypofractionated radiation therapy)   
 
10. 
 Have provided tissue from an archival tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion. 
 
11. 
Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
12. 
Demonstrate adequate organ function as defined in below, based on screening labs 
should be performed within 10 days of treatment initiation.  
− 
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 > 60 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) 
= 
Weight (kg) x (140 – Age)       . 
72 x serum creatinine (mg/dL) 
 
 
 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)        x 0.85 
72 x serum creatinine (mg/dL) 
 
 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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13. 
Evidence of post-menopausal status OR negative urinary or serum pregnancy test for 
female pre-menopausal patients. Women will be considered post-menopausal if they 
have been amenorrheic for 12 months without an alternative medical cause. The 
following age-specific requirements apply:  
− 
Women <50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone and follicle-
stimulating hormone levels in the post-menopausal range for the institution or 
underwent surgical sterilization (bilateral oophorectomy, or hysterectomy).  
− 
Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 
year ago, had chemotherapy-induced menopause with last menses >1 year ago, 
or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy). 
 
14. 
Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
15. 
Female subjects of childbearing potential should be willing to use 1 method of highly 
effective birth control or be surgically sterile, or abstain from heterosexual activity for 
the course of the study through 180 days after the last dose of study medication 
(Reference Section 7.1).  Subjects of childbearing potential are those who have not 
been surgically sterilized or have not been free from menses for > 1 year.  
16. 
Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 180 days after the last dose of study therapy. 
17. 
Patient is ≥ 5 years free of another primary malignancy, except: a) if the other 
malignancy is basal cell carcinoma or cervical carcinoma in situ or b) if the other 
primary malignancy is not considered clinically significant and is requiring no active 
intervention 
 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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Exclusion Criteria: 
The subject must be excluded from participating in the trial if the subject: 
 
1. 
Has a body weight ≤40kg at the time of enrollment 
 
2. 
Is currently participating in or has participated in a study of an investigational agent or 
using an investigational device within 4 weeks of the first dose of treatment. 
 
3. 
Has a target lesion/s for radiotherapy that is > 5 cm (> 50 cc) in greatest dimension 
 
4. 
Has a target lesion/s in a region that previously received high dose RT (>50 Gy) 
demonstrating any of the following:  
a. carotid artery encasement (> 180 degrees)  
b. unprotected carotid artery (i.e. skin is directly over the carotid without 
intervening soft tissue, especially after prior neck dissection without a 
vascularized free flap) (a&b due to risk of carotid blow out) 
c. skin infiltration by tumor (due to risk of fistula) 
d. located in the larynx/hypopharynx primaries (due airway threat) 
e. treated with high dose radiation therapy (>50 Gy) within 6 months or less of 
trial enrollment 
 
5. 
Any prior Grade ≥3 immune-related adverse event (irAE) while receiving a prior 
immunotherapy agent, or any unresolved irAE >Grade 1 
 
6. 
Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab or tremelimumab. The following are exceptions to this criterion: 
-     Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular 
injection) 
- 
Systemic corticosteroids at physiologic doses not to exceed  10 mg/day of 
prednisone or its equivalent 
- 
Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication 
7.         Has received a prior monoclonal antibody within 4 weeks prior to study Day 1 or who 
has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier.  

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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8.         Has received prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
            -Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
            -Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
 
9. 
Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy.  
 
10.         Has known brain metastases or spinal cord compression unless the patient is stable 
(asymptomatic; no evidence of new or emerging brain metastases; and stable and off 
steroids  for at least 14 days prior to start of study treatment). Following radiotherapy 
and/or surgery of the brain metastases patients must wait 4 weeks following the 
intervention and before initiating study treatment with imaging to confirm stability.   
 
11. 
Has an active autoimmune disease requiring systemic treatment within the past 2 years 
or a documented history of clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents.  Subjects with vitiligo or 
resolved childhood asthma/atopy would be an exception to this rule.  Subjects that 
require intermittent use of bronchodilators or local steroid injections would not be 
excluded from the study.  Subjects with hypothyroidism stable on hormone 
replacement will not be excluded from the study. 
 
12. 
Has evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history 
of ILD or pneumonitis requiring oral or intravenous glucocorticoids. 
 
13.       Has an active infection requiring systemic therapy. 
 
14.       Requires therapeutic anticoagulation or has known active bleeding diathesis 
 
15.       Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator. 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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16.      Has known psychiatric or substance abuse disorders that would interfere with cooperation  
with the requirements of the trial. 
 
17.       Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
180 days after the last dose of trial treatment. 
 
18.       Has received prior therapy with an anti-Cytotoxic T-lymphocyte-associated antigen-4 
(CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways).  
 
19.       Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
20.       Has evidence of acute or chronic hepatitis B, or hepatitis C 
 
21. 
Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
 
22. 
Has a Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using     Fredericia’s Correction  
 
23. 
Has a history of primary immunodeficiency or an  allogeneic organ transplant  
 
24. 
Has a history of hypersensitivity to durvalumab  or tremelimumab excipient  
 
25. 
Known history of previous clinical diagnosis of tuberculosis 
 
26. 
Uncontrolled intercurrent illness including, but not limited to symptomatic congestive 
heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, 
active peptic ulcer disease or gastritis, seizures 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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Investigational Product(s), Dose, and Mode of Administration: 
Durvalumab, 1500 mg Q4W (equivalent to 20 mg/kg Q4W) via IV infusion for up to 13 doses 
(fixed dose for patients > 30kg) 
Tremelimumab 75 mg Q4W (equivalent to 1 mg/kg Q4W) via IV infusion for up to 4 doses 
(fixed dose for patients > 30kg)  
 
Study Assessments and Criteria for Evaluation: 
Safety Assessments: 
Patients enrolled in the study will be evaluated by the investigator/co-investigator prior to each 
dose of durvalumab and tremelimumab (more frequently if clinically indicated), and assessed 
for adverse events.  All adverse events will be graded via CTCAE v. 4. 
 
Efficacy Assessments: 
RECIST criteria 1.1 will be used to evaluate treatment responses in all patients enrolled on the 
study. Patients will have baseline imaging obtained within 4 weeks of starting the investigational 
agents. Repeat imaging will be performed every 8 weeks (+/- 1 week). 
 
Pharmacodynamic / Pharmacokinetic Assessments (if applicable):  
None 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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Statistical Methods and Data Analysis: 
 
The primary objective of this study is to evaluate the safety and tolerability of durvalumab and 
tremelimumab with hypofractionated radiation therapy in patients with recurrent head and neck 
cancer who have previously received immunotherapy. The total sample size for this evaluation 
is 20 patients evaluated in a dose de-escalation design.  Initially, durvalumab dosing will be 
1500 mg IV Q4weeks and tremelimumab dosing will be 75mg IV Q4W.   
 
Both durvalumab and tremelimumab have well established toxicity profiles as a single agent 
and in combination.  However, the combination of durvalumab tremelimumab and palliative 
radiation has not been previously studied, this study will include a formal safety analysis in the 
first 6 patients accrued.  Enrollment will be halted until these first 6 patients complete the first 
two cycles of treatment (8 weeks), and are evaluable for acute toxicities (toxicities reported 
within the 1st 8 weeks after treatment initiation). Specifically, if 2 or more DLTs (Refer to 
Section 6.4) are observed, then, durvalumab dosing will be modified to 1500 mg IV Q6 weeks 
x 9 doses and tremelimumab 75mg IV Q6 weeks x 3 doses for the remaining 14 patients (fixed 
dosing for patients > 30kg). If 1 or fewer DLTs are observed, then an additional 14 patients will 
be enrolled and treated at the initial dose and schedule of durvalumab and tremelimumab. 
Patients in the run in phase who experience DLTs will undergo dose modifications described in 
Appendix 1. 
 
Toxicities will be graded based on CTCAE v. 4 and summarized as the number and percentage 
of patients with each type of toxicity. Responses will be summarized as frequencies and 
percentages. The Kaplan Meier method will be used to estimate overall survival and progression 
free survival. Outcomes will be calculated from the date of study entry to the date of the 
corresponding event. 
 
We will use multivariate statistics to test the hypotheses that pretreatment intratumoral immune 
cell phenotype and PD-L1 expression predict response to therapy, and that therapy alters 
systemic immunophenotype. 
 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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Sample Size Determination: 
There are multiple ongoing studies in various tumor types exploring the activity of durvalumab 
and tremelimumab. In a published report of the combination in patients with advanced NSCLC 
treated on a phase Ib study, Grade 3-4 toxicity was observed in 17% of patients. Similarly, in 
single institution reports of SBRT with the monoclonal antibody, grade 3 or higher toxicity was 
reported in 6-16% of patients.  With a 20 patient accrual goal, toxicity rates can be estimated to 
within 22% with 95% confidence. Any toxicity with at least 10% prevalence has at least an 87% 
chance of being observed. This design allows us to reasonably exclude a clinically significant 
increase in toxicity with the addition of radiation therapy to the durvalumab and tremelimumab 
combination as defined by the upper bound of the confidence interval. 
 
The response rates to dual CTLA and PDL1 blockade and radiation therapy after prior 
immunotherapy are unknown.  If objective responses are demonstrated, or encouraging 
progression free survival is observed in the 20 patients enrolled on the study, it would merit 
further investigation in a larger study powered to examine efficacy endpoints. 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
15 
 
 
 
 
SCHEDULE OF STUDY ASSESSMENTS 
 
 
Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject 
Screening 
all assessments to be performed pre-infusion unless stated otherwise 
cycle 1 
cycle 2 - 4 
cycle 5 -13 
 
week 1 
week 3 
week 1 
week 1 
end of treatment 
Day 
- 28 to - 1 
Day 1 of the Week 
 
Week 
-4 to -1 
(±3 days) 
(±7 days) 
 
Written informed consent 
X 
  
  
  
  
  
  
Demography and history of 
tobacco and alcohol use 
X 
  
  
  
  
  
  
Previous treatments for head 
and neck cancer 
X 
  
  
  
  
  
  
Tumor tissue sample (Section 
8.3.2) 
X 
  
  
  
  
  
  
Formal verification of eligibility 
criteria 
X 
  
  
  
  
  
  
Medical and surgical history 
X 
  
  
  
  
  
  
 
 
 
 
 
 
 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject 
Screening 
all assessments to be performed pre-infusion unless stated otherwise 
cycle 1 
cycle 2 - 4 
cycle 5 - 13 
 
 
week 1 
week 3 
week 1 
week 1 
end of treatment 
LTFM  
Day 
- 28 to - 1 
Day 1 of the Week 
 
 
Week 
-4 to -1 
(±3 days) 
(±7 days) 
 
 
Urine hCG or serum βhCGb 
X 
 
 
 
 
 
 
Physical examinationc 
X 
X  
X  
X  
X  
X 
  
Vital signs  
X 
 X 
X  
X  
X  
X  
  
Weight 
X 
 X 
  
X  
X  
  
  
Electrocardiogramd 
X  
  
  
  
  
  
  
Durvalumab administratione   
 
X 
  
 X 
X  
  
  
Tremelimumab administratione 
 
  
X  
  
X  
  
X  
  
Adverse event/serious adverse 
event assessment 
X 
All Visits 
Radiation therapy evaluation 
and  radiation 
planning/simulation 
       X 
   
  
Palliative Radiation therapy 
 
XRT to begin 2 weeks after the first dose of Durvalumab and tremelimumab and to be completed in 2 weeks 
ECOG performance status 
X 
X 
X  
x 
 X 
 X 
  
 
 
 
 
 
 

Clinical Study Protocol 9881 
Drug Substance Palliative hypofractionated radiation therapy 
IND 136230  
 
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Assessments to be performed 
at the times stipulated in the 
table and as clinically required 
in the management of the 
subject 
Screening 
all assessments to be performed pre-infusion unless stated otherwise 
cycle 1 
cycle 2 - 4 
cycle 5 - 13 
 
 
week 1 
week 3 
week 1 
week 1 
end of treatment 
LTFM  
Day 
- 28 to - 1 
Day 1 of the Week 
 
 
Week 
-4 to -1 
(±3 days) 
(±7 days) 
 
 
TSH with reflexive free T4 f 
 
X 
 
X f 
X f 
 
 
Complete blood countg 
X 
X 
X 
X 
X 
X 
 
Serum chemistryg 
X 
X 
 X 
X  
X  
X  
  
Urinalysish 
X 
  
X 
  
  
  
  
Coagulation parametersi 
X 
as clinically indicated  
Correlative blood samples j 
X 
 
 
X j 
 
 
 
Tumor assessmentsk  
X 
  
  
X  
   
X  
 X 
  
a A maximum of 20 patients will be included in the trial. 
b  Pre-menopausal female subjects of childbearing potential only 
c Full physical examination at baseline; targeted physical examination at other time points 
d ECG during screening. Thereafter as clinically indicated. Baseline and abnormal ECG at any time in triplicate.  
e The administration of durvalumab and tremelimumab will be held if weight <30kg. 
f  Add free T4 if TSH is abnormal. Repeat at least every 12 weeks. 
g If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to be repeated at Day 1. Results for safety blood test must be available and reviewed 
before commencing an infusion.  
h Urinalysis performed at Screening and then as clinically indicated. 
i Coagulation tests: prothrombin time, aPTT and INR – only performed at Screening and then as clinically indicated. 
j Correlative blood samples will be collected to prior to the first dose and prior to c2 and c4. 
k Timing of CT scans for tumor assessments will be every 8 weeks (+/- 1 week). 

9881 
18 
 
   TABLE OF CONTENTS 
PAGE 
PROTOCOL SYNOPSIS ......................................................................................... 2 
TABLE OF CONTENTS ....................................................................................... 18 
ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 20 
1. 
INTRODUCTION ................................................................................................. 25 
1.1 
Disease Background ............................................................................................... 25 
1.2 
Research hypothesis ............................................................................................... 31 
1.3 
Rationale for conducting this study ....................................................................... 34 
1.4 
Benefit/risk and ethical assessment........................................................................ 37 
2. 
STUDY OBJECTIVE ............................................................................................ 45 
2.1.1 
Primary objective(s) ............................................................................................... 45 
2.1.2 
Secondary objective(s) ........................................................................................... 45 
2.1.3 
Exploratory objective(s) ......................................................................................... 45 
3. 
STUDY DESIGN ................................................................................................... 45 
3.1 
Overview of study design ...................................................................................... 45 
3.2 
Study schema ......................................................................................................... 43 
3.3 
Study Oversight for Safety Evaluation .................................................................. 46 
4.                PATIENT SELECTION, ENROLLMENT, RANDOMIZATION,  
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................................... 47 
4.1 
Inclusion criteria .................................................................................................... 47 
4.2 
Exclusion criteria ................................................................................................... 50 
4.3 
Withdrawal of Subjects from Study Treatment and/or Study ................................ 53 
4.4 
Replacement of subjects ........................................................................................ 55 
5. 
INVESTIGATIONAL PRODUCT(S) ................................................................... 55 
5.1 
Durvalumab and tremelimumab ............................................................................ 55 
5.1.1 
Formulation/packaging/storage .............................................................................. 55 
5.2 
Dose and treatment regimens ................................................................................. 56 
5.2.1 
Treatment regimens ............................................................................................... 56 
5.2.2 
Duration of treatment and criteria for retreatment ................................................. 56 
5.2.3 
Study drug preparation of durvalumab and tremelimumab ................................... 57 
5.2.4 
Monitoring of dose administration ......................................................................... 60 
5.2.5 
Accountability and dispensation ............................................................................ 61 
5.2.6 
Disposition of unused investigational study drug .................................................. 61 

9881 
19 
 
5.3 
Radiation therapy ................................................................................................... 59 
5.3.1 
Radiotherapy targeting and treatment ...................  Error! Bookmark not defined. 
5.3.2 
Target contouring ..................................................  Error! Bookmark not defined. 
5.3.3         Treatment planning, dose fractionation and specification  .. Error! Bookmark not 
defined. 
6. 
TREATMENT PLAN ............................................................................................ 66 
6.1 
Subject enrollment ................................................................................................. 67 
6.1.1 
Procedures for enrollment ...................................................................................... 67 
6.1.2 
Procedures for handling subjects incorrectly enrolled ........................................... 69 
6.2 
Dosage and Administration .................................................................................... 69 
6.4 
Dose Escalation Decision Rules ............................................................................ 69 
6.5 
Definition of DLT .................................................................................................. 70 
6.6 
Dose Modification and Toxicity Management ...................................................... 71 
6.6.1 
Durvalumab and tremelimumab ............................................................................ 71 
7. 
RESTRICTIONS 
DURING 
THE 
STUDY 
AND 
CONCOMITANT 
TREATMENT(S) ................................................................................................................... 72 
7.1 
Restrictions during the study ................................................................................. 72 
7.2 
Concomitant treatment(s) ....................................................................................... 75 
7.2.1 
Permitted concomitant medications ....................................................................... 75 
7.2.2 
Excluded Concomitant Medications ...................................................................... 75 
8. 
STUDY PROCEDURES ....................................................................................... 77 
8.1 
Schedule of study procedures ................................................................................ 77 
8.1.1 
Screening Phase ..................................................................................................... 77 
8.1.2 
Treatment Phase ..................................................................................................... 78 
8.1.3 
End of Treatment ................................................................................................... 78 
8.2 
Description of study procedures ............................................................................ 79 
8.2.1 
Medical history and physical examination, electrocardiogram, weight and 
vital signs ............................................................................................................... 79 
8.2.2 
Physical examination ............................................................................................. 79 
8.2.3 
Electrocardiograms ................................................................................................ 80 
8.2.4 
Vital signs .............................................................................................................. 80 
8.2.5 
Clinical laboratory tests ......................................................................................... 80 
8.3 
Biological sampling procedures ............................................................................. 81 
8.3.1 
Research blood collection ...................................................................................... 81 
8.3.2 
Correlative tissue collection ................................................................................... 82 
 
8.3.3 
Withdrawal of informed consent for donated biological samples ......................... 89 
9. 
DISEASE EVALUATION AND METHODS ...................................................... 91 
9.1.1       Progression free and overall survival …………………………….………….…….92 

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10. 
ASSESSMENT OF SAFETY ................................................................................ 92 
10.1.1 
Safety Parameters ................................................................................................... 92 
10.1.1.1 Definition of adverse events .................................................................................. 92 
10.1.2 
Definition of serious adverse events ...................................................................... 93 
10.1.3 
Durvalumab + tremelimumab adverse events of special interest .......................... 93 
10.1.4 
Immune-related adverse events .............................................................................. 96 
10.2 
Assessment of safety parameters ........................................................................... 98 
10.2.1 
Assessment of severity ........................................................................................... 98 
10.2.2 
Assessment of relationship .................................................................................... 98 
10.3 
Recording of adverse events and serious adverse events ....................................... 99 
10.3.1 
Study recording period and follow-up for adverse events and serious 
adverse events ...................................................................................................... 100 
10.3.2 
Reporting of serious adverse events..................................................................... 101 
10.3.2.1 Reporting of deaths .............................................................................................. 102 
10.3.3 
Other events requiring reporting .......................................................................... 103 
10.3.3.1 Overdose .............................................................................................................. 103 
10.3.3.2 Hepatic function abnormality .............................................................................. 103 
10.3.3.3 Pregnancy ............................................................................................................. 104 
10.3.3.4 Maternal exposure ................................................................................................ 104 
10.3.4 
Paternal exposure ................................................................................................. 104 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .......... 105 
11.1 
Description of analysis sets .................................................................................. 105 
11.2 
Methods of statistical analyses ............................................................................. 105 
11.2.1 
Safety Analyses .................................................................................................... 105 
11.2.2 
Efficacy Analyses ................................................................................................ 105 
11.2.3 
Exploratory Analyses ........................................................................................... 105 
11.2.4 
Interim analyses ................................................................................................... 105 
11.3 
Determination of sample size ............................................................................... 106 
12. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 106 
12.1 
Ethical conduct of the study ................................................................................. 106 
12.2 
Ethics and regulatory review................................................................................ 106 
12.3 
Informed consent ................................................................................................. 106 
12.4 
Changes to the protocol and informed consent form ........................................... 107 
12.5 
Audits and inspections ......................................................................................... 107 
13. 
STUDY MANAGEMENT .................................................................................. 107 
13.1 
Training of study site personnel ........................................................................... 107 
13.2 
Monitoring of the study ....................................................................................... 107 
13.2.1 
Source data ........................................................................................................... 107 

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13.3 
Study timetable and end of study ......................................................................... 107 
14. 
DATA MANAGEMENT ..................................................................................... 107 
14.1 
Study governance and oversight .......................................................................... 108 
15. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................. 109 
15.1 
Identity of investigational product(s) ................................................................... 109 
16. 
LIST OF REFERENCES ..................................................................................... 109 
 
LIST OF TABLES 
Table 1. Conformality of prescribed dose for calculations ased on deposition of 
photon beam enery in heterogeneous tissue  ............................................ 64 
Table 2. Highly effective methods of  contraception………………………………………...73 
Table 3. Effective methods of contraception…………………………………………………74  
Table 4. Prohibited and Rescue Medications  ........................................................................ 76 
Table 5. Hematology Laboratory Tests  ................................................................................. 81 
Table 6. Clinical chemistry (Serum or Plasma) Laboratory Tests  ........................................ 81 
Table 7. Urinalysis Test  ......................................................................................................... 81 
Table 8. List of investigational products for this study  ....................................................... 109 
 
 
 

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LIST OF APPENDICES 
 
Appendix 1. Dose modification and toxicity management guidelines for immune-
mediated, infusion-related, and non immuned-mediated reactions 
for the combination of durvalumab and tremelimumab ......................... 120 
Appendix 2. Schedule of study procedures: follow-up for subjects who have 
completed durvalumab and tremelimumab treatment and achieved 
disease control (until confirmed progression of disease) and 
subjects who have discontinued durvalumab or tremelimumab due 
to toxicity in the absence of confirmed progression of disease  ............. 141 
Appendix 3. Schedule of study procedures: follow-up for subjects who have 
discontinue durvalumab and tremelimumab treatment due to 
confirmed progression of disease at the investigator discretion  ............ 142 
 

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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation 
or 
special term 
Explanation 
3D CRT 
AChE 
3-dimensional conformal radiotherapy 
Acetylcholine esterase 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
APF12 
Proportion of patients alive and progression free at 12 months from 
randomization 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0-28day 
Area under the plasma drug concentration-time curve from time zero to Day 
28 post-dose 
AUCss 
Area under the plasma drug concentration-time curve at steady state 
BICR 
Blinded Independent Central Review 
BoR 
Best objective response 
BP 
Blood pressure 
C 
Cycle 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
Cmax,ss 
Maximum plasma concentration at steady state 
CR 
Complete response 
CSA 
Clinical study agreement 
CSR 
Clinical study report 

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Abbreviation 
or 
special term 
Explanation 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T–lymphocyte-associated antigen 4 
Ctrough,ss 
Trough concentration at steady state 
CXCL 
Chemokine (C-X-C motif) ligand 
DoR 
Duration of response 
EC 
Ethics Committee, synonymous to Institutional Review Board and 
Independent Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDoR 
Expected duration of response 
EGFR 
Epidermal growth factor receptor 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
hCG 
HIGRT 
Human chorionic gonadotropin 
Hypofractionated Image Guided Radiotherapy 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IFN 
Interferon 
IgE 
Immunoglobulin E 

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Abbreviation 
or 
special term 
Explanation 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL 
Interleukin 
ILS 
Interstitial lung disease 
IM 
IMRT 
Intramuscular 
Intensity modulated radiotherapy 
IMT 
Immunomodulatory therapy 
IP 
Investigational product  
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
mAb 
Monoclonal antibody 
MDSC 
Myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Minister of Health, Labor, and Welfare 
miRNA 
Micro-ribonucleic acid 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NSCLC 
Non–small-cell lung cancer 
OAE 
Other significant adverse event 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 

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Abbreviation 
or 
special term 
Explanation 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PDx 
Pharmacodynamic(s) 
PFS 
Progression-free survival 
PFS2 
Time to second progression 
PGx 
Pharmacogenetic research 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
q6w 
Every 6 weeks 
q8w 
Every 8 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RNA 
Ribonucleic acid 
RR 
Response rate 
RT-QPCR 
Reverse transcription quantitative polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
SBRT 
Safety analysis set 
Stereotactic ablative Body Radiotherapy 
SD 
Stable disease 
SNP 
Single nucleotide polymorphism 
SoC 
Standard of Care 
sPD-L1 
Soluble programmed cell death ligand 1 
 
 
T4 
Thyroxine 

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Abbreviation 
or 
special term 
Explanation 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WBDC 
Web-Based Data Capture 
WHO 
World Health Organization 
 

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1. 
INTRODUCTION 
The immune checkpoint inhibitors have activity in patients with recurrent metastatic head and 
neck squamous cell carcinomas. However, current clinical data indicates that a minority of 
patients benefit from this approach, with objective response rates ranging from 13-27%, in 
various reported clinical trials using both anti-PD1 and anti-PDL1 antibodies as single agents. 
There is now increasing interest in studying mechanisms of immune escape in patients who do 
not respond to these immune checkpoint inhibitors. 
The dual inhibition of PDL-1 and CTLA-4 is an approach that has garnered significant 
enthusiasm, due to robust preclinical data showing synergistic antitumor efficacy. This data is 
supported by prospectively collected clinical data, in immunotherapy naive melanoma 
patients, wherein improved objective response rates and progression free response rates were 
observed with the combination of nivolumab and ipilimumab compared to either agent alone. 
Multiple ongoing studies in other tumor types are examining the activity of this combination. 
In addition, responses with the anti-CTLA4 antibodies after non-response to prior PD-1 or 
PDL-1 monoclonal antibodies have been described in melanoma patients. 
The role of radiation therapy in transforming the tumor microenvironment to increase the 
activity of immune checkpoint inhibition is an area of significant scientific interest. There is 
preclinical data supporting that the exposure to immune checkpoint inhibitors prior to 
therapeutic radiation is associated with increased antitumor activity. The clinical observation 
of the abscopal effect further supports the potential clinical utility of radiation therapy in 
inducing responses to immune check point inhibition. 
We hypothesize that the combination of durvalumab, tremelimumab and palliative 
hypofractionated radiation among patients previously treated with immune checkpoint 
inhibitors is not only safe and feasible, but will result in the induction or restoration of 
responses to immune checkpoint inhibition and subsequent clinical benefit and improved 
survival in this refractory patient population. 
1.1 
Disease Background 
Immune responses directed against tumors are one of the body’s natural defences against the 
growth and proliferation of cancer cells. However, over time and under pressure from immune 
attack, cancers develop strategies to evade immune-mediated killing allowing them to develop 
unchecked. One such mechanism involves upregulation of surface proteins that deliver 
inhibitory signals to cytotoxic T cells. Programmed cell death ligand 1 (PD-L1) is one such 
protein, and is upregulated in a broad range of cancers with a high frequency, with up to 88% 
expression in some tumor types. In a number of these cancers, including lung (Mu et al, 2011), 
renal (Thompson et al, 2005; Thompson et al, 2006; Krambeck et al, 2007), pancreatic (Nomi 
et al, 2007; Loos et al, 2008; Wang et al, 2010), ovarian cancer (Hamanishi et al, 2007), and 
hematologic malignancies (Andorsky et al, 2011; Brusa et al, 2013) tumor cell expression of 
PD-L1 is associated with reduced survival and an unfavorable prognosis. 

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Programmed cell death ligand 1 is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation. PD-L1 acts at multiple sites in the body to help regulate 
normal immune responses and is utilized by tumors to help evade detection and elimination by 
the host immune system tumor response. In the lymph nodes, PD-L1 on antigen-presenting cells 
binds to PD-1 or CD80 on activated T cells and delivers an inhibitory signal to the T cell (Keir 
et al, 2008; Park et al, 2010). This results in reduced T-cell activation and fewer activated T 
cells in circulation. In the tumor microenvironment, PD-L1 expressed on tumor cells binds to 
PD-1 and CD80 on activated T cells reaching the tumor. This delivers an inhibitory signal to 
those T cells, preventing them from killing target cancer cells and protecting the tumor from 
immune elimination (Zou and Chen, 2008). 
T cells play a critical role in antitumor immunity and their infiltration and activity have been 
linked to improved prognosis in a number of cancers (Pagès et al, 2010; Nakano et al, 2001; 
Suzuki et al, 2011; Burt et al, 2011). Immune evasion, primarily through suppression of T-cell 
activity, is now recognized as one of the hallmarks of cancer. Such evasion can occur via a 
range of mechanisms including production of suppressive cytokines such as IL-10, secretion of 
chemokines and growth factors that recruit and sustain suppressive regulatory T cells (Tregs) 
and inflammatory macrophages, and expression of inhibitory surface molecules such as B7-H1. 
Tumor types characterized as being responsive to immunotherapy-based approaches include 
melanoma (Weber et al, 2012), renal cell carcinoma (RCC; McDermott, 2009), bladder cancer 
(Kresowik and Griffith, 2009), and malignant mesothelioma (Bograd et al, 2011). Inhibition of 
CTLA-4 signaling is a validated approach to cancer therapy, as shown by the approval in 2011 
of ipilimumab for the treatment of metastatic melanoma based on statistically significant and 
clinically meaningful improvement in OS (Hodi et al, 2010; Robert et al, 2011).  
In general, tumor response rates to anti-CTLA-4 therapy are low (~10%). However, in patients 
who respond, the responses are generally durable, lasting several months even in patients with 
aggressive tumors such as refractory metastatic melanoma. Because these agents work through 
activation of the immune system and not by directly targeting the tumor, responses can occur 
late and some patients may have perceived progression of their disease in advance of developing 
disease stabilization or a tumor response. In some cases, early growth of pre-existing lesions or 
the appearance of new lesions may have been due to immune-cell infiltration into the tumor and 
not due to proliferation and extension of neoplastic cells, per se (Wolchok et al, 2009). Overall, 
although the impact on conventionally-defined PFS can be small, durable response or stable 
disease seen in a proportion of patients can lead to significant prolongation of OS. The 
melanoma data with ipilimumab clearly demonstrate that a small proportion of patients with an 
objective response had significant prolongation of OS, supporting the development of this class 
of agents in other tumors. Although Phase 2 and Phase 3 studies of tremelimumab in metastatic 
melanoma did not meet the primary endpoints of response rate and OS, respectively, the data 
suggest activity of tremelimumab in melanoma (Kirkwood et al, 2010; Ribas et al, 2013). In a 

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large 
Phase 3 
randomized 
study 
comparing 
tremelimumab 
with 
dacarbazine 
(DTIC)/temozolomide in patients with advanced melanoma, the reported median OS in the final 
analysis was 12.58 months for tremelimumab versus 10.71 months for DTIC/temozolomide 
(HR = 1.1416, p = 0.1272; Ribas et al, 2013).   
 
1.1.1 
Immunotherapies 
It is increasingly understood that cancers are recognized by the immune system, and, under 
some circumstances, the immune system may control or even eliminate tumors (Dunn 
et al 2004).  Studies in mouse models of transplantable tumors have demonstrated that 
manipulation of co-stimulatory or co-inhibitory signals can amplify T-cell responses against 
tumors (Peggs et al 2009).  This amplification may be accomplished by blocking co-inhibitory 
molecules, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell 
death 1 (PD-1), from binding with their ligands, B7 or B7-H1 (programmed cell death ligand 1 
[PD-L1]).   
1.1.2 
Durvalumab  
The non-clinical and clinical experience is fully described in the current version of the 
durvalumab Investigator’s Brochure (IB Version 10).   
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune 
for use in the treatment of cancer.  (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.)  As 
durvalumab is an engineered mAb, it does not induce antibody-dependent cellular cytotoxicity 
or complement-dependent cytotoxicity.  The proposed mechanism of action for durvalumab is 
interference of the interaction of PD-L1. 
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some types 
of cancers.  In a number of these cancers, including lung, the expression of PD-L1 is associated 
with reduced survival and an unfavorable prognosis.  In lung cancer, only 12% of patients with 
tumors expressing PD-L1 survived for more than 3 years, compared with 20% of patients with 
tumors lacking PD-L1 (Mu et al 2011).  Based on these findings, an anti-PD-L1 antibody could 
be used therapeutically to enhance anti-tumor immune responses in patients with cancer.  
Results of several non-clinical studies using mouse tumor models support this hypothesis, where 
antibodies directed against PD-L1 or its receptor PD-1 showed anti-tumor activity 
(Hirano et al 2005, Iwai et al 2002, Okudaira et al 2009. Zhang et al 2008). 

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To date durvalumab has been given to more than 1800 patients as part of ongoing studies either 
as monotherapy or in combination with other anti-cancer agents. Details on the safety profile of 
durvalumab monotherapy are summarized Section 14.2.1 and in the durvalumab IB version 10.0 
which details the complete summary of non-clinical and clinical information including safety, 
efficacy and pharmacokinetics.  
As of 09Feb2015, PK data were available for 378 subjects in the dose-escalation and dose-
expansion phases of Study CD-ON-durvalumab-1108 following treatment with durvalumab 
0.1 to 10 mg/kg every 2 weeks (Q2W) or 15 mg/kg every 3 weeks (Q3W). The maximum 
observed concentration (Cmax) increased in an approximately dose-proportional manner over the 
dose range of 0.1 to 15 mg/kg. The area under the concentration-time curve from 0 to 14 days 
(AUC0-14) increased in a greater than dose-proportional manner over the dose range of 0.1 to 
3 mg/kg and increased dose-proportionally at ≥ 3 mg/kg. These results suggest durvalumab 
exhibits nonlinear PK likely due to saturable target-mediated CL at doses < 3 mg/kg and 
approaches linearity at doses ≥ 3 mg/kg. Near complete target saturation (soluble programmed 
cell death ligand 1 [sPD-L1] and membrane bound) is expected with durvalumab ≥ 3 mg/kg 
Q2W. Exposures after multiple doses showed accumulation consistent with PK parameters 
estimated from the first dose. In addition, PK simulations indicate that following durvalumab 
10 mg/kg Q2W dosing, > 90% of subjects are expected to maintain PK exposure ≥ 40 µg/mL 
throughout the dosing interval. 
As of 09Feb2015, a total of 388 subjects provided samples for ADA analysis. Only 8 of 
388 subjects (1 subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjects in 10 mg/kg 
cohort) were ADA positive with an impact on PK/pharmacodynamics in 1 subject in the 
3 mg/kg cohort. 
1.1.3 
Tremelimumab 
The non-clinical and clinical experience is fully described in the current version of the 
tremelimumab Investigator’s Brochure (IB Version 7.0).   
Tremelimumab is an IgG 2 kappa isotype mAb directed against the cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) also known as CD152 (cluster of differentiation 152).  This is 
an immunomodulatory therapy (IMT) that is being developed by AstraZeneca for use in the 
treatment of cancer.   
Binding of CTLA-4 to its target ligands (B7-1 and B7-2) provides a negative regulatory signal, 
which limits T-cell activation.  Anti-CTLA-4 inhibitors antagonize the binding of CTLA-4 to 
B7 ligands and enhance human T-cell activation as demonstrated by increased cytokine 
(interleukin [IL]-2 and interferon [IFN] gamma) production in vitro in whole blood or peripheral 
blood mononuclear cell (PBMC) cultures (Error! Reference source not found.).  In addition, 

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blockade of CTLA-4 binding to B7 by anti-CTLA-4 antibodies results in markedly enhanced 
T-cell activation and anti-tumor activity in animal models, including killing of established 
murine solid tumors and induction of protective anti-tumor immunity.  (Refer to the 
tremelimumab IB, Edition 5.0, for more information.)  Therefore, it is expected that treatment 
with an anti-CTLA-4 antibody, such as tremelimumab, will lead to increased activation of the 
human immune system, increasing anti-tumor activity in patients with solid tumors.   
An extensive program of non-clinical and clinical studies has been conducted for tremelimumab 
both as monotherapy and combination therapy with conventional anticancer agents to support 
various cancer indications using different dose schedules.  To date tremelimumab has been 
given to more than 1000 patients as part of ongoing studies either as monotherapy or in 
combination with other anticancer agents. Details on the safety profile of tremelimumab 
monotherapy are summarized in Section.1.4.2.2. Refer to the current tremelimumab 
Investigator’s Brochure (v.7) for a complete summary of non-clinical and clinical information 
including safety, efficacy and pharmacokinetics. 
Tremelimumab exhibited a biphasic PK profile with a long terminal phase half-life of 22 days.  
Overall, a low incidence of ADAs (<6%) was observed for treatment with tremelimumab.   
1.1.4 
Durvalumab in combination with tremelimumab 
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity (Pardoll 
2012) because the mechanisms of action of CTLA-4 and PD-1 are non-redundant; therefore, 
AstraZeneca is also investigating the use of durvalumab + tremelimumab combination therapy 
for the treatment of cancer. 
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, PK/PDx, and 
preliminary anti-tumor activity of durvalumab + tremelimumab combination therapy in patients 
with advanced NSCLC.  The dosing schedule utilized is durvalumab every 2 weeks (q2w) or 
every 4 weeks (q4w) up to Week 50 and 48 (12 months), combined with tremelimumab q4w up 
to Week 24 for 7 doses then every 12 weeks for 2 additional doses for up to 12 months.  The 
study is ongoing and continues to accrue.   
Study D4190C00006: As of 20Feb2015, durvalumab PK (n = 55) and tremelimumab PK 
(n = 26) data were available from 10 cohorts (1a, 2a, 3a, 3b, 4, 4a, 5, 5a, 8, and 9) following 
durvalumab every 4 weeks (Q4W) or Q2W dosing in combination with tremelimumab Q4W 
regimens. An approximately dose-proportional increase in PK exposure (Cmax and area under 
the concentration-time curve from 0 to 28 days [AUC0-28]) of both durvalumab and 
tremelimumab was observed over the dose range of 3 to 15 mg/kg durvalumab Q4W and 1 to 
10 mg/kg tremelimumab Q4W. Exposures following multiple doses demonstrated accumulation 
consistent with PK parameters estimated from the first dose. It is to be noted that steady state 
PK parameters are based on limited numbers of subjects. The observed PK exposures of 

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durvalumab and tremelimumab following combination were consistent with respective 
monotherapy data, indicating no PK interaction between these 2 agents. 
As of 20Feb2015, ADA data were available from 60 subjects for durvalumab and 53 subjects 
for tremelimumab in Study D4190C00006. Four of 60 subjects were ADA positive for 
anti-durvalumab antibodies post treatment. One of 53 subjects was ADA positive for 
anti-tremelimumab antibodies post treatment. There was no clear relationship between ADA 
and the dose of either durvalumab or tremelimumab, and no obvious association between ADA 
and safety or efficacy. 
Durvalumab has also been combined with other anticancer agents, including gefitinib, 
dabrafenib, and trametinib. To date, no PK interaction has been observed between durvalumab 
and these agents.  
 
1.1.5 
Radiation therapy 
Uncontrolled loco regional disease is a major concern in head and neck cancer as it severely 
compromises a patient’s quality of life with pain, ulceration, bleeding, foul odor, speech, 
swallowing, and breathing difficulties etc.  Historically, radiation therapy has underpinned any 
and all attempts at providing durable disease control in the head and neck region. 
In this protocol, palliative radiation therapy will be administered using either hypofractionated 
Image guided Radiotherapy (HIGRT) or Stereotactic ablative body radiotherapy (SBRT). These 
two techniques involve precise delivery of large tumoricidal/ablative doses of radiation 
treatments to a smal tumor over 1-5 fractions using image guidance and elaborate treatment 
planning process aimed at providing steep dose gradients especially near critical organs. 
Distinct nontraditional radiobiological mechanisms may be involved with the high dose 
fractions (>/= 6 Gy) used with HIGRT/SBRT, as compared with conventionally fractionated 
(1.8-2 Gy) radiotherapy that is commonly used in the curative setting. HIGRT/SBRT may 
produce biological effects mediated through enhanced immune stimulation and endothelial 
damage of the tumor micro environment. (Karam et al. Future Oncol. 2015). As a primary 
modality for medically unfit patients, SBRT has offered reasonable local control with 
acceptable toxicity. In the re-irradiation setting, SBRT is associated with higher rates of 
morbidity (10-50%) and even mortality (1-5%) in the face of promising local control. 
There is now increasing data on the feasibility of hypofractionated radiation administered 
concurrent with immune checkpoint inhibition. Recent publication of the randomized phase 2 
SABR-COMET study (Palma et al. Lancet 2019) (SBRT) in the oligometastatic setting 
significantly improves overall survival and progression free survival compared to palliative 
standard of care. This trial targeted all known metastatic lesions and was not in combination 

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with immunotherapy. However, it does indicate a role for hypofractionated ablative 
radiotherapy in the metastatic setting and demonstrates that it can be used safely to prolong 
survival. McBride, et al, presented preliminary data in abstract form (ASCO 2018 abstract 
#6009), randomizing 53 patients with recurrent/metastatic head and neck cancer to nivolumab 
alone, or nivolumab with SBRT. Although no survival advantage was noted in the nivolumab 
+ SBRT arm was noted int this study, the benefit of dual PD1 and CTLA 4 inhibition with SBRT 
is unknown in this population, and it supported by compelling preclinical data (Twyman St. 
Victor, Nature 2015).  Additionally, Lemons et al (ASCO-SITC 2018 Abstract #20) presented 
data on a phase I clinical trial of pembrolizumab and SBRT in 73 patients with various solid 
tumors.  No radiation dose reductions were necessary, 13.2% of patients had an abscopal 
response.   
1.2 
Research hypothesis 
Based on the prior experience with the combination of durvalumab and tremelimumab, we 
hypothesize that the combination of these two at the fixed dose of 1500 mg and 75 mg Q28 
days respectively given with hypofractionated radiation therapy (either HIGRT or SBRT), 
would be a well-tolerated and feasible treatment for patients (> 30kg) with head and neck 
cancer previously treated with immunotherapy.    
There is also no available data on the activity of the combination blockade of CTLA4 and 
PD1 in the setting of prior exposure to an anti-PD1 or PDL1 agent, therefore, hypothesis 
generating data on the objective response rates in this population will be collected and used to 
determine if further study of this combination is worth pursuing. 
1.3 
Rationale for conducting this study 
As an antibody that blocks the interaction between PD-L1 and its receptors, durvalumab may 
relieve PD-L1-dependent immunosuppressive effects and, therefore, enhance the cytotoxic 
activity of anti-tumor T-cells.  This hypothesis is supported by emerging clinical data from other 
mAbs targeting the PD-L1/PD-1 pathway, which provide early evidence of clinical activity and 
a manageable safety profile (Brahmer et al 2012).  Responses have been observed in patients 
with PD-L1-positive tumors and patients with PD-L1-negative tumors.  In addition, durvalumab 
monotherapy has shown durable responses in NSCLC in Study 1108 (see Section 1.4.1.1). 
The rationale for combining durvalumab and tremelimumab is that the mechanisms of 
CTLA-4 and PD-1 are non-redundant, suggesting that targeting both pathways may have 
additive or synergistic activity (Pardoll 2012).  In fact, combining immunotherapy agents has 
been shown to result in improved response rates (RRs) relative to monotherapy.  For example, 
the concurrent administration of nivolumab and ipilimumab to patients with advanced 
melanoma induced higher objective response rates (ORRs) than those obtained with single-
agent therapy.  Importantly, responses appeared to be deep and durable (Wolchock et al, 
2013). Similar results have been observed in an ongoing study of durvalumab + 

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tremelimumab in NSCLC (), with further updated details presented in this clinical study 
protocol.   
1.3.1 
Durvalumab  + tremelimumab combination therapy dose rationale 
The durvalumab + tremelimumab doses and regimen selected for this study are based on the 
goal of selecting an optimal combination dose of durvalumab and tremelimumab that would 
yield sustained target suppression (sPD-L1), demonstrate promising efficacy, and have an 
acceptable safety profile.   
In order to reduce the dosing frequency of durvalumab to align with the q4w dosing of 
tremelimumab, while ensuring an acceptable PK/PDx, safety, and efficacy profile, cohorts were 
narrowed to 15 and 20 mg/kg durvalumab q4w.  PK simulations from the durvalumab 
monotherapy data indicated that a similar area under the plasma drug concentration-time curve 
at steady state (AUCss; 4 weeks) was expected following both 10 mg/kg q2w and 20 mg/kg q4w 
durvalumab.  The observed durvalumab PK data from the D4190C00006 study were well in 
line with the predicted monotherapy PK data developed preclinically.  This demonstrates similar 
exposure of durvalumab 20 mg/kg q4w and 10 mg/kg q2w, with no alterations in PK when 
durvalumab and tremelimumab (doses ranging from 1 to 3 mg/kg) are dosed together.  While 
the median Cmax at steady state (Cmax,ss) is expected to be higher with 20 mg/kg q4w 
(approximately 1.5 fold) and median trough concentration at steady state (Ctrough,ss) is expected 
to be higher with 10 mg/kg q2w (approximately 1.25 fold), this is not expected to impact the 
overall safety and efficacy profile, based on existing preclinical and clinical data. 
Monotonic increases in PDx activity were observed with increasing doses of tremelimumab 
relative to the activity observed in patients treated with durvalumab monotherapy.  There was 
evidence of augmented PDx activity relative to durvalumab monotherapy with combination 
doses containing 1 mg/kg tremelimumab, inclusive of both the 15 and 20 mg/kg durvalumab 
plus 1 mg/kg tremelimumab combinations.  
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events 
(AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs.  Between 
the 10 mg/kg durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 3 mg/kg 
tremelimumab cohorts treated at the q2w schedule, the number of patients reporting any AE, 
Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg durvalumab + 
3 mg/kg tremelimumab cohort than the 10 mg/kg durvalumab + 1 mg/kg tremelimumab cohort.  
A similar pattern was noted in the q4w regimens, suggesting that, as the dose of tremelimumab 
increased above 1 mg/kg, a higher rate of treatment-related events may be anticipated.  Further, 
the SAEs frequently attributed to immunotherapy, pneumonitis and colitis, were more 
commonly seen in cohorts using either 3 or 10 mg/kg of tremelimumab compared to the 1-

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mg/kg dose cohorts.  Together, these data suggest that a combination using a tremelimumab 
dose of 1 mg/kg appeared to minimize the rate of toxicity when combined with durvalumab.  
As a result, all combination doses utilizing either the 3 or 10 mg/kg doses of tremelimumab 
were eliminated in the final dose selection.   
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of tremelimumab 
did not show an increase in the rate of AEs.  The data suggested that increasing doses of 
durvalumab may not impact the safety of the combination as much as the tremelimumab dose.  
Further, safety data between the 10-mg/kg and 20-mg/kg cohorts were similar, with no change 
in safety events with increasing dose of durvalumab.  
In Study D4190C00006, of all treatment cohorts, the cohort of 11 patients treated in the 
20 mg/kg durvalumab + 1 mg/kg tremelimumab group had the fewest AEs, Grade ≥3 AEs, 
SAEs, and treatment discontinuations due to AEs, but still showed strong evidence of clinical 
activity.  This cohort had a lower number of treatment-related Grade ≥3 AEs or 
treatment-related SAEs.  No dose-limiting toxicities were reported.   
Preliminary clinical activity of the durvalumab and tremelimumab combination did not appear 
to change with increasing doses of tremelimumab.  The 15- and 20-mg/kg durvalumab q4w 
cohorts demonstrated objective responses at all doses of tremelimumab, and increasing doses 
of tremelimumab did not provide deeper or more rapid responses. 
Efficacy data suggested that the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort 
may demonstrate equivalent clinical activity to other dose combinations.  A total of 5 of 
11 patients in the 20 mg/kg durvalumab + 1 mg/kg tremelimumab cohort were evaluable for 
efficacy with at least 8 weeks of follow-up.  Of these, there were 2 patients (40%) with partial 
response (PR), 1 patient (20%) with stable disease (SD), and 1 patient (20%) with progressive 
disease (PD).  (The fifth patient had only a single scan, which was conducted outside the 
window for these evaluations.) 
Additionally, of all cohorts, the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort 
had the fewest AEs, Grade ≥3 AEs, SAEs, and treatment discontinuations due to AEs, but still 
showed some evidence of clinical activity.  Altogether, the data suggested that a 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab dose combination should be selected for further 
development.   
1.3.2 
Rationale for 4 cycles of combination therapy followed by durvalumab  
monotherapy 
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 targeting 
antibody (dosed every 3 weeks [q3w] for 4 doses and then discontinued), shows that patients 
responding to ipilimumab derive long-term benefit, with a 3-year OS rate of approximately 

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22%.  Furthermore, the survival curve in this population reached a plateau at 3 years and was 
maintained through 10 years of follow up (Error! Reference source not found.).  
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies:  
Nivolumab (anti-PD-1) was dosed q2w for up to 96 weeks in a large Phase I dose-escalation 
and expansion study, and showed responses were maintained for a median of 22.94 months for 
melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months for NSCLC (doses 1, 3, and 10 mg/kg), 
and 12.9 months for renal cell carcinoma patients (doses 1 and 10 mg/kg) at the time of data 
analysis (Hodi et al 2014, Brahmer et al 2014, Drake et al 2013).  Furthermore, responses were 
maintained beyond treatment discontinuation in the majority of patients who stopped nivolumab 
treatment (either due to protocol specified end of treatment, complete response [CR], or 
toxicity) for up to 56 weeks at the time of data analysis (Error! Reference source not found.). 
MPDL3280a (anti-PD-L1) and the combination of nivolumab with ipilimumab, in which 
patients were dosed for a finite time period and responses maintained beyond treatment 
discontinuation have been reported (Herbst et al 2013, Error! Reference source not found.). 
Similar long term results may be expected with use of other immune-mediated cancer 
therapeutics including anti-CTLA-4 antibodies such as tremelimumab, anti PD-L1 antibodies 
such as durvalumab, or the combination of the two.   
1.3.3 
Rationale for the combination of durvalumab, tremelimumab and 
hypofractionated radiation therapy (HIGRT or SBRT) 
 
There are both preclinical and clinical data supporting the immunogenic potential of radiation 
therapy.  Exposure to radiation therapy appears to result in priming the anti-tumor T cells within 
the tumor microenvironment to tumor antigens.  There is also data supporting the increased 
efficacy of hypofractionated radiation in stimulation of the immune system against tumor 
antigens.  This therapeutic approach is currently being actively tested in various tumor types 
including head and neck cancer.  
 
1.4 
Benefit/risk and ethical assessment 
1.4.1 
Potential benefits 
1.4.1.1 
Durvalumab 
The majority of the safety and efficacy data currently available for durvalumab are based on the 
first time in-human, single-agent study (Study 1108) in patients with advanced solid tumors.  

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Data from Study 1108 were presented at the European Society for Medical Oncology 2014 
Congress.  Overall, 456 of 694 subjects treated with durvalumab 10 mg/kg Q2W were evaluable 
for response (defined as having ≥ 24 weeks follow-up, measurable disease at baseline, and ≥ 1 
follow-up scan, or discontinued due to disease progression or death without any follow-up 
scan). In PD-L1 unselected patients, the objective response rate (ORR), based on investigator 
assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, ranged from 0% 
in uveal melanoma (n = 23) to 20.0% in bladder cancer (n = 15), and disease control rate at 
24 weeks (DCR-24w) ranged from 4.2% in triple-negative breast cancer (TNBC; n = 24) to 
39.1% in advanced cutaneous melanoma (n = 23). PD-L1 status was known for 383 of the 
456 response evaluable subjects. Across the PD-L1-positive tumors, ORR was highest for 
bladder cancer, advanced cutaneous melanoma, hepatocellular carcinoma (HCC; n = 3 each, 
33.3% each), NSCLC (n = 86, 26.7%), and squamous cell carcinoma of the head and neck 
(SCCHN; n = 22, 18.2%). In the PD-L1-positive subset, DCR-24w was highest in advanced 
cutaneous melanoma (n = 3, 66.7%), NSCLC (n = 86, 36.0%), HCC and bladder cancer (n = 3 
each, 33.3% each), and SCCHN (n = 22, 18.2%). (Antonia et al 2014b).   
1.4.1.2 
Tremelimumab 
In a single-arm, Phase II study (Study A3671008) of tremelimumab administered at 15 mg/kg 
every 90 days to patients with refractory melanoma, an RR of 7% and a median OS of 10 months 
in the second-line setting (as compared to approximately 6 months with best supportive care 
reported from a retrospective analysis; Korn et al 2008) were observed (Kirkwood et al 2010).  
In a randomized, open-label, first-line Phase III study of tremelimumab (administered at 
15 mg/kg every 90 days) versus chemotherapy (dacarbazine or temozolomide) in advanced 
melanoma (Study A3671009), results of the final analysis showed an RR of 11% and a median 
OS of 12.58 months in this first-line setting as compared to 10.71 months with standard 
chemotherapy; however, these results were not statistically significant (Error! Reference 
source not found.).  Additionally, a Phase II maintenance study (Study A3671015) in patients 
with Stage IIIB or IV NSCLC who had responded or remained stable failed to achieve statistical 
significance.  The primary endpoint of PFS at 3 months was 22.7% in the tremelimumab arm 
(15 mg/kg) compared with 11.9% in the best supportive care arm (Study A3671015).   
1.4.1.3 
Durvalumab + tremelimumab 
The preclinical and clinical justification for this combination as noted in Section 1.1.4 also 
supports the synergy of this combination.  Available data, such as those presented by 
Wolchok et al, suggest that the combination of agents targeting PD-1/PD-L1 and CTLA-4 may 
have profound and durable benefits in patients with melanoma (Error! Reference source not 
found.).  Of the 102 subjects with advanced NSCLC treated with durvalumab in combination 
with tremelimumab in Study D4190C00006, 63 subjects with at least 16 weeks of follow-up 

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were evaluable for response (defined as measurable disease at baseline and at least 1 follow-up 
scan; this included discontinuations due to disease progression or death without follow-up scan). 
Of the 63 evaluable subjects, 17 (27%) had a best overall response of PR, 14 (22%) had SD, 22 
(35%) had PD, and 10 (16%) were not evaluable. The ORR (confirmed and unconfirmed CR or 
PR) was 27% and the DCR (CR, PR, or SD) was 49% as assessed by RECIST v1.1. 
Current experience with single-agent IMT studies suggests that clinical responses may be 
restricted to a subset of any given patient population and that it might be beneficial to enrich the 
patient population by selecting patients likely to respond to therapy.  To date, no assay has been 
established or validated, and no single approach has proven accurate, for patient enrichment for 
IMTs.  However, independent data from multiple sources using different assays and scoring 
methods suggests that PD-L1 expression on tumor cells and/or tumor infiltrating cells may be 
associated with greater clinical benefit. 
Data from ongoing studies with durvalumab and other agents targeting the PD-1/PD-L1 
pathway suggest, as shown in a number of tumor types (eg, NSCLC, renal cell carcinoma, and 
melanoma), that monotherapy may be more efficacious (in terms of ORR) in patients who are 
PD-L1-positive.  
Given these findings, a number of ongoing studies are assessing the activity of agents in patients 
with PD-L1–positive tumors.  There is also an unmet medical need in patients with PD-L1–
negative tumors that needs to be addressed.  Data, as of 27 January 2015 from Study 006 show 
that with the addition of tremelimumab to durvalumab, the ORR can be increased to 25% in 
patients with PD-L1 negative NSCLC.  As patients with PD-L1 positive disease can also have 
an increase in ORR, from 25% with durvalumab monotherapy, to 36% with the combination of 
durvalumab and tremelimumab, the study will enroll all patients with NSCLC, with an emphasis 
on those determined to be PD-L1 negative.   
1.4.1.4 
Radiation therapy 
Squamous cell carcinomas are known to be sensitive to radiation therapy, and therefore it is a 
treatment modality that has well defined roles in the definitive setting. Radiation therapy is 
likewise a useful therapeutic modality in patients who require local therapy for palliation of 
symptoms.  In addition to the potential benefit of local control and alleviation of tumor burden 
related symptoms, encouraging data is emerging that associates hypofractionated radiation 
potential with release of tumor related antigens, and possible synergy with immune checkpoint 
inhibition. Furthermore, The SABR-COMET study (Palma et al. Lancet 2019) indicates that 
stereotactic ablative radiotherapy (SBRT) in the oligometastatic setting significantly improves 
overall survival and progression free survival compared to palliative standard of care.  

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1.4.2 
Potential risks 
1.4.2.1 
Durvalumab 
Potential risks, based on the mechanism of action of durvalumab and related molecules, include 
immune-mediated reactions, such as enterocolitis, dermatitis, hepatitis/hepatotoxicity, 
endocrinopathy, pneumonitis, and neuropathy or neurologic events.  Additional important 
potential risks include infusion-related reactions, hypersensitivity, anaphylaxis or serious 
allergic reactions, serious infections, and immune complex disease.   
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 received 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 07May2015, 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). A majority of the treatment-related 
SAEs were ≥ Grade 3 in severity and resolved with or without sequelae. 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 

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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 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 distress, 
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. 
1.4.2.2 
Tremelimumab 
Potential risks, based on the mechanism of action of tremelimumab and related molecules 
(ipilimumab) include potentially immune-mediated gastrointestinal (GI) events including 
enterocolitis, intestinal perforation, abdominal pain, dehydration, nausea and vomiting, and 
decreased appetite (anorexia); dermatitis including urticaria, skin exfoliation, and dry skin; 
endocrinopathies including hypophysitis, adrenal insufficiency, and hyperthyroidism and 
hypothyroidism; hepatitis including autoimmune hepatitis and increased serum ALT and AST; 
pancreatitis including autoimmune pancreatitis and lipase and amylase elevation; respiratory 

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tract events including pneumonitis and interstitial lung disease (ILD); nervous system events 
including encephalitis, peripheral motor and sensory neuropathies, and Guillain-Barré 
syndrome; cytopenias including thrombocytopenia, anemia, and neutropenia; infusion-related 
reactions; anaphylaxis; and serious allergic reactions.  The profile of AEs and the spectrum of 
event severity have remained stable across the tremelimumab clinical program and are 
consistent with the pharmacology of the target.  To date, no tumor type or stage appears to be 
associated with unique AEs (except for vitiligo that appears to be confined to patients with 
melanoma).  Overall, 944 of the 973 patients (97.0%) treated with tremelimumab monotherapy 
as of the data cutoff date of 12 November 2014 (for all studies except D4190C00006 that has a 
cutoff date of 04 December 2014 and not including 497 patients who have been treated in the 
ongoing blinded Phase IIb Study D4880C00003) experienced at least 1 AE.  The events resulted 
in discontinuation of tremelimumab in 10.0% of patients, were serious in 36.5%, were Grade 
≥3 in severity in 49.8%, were fatal in 67.7%, and were considered to be treatment related in 
79.1% of patients.  The frequency of any AEs and Grade ≥3 AEs was generally similar across 
the tremelimumab dose groups.  However, a higher percentage of patients in the 10 mg/kg every 
28 days and 15 mg/kg every 90 days groups compared with the All Doses <10 mg/kg group 
experienced treatment-related AEs, SAEs, AEs resulting in discontinuation of investigational 
product (IP), and deaths.   
1.4.2.3 
Durvalumab + tremelimumab 
No safety studies in animals have been performed combining tremelimumab with durvalumab.  
As both CTLA-4 and PD-L1 have mechanisms of actions that enhance activation of immune 
cells, their potential to induce cytokine release was tested in a whole-blood assay system.  
Durvalumab and tremelimumab, either alone or in combination, did not induce cytokine release 
in blood from any donor. 
Study D4190C00006: The safety profile of durvalumab and tremelimumab combination 
therapy in the 102 subjects with advanced NSCLC in Study D4190C00006 is generally 
consistent with that observed across 177 subjects treated with durvalumab and tremelimumab 
combination therapy (not including subjects treated with blinded investigational product). As 
of 15Apr2015, 95 of 102 subjects (93.1%) reported at least 1 AE. All subjects in the 
tremelimumab 3 and 10 mg/kg dose cohorts experienced AEs; subjects in the durvalumab 
20 mg/kg and tremelimumab 1 mg/kg Q4W cohort experienced the lowest AE rate (77.8%). 
Treatment-related AEs were reported in 74 of 102 subjects (72.6%), with events occurring in 
> 10% of subjects being diarrhea (27.5%), fatigue (22.5%), increased amylase and pruritus 
(14.7% each), rash (12.7%), colitis (11.8%), and increased lipase (10.8%). Treatment-related 
≥ Grade 3 AEs reported in ≥ 5% of subjects were colitis (8.8%), diarrhea (7.8%), and increased 
lipase (5.9%). Five subjects reported treatment-related Grade 4 events (sepsis, increased ALT, 
and increased AST in 1 subject; increased amylase in 2 subjects; myasthenia gravis in 1 subject; 
and pericardial effusion in 1 subject) and 2 subjects had treatment-related Grade 5 events 

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(polymyositis and an uncoded event of neuromuscular disorder [VT]); the Grade 4 event of 
myasthenia gravis and Grade 5 polymyositis occurred in 1 subject. There were 2 subjects (both 
in the MEDI4736 20 mg/kg + tremelimumab 3 mg/kg Q4W cohort) with dose-limiting toxicities 
(DLTs): 1 subject with Grade 3 increased AST, and 1 subject with Grade 3 increased amylase 
and Grade 4 increased lipase. Fifty-six subjects (54.9%) reported SAEs, with events occurring 
in > 5% of subjects being colitis (9.8%) and diarrhea (7.8%). Thirty-six subjects (35.3%) 
experienced treatment-related SAEs. Twenty-seven subjects (26.5%) permanently discontinued 
treatment due to AEs. Treatment-related AEs resulting in discontinuation in ≥ 2 subjects were 
colitis (7 subjects), pneumonitis (5 subjects), diarrhea (3 subjects), and increased AST 
(2 subjects).Additional safety results from this study are presented in Section 1.3.1 and the 
durvalumab IB.  
In the literature (Error! Reference source not found.), using the combination of the same class 
of drugs (eg, anti-PD-1 and anti-CTLA4 antibodies), specifically nivolumab + ipilimumab in a 
study involving patients with malignant melanoma, the safety profile of this combination had 
shown occurrences of AEs assessed by the Investigator as treatment-related in 93% of treated 
patients, with the most frequent events being rash (55% of patients), pruritus (47% of patients), 
fatigue (38% of patients), and diarrhea (34% of patients).  Grade 3 or 4 AEs, regardless of 
causality, were noted in 72% of patients, with Grade 3 or 4 events assessed by the Investigator 
as treatment-related in 53%.  The most frequent of these Grade 3 or 4 events assessed by the 
Investigator as treatment-related include increased lipase (in 13% of patients), AST (in 13%), 
and ALT levels (in 11%).  Frequent Grade 3 or 4 selected AEs assessed by the Investigator as 
treatment-related in the combination therapy included hepatic events (in 15% of patients), GI 
events (in 9%), and renal events (in 6%).  Isolated cases of pneumonitis and uveitis were also 
observed.   
1.4.2.4 
Fixed Dosing for durvalumab and tremelimumab  
A population PK model was developed for durvalumab using monotherapy data from a Phase 
1 study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
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) and fixed dosing (750 
mg Q2W) 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 was 
selected to approximate 10 mg/kg (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.   
 

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Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) 
[Wang et al. 2014]. Population PK model indicated minor impact of body WT on PK of 
tremelimumab (coefficient of ≤ 0.5). The WT-based (1 mg/kg Q4W) and fixed dosing (75 
mg/kg Q4W; based on median body WT of ~75 kg) regimens were compared using predicted 
PK concentrations (5th, median and 95th percentiles) using population PK model in a simulated 
population of 1000 patients with body weight distribution of 40 to 120 kg. Similar to 
durvalumab, simulations indicated that both body WT-based and fixed dosing regimens of 
tremelimumab yield similar median steady state PK concentrations with slightly less between-
subject variability with fixed dosing regimen.  
 
Similar findings have been reported by others [Ng et al 2006, Wang et al. 2009, Zhang et al, 
2012, Narwal et al 2013]. Wang and colleagues investigated 12 monoclonal antibodies and 
found that fixed and body size-based dosing perform similarly, with fixed dosing being better 
for 7 of 12 antibodies . In addition, they investigated 18 therapeutic proteins and peptides and 
showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-subject 
variability in pharmacokinetic/pharmacodynamics parameters [Zhang et al 2012].  
 
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 weight of 
75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) and 75 mg 
Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is included in the current study.  
 
Fixed dosing of durvalumab and tremelimumab 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 will not be included in this study.   
 
1.4.2.5 
Hypofractionated radiation therapy (HIGRT or SBRT) 
The potential benefit of combining HIGRT or SBRT with immune therapy is to synergize the 
local immune stimulatory properties of hypofractionated radiation therapy with the systemic 
immune stimulatory properties of a CTLA-4 (Tremelimumab) and an anti PDL-1 inhibitor 
(Durvalumab). In animal models, it is known that compared to multiple fractions of RT, fewer 
fractions of RT minimize the killing of the exquisitely sensitive T lymphocytes that folk to the 
immunogenic tumor microenvironment (Lee et al Blood 2009;114:589-95). 
Radiation therapy is not without toxicity, and therefore to limit adverse radiation related 
events, the inclusion and exclusion criteria will include parameters for the HIGRT or SBRT 
treated lesions.  Specifically, only 1-5 lesions will be treated, these should be non-overlapping 

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lesions, that are either previously not radiated, or if previously radiated to >50Gy, a 6 month 
time interval between the last dose of RT and HIGRTor SBRT will be required.  
2. 
STUDY OBJECTIVES 
2.1.1 
Primary objective 
The primary objective of this study is to demonstrate safety and tolerability of durvalumab and 
tremelimumab and palliative radiation therapy in patients with recurrent metastatic squamous 
cell carcinomas of the head and neck previously exposed to an anti PD-1 or PDL-1 monoclonal 
antibody 
2.1.2 
Secondary objective(s) 
2.1.2.1 
Measure objective response rates based on RECIST 1.1. criteria in patients 
receiving the durvalumab, tremelimumab and palliative RT combination 
2.1.2.1     Determine overall and progression free survival in patients enrolled in the study 
2.1.3 
Exploratory objective(s) 
2.1.3.1     Collect serum and archived (or fresh) tissue for correlative studies. 
3. 
STUDY DESIGN 
3.1 
Overview of study design 
This study will be carried out as a single institution, single arm phase I/II unblinded trial.  A 
maximum of 20 patients will be enrolled.  Each patient will be treated with durvalumab, 
tremelimumab and palliative hypofractionated radiation therapy using either HIGRT or SBRT. 
Durvalumab will be continued for 13  
 

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cycles, unless evidence of unacceptable toxicity, disease progression or withdrawal of patient 
consent were to occur.   
 
3.2   
Study Schema   
  
 
The first 6 patients of this study will represent the initial run-in phase of the triplet combination 
of durvalumab, tremelimumab and HIGRTor SBRT.  Fixed doses of Durvalumab and 
Tremelimumab will be administered on day 1 of therapy.  Radiation will be initiated on Week 
3 of the 28 day cycle.  Radiation will be delivered to a total dose of 24 Gy, given in 3 fractions 
of 8Gy every other day.  Durvalumab will be continued for a total of 13 cycles, and 
tremelimumab for a total of 4 cycles unless patient withdraws consent, has confirmed disease 
progression, and/or develops toxicity that results in treatment discontinuation. 
Serum correlative studies will be collected at the following timepoints: at baseline, prior to cycle 
#2, and prior to cycle#4 of treatment. Archived formalin fixed paraffin embedded tissue will be 
collected from patients enrolled.  If the patient does not have archived tissue available, a fresh 
biopsy will be obtained.  
3.3   
Study Oversight for Safety Evaluation 
The primary endpoint of this study is safety and tolerability. Durvalumab and tremelimumab 
will be given at the recommended fixed dosing in patients > 30kg (see section 1.3.1), which has 
been shown to result in minimal toxicity, but encouraging efficacy in NSCLC patients. Since 
the concurrent administration of radiation therapy is previously unstudied in this cohort, the first 
6 patients will represent a run-in phase, and enrollment will be halted until all patients complete 
Screening 
and 
enrolment 
Cycle 1 
 
Day 1 Week 1 
 
Durvalumab1500 mg IV x 1 
Q28 days 
and 
Tremelimumab75mg IV x 1 
Q28 days 
 
Week 3 
 
Radiation therapy every other 
day to a total dose of 24Gy  
Cycles 2-4 
 
Durvalumab 1500 mg IV x 1 
Q28 days 
 
and 
 
Tremelimumab 75mg IV x 1 
Q28 days 
Cycles 5 -13  
 
 
Durvalumab1500 mg IV x 1 Q28 
days 
 
 

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the first two cycles of treatment (8weeks) These 6 patients will be assessed for DLTs and will 
determine if a modified dosing schedule of durvalumab and tremelimumab will be applied in 
the expansion phase.   
In keeping with the study primary endpoint, a stopping rule will be implemented in the 
unlikely event that the combination under study is deemed to have unacceptably high 
toxicities. Enrollment will be halted if more than 3 patients experience a Grade 4 or higher 
drug related toxicity (CTCAE v. 4) during the trial or up to 30 days after the last 
investigational drug infusion. The likelihood of observing 3 or more Grade 4+ drug-related 
DLTs is 80% if the true rate is 20% and the likelihood is 91% if the true rate is 25%.   This 
rule has an 83% chance of stopping in the 1st 10 patients if the true rate is 40%.  Section 10.2.2 
provides some guidelines on the attribution of toxicity to the drug and radiation combination. 
The study will be reviewed by the University of Washington/Fred Hutchinson Cancer 
Research Center Data Safety and monitoring board. 
4. 
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL  
 
Each patient must meet all of the inclusion criteria (Section 4.1) and none of the exclusion 
criteria (Section 4.2) for this study.  Under no circumstances will there be exceptions to this 
rule.   
4.1 
Inclusion criteria 
 
1.  
Histologically proven recurrent/metastatic squamous cell carcinoma arising from a 
previous head and neck primary site, and located within the head and neck region, lung 
mediastinum, lymph nodes, soft tissue metastases or bone, and who are not candidates 
for curative intent therapy. 
 
2.         Be ≥18 years old at the time of signing informed consent and have an actual body 
weight > 40kg. 
 
3.         Demonstrated disease progression during, or after discontinuation, of the most recent 
line of systemic therapy. 
 

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4.         Have received any number lines of prior systemic therapy (including systemic therapy 
in the curative intent setting, and including a platinum containing regimen). 
 
5.          Have received an anti-PD1 or anti PDL1 monoclonal antibody. 
 
6.        Have a target lesion/s deemed suitable by the treating physicians for hypofractionated 
radiation therapy (HIGRT or SBRT) with the intent of palliation or prevention of 
symptoms. This lesion must be: a) 1-3 non overlapping sites in the head and neck region 
OR b) metastatic lesions outside the H&N region in the lung mediastinum, soft tissue 
metastases, lymph nodes or bone (a minimum of 1 and a maximum 5 lesions will be 
irradiated), provided there is no significant overlap between the lesions.  Patients should 
have RECIST 1.1 criteria measurable disease in addition to the lesion/s treated with 
radiation. If the site/s of radiation were previously radiated to high dose RT (>50Gy), 
there should be >6 month time interval between the last dose of radiation and the start 
of radiation. .  
 
7.        Have the ability to tolerate required radiotherapy-related procedures(eg: lie flat and 
hold position for treatment) as determined    by the treating physician 
 
8.        Be willing and able to provide written informed consent for the trial and comply with 
the study visit requirements 
 
9.         Have measurable disease based on RECIST 1.1. (in addition to the lesion/s that will be 
treated with hypofractionated radiation therapy) 
 
10.      Have provided tissue from an archival tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion. 
 
11.      Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
12.      Demonstrate adequate organ function as defined in below, based on screening labs 
should be performed within 10 days of treatment initiation.  

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− 
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>60 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) 
= 
Weight 
(kg) 
x 
(140 
– 
Age) 
 
 
 
 
 
 
. 
72 x serum creatinine (mg/dL) 
 
 
 
Females: 
 
 
Creatinine 
CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)        x 
0.85 
72 x serum creatinine (mg/dL) 
 
 
13.       Evidence of post-menopausal status OR negative urinary or serum pregnancy test for 
female pre-menopausal patients. Women will be considered post-menopausal if they 
have been amenorrheic for 12 months without an alternative medical cause. The 
following age-specific requirements apply:  
− 
Women <50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone and follicle-
stimulating hormone levels in the post-menopausal range for the institution or 
underwent surgical sterilization (bilateral oophorectomy, or hysterectomy).  

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− 
Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 
year ago, had chemotherapy-induced menopause with last menses >1 year ago, 
or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy). 
 
14.       Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required. 
   
15. 
Female subjects of childbearing potential should be willing to use 1 method of highly 
effective birth control or be surgically sterile, or abstain from heterosexual activity for 
the course of the study through 180 days after the last dose of study medication 
(Reference Section 7.1).  Subjects of childbearing potential are those who have not 
been surgically sterilized or have not been free from menses for > 1 year.  
16. 
Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 180 days after the last dose of study therapy. 
17. 
Patient is ≥ 5 years free of another primary malignancy, except: a) if the other 
malignancy is basal cell carcinoma or cervical carcinoma in situ or b) if the other 
primary malignancy is not considered clinically significant and is requiring no active 
intervention 
 
 
4.2 
Exclusion criteria 
The subject must be excluded from participating in the trial if the subject: 
 
1. 
  Has a body weight ≤40kg at the time of enrollment 
        
2. 
Is currently participating in or has participated in a study of an investigational agent or 
using an investigational device within 4 weeks of the first dose of treatment. 
 
3.           Has a target lesion/s for radiotherapy that is > 5 cm (> 50 cc) in greatest dimension 

9881 
 
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4.          Has a target lesion/s in a region that previously received high dose RT (>50 Gy) 
demonstrating any of the following:  
a. carotid artery encasement (> 180 degrees)  
b. unprotected carotid artery (i.e. skin is directly over the carotid without 
intervening soft tissue, especially after prior neck dissection without a 
vascularized free flap) (a&b due to risk of carotid blow out) 
c. skin infiltration by tumor (due to risk of fistula) 
d. located in the larynx/hypopharynx primaries (due airway threat) 
treated with high dose radiation therapy (>50 Gy) within 6 months or less of 
trial enrollment 
 
 
5.  
Any prior Grade ≥3 immune-related adverse event (irAE) while receiving a prior 
immunotherapy agent, or any unresolved irAE >Grade 1 
 
6. 
Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab or tremelimumab. The following are exceptions to this criterion: 
-     Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular 
injection) 
- 
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent 
- 
Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication 
7.         Has received a prior monoclonal antibody within 4 weeks prior to study Day 1 or who 
has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier.  
 
8.         Has received prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 
or at baseline) from adverse events due to a previously administered agent. 
            -Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 

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            -Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
 
9. 
Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy.  
 
10.         Has known brain metastases or spinal cord compression unless the patient is stable 
(asymptomatic; no evidence of new or emerging brain metastases; and stable and off 
steroids  for at least 14 days prior to start of study treatment). Following radiotherapy 
and/or surgery of the brain metastases patients must wait 4 weeks following the 
intervention and before initiating study treatment with imaging to confirm stability.   
 
11. 
Has an active autoimmune disease requiring systemic treatment within the past 2 years 
or a documented history of clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents.  Subjects with vitiligo or 
resolved childhood asthma/atopy would be an exception to this rule.  Subjects that 
require intermittent use of bronchodilators or local steroid injections would not be 
excluded from the study.  Subjects with hypothyroidism stable on hormone 
replacement will not be excluded from the study. 
 
12. 
Has evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history    
of ILD or pneumonitis requiring oral or intravenous glucocorticoids 
 
13.       Has an active infection requiring systemic therapy. 
 
14.    Requires therapeutic anticoagulation or has known active bleeding diathesis  
 
15.       Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator. 
 
16.       Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 

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17.       Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
180 days after the last dose of trial treatment. 
 
18.       Has received prior therapy with an anti-Cytotoxic T-lymphocyte-associated antigen-4 
(CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways).  
 
19.       Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
20.      Has evidence of acute or chronic hepatitis B, or   hepatitis C 
 
21. 
Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
 
22. 
Has a Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using  Fredericia’s Correction  
 
23. 
Has a history of primary immunodeficiency or an allogeneic organ transplant 
  
24. 
Has a history of hypersensitivity to durvalumab or tremelimumab excipient  
 
25. 
Known history of previous clinical diagnosis of tuberculosis 
 
26. 
Uncontrolled intercurrent illness including, but not limited to symptomatic congestive 
heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active 
peptic ulcer disease or gastritis, seizures 
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3. 
Withdrawn patients will not be replaced. 
4.3 
Withdrawal of Subjects from Study Treatment and/or Study 
Permanent discontinuation of durvalumab and or tremelimumab   
 
An individual subject will not receive any further investigational product if any of the following 
occur in the subject in question: 

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• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmation of PD and investigator determination that the subject is no longer 
benefiting from treatment with durvalumab + tremelimumab 
• Any AE that meets criteria for discontinuation as defined in Section 10.3. 
• Adverse event that, in the opinion of the investigator or the sponsor, contraindicates 
further dosing 
• Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; e.g., refusal to adhere to scheduled visits 
• Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 13 cycles of durvalumab 
• Grade ≥ 3 infusion reaction 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.   
Subjects who are permanently discontinued from receiving investigational product will be 
allowed for safety per Appendix 2 or 3, including the collection of any protocol-specified blood 
specimens, unless consent is withdrawn or the subject is lost to follow-up or enrolled I another 
clinical study.  All subjects will be followed for survival.  Subjects who decline to return to the 
site for evaluations will be offered follow-up by phone every 3 months as an alternative. 

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4.4 
Replacement of subjects 
Replacement of Patients in Run in Phase 
Patients who received <90% of the durvalumab and tremelimumab  infusion in Cycle 1 (e.g., 
because the infusion had to be discontinued due to an infusion reaction) and did not experience 
a DLT will not be taken into account in the assessment of the overall DLT rate for the phase I 
run in cohort and need to be replaced. 
If a patient experiences a DLT in Cycle 1, study therapy may be discontinued following 
discussion and agreement between the Sponsor and Investigator.  
5. 
INVESTIGATIONAL PRODUCT(S) 
5.1 
Durvalumab and tremelimumab 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
durvalumab and tremelimumab to the investigator as solutions for infusion after dilution.   
5.1.1 
Formulation/packaging/storage 
Durvalumab 
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 10.0 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. 
Tremelimumab 
Tremelimumab will be supplied by AstraZeneca as a 400-mg or 25-mg vial solution for infusion 
after dilution. The solution contains 20 mg/mL of tremelimumab, 20 mM histidine/histidine 
hydrochloride, 222 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, and 0.27 mM 
disodium edetate dihydrate (EDTA); it has a pH of 5.5. The nominal fill volume is 20.0 mL. 
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Tremelimumab must be used within the individually assigned expiry date on the label. 

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5.2 
Dose and treatment regimens 
5.2.1 
Treatment regimens 
Durvalumab + tremelimumab combination therapy 
Patients (> 30kg in weight) will receive 1500 mg durvalumab via IV infusion q4w for up to 4 
doses/cycles and 75 mg tremelimumab via IV infusion q4w for up to 4 doses/cycles, and then 
continue 1500 mg durvalumab q4w starting on Week 16 for a total of 13 doses.  Dosing outside 
the window should be discussed with the Study Physician.  Tremelimumab will be administered 
first.  Durvalumab infusion will start 1 hour (+/- 5 mins.) after the end of tremelimumab 
infusion.  The duration will be 1 hour(+/- 5 mins.)  for each infusion.  A 1 hour (+/- 5 mins.) 
observation period is required after the first infusion of durvalumab and tremelimumab.  If no 
clinically significant infusion reactions are observed during or after the first cycle, subsequent 
infusion observation periods can be at the Investigator’s discretion (suggested a minimum of 30 
minutes after each durvalumab and tremelimumab infusion).   
5.2.2 
Duration of treatment and criteria for retreatment 
For patients receiving durvalumab + tremelimumab, retreatment is allowed (once only) for 
patients meeting the retreatment criteria below.  The same treatment guidelines followed during 
the initial 12-month treatment period will be followed during the retreatment period, including 
the same dose and frequency of treatments and the same schedule of assessments.  Radiotherapy 
is not required during retreatment, although it may be considered per the discretion of the 
treating physician. 
Patients receiving the combination of durvalumab and tremelimumab may undergo retreatment 
in 2 clinical scenarios, described below:   
1. Patients who achieve and maintain disease control (ie, CR, PR, or SD) through to the 
end of the 12-month treatment period may restart treatment with the combination upon 
evidence of PD, with or without confirmation according to RECIST 1.1, during follow-
up.  
2. Patients who complete the 4 dosing cycles of the combination of durvalumab and 
tremelimumab portion of the regimen (with clinical benefit per Investigator judgment), 
but subsequently have evidence of PD during the durvalumab monotherapy portion of 
the combination regimen, with or without confirmation according to RECIST 1.1, may 
restart treatment with the combination.   
3. For the durvalumab + tremelimumab treatment group, before restarting their assigned 
treatment, the Investigator should ensure that the patient:   

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a. Does not have any significant, unacceptable, or irreversible toxicities that 
indicate continuing treatment will not further benefit the patient 
b. Still fulfils the eligibility criteria for this study, including re-consenting to restart 
durvalumab and tremelimumab 
c. Has not have received an intervening systemic anticancer therapy after their 
assigned treatment discontinuation.   
d. Has had a baseline tumor assessment within 28 days of restarting their assigned 
treatment; all further scans should occur with the same frequency as during the 
initial 12 months of treatment (relative to the date of randomization) until study 
treatment is stopped (maximum of 13 cycles).   
During the retreatment period, patients (> 30kg) receiving durvalumab + tremelimumab may 
resume durvalumab dosing at 1500 mg q4w with 75 mg of tremelimumab q4w for 4 doses each.  
Patients will then continue with durvalumab monotherapy at 1500 mg q4w, beginning at Week 
16, for a total of 13 doses.   
Treatment through progression is at the Investigator’s discretion, and the Investigator should 
ensure that patients do not have any significant, unacceptable, or irreversible toxicities that 
indicate that continuing treatment will not further benefit the patient.  A patient with a confirmed 
progression receiving durvalumab + tremelimumab  cannot continue therapy or obtain 
retreatment if dosing is ongoing in the combination portion of therapy (q4w dosing). 
Patients who AstraZeneca and/or the Investigator determine may not continue treatment will 
enter follow-up.   
5.2.3 
Study drug preparation of durvalumab and tremelimumab 
Based on average body WT of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 
20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is included in 
the current study.  for patients > 30kg in weight.  
 
In patients whose weight falls to 30kg or less dosing should be delayed (for up to a maximum 
of 2 treatment cycles) until their weight returns to 30kg or higher when dosing can be resumed 
at the next cycle. If the weight does not return to 30kg or higher after a maximum 2 cycle delay 
then dosing should be permanently discontinued). Patients whose weight is below 30kg should 
not be dosed as they would be exposed to endotoxin levels that exceed the USP specification 
limit). 
 

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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.  
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have 
been observed. Dose of 1500mg durvalumab for patients >30 kg will be administered using an 
IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, 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.  Add 30.0 mL of durvalumab (ie, 1500 mg of durvalumab) to 
the IV bag. The IV bag size should be selected such that the final concentration is within 1 to 
20 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled 
infusion 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 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 

9881 
 
59 
 
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 in 
the table, a new dose must be prepared from new vials.  Durvalumab does not contain 
preservatives, and any unused portion must be discarded. 
Preparation of tremelimumab doses for administration with an IV bag 
The dose of tremelimumab 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 
tremelimumab 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 storage time exceeds these limits, a new dose must be prepared from new vials. The infusion 
solutions in the prepared final IV bag should be equilibrated to room temperature prior to 
administration.  
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin IV bags have 
been observed. However, administration sets containing cellulose-based filters should not be 
used with tremelimumab. Doses of 75 mg tremelimumab for patients >30 kg will be 
administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final 
tremelimumab concentration ranging from 0.10 mg/mL to 10 mg/mL, and delivered through an 
IV administration set with a 0.2- μm or 0.22 μm in-line filter. Add 3.8 mL (ie, 75 mg of 
tremelimumab) to the IV bag. In the event that a 50mg tremelimumab dose is required, add 2.5 
mL (ie, 50 mg of tremelimumab) to the IV bag. The IV bag size should be selected such that 
the final concentration is within 0.10 to 10 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag. 
Tremelimumab will be administered at room temperature (approximately 25°C) by controlled 
infusion into a peripheral or central vein. Following preparation of tremelimumab, 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. 

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The IV line will be flushed with a volume IV solution 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. 
Tremelimumab 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 in 
the table, a new dose must be prepared from new vials.  Tremelimumab does not contain 
preservatives, and any unused portion must be discarded. 
 
5.2.4 
Monitoring of dose administration 
Patients will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the Study Protocol. 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion.  For patients with a ≤Grade 2 infusion-related 
reaction, subsequent infusions may be administered at 50% of the initial rate.  Acetaminophen 
and/or an antihistamine (eg, 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. 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis.  The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
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5.2.5 
Accountability and dispensation 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational products in accordance with the protocol and any applicable laws and 
regulations. Clinical supplies will be provided by AstraZeneca and affixed with a clinical label 
in accordance with regulatory requirements. Clinical supplies must be stored in a secure, 
limited-access location under the storage conditions specified on the label. Receipt and 
dispensing of trial medication must be recorded by an authorized person at the trial site. Clinical 
supplies may not be used for any purpose other than that stated in the protocol. 
5.2.6 
Disposition of unused investigational study drug 
The site will account for all investigational study drug dispensed and also for appropriate 
destruction.  Certificates of delivery and destruction must be signed. 
 
5.3 
Radiation therapy 
 
All subjects will be immobilized in a custom designed device in the appropriate position to 
isolate the index lesion. Radiotherapy treatment planning CT scans (with contrast, unless 
contraindicated) will be required to define the gross target volume (GTV) Clinical target volume 
(CTV) and planning target volume (PTV). The use of IV contrast is left to the discretion of the 
treating physician PET-CT and/or MRI imaging are preferred although not required to delineate 
volumes as accurately as possible. The treatment planning CT scan should be acquired with the 
subject in the same position and immobilization device, as for the treatment. Treatment planning 
will be performed using a 3D CT based treatment planning system. All tissues to be irradiated 
must be included in the CT scan. Planning CT scan will be obtained with a uniform slice 
thickness of less than or equal to 3 mm throughout and encompass the region of interest with 
sufficient margin for treatment planning. 
All lesions with potential for respiratory motion should be evaluated by appropriate means 
including 4D CT scan and/or implanted fiducial marker(s). Respiratory motion management 
including but not limited to abdominal compression, active-breathing control (ABC), 
respiratory gating and fiducial marker tracking, will be employed for qualifying patients per 
standard clinical practice. 

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Daily image guidance will be employed for target localization. This is most commonly 
performed with volumetric imaging (cone-beam CT). 
5.3.1 Radiotherapy Targeting and Treatment 
HIGRT and SBRT have now been formally defined and described in a published guideline from 
the American College of Radiology and American Society for Therapeutic Radiology and 
Oncology (Potters 2004). This protocol will respect that guideline. The term stereotactic, for the 
purposes of this protocol, implies the targeting, planning, and directing of therapy using beams 
of radiation along any trajectory in 3-D space toward a target of known 3-D coordinates. The 
coordinate system is defined by reliable “fiducial” markers. This differs from conventional 
radiation therapy, in which therapy is directed toward less-than-reliable skin marks or bony 
landmarks that are indirectly referenced to the tumor (surrogates). This protocol will require 
treatments to be conducted with the use of a fixed 3-D coordinate system defined by fiducials. 
The coordinate system defined by the fiducials should be directly related to the radiation-
producing device in a reproducible and secure fashion. Capability should exist to define the 
position of targets within the patient according to this same 3-D coordinate system. As such, the 
patient is set up for each treatment with the intention of directing the radiation toward a target 
according to the known 3-D coordinates as determined in the process of treatment planning. 
The nature of the fiducials themselves may include radiopaque markers or rods placed at known 
locations in a frame or fixed structure adjacent to the patient as well as use of the tumor itself 
as a fiducial (For example acquiring tomographic views of the tumor simultaneously with the 
treatment with a cone beam CT scan (CBCT)). Metallic “seeds” placed within the tumor will 
be allowed to constitute a fiducial so long as the methods are validated and a plan is in place to 
identify seed migration (e.g., redundant seeds placed). 
 
 
5.3.2. Target Contouring 
Gross Tumor Volume (GTV) is defined as all known gross disease encompassing the selected 
index lesion. The GTV will consist of the index lesion as visualized on CT +/- PET/CT, 
and/or MRI. Image fusion is encouraged when using multiple modalities to define the GTV. 
Clinical Target Volume (CTV) will be the same as GTV for most cases. In case of 
uncertainty, GTV may be expanded to CTV by 2-3mm per clinician discretion.  
Internal Gross Tumor Volume (IGTV) is defined for mobile index lesions at the discretion of 
the treating physician. For mobile index lesions, a 4-D CT scan will be acquired in order to 
account for the motion of the lesion during treatment. The IGTV will be defined as the union 
of the visualized index lesion on all gated CT data sets. 

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Planning Target Volume (PTV) will be defined as per convention for photon beam 
radiotherapy. A 3-dimensional margin of 3-5mm will be created on the CTV or IGTV (if 
available) to allow for daily set-up variance. For Proton beam radiotherapy, an additional 
range uncertainty is added during planning. 
Organ at risk volume (OAR) is contoured as visualized on the planning CT or MR scan. 
Planning organ at risk volume (PRV) is the OAR expanded for setup uncertainty or organ 
motion. The physician will contour the OAR. The dosimetrist will create the PRV by 
expanding the OAR by 1-3 mm, depending on the situation.  
Pertinent Organs at Risk (OARs) in the index region are contoured as applicable to the region 
being treated by HIGRTor SBRT: 
 
 
Spinal cord, Brain stem, Brachial plexus (roots & trunks), Cauda equina,  
                        Sacral plexus 
 
 
Optic pathways – optic nerves, optic chiasm, Retina, Cornea 
 
 
Carotid artery (Internal & common),  
 
 
Cochlea & vestibular apparatus 
  
 
Parotid and Sub mandibular glands 
 
 
Skin (3-5 mm of body outline) 
Larynx (infrahyoid supraglottis to bottom of cricoid. Only include the 
endolarynx within the cartilaginous framework                                               
 
 
Other uninvolved mucosal structures eg: oral cavity & pharynx 
 
 
Facial Bones : Mandible, Maxilla, temporal bone that pertain to index region 
                        Esophagus 
                        Heart and Pericardium 
                        Lungs 
                        Ribs 
                        Trachea and Large/Central Bronchi 

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                        Bronchii – smaller airways 
Liver 
Stomach, Duodenum, Small Bowel 
 5.3.3. Radiation Treatment planning, dose fractionation and organs at risk specification 
Computer based planning & quality assurance (QA) will be performed using our standard 
institutional HIGRT and SBRT guidelines, to deliver HIGRT or SBRT to the index lesion(s), 
including static 3D coplanar and/or non-coplanar beam arrangements as well as dynamic 
conformal arcs. Corrections for tissue heterogeneity, and robustness analysis (for Proton 
therapy) will be made. Treatment planning may be performed with 3D-CRT, IMRT, VMAT 
or, Proton beam RT (Pencil beam RT or Uniform scanning). 
3D coplanar or non-coplanar beam arrangements will be custom designed for each case to 
deliver highly conformal prescription dose distributions. Non-opposing, non-coplanar beams 
are preferable. Typically, >/= 5-10 beams of radiation will be used with roughly equal 
weighting. Generally, more beams are used for lesions that are in very close proximity to a 
critical OAR to produce appropriately protective concave dose distributions with a steep dose 
gradient between the target lesion and the OAR. 
For arc rotation techniques, a minimum of 340 degrees (cumulative for all beams) should be 
utilized.  
Proton beam planning is performed with 2-4 beams.  In order to obtain acceptable coverage, 
field aperture size and shape should correspond nearly identically to the projection of the PTV 
along a beam’s eye view (i.e., no additional “margin” for dose buildup at the edges of the 
blocks or MLC jaws beyond the PTV). The only exception should be when observing the 
minimum field dimension of 3.5 cm when treating small lesions (see above).  
Radiotherapy prescription: The dose prescription will be as follows: 24 Gy given in 3 
fractions to PTV (80-95% IDL)  delivered at 8 Gy per fraction every other day. however, a 
dose reduction to 6 Gy per fraction will be permitted if 8 Gy is not achievable due to dose 
constraints. 
Dose Uniformity: 95% of the planning target volume (PTV) should be covered by the 
prescription dose (PTV V95%RX = 100%) and 99% of the planning target volume (PTV) 
should receive a minimum of 90% of the prescription dose (PTV V99%RX > 90%). 99% of 
the CTV should receive a minimum of 98% of the prescribed dose (CTV V99%RX >98%); 
however, higher isodoses (hotspots) of > 105% of prescribed dose must be manipulated to 
occur within the target and not in adjacent normal tissue.  
Dose rate: For the purpose of this study, dose rate utilized will be that which is commissioned 
by the manufacturer and the medical physics group for external beam radiotherapy delivery by 

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the  treating institution. There will be no special dose rate modifications required for this 
study. 
Critical Organ Doses: For de novo cases (no prior RT) all the following critical organ dose-
volume limits will be respected. 
 
The following PRV dose constraints may be used as guidelines: (adopted from Timmerman 
RD. An overview of hypofractionation. Seminars of Radiation Oncology 2008 Oct;18(4):215-
222 and Lo SS et al. Serious Complications Associated with Stereotactic Ablative 
Radiotherapy and Strategies to Mitigate the Risk. Clinical Oncology 2013 Jun;25(6):378-387). 
Spinal cord  PRV max 20 Gy 
Spinal cord max 18 Gy 
Brain stem max 22.5 Gy, 18 Gy (< 0.5cc) 
Optic chiasm max 15 Gy, 12 Gy (< 0.2cc) (for bilateral blindness risk) 
Ipsilateral Optic nerve max 18 Gy, 15 Gy (< 0.2cc) 
Contralateral optic nerve max 12 Gy, 10 Gy (< 0.5cc)  
Carotid artery max 15 Gy, (V12 Gy to < 30% of carotid volume) 
Brachial plexus max 24 Gy, 20 Gy (< 3cc)   
Esophagus* max 24 Gy, 17 Gy (< 5cc) 
Heart/Pericardium max 27 Gy, 24 Gy (< 15cc) 
Trachea*  max 24 Gy, 15 Gy (< 4cc) 
Bronchus max 24 Gy, 15 Gy (< 1cc) 

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Ribs max 27 Gy, 24 Gy (< 5cc) 
Skin max 27 Gy, 24 Gy (<10cc) 
Lung (Right & Left) – V20 < 10%, 11.4 Gy (< 1000cc) 10.5 Gy (< 1500cc) 
Great vessels, non-adjacent wall max 27 Gy, 24 Gy ( < 10cc) 
Liver – spare >700cc to </=17.1 Gy 
Stomach – max 22.2 Gy, 16.5 Gy to < 10cc 
Colon – max 27 Gy, 24 Gy (<20cc) 
Renal cortex (right and left) 15 Gy (>65%), 14.4 Gy (200cc) 
Rest of OARS = ALARA 
* avoid circumferential radiation 
For re-irradiation cases, the above constraints do not apply. The treating physician’s discretion 
would be used in such cases based on the previous dose exposure to various OARs as 
determined from the prior treatment plan and clinical goals. 
Planning Priorities and Dose specifications 
Every attempt will be made to successfully satisfy all of the planning goals and OAR criteria 
without deviation. All critical organ dose-volume limits will be respected. As far as possible, 
all OAR constraints will be met while providing full coverage to the PTV. In some cases, it 
may not be possible to meet all planning goals. In such cases, OAR constraints and PTV 
coverage will be balanced per the discretion of the treating physician. Brain stem, optic 
nerves, optic chiasm, spinal cord, brachial plexus, cauda equine and sacral plexus dose 
constraints must be respected over PTV coverage. In cases of other OAR constraints, which 
are not well validated, PTV coverage and OAR constraints must be balanced per clinical 
practice at the discretion of the treating physician. 

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Image Guidance: 
Image guided RT (IGRT) is required with physician review per institutional QA requirements 
before each treatment is delivered. Cone beam CT will be matched to target volume to be 
treated and bony anatomy or other defined fixed fiducials. If CBCT is unavailable, orthogonal 
pair KV imaging matched to stable bony anatomy closest to PTV is acceptable. 
 
6.  TREATMENT PLAN 
The Trial Flow Chart – in Protocol Synopsis, summarizes the trial procedures to be performed 
at each visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
AstraZeneca for reasons related to subject safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations 
6.1 Subject enrollment  
6.1.1 Procedures for enrollment 
Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 

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subject’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature. 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
Prior and Concomitant Medications Review 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement. 
 
Disease Details and Treatments 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 

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first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
6.1.2 
Procedures for handling subjects incorrectly enrolled patients  
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 
4.3 
 
6.2.  Dosage and Administration 
The treatment to be used in the run in phase of this trial for patients > 30kg is outlined in the 
Table below: 
Drugs 
Dose/Potency 
Dose Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
1. Durvalumab 
 
 
1500 mg 
 
Q4 weeks  
 
IV infusion 
Maximum of 13 doses 
 
2. Tremelimumab 
75mg 
Q4 weeks 
IV infusion 
Maximum of  4 doses 
If 2 or more DLTs (defined in Section 6.4) are observed in the run-in phase, the following 
treatment will be used for the remaining 14 patients to be treated on the clinical trial protocol: 
Drugs 
Dose/Potency 
Dose Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
1. Durvalumab 
 
 
1500 mg 
 
Q6 weeks  
 
IV infusion 
Maximum of 9 doses 
 
2. Tremelimumab 
75mg 
Q6 weeks 
IV infusion 
Maximum of  3 doses 
 
Patients who experience a DLT in the run in phase, will have dose interruptions/modifications 
as outlined in Appendix 1. 
6.3 Dose Escalation Decision Rules 
There will be no dose escalations performed on this study.  

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6.4 Definition of DLT 
Dose-limiting toxicities (DLTs) will be evaluated during the run in phase consisting of the first 
6 patients enrolled in this trial.  The period for evaluating DLTs will be from the time of first 
administration of durvalumab or tremelimumab until 28 days (cycle 1).  Adverse event 
monitoring will continue for these subjects throughout the course of their treatment (beyond 
cycle 1) as outlined in the Schedule of Study Assessments, these adverse events will include 
potential XRT related toxicities.  Subjects who do not remain on the study up to this time for 
reasons other than DLT will be replaced with another subject. Grading of DLTs will follow the 
guidelines provided in the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0.   
A DLT will be defined as any Grade 3 or higher toxicity that occurs during the DLT evaluation 
period. Toxicity that is clearly and directly related to the primary disease or to another etiology 
is excluded from this definition. The following will be DLTs: 
• 
Any Grade 4 irAE 
• 
Any ≥ Grade 3 colitis 
• 
Any Grade 3 or 4 noninfectious pneumonitis irrespective of duration 
• 
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 or pneumonitis, 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 > 8 × ULN or total bilirubin > 5 × ULN 
• 
Any ≥ Grade 3 non-irAE, except for the exclusions listed below 
• 
Grade 3 fatigue lasting ≤ 7 days 
• 
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the subject is asymptomatic 
• 
Grade 3 inflammatory reaction attributed to a local antitumor response (eg, 
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 

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• 
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 
 
• Prolonged delay (>2 weeks) in initiating cycle 2 due to treatment-related toxicity 
• Grade 5 toxicity, i.e. death 
 
Dose modification/delays according to Section 6.5.1 and Appendix 1 will apply to the patients 
who experience DLTs in the run in phase. 
Immune-related AEs are defined as AEs of an immune nature (ie, inflammatory) in the absence 
of a clear alternative etiology. In the absence of a clinically significant abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings prior to 
designation as a DLT.  
6. 5 Dose Modification and Toxicity Management 
6.5.1 Durvalumab and tremelimumab 
For adverse events (AEs) that are considered at least partly due to administration of 
durvalumab (or durvalumab and tremelimumab for cycles 1-4) the following dose adjustment 
guidance may be applied: 
• 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 or durvalumab and tremelimumab along 
with appropriate continuing supportive care.  If medically appropriate, dose 
modifications are permitted for durvalumab and tremelimumab (see Appendix 1). 
• All dose modifications should be documented with clear reasoning and documentation 
of the approach taken. 
 
In addition, there are certain circumstances in which durvalumab or tremelimumab should be 
permanently discontinued.(see Section 4.3) 
 

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Following the first dose of durvalumab or tremelimumab, subsequent administration of 
durvalumab or tremelimumab can be modified based on toxicities observed (see Appendix 1).   
Based on the mechanism of action of durvalumab or tremelimumab 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 are 
detailed in Appendix 1.   
In addition, management guidelines for adverse events of special interest (AESIs) are detailed 
in Section 10.1.3. All toxicities will be graded according to NCI CTCAE v4.03.  
 
 
7. RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) 
7. 1 Restrictions during the study 
 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after: 
Female patient of child-bearing potential 
− 
Females of childbearing potential who are sexually active with a non-sterilized 
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 for 180 days after the last dose of durvalumab  + tremelimumab 
combination therapy or 90 days after the last dose of durvalumab monotherapy. 
Non-sterilized male partners of a female patient must use male condom plus 
spermicide throughout this period. Cessation of birth control after this point 

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should be discussed with a responsible physician. Not engaging in sexual 
activity for the total duration of the drug treatment and the drug washout period 
is an acceptable practice; however, periodic abstinence, the rhythm method, and 
the withdrawal method are not acceptable methods of birth control. Female 
patients should also refrain from breastfeeding throughout this period. 
Male patients with a female partner of childbearing potential 
− 
Non-sterilized males who are sexually active with a female partner of 
childbearing potential must use a male condom plus spermicide from screening 
through 180 days after receipt of the final dose of durvalumab  + tremelimumab 
combination therapy or 90 days after receipt of the final dose of durvalumab 
monotherapy. Not engaging in sexual activity is an acceptable practice; 
however, occasional abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of contraception. Male patients should 
refrain from sperm donation throughout this period. 
− 
Female partners (of childbearing potential) of male patients must also use a 
highly effective method of contraception throughout this period (Table ).  
Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.  
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply:  
• 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
• 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy). 
Highly effective methods of contraception, defined as one that results in a low failure rate (ie, 
less than 1% per year) when used consistently and correctly are described in Table 2. Note that 
some contraception methods are not considered highly effective (eg. male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-
copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills 

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where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel 
which is considered highly effective]; and triphasic combined oral contraceptive pills). 
Table 2. Highly effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a 
 
• 
Etonogestrel implants: eg, Implanon or 
Norplan 
• 
Intravaginal device: eg, ethinylestradiol 
and etonogestrel 
• 
Medroxyprogesterone injection: eg, 
Depo-Provera  
• 
Normal and low dose combined oral 
contraceptive pill 
• 
Norelgestromin/ethinylestradiol 
transdermal system 
• 
Cerazette (desogestrel) 
a 
This is also considered a hormonal method 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after: 
Females of childbearing potential who are sexually active with a non-sterilized male partner 
must use 2 methods of effective contraception (Table 1) from the time of screening and must 
agree to continue using such precautions for 180 days after the last dose of durvalumab + 
tremelimumab combination therapy or 90 days after the last dose of durvalumab 
monotherapy, whichever is the longer time period; cessation of birth control after this point 
should be discussed with a responsible physician.  Periodic abstinence, the rhythm method, 
and the withdrawal method are not acceptable methods of birth control. 
− Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) 
or post-menopausal (defined 12 months with no menses without an alternative 
medical cause). 
Non-sterilized males who are sexually active with a female partner of childbearing potential 
must use 2 acceptable methods of effective contraception (see Table 1) from 
screening through 180 days after receipt of the final dose of durvalumab + 
tremelimumab combination therapy or 90 days after receipt of the final dose of 
durvalumab monotherapy, whichever is the longer time period.   
Restrictions relating to concomitant medications are described in Section 7.2. 

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Table 3. Effective methods of contraception (2 methods must be used) 
Barrier methods 
Intrauterine device methods 
Hormonal methods 
Male condom plus spermicide 
Cap plus spermicide 
Diaphragm plus spermicide 
Copper T 
Progesterone Ta  
Levonorgestrel-releasing 
intrauterine 
system 
(eg, Mirena®)a 
Implants 
Hormonal shot or injection 
Combined pill 
Minipill 
Patch 
a 
This is also considered to be a hormonal method. 
Blood donation 
Subjects should not donate blood while participating in this study or for at least 90 days 
following the last infusion of durvalumab or tremelimumab.   
 
7. 2 Concomitant treatment(s) 
The Principal Investigator must be informed as soon as possible about any medication taken 
from the time of screening until the end of the clinical phase of the study (final study visit).  
Restricted, prohibited, and permitted concomitant medications are described in the following 
sections.  Refer to Appendix 1 for guidance on management of IP-related toxicities. 
7.2.1 Permitted concomitant medications 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” as listed in Section 6.2.2. 
7.2.2Excluded Concomitant Medications 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy other than the protocol specified therapies. 
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment.  Concurrent use of 
hormones for noncancer-related conditions (e.g., insulin for diabetes and hormone 
replacement therapy) is acceptable.   

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3. Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses not 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 and tremelimumab dosing (ie, 
30 days prior to the first dose, during treatment with durvalumab and tremelimumab 
for 30 days post discontinuation of durvalumab and tremelimumab.  Inactivated 
vaccines, such as the injectable influenza vaccine, are permitted. 
   
Table 4. Prohibited and Rescue Medications 
Prohibited medication/class of drug: 
Usage: 
Additional investigational anticancer therapy 
concurrent with those under investigation in this 
study 
Should not be given whilst the patient is on IP 
treatment   
mAbs against CTLA-4, PD-1, or PD-L1 
Should not be given whilst the patient is on IP 
treatment through 90 days after the last dose of IP. 
Any concurrent chemotherapy, local therapy 
(except palliative radiotherapy for non-target 
lesions, 
eg, 
radiotherapy, 
surgery, 
radiofrequency ablation), biologic therapy, or 
hormonal therapy for cancer treatment 
Should not be given whilst the patient is on IP 
treatment. 
(Concurrent 
use 
of 
hormones 
for 
non-cancer-related conditions [eg, insulin for diabetes 
and hormone replacement therapy] is acceptable.) 
Immunosuppressive medications, including, 
but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or its 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor α blockers   
Should not be given whilst the patient is on IP 
treatment. (Use of immunosuppressive medications for 
the management of IP-related AEs or in patients with 
contrast allergies is acceptable.  In addition, use of 
inhaled, topical, and intranasal corticosteroids is 
permitted. 
Live attenuated vaccines 
Should not be given through 30 days after the last dose 
of IP during the study 

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Prohibited medication/class of drug: 
Usage: 
VEGF inhibitors such as sunitinib, sorafenib 
and bevacizumab 
Should not be given 90 days prior to first dose of 
investigational drug and with 30 days after last dose of 
investigational drug 
 
Rescue/supportive medication/class of drug: 
Usage: 
Concomitant 
medications 
or 
treatments 
(eg, acetaminophen 
or 
diphenhydramine) 
deemed necessary by the Investigator to provide 
adequate prophylactic or supportive care, 
except for those medications identified as 
“prohibited” as listed above 
To be administered as prescribed by the Investigator 
Best supportive care (including antibiotics, 
nutritional support, growth factor support, 
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc]) 
Should be used when necessary for all patients 
8. STUDY PROCEDURES 
8.1 Schedule of study procedures 
 
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations are outlined.  The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments.  Clinical 
evaluations and laboratory studies may be repeated more frequently if clinically indicated.  The 
Schedules of Assessments during the screening and treatment period is provided following the 
Protocol Synopsis 
8.1.1 Screening Phase 
Screening procedures will be performed up to 28 days before Day 1, unless otherwise specified.  
All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF before any 
study-specific screening procedures are performed.  After signing the ICF, completing all 
screening procedures, and being deemed eligible for entry, subjects will be enrolled in the study.  

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Procedures that are performed prior to the signing of the ICF and are considered standard of 
care may be used as screening assessments if they fall within the 28-day screening window.  
 
 
The following procedures will be performed during the Screening Visit: 
• Informed Consent 
• Review of eligibility criteria 
• Medical history and demographics 
• Complete physical exam  
• ECOG Performance Status 
• Vitals signs, weight  
• 12-lead ECG (in triplicate [2-5 minutes apart]) 
• Archived tissue or tumor biopsy 
• Review of prior/concomitant medications  
• Imaging by CT/MRI 
• Clinical laboratory tests for: 
o Hematology (see Table 3) 
o Clinical chemistry (see Table 4) 
o TSH with reflexive free T4 
o Coagulation (PT, aPTT, INR) 
o Creatinine Clearance 
o Serum or urine pregnancy test (for women of childbearing potential only) 
o Urinalysis (see Table 7) 
8.1.2 Treatment Phase  
Procedures to be conducted during the treatment phase of the study are presented in the Schedule 
of Assessments.  Screening procedures performed within 72 hours of Cycle 1 Day 1 (C1D1) do 
not need to be repeated on C1D1. 
 
8.1.3 End of Treatment 
 

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End of treatment is defined as the last planned dosing visit within the 12-month dosing period. 
For subjects who discontinue durvalumab or tremelimumab prior to completing all13 cycles, 
end of treatment is considered the last visit where the decision is made to discontinue treatment. 
All required procedures may be completed within  ± 7 days of the end of treatment visit.  
Assessments for subjects who have completed durvalumab and tremelimumab treatment and 
achieved disease control, or have discontinued durvalumab or tremelimumab due to toxicity in 
the absence of confirmed progressive disease are provided in APPENDIX 2.  
Assessments for subjects who have discontinued durvalumab or tremelimumab treatment due 
to confirmed PD are presented in APPENDIX 3. 
All subjects will be followed for survival until the end of the study regardless of further 
treatments, or until the sponsor ends the study. 
 
8. 2 Description of study procedures 
8.2.1  Medical history and physical examination, electrocardiogram, weight and vital signs 
 
Findings from medical history (obtained at screening) and physical examination shall be given 
a baseline grade according to the procedure for AEs. Increases in severity of pre-existing 
conditions during the study will be considered AEs, with resolution occurring when the grade 
returns to the pre-study grade or below. 
Physical examinations will be performed on study days noted in the Schedule of Assessments. 
8.2.2  Physical examination 
Physical examinations will be performed according to the assessment schedule.  Full physical 
examinations will include assessments of the head, eyes, ears, nose, and throat and the 
respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological, 
hematologic/lymphatic, and endocrine systems.  Targeted physical examinations are to be 
utilized by the Investigator on the basis of clinical observations and symptomatology.  Situations 
in which physical examination results should be reported as AEs are described in Section 10   

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8.2.3 Electrocardiograms 
Resting, triplicate 12-lead ECGs will be recorded at screening and as clinically indicated 
throughout the study.  ECGs should be obtained after the patient has been in a supine position 
for 5 minutes and recorded while the patient remains in that position. 
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm 
the finding.   
Situations in which ECG results should be reported as AEs are described in Section 10.0.   
8.2.4  Vital signs 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules.   
On infusion days, patients receiving durvalumab + tremelimumab treatment will be monitored 
during and after infusion of IP Per standard clinical practice. 
Body weight is also recorded along with vital signs.   
Situations in which vital signs results should be reported as AEs are described in Section 10.3.   
8.2.5 Clinical laboratory tests 
The following clinical laboratory tests will be performed (see the Schedule of Assessments) 
• Coagulation parameters: Activated partial thromboplastin time and International normalised 
ratio to be assessed at baseline and as clinically indicated  
• Pregnancy test (female subjects of childbearing potential only) 
o 
Urine human chorionic gonadotropin (at screening only) OR 
o 
Serum beta-human chorionic gonadotropin (at screening only) 
• Thyroid Stimulating Hormone 
o 
free T4 only if TSH is abnormal 
 

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Table 5. 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 6. Clinical chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
Lactate dehydrogenase 
Alanine aminotransferase 
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 7. 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 
 

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8.3 Biological Sampling Procedures 
 
8.3.1 Research Blood Collection 
Blood will be collected for research purposes on three occasions: at baseline, prior to the second 
dose of durvalumab and tremelimumab and prior to the 4th dose of durvalumab and 
tremelimumab. Blood will be separated into cellular and serum components for preservation 
and batch analysis.  Flow cytometric evaluation of CD3, CD4, CD8, CD14, PD-1, PD-L1, PD-
L2 on peripheral blood mononuclear cells. 
Specimen Requirements: Submission for flow cytometry 
• 
A 5-10 mL specimen of peripheral blood in a lavender- (EDTA) or green- 
(sodium heparin) tube is acceptable for each draw. 
• 
Storage/Transport Temperature: Specimens can be transported with a cold pack 
or wet ice, but do not fix or freeze specimens. 
• 
Unacceptable Conditions: Frozen specimens, specimens greater than 48 hours 
old, specimens fixed in formalin for flow cytometry 
• 
Address for shipping specimens:  
Attn: Katy Dougherty, Hematopathology Lead 
Seattle Cancer Care Alliance 
Hematopathology Laboratory G7800 
825 Eastlake Ave E. 
Seattle, WA  98109 
 
8.3.2. Correlative tissue collection 
All patients will be required to submit archival tissue as part of study participation.  In patients 
who do not have archival tissue, a pretreatment tumor biopsy will be performed, unless deemed 
contraindicated by the treating physician. These samples will be submitted centrally for 
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CD69 and FOXP3.  Acceptable archival tissue for correlative studies include formalin fixed 
paraffin embedded tissue collected within 3 years of study enrollment. Patients who do not have 
acceptable FFPE tissue will be required to undergo a study related biopsy to obtain fresh tissue. 
In cases where biopsies yield insufficient tissue for both tumor slice culture (TSC) and PDL1 
testing, TSC testing will take priority. Any tissue not used for tumor slice culture will be 
submitted for PDL1 testing. 
 
PD-L1 Testing 
To ensure comparability of data across all studies of durvalumab and/or tremelimumab and to 
gain real world experience on the performance of this assay, it is strongly encouraged that all 
studies that include PD-L1 testing utilize the Ventana SP263 assay.  Testing should be restricted 
to the Ventana SP263 assay and should be performed in accordance with the package insert on 
the Ventana Benchmark platform (Ultra or XT).   
The Ventana SP263 assay is fully analytically validated test characterized through to the 
completion of reader precision studies in the non-small cell lung cancer (NSCLC) and squamous 
cell carcinoma of the head & neck (SCCHN).  For these tumors, the Ventana SP263 assay has 
a fully reproducibility data package supporting cut-off and scoring algorithm.  Following 
completion of ATLANTIC and HAWK clinical trials, the assay will be associated with clinical 
utility.  In other cancer types (bladder, pancreatic, gastric, hepatocellular, triple negative breast, 
ovarian, esophageal, nasopharyngeal, glioblastoma, soft tissue sarcoma, cholangiocarcinoma, 
small cell lung, melanoma and cervical HPV+ cancers), the Ventana SP263 assay has only 
limited clinical performance data.   
Sample collection for PD-L1 testing 
• The preferred tumor sample for the determination of a patient’s PD-L1 status is the one 
taken following the completion of the most recent prior line of therapy.  Samples taken 
at this time reflect the current PD-L1 status of the tumor and considered clinically most 
relevant.   
• Samples should be collected via a core needle of 18 gauge or larger or be collected by 
an incisional or excisional tumor biopsy.  Where institutional practice uses a smaller 
gauge needle, samples should be evaluated for tumor cell quantity (i.e. >100 tumor cells) 
to allow for adequate PD-L1 immunohistochemistry analyses.   
• When the collection of a new sample is not clinically appropriate, archival samples may 
be utilized provided the specimen it is not older than 3 years of age.  When archival 

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samples are used to assess PD-L1 status, the age of the sample / date of collection should 
be captured.   
• Samples submitted for PD-L1 testing should be formalin fixed and embedded in 
paraffin.  Samples from fine needle aspirates (FNA) or decalcified bone are not 
appropriate for PD-L1 analysis.   
Sample data collection for PD-L1 testing 
The following fields of data should be collected from the site/institution collecting and if, 
indicated shipping of the samples:   
• Patient identifier (ecode or unique identifier) 
• Specimen identifier (written on the specimen) 
• Site identifier 
• Specimen collection date 
• Type of specimen submitted 
• Quantity of specimen 
• Date of sectioning 
• Archival of fresh tumor 
• Tumor type 
• Primary tumor location 
• Metastatic tumor location (if applicable) 
• Fixative 
The following fields of data should be collected from PD-L1 testing laboratory: 
• Are the negative and positive controls stained correctly 
• Is the H&E material acceptable 
• Is morphology acceptable 
• Total percent positivity of PD-L1 in tumor cells 
• PD-L1 status (positive, negative or NA) in tumor cells  
• Total percent positivity of PD-L1 in infiltrating immune cells 
The Ventana SP263 assay to measure PD-L1 in tumors is experimental.  As with all tests, there 
is a chance of false positive (the test shows high PD-L1 when it is not there) or false negative 
(the test does not show PD-L1 when it is there) results may occur.   
Sample processing and if indicated submission process for PD-L1 testing 
Preparing Stored samples for testing 

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• Where samples already exist, they should be retrieved from the Bio-Bank storage 
location.  These blocks should undergo quality review, prior to evaluation or shipment.  
Where it is not possible or indicated to ship the block to a testing laboratory, unstained 
slides should be prepared from the paraffin-embedded tumor sample block (described 
below) prior to evaluation or shipment.   
Preparing newly acquired samples for PD-L1 testing 
• If patients are undergoing a biopsy procedure that provides the option to submit newly 
acquired samples, this sample should be used to determine PD-L1 status.  Where 
clinically acceptable, a minimum of 2 core biopsies should be collected and processed 
to FFPE in a single block.  The provision of 2 cores is advised in order to provide 
sufficient tissue for PD-L1 assessment.  
• It is recommended that core needle tumor biopsies are collected using an 18 gauge or 
larger needle and the process should be image-guided.  Excisional or incisional samples 
are also adequate.  If this is not per the institutions normal practice and a smaller gauge 
needle is used then the number of cores collected should be increased to allow sufficient 
material for successful PD-L1 testing (>100 tumor cells) and embedded in the same 
block.  If available, a single excisional biopsy of at least 4 mm in diameter may substitute 
for all core biopsies.  
Fixation of biopsy samples for PD-L1 testing 
• Previously frozen tissue is not acceptable for processing to FFPE for PD-L1 testing.  To 
fix newly acquired tissue, place immediately (within 30 min of excision) into an 
adequate volume of 10% v/v neutral buffered formalin (NBF).  Samples should remain 
in fixative for 24 – 48 hours at room temperature.   
• It is vital that there is an adequate volume of fixative relevant to the tissue (at least a 10 
volume excess) and that large specimens (if any) are incised prior to fixation to promote 
efficient tissue preservation.   
Embedding in paraffin for PD-L1 testing 
• An overnight processing schedule into paraffin wax is recommended  
• Below is the suggested routine overnight processing schedule: 
Storage of tumor blocks for PD-L1 testing 

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• FFPE blocks should be stored at ambient temperature and protected from light until 
shipment by courier at ambient temperature. FFPE blocks are stable under these 
conditions for an indefinite period. 
Quality control of samples to be used for PD-L1 testing 
• Tissue should be assessed by the site pathologist prior to PD-L1 testing.   
• Each sample should be reviewed for: 
• Adequate fixation 
• Good preservation of morphology 
• Presence of tumor tissue 
• Histopathology consistent with indication 
 
• Greater than 100 tumor cells are required to determine PD-L1 status – tumor cell 
content must be reviewed prior to testing in order for PD-L1 obtain a valid result.   
If indicated, shipping samples to a PD-L1 testing laboratory 
• When submitting sample to for PD-L1 testing the recommendation is to ship the block 
in order for sectioning to occur at the laboratory.  Blocks should be shipped  - containing 
enough  material to  be provided to allow a minimum of 5, and preferably 10, sections 
to be cut (each 4  micron thick) to be used for PD-L1 testing.    
Sectioning instructions 
• Where it is not possible or indicated to ship the block to laboratory for PD-L1 testing, 
unstained slides should be prepared from the paraffin-embedded tumor sample block as 
described below:   
• A minimum of 5-10 x 4 micron (μm) thick, unstained sections should be 
provided for PD-L1 testing 
• A new disposable microtome blade must be used for each block to prevent 
contamination between Slides are stable under these conditions for 6 months. 
• patient samples 
• Apply one section per slide to positively-charged Superfrost glass slides  
• The sections should be dried overnight between room temperature and 37°C. Do 
not dry sections at temperatures above 37°C. 

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Sections should be stored at ambient temperature and protected from light until use or shipment 
to testing lab by courier at ambient temperature.  It is recommended that slides are cut freshly 
prior to PD-L1 testing and they are used within 90 days of being cut to obtain PD-L1 status 
 
Fresh tumor biopsies for tumor slice culture 
Patients who do not have suitable archival tissue will be consented for fresh tissue biopsies.  
Dr. Venu Pillarisetty’s lab will oversee the collection of fresh tissue during this biopsy. Tissue 
will be collected for tumor slice culture (TSC) preparation as described below. In cases where 
biopsies yield insufficient tissue for both TSC and PDL1 testing, TSC testing will take 
priority. Any tissue not used for tumor slice culture will be submitted for PDL1 testing. 
TSC Preparation 
Fresh treatment biopsy tissue in excess of that required for central IHC will be mounted and 
sliced (250 µm) using a Leica vibrating microtome. This tissue will be placed in 24-well 
plates in an air-liquid interface culture system using media optimized by our group for TSC. 
Experiment #1 – Immune cell populations 
TSC will be cultured for 1 to 6 days with control antibody, DMSO control, durvalumab (dose 
to be determined) alone, tremelimumab(1 µM) alone, or a combination of both drugs.  
 
IHC for CD4, CD8, FOXP3, CD68  
When adequate tissue is available for replicates, we will perform flow cytometry on enzyme-
digested, disaggregated slices to measure: 
Macrophage phenotype (CD68, HLA-DR, CD163, CD115, CD206) 
T cell phenotype (general): CD3, CD4, CD8, CD25 
T cell memory phenotype (CD45RO, CD127, CD28, CD27, CD62L, CCR7) 
T cell inhibitor phenotype (PD-1, CTLA-4, LAG3, TIM3) 
Tumor immune related markers (PD-L1, class I MHC, HLA-DR) 
 

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Experiment #2 – Induction of CD8+ T cell function 
Upon completion of each culture period after drug treatment, slices will be treated with SR-
FLICA caspase 3/7 assay reagent (Immunochemistry Technologies) for 1 hr, fixed, and then 
stained with DAPI prior to imaging by confocal microscopy to measure apoptosis. Fixed 
tumor slices will then be paraffin embedded and sectioned. IHC will be performed for CD8 
and Ki67 (to measure proliferation) or granzyme B (to measure cytotoxic activity) or cleaved 
caspase 3 (to measure apoptosis). Number of positive cells for each marker will be 
determined. 
 
Experiment #3 – Correlation of induction of cytotoxic T cell function with PD-L1 expression 
We hope to have access to the centrally determined PD-L1 expression so that we will be able 
to correlate our CD8+ T cell functional data with induction of CD8+ T cell function. 
 
Experiment #4 – Correlation of induction of cytotoxic T cell function with clinical response 
We will use multivariate statistics to test the hypothesis that the degree of immune checkpoint 
inhibition-triggered CD8+ T cell activation and carcinoma cell death in TSC predicts response 
in our ongoing clinical trial. 
  
Experiment #5 – Rescue of drug-refractory CD8+ T cell activation   
Biopsies from patients with lack of clinical response will be placed in TSC and treated with 
combinations of durvalumab and tremelimumab and monoclonal antibodies designed to block 
additional immune checkpoints (GITR, LAG-3, TIM-3, CTLA-4), as this strategy may 
overcome T cell exhaustion.(Lu et al., 2014)  
 
Experiment #6 – Correlation between T cell infiltrate and immunosuppressive signals 
IHC of tumor tissue for cellular subtypes (CD3, CD4, CD8, FOXP3, CD68) and 
immunosuppressive molecules (PD-1, PD-L1, TIM-3, LAG-3, CTLA-4, IL-10, TGF-beta1, 
IDO, FASL). We will use multivariate statistics to correlate T cell infiltrate density and level 
of immunosuppressive signaling. Furthermore, we will be able to confirm whether the tumors 

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fall into their expected category of level of T cell infiltration, as we believe that the 
immunophenotype is more important than traditional histology in determining response to 
immune checkpoint inhibition. 
 
Experiment #7 – CD8+ T cell suppression 
The proliferation of CD8+ TIL from TSC (cultured with or without exogenous IL-2 +/- 
CD3/CD28 beads) will be measured in two ways: directly by Ki67 staining, and indirectly by 
treating the TSC with BrdU and then subsequently staining for it. In both cases TSC will be 
fixed, embedded and double stained after 1 to 6 days in culture to determine what percentage 
of CD8+ T cells are cycling. Duplicate slices will be digested with collagenase-DNAse-
hyaluronidase cocktail in rotating flasks to obtain a single-cell suspension. CD8+ T cell 
proliferation and activation state, as well as macrophage polarization, will be tested using a 
multi-color flow cytometry panel. We will correlate these data with those from Experiment #1 
to determine if high-level expression of multiple immunosuppressive signals has functional 
consequences in the TSC. 
 
Experiment #8 – Combination immune checkpoint inhibition 
TSC will be cultured for 1 to 6 days with control antibody or durvalumab (dose to be 
determined). 
Upon completion of each culture period, slices will be treated with SR-FLICA caspase 3/7 
assay reagent (Immunochemistry Technologies) for 1 hr, fixed, and then stained with DAPI 
prior to imaging by confocal microscopy to measure apoptosis. Fixed tumor slices will then be 
paraffin embedded and sectioned. IHC will be performed for CD8 and Ki67 (to measure 
proliferation) or granzyme B (to measure cytotoxic activity) or cleaved caspase 3 (to measure 
apoptosis). 
 
To determine whether immune checkpoints in fact inhibit the proliferation of T cells in the 
TSC, each of the known checkpoint molecules will be inhibited, either by antibody (PD-1, 
TIM-3, LAG-3, CTLA-4, IL-10, TGF-beta1, FASL) or using a small molecule (IDO) in the 
organotypic cultures. If the checkpoint is suppressing cytotoxic T cell proliferation, we would 
expect to see increased Ki-67 staining, and increased BrdU uptake by CD8+ T cells in the 
TSC.  In tumors that express multiple checkpoint molecules, inhibition of several pathways 

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ma y be re q uir e d t o o ver c o me T cell f u ncti o nal e x ha usti o n; i n t hese cases, t he effects of 
c o m bi nati o n of c hec k p oi nt i n hi bit ors o n T cell pr oliferati o n will be i n vesti gate d.  Assess me nt 
of T -cell e x h a usti o n a n d resc ue will be base d o n t he stim ulate d e x pressi o n of I F N . Si n gle-
cell s us pe nsi o ns fr o m t u m or slices will be treate d wit h G ol gi pl u g a n d sti m ulate d wit h 
C D 3/ C D 2 8 bea ds (f or T C R a n d c osti m ulati o n) or P M A/i o n o m yci n ( b y passi n g T C R si g nali n g) 
pri or t o perf or mi n g i ntracell ular c yt o ki ne stai ni n g f or fl o w c yt o metr y.  T h e pr o p orti o n of 
I F N- e x pressi n g C D 8 + T cells i n t he T S C will be c o m pare d bet wee n treat me nt a n d c o ntr ol 
sa m ples.  F or all i m m u n o hist ol o gical a n d fl o w c yt o metric a nal yses, a mi ni m u m of 1 0 0 cells of 
i nterest will be sc ore d f or eac h e n d p oi nt.  Res ults bet wee n treate d a n d c o ntr ol gr o u ps will be 
a nal yze d b y t-t est a n d A N O V A. D ata will be a nal yze d acr oss t u m ors wit h relati o n t o le vel of 
T cell i nfiltrati o n a n d i m m u n os u p pressi ve si g nal e x pressi o n.  
8. 3. 3 Wit h dr a w al of i nf or m e d c o nse nt f or d o n ate d bi ol o gic al s a m ples 
If  a  s u bject  wit h dra ws  c o nse nt  t o  t he  use  of  d o nate d  sa m ples,  t he  sa m ples  will  be  dis p ose d 
of/ destr o ye d, a n d t he acti o n d oc u me nte d.  As c ollecti o n of t he bi ol o gical sa m ples is a n i nte gral 
part of t he st u d y, t he n t he s u bject is wit h dra w n fr o m f urt her st u d y partici pati o n. 
T he Pri nci pal I n vesti gat or: 
•  E ns ures  t hat  bi ol o gical  sa m ples  fr o m  t hat  s u bject,  if  st ore d  at  t he  st u d y  site,  are 
i m me diatel y i de ntifie d, dis p ose d of / destr o ye d, a n d t he acti o n d oc u me nte d 
•  E ns ures  t he  la b or at or y(i es)  h ol di n g  t he  sa m ples  is/are  i nf or me d  a b o ut  t he  wit h dra w n 
c o nse nt i m me diatel y a n d t hat sa m ples are dis p ose d/ destr o ye d, t he acti o n d oc u me nte d 
a n d t he si g ne d d oc u me nt ret ur ne d t o t he st u d y site 
•  E ns ures t hat t he s u bject is i nf or me d a b o ut t he sa m ple dis p osal.  
 

 
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9.   DISEASE EVALUATION AND METHODS 
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013): 
• Response to immunotherapy may be delayed 
• Response to immunotherapy may occur after PD by conventional criteria 
• The appearance of new lesions may not represent PD with immunotherapy 
• SD while on immunotherapy may be durable and represent clinical benefit. 
 
Based on the above-described unique response to immunotherapy and based on guidelines from 
regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of anti-
cancer medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune modulating anti-
cancer compounds, the study may wish to implement the following in addition to standard 
RECIST 1.1 criteria: 
• RECIST will be modified so that PD must be confirmed at the next scheduled visit, 
preferably, and no earlier than 4 weeks after the initial assessment of PD in the absence 
of clinically significant deterioration.  Treatment with durvalumab + tremelimumab 
would continue between the initial assessment of progression and confirmation for 
progression.  
• In addition, subjects may continue to receive durvalumab + tremelimumab beyond 
confirmed PD in the absence of clinically significant deterioration and if investigators 
consider that subjects continue to receive benefit from treatment.  
Modification of RECIST as described may discourage the early discontinuation of durvalumab 
+ tremelimumab and provide a more complete evaluation of its anti-tumor activity than would 
be seen with conventional response criteria.  Nonetheless, the efficacy analysis will be 
conducted by programmatically deriving each efficacy endpoint based on RECIST 1.1 criteria. 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anti-cancer therapy other than durvalumab + tremelimumab or with 
symptomatic progression that requires urgent medical intervention (e.g., central nervous system 
metastasis, respiratory failure due to tumor compression, spinal cord compression).>> 
9.1   Progression free and Overall survival 
Data on disease progression by RECIST criteria, and patient death will be recorded and used to 
calculate PFS and OS.  Patients who have discontinued study therapy due to disease progression, 
toxicity, or withdrawal of consent will continue to be followed to collect data for this endpoint.  

 
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Subjects who have disease control following completion of 12 months of treatment or subjects 
who are withdrawn from durvalumab + tremelimumab treatment for reasons other than 
confirmed PD will continue to have objective tumor assessments (see Appendix 3).   
10.  ASSESSMENT OF SAFETY 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
10. 1 Safety Parameters 
10.1.1. Definition of adverse events 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP) E6 (R1) defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. An abnormal laboratory finding (including ECG finding) that requires 
an action or intervention by the investigator, or a finding judged by the investigator to represent 
a change beyond the range of normal physiologic fluctuation, should be reported as an AE. 
Adverse events may be treatment emergent (ie, occurring after initial receipt of investigational 
product) or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the subject has received investigational product.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition, that did not 
worsen from baseline, is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE. 
The term AE is used to include both serious and non-serious AEs. 

 
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10.1.2. Definition of serious adverse events 
A serious adverse event is an AE that fulfils one or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability or incapacity  
• Is a congenital abnormality or birth defect in offspring of the subject 
• Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above:  
Medical or scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in this situation. Examples of medically important events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalizations; or development of drug dependency or 
drug abuse. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to AstraZeneca. 
10.1.3 Durvalumab + tremelimumab adverse events of special interest 
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 and tremelimumab 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 etiology. 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.  

 
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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 and tremelimumab include: 
• Colitis 
• Pneumonitis 
• ALT/AST increases / hepatitis / hepatotoxicity  
• Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
• Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
• Dermatitis 
• Nephritis 
• Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , increased serum 
amylase)   
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab and tremelimumab Investigator Brochure. For durvalumab and 
tremelimumab, AESIs will comprise the following:    
Pneumonitis 
AEs of pneumonitis are also of interest for AstraZeneca, as pneumonitis has been observed with 
use of anti-PD-1 mAbs (but not with anti-PD-L1 mAbs).  Initial work-up should include a high-
resolution CT scan, ruling out infection, and pulse oximetry.  Pulmonary consultation is highly 
recommended. Guidelines for the management of patients with immune-related AEs (irAEs) 
including pneumonitis are provided in Appendix 1.   
Infusion reactions 
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to 
AstraZeneca and are defined, for the purpose of this protocol, as all AEs occurring from the 
start of IP infusion up to 48 hours after the infusion start time.  For all infusion reactions, SAEs 
should be reported to AstraZeneca Patient safety as described in Section 10.3.   
Hypersensitivity reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy (Brahmer et al 2012).  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 (IgE-mediated) and anaphylactoid 
reactions against the mAbs and serum sickness.  Acute allergic reactions may occur, may be 

 
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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 the management of patients with hypersensitivity 
(including anaphylactic reaction) and infusion-related reactions are provided in Table 1.    
Hepatic function abnormalities (hepatotoxicity) 
Immune-mediated hepatic function abnormalities include transaminitis, hepatitis and 
hepatotoxicity of any grade on concurrent tests. 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 (eg, cholelithiasis and bile duct obstruction with distended 
gallbladder) or an agent other than the IP.  Guidelines for management of patients with hepatic 
function abnormality are provided in Appendix 1.   
Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need to be 
reported as SAEs. Please refer to Appendix 1 for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s law. 
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 tremelimumab are provided in Table 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 Table 1. 
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 Table 1. 

 
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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 Table 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 Table 
1. 
10.1.4 Immune-related adverse events 
Based on the mechanism of action of durvalumab and tremelimumab leading to T-cell activation 
and proliferation, there is a possibility of observing irAEs during the conduct of this study.  
Potential irAEs may be similar to those seen with the use of ipilimumab, BMS-936558 (anti-PD-
1 mAb), and BMS-936559 (anti-PD-L1 mAb) and may include immune-mediated enterocolitis, 
dermatitis, hepatitis (hepatotoxicity), pneumonitis, and endocrinopathies (Hodi et al 2010, 
Brahmer et al 2012, Error! Reference source not found.).  These AEs are inflammatory in 
nature and can affect any organ.  With anti-PD-L1 and anti-CTLA-4 combination therapy, the 
occurrence of overlapping or increasing cumulative toxicities that include irAEs could 
potentially occur at higher frequencies than with either durvalumab or tremelimumab 
monotherapy.  Patients should be monitored for signs and symptoms of irAEs.  In the absence 
of an alternate etiology (eg, infection or PD), an immune-related etiology should be considered 
for signs or symptoms of enterocolitis, dermatitis, pneumonitis, hepatitis, and endocrinopathy.  
In addition to the dose modification guidelines provided in Table 1, it is recommended that 
irAEs are managed according to the general treatment guidelines outlined for ipilimumab 
(Error! Reference source not found.). These guidelines recommend the following: 
• 
Patients should be evaluated to identify any alternative etiology. 
• 
In the absence of a clear alternative etiology, all events of an 
inflammatory nature should be considered immune related. 

 
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• 
Symptomatic and topical therapy should be considered for low-grade 
events. 
• 
Systemic corticosteroids should be considered for a persistent low-
grade event or for a severe event. 
• 
More potent immunosuppressives should be considered for events not 
responding to systemic steroids (eg, infliximab or mycophenolate). 
• 
If the Investigator has any questions in regards to an AE being an 
irAE, the Investigator should immediately contact the Study 
Physician.  

 
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10.2 Assessment of safety parameters 
10.2.1 Assessment of severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the NCI CTCAE v4.03. 
The determination of severity for all other events not listed in the CTCAE should be made by 
the investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below.>> 
Grade 1 (mild)  
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
 
Grade 2 (moderate)  An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the subject. 
 
Grade 3 (severe)  
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the clinical 
status of the subject. 
 
Grade 4 (life threatening) An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental disabilities that affect 
or limit the ability of the subject to perform activities of daily living (eating, 
ambulation, toileting, etc). 
 
Grade 5 (fatal)  
Death (loss of life) as a result of an event. 
 
 
It is important to distinguish between serious criteria and severity of an AE. Severity is a measure 
of intensity whereas seriousness is defined by the criteria in Section 9.2.1. A Grade 3 AE need not 
necessarily be considered an SAE. For example, a Grade 3 headache that persists for several hours 
may not meet the regulatory definition of an SAE and would be considered a nonserious event, 
whereas a Grade 2 seizure resulting in a hospital admission would be considered an SAE. 
 
10.2.2 Assessment of relationship 
An investigator who is a qualified provider will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.03. Any adverse event which 

 
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changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
The determination of the likelihood that durvalumab and or tremelimumab caused the adverse 
event will be provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the causality noted on 
the AE form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between durvalumab and/or 
tremelimumab and the AE; the greater the correlation with the components and their respective 
elements (in number and/or intensity), the more likely that durvalumab and/or tremelimumab 
caused the adverse event (AE): 
 
• 
Is there evidence that the subject was actually exposed to durvalumab and 
tremelimumab such as: reliable history, acceptable compliance assessment expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
• 
Did the AE follow in a reasonable temporal sequence from administration of 
durvalumab and tremelimumab? 
• 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials 
with investigational medicinal product)? 
• 
Is the AE not reasonably explained by another etiology such as underlying disease, 
other drug(s)/vaccine(s), or other host or environmental factors 
 
10. 3 Recording of adverse events and serious adverse events 
Adverse events will be recorded using a recognized medical term or diagnosis that accurately 
reflects the event. Adverse events will be assessed by the investigator for severity, relationship to 
the investigational product, possible etiologies, and whether the event meets criteria of an SAE 
and therefore requires immediate notification to AstraZeneca/MedImmune Patient Safety.  
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Changes in NCI CTCAE grade and the maximum CTC grade attained 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against durvalumab or tremelimumab (yes or no)  

 
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• 
Action taken with regard to durvalumab + tremelimumab/comparator/combination 
agent 
• 
Outcome 
• 
 
In addition, the following variables will be collected for SAEs as applicable: 
• 
Date AE met criteria for serious AE 
• 
Date of hospitalization and discharge, if applicable 
• 
Date of death and probable cause, if applicable 
• 
Autopsy performed 
• 
Description of AE 
• 
Causality assessment in relation to Study procedure(s) 
• 
Causality assessment in relation to palliative hypofractionated  radiation therapy  
 
Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. 
10.3.1 Study recording period and follow-up for adverse events and serious adverse events 
Adverse events and serious adverse events will be recorded from time of administration of the 
first dose of investigational drug, throughout the treatment period and including the follow-up 
period (90 days after the last dose of durvalumab + tremelimumab). 
During the course of the study all AEs and SAEs should be proactively followed up for each 
subject. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
If a subject discontinues from treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments, drug or procedure-related SAEs must be captured until the 
patient is considered to have confirmed PD and will have no further tumor assessments. 
The investigator is responsible for following all SAEs until resolution, until the subject returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain chronic, 
even if this extends beyond study participation. 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the CRF.  After 
90 days, only subjects with ongoing investigational product-related SAEs will continue to be 
followed for safety. 

 
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AstraZeneca/MedImmune retains the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Post study events 
 
After the subject has been permanently withdrawn from the study, there is no obligation for the 
investigator to actively report information on new AE or SAEs occurring in former study subjects 
after the 90-day safety follow-up period for patients treated with durvalumab + tremelimumab.  
However, if an investigator learns of any SAEs, including death, at any time after the subject has 
been permanently withdrawn from study, and he/she considers there is a reasonable possibility 
that the event is related to study treatment, the investigator should notify the study sponsor and 
AstraZeneca/MedImmune Drug Safety. 
 
10.3.2 Reporting of serious adverse events 
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 + tremelimumab or until the initiation of alternative anticancer therapy.  The 
investigator and/or Sponsor are responsible for informing the Ethics Committee and/or the 
Regulatory Authority of the SAE as per local requirements. 
NOTE TO AUTHOR: For trials conducted in the United States, the following must be included 
(similar language must be included , referencing the appropriate health authority and reporting 
mechanism, for studies conducted outside of the United States). Note that all serious or 
unexpected adverse events must be reported to AstraZeneca regardless of the country where the 
study is conducted: 
The investigator and/or 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” 

 
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• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number (ESR-16-
11857) 
* 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 
 
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.  
10.3.2.1 Reporting of deaths 
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of 
durvalumab + tremelimumab safety follow-up period must be reported as follows: 
• 
Death that is clearly the result of disease progression should be 
documented but should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease 
under study, the AE causing the death must be reported to as a SAE 
within 24 hours (see Section 10.3.2 for further details).  The report 
should contain a comment regarding the co-involvement of progression 
of disease, if appropriate, and should assign main and contributory 
causes of death.   
• 
Deaths with an unknown cause should always be reported as a SAE.   
Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab safety 
follow-up period will be documented as events for survival analysis, but will not be reported as 
an SAE. 

 
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10.3.3 Other events requiring reporting 
10.3.3.1 Overdose 
An overdose is defined as a subject receiving a dose of durvalumab + tremelimumab in excess of 
that specified in the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with durvalumab + tremelimumab, 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 10.3 and Section 10.3.2). 
There is currently no specific treatment in the event of an overdose of durvalumab or 
tremelimumab.  
 
The investigator will use clinical judgment to treat any overdose. 
10.3.3.2 Hepatic function abnormality 
Hepatic function abnormality (as defined in Section 10.1.3.) 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. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune.  

 
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10.3.3.3 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 
180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after 
the last dose of durvalumab monotherapy, whichever is the longer time period.   
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.   

 
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11.0  STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
 
11.1  Description of analysis sets 
All patients enrolled in the study, including those who were replaced in the run-in phase (see 
Section 4.4)  will be included in the analysis of toxicity and efficacy. 
11.2 Methods of statistical analyses 
 
11.2.1 Safety Analyses 
Safety and tolerability is the primary endpoint of this study, and all patients enrolled (including 
those replaced in the run in phase) will be assessed for this endpoint. Adverse events will be 
recorded and graded based on CTCAE v. 4, and their relationship to the experimental agents 
reported.  
11.2.2 Efficacy Analyses 
All patients enrolled in the study (i.e. the initial 6 patient cohort, and the additional 14 patient 
expansion) will be included in the efficacy analyses.  Clinical responses to the combination of 
durvalumab, tremelimumab and hypofractionated radiation will be based on RECIST 1.1 
criteria.  Oncologic outcome endpoints such as progression free and overall survival will be 
calculated from the date of study enrollment, until disease progression  or death from any cause, 
respectively. Survival estimates will be calculated using the Kaplan-Meier method.  
11.2.3. Exploratory Analyses 
Exploratory endpoints of this study include correlative work performed on research serum and 
tissue samples. These are detailed in Section 8.2  
11.2.4 Interim analyses 
No interim analysis is planned for this study.  

 
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11.3  Determination of sample size 
There are multiple ongoing studies in various tumor types exploring the activity of durvalumab and 
tremelimumab. In a published report of the combination in patients with advanced NSCLC treated on a 
phase Ib study, Grade 3-4 toxicity was observed in 17% of patients. Similarly, in single institution reports 
of SBRT with the monoclonal antibody, grade 3 or higher toxicity was reported in 6-16% of patients.  With 
20 patients, toxicity rates can be estimated to within 22% with 95% confidence. Any toxicity with at least 
10% prevalence has at least an 87% chance of being observed. With these properties, this design, allows 
us to reasonably exclude a clinically significant increase in toxicity with the addition of radiation therapy 
to the durvalumab and tremelimumab combination as defined by the upper bound of the confidence 
interval. 
 
The response rates to dual CTLA and PDL1 blockade and radiation therapy after prior immunotherapy are 
unknown.  If objective responses are demonstrated, or encouraging progression free survival is observed 
in the 20 patients enrolled on the study, it would merit further investigation in a larger study powered to 
examine efficacy endpoints 
 
12. ETHICAL AND REGULATORY REQUIREMENTS 
12.1 Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Subject data protection. 
12.2 Ethics and regulatory review 
The protocols will be approved and reviewed by the Cancer Consortium Scientific Review 
Committee (SRC) and the Institutional Review Board (IRB). The protocol once activated will be 
reviewed at least annually by both institutional entities. 
12.3 Informed consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 

 
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opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature. 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
12.4 Changes to the protocol and informed consent form 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 
Cancer Consortium IRB and Scientific Review Committee (SRC).  Any changes made to the 
protocol will be submitted as a modification and will be approved by the IRB prior to 
implementation.   
12. 5Audits and inspections 
The study will be audited and inspected by the Cancer Center Consortium. 
13. STUDY MANAGEMENT 
13.1 Training of study site personnel 
All investigators on the protocol will receive formal training in the ethical conduct of human 
research. Institutional support of trial auditing is provided in accordance with the Cancer 
Consortium’s data and safety monitoring plan 
13.2 Monitoring of the study 
13.2.1 Source data 
The Fred Hutchinson/University of Washington Consortium Data and Safety Monitoring 
Committee (DSMC) will be the monitoring entity for this study in accordance with the Cancer 
Consortium’s Data Safety Monitoring Plan. 
13.3 Study timetable and end of study 
The end of the study is defined as the last visit of the last patient undergoing the study. Either 
AstraZeneca or the Investigator may terminate the entire study prematurely if concerns for 
safety arise within this study or other durvalumab studies.

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14. DATA MANAGEMENT 
The Protocol Director, or her designees, will prepare and maintain adequate and accurate 
participant case histories with observations and other data pertinent to the study.  Original source 
documents should be transcribed to Case Report Forms (CRFs) and used to analyze the study 
data.  Source documents include hospital records, clinical charts, laboratory and pharmacy 
records, and recorded electronic data. 
All data required by the trial will be entered onto paper and electronic case report forms. Any 
corrections to data required into the paper case report forms must be made in such a way that 
the original entry is not obscured. Only designated study staff will enter data for study 
participants after study visits. Case report forms will be checked against source document data 
by study staff. 
Patient records will be kept in a secure location at the University of Washington  accessible only 
to research authorized personnel. The patient identity will be kept as confidential as possible as 
required by law. Except as required by law, the patient will not be identified by name, social 
security number, address, telephone number, or any other direct personal identifier. Study 
subjects will be assigned an ID code. Information about the code will be kept in a secure location 
and access limited to research study personnel. The results of this research study may be 
presented at scientific or medical meetings or published in scientific journals. However, the 
patient identity will not be disclosed. The patient's personal data which may be included in the 
investigator’s database shall be treated in compliance with all applicable laws and regulations. 
Trial oversight will be carried out by the protocol director, Dr. Cristina Rodriguez, and her 
research staff. They will meet weekly to review recently acquired data and adverse events. 
The data recorded within the research charts and protocol database is compared with the 
actual data that is available from the medical record and/or clinical histories. Data detailed in 
the research case report forms includes the nature and severity of all toxicities, which are also 
reported as described above.  
14.1 Study governance and oversight 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators. 

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15. INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
15.1 Identity of investigational product(s) 
Table 8. List of investigational products for this study 
Investigational product 
Dosage form and strength 
Manufacturer 
Durvalumab (MEDI4736) 
50 mg/mL solution for infusion 
after dilution 
AstraZeneca/MedImmune 
Tremelimumab 
20mg/mL solution for infusion 
after dilution 
AstraZeneca/MedImmune 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16. LIST OF REFERENCES 
Andorsky et al 2011 
Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, and Timmerman JM.  Programmed 
death ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-
associated T cells.  Clin Cancer Res. 2011. 17(13):4232-4244 
Antonia et al 2014b 
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APPENDIX 1 
Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions (MEDI4736 
Monotherapy or Combination therapy with Tremelimumab or 
Tremelimumab Monotherapy) 19 August 2016 Version 
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. 
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. 
It is recommended that management of irAEs follows the 
guidelines presented in this table: 
− 
Patients should be thoroughly evaluated to rule 
out any alternative etiology (eg, disease 
progression, concomitant medications, and 
infections). 
− 
In the absence of a clear alternative etiology, all 
events should be considered potentially immune 
related. 
− 
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. 
− 
If symptoms recur or worsen during 
corticosteroid tapering (28 days of taper), 
increase the corticosteroid dose (prednisone dose 
[eg, 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 (eg, infliximab) (also refer to the 
individual sections of the irAE for specific type of 
immunosuppressive) should be considered for 
events not responding to systemic steroids. 
− 
Discontinuation of study drug/study regimen is 
not mandated for Grade 3/Grade 4 inflammatory 
reactions attributed to local tumor response 
(eg, inflammatory reaction at sites of metastatic 
disease and lymph nodes). Continuation of study 
drug/study regimen in this situation should be 
based upon a benefit/risk analysis for that 
patient. 

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Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions (MEDI4736 
Monotherapy or Combination therapy with Tremelimumab or 
Tremelimumab Monotherapy) 19 August 2016 Version 
Dose Modifications 
Toxicity Management 
Note: For Grade 3 and above asymptomatic amylase or 
lipase levels hold study drug/regimen and if complete 
work up shows no evidence of pancreatitis, may continue 
or resume study drug/regimen 
(i) 
AE  Adverse event; CTC  Common Toxicity Criteria; CTCAE  Common Terminology Criteria for Adverse Events; 
irAE  Immune-related adverse event; IV  intravenous; NCI  National Cancer Institute; PO  By mouth. 

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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/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 
(eg, 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 
methylprednisone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive therapy 
such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 

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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
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-
PCP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
(Category 2B recommendation)a 
− 
Consider pulmonary and 
infectious disease consult. 
− 
Consider, as necessary, 
discussing with study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; 
limiting self-care 
ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated [eg, 
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. 
− 
Hospitalize the patient. 
− 
Supportive care (eg, 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 
(eg, 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 patients is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and, in 
particular, anti-PCP treatment 
(refer to current NCCN 
guidelines for treatment of 

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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
cancer-related infections 
(Category 2B recommendation).a 
Diarrhea/Enterocolitis 
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 (eg, 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 
(stool frequency 
of 
<4 over baseline 
per day) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening 
symptoms. 
− 
Consider symptomatic 
treatment, including hydration, 
electrolyte replacement, dietary 
changes (eg, American Dietetic 
Association colitis diet), and 
loperamide. Use probiotics as 
per treating physician’s clinical 
judgment. 
Grade 2 
(stool frequency 
of 4 to 6 over 
baseline per day) 
Hold study drug/study 
regimen until resolution to 
Grade ≤1 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
For Grade 2: 
− 
Consider symptomatic 
treatment, including hydration, 
electrolyte replacement, dietary 
changes (eg, American Dietetic 
Association colitis diet), and 
loperamide and/or budesonide. 

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Adverse Events 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
• 
If toxicity improves to 
Grade ≤1, then study 
drug/study regimen 
can be resumed after 
completion of steroid 
taper. 
− 
Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 
3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day 
PO or IV equivalent, GI consult 
should be obtained for 
consideration of further workup, 
such as imaging and/or 
colonoscopy, to confirm colitis 
and rule out perforation, and 
prompt treatment with IV 
methylprednisolone 2 to 4 
mg/kg/day started. 
− 
If still no improvement within 3 
to 5 days despite 2 to 4 mg/kg IV 
methylprednisolone, promptly 
start immunosuppressives such 
as infliximab at 5 mg/kg once 
every 2 weeks. Caution: it is 
important to rule out bowel 
perforation and refer to 
infliximab label for general 
guidance before using 
infliximab. 
− 
Consult study physician if no 
resolution to Grade ≤1 in 3 to 
4 days. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PCP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3: stool 
frequency of ≥7 
over baseline per 
day; 
 
Grade 4: life 
threatening 
consequences) 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and 
volume and maintain hydration. 
− 
Urgent GI consult and imaging 
and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 
to 5 days of IV 

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the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
methylprednisolone 2 to 4 
mg/kg/day or equivalent, 
promptly start further 
immunosuppressives (eg 
infliximab at 5 mg/kg once every 
2 weeks). Caution: Ensure GI 
consult to rule out bowel 
perforation and refer to 
infliximab label for general 
guidance before using 
infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PCP 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. 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver 
function test: AST, ALT, ALP, and 
TB. 
− 
Evaluate for alternative 
etiologies (eg, viral hepatitis, 
disease progression, 
concomitant medications). 
Grade 1 
AST or ALT > to 3 
× ULN and/or TB 
> to 1.5 × ULN) 
No dose modifications. 
• 
If it worsens, then treat 
as Grade 2 event. 
For Grade 1: 
− 
Continue LFT monitoring per 
protocol. 
Grade 2 
(AST or ALT > 3 to 
5 × ULN and/or 
TB >1.5 to 3.0 × 
ULN) 
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 2: 
− 
Regular and frequent checking 
of LFTs (eg, every 1 to 2 days) 
until elevations of these are 
improving or resolved. 
− 
If no resolution to Grade ≤1 in 1 
to 2 days, discuss 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 

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Dose Modifications 
Toxicity Management 
or IV equivalent, consider 
additional workup 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 
(mycophenolate mofetil)a 
Discuss with study physician if 
mycophenolate mofetil is not 
available. Infliximab should NOT 
be used. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PCP 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 to 
20 × ULN and/or 
TB >3.0 to 10 × 
ULN) 
 
(Grade 4: AST or 
ALT >20 × ULN 
and/or TB 
>10 × 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 
• 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 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 
(mycophenolate mofetil). 
Discuss with study physician if 
mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Perform hepatology consult, 
abdominal workup, and imaging 
as appropriate. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PCP treatment (refer to current 
NCCN guidelines for treatment 

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Adverse Events 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
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. 
of cancer-related infections 
[Category 2B 
recommendation]).a 
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 (eg, 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 (eg, disease 
progression or infections). 
− 
Steroids should be considered in 
the absence of clear alternative 
etiology even for low-grade 
events (Grade 2), in order to 
prevent potential progression to 
higher grade event. 
Grade 1 
(Serum creatinine 
> 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 

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the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
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-
PCP 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. 

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Adverse Events 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
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 prophylactic 
antibiotics, antifungals, and anti-
PCP 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 (eg, 
diphenhydramine or 
hydroxyzine) and topical therapy 
(eg, 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. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic 
treatment, including oral 
antipruritics (eg, 
diphenhydramine or 

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Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
• 
If toxicity worsens, 
then treat as Grade 3. 
• 
If toxicity improves to 
Grade ≤1 or baseline, 
then resume 
drug/study regimen 
after completion of 
steroid taper. 
hydroxyzine) and topical therapy 
(eg, 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, discuss 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: 
Permanently discontinue 
study drug/study regimen. 
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-
PCP treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 
− 
Discuss with study physician. 
Endocrinopathy 
(eg, hyperthyroidism, 
hypothyroidism, 
hypopituitarism, and 
adrenal insufficiency) 
Any Grade 
(depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE v4.03 for 
General Guidance 
For Any Grade: 
− 
Consult endocrinologist. 
− 
Monitor patients for signs and 
symptoms of endocrinopathies. 
Non-specific symptoms include 
headache, fatigue, behavior 

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the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
defining the CTC 
grade/severity) 
changes, changed mental status, 
vertigo, abdominal pain, unusual 
bowel habits, hypotension, and 
weakness. 
− 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (eg, disease 
progression including brain 
metastases, or infections). 
− 
Monitor and evaluate thyroid 
function tests: TSH, free T3 and 
free T4 and other relevant 
endocrine labs depending on 
suspected endocrinopathy. 
− 
If a patient experiences an AE 
that is thought to be possibly of 
autoimmune nature (eg, 
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. 
− 
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 endocrinology consult. 
Grade 2 
For Grade 2 endocrinopathy 
other than hypothyroidism, 
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. 
For Grade 2 (including those with 
symptomatic endocrinopathy): 
− 
Isolated hypothyroidism may be 
treated with replacement 
therapy without treatment 
interruption and without 
corticosteroids. 
− 
Initiate hormone replacement as 
needed for management. 
− 
Evaluate endocrine function, 
and as clinically indicated, 
consider pituitary scan. 

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Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
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 ≤10 mg/day or 
equivalent. 
− 
For patients with abnormal 
endocrine work up, except for 
those with isolated 
hypothyroidism, consider 
short-term corticosteroids (eg, 1 
to 2 mg/kg/day 
methylprednisolone or IV 
equivalent) and prompt 
initiation of treatment with 
relevant hormone replacement 
(eg, levothyroxine, 
hydrocortisone, or sex 
hormones). - 
− 
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 
− 
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, 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. 
For Grade 3 or 4: 
− 
Consult endocrinologist. 
− 
Isolated hypothyroidism may be 
treated with replacement 
therapy without treatment 
interruption and without 
corticosteroids. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 
2 mg/kg/day or equivalent 
− 
Administer hormone 
replacement therapy as 
necessary. 
− 
For adrenal crisis, severe 
dehydration, hypotension, or 
shock, immediately initiate IV 
corticosteroids with 
mineralocorticoid activity. 
− 
Once the patient is improving, 
gradually taper 

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Dose Modifications 
Toxicity Management 
immunosuppressive 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 
− 
Discuss with study physician. 
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 
(eg, disease progression, 
infections, metabolic 
syndromes, or medications). 
− 
Monitor patient for general 
symptoms (headache, nausea, 
vertigo, behavior change, or 
weakness). 
− 
Consider appropriate diagnostic 
testing (eg, 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 
For Grade 2: 
− 
Discuss with the study physician. 
− 
Obtain neurology consult. 
− 
Sensory 
neuropathy/neuropathic pain 
may be managed by appropriate 
medications (eg, 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 

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the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
after completion of steroid 
taper. 
immunosuppressive therapy (eg, 
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 irAE does not 
resolve to Grade ≤1 within 
30 days. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
− 
Discuss with study physician. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 
days despite IV corticosteroids, 
consider additional workup and 
promptly treat with additional 
immunosuppressants (eg, 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 
(eg, 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 

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Dose Modifications 
Toxicity Management 
importance of prompt and 
accurate diagnosis, it is essential 
to have a low threshold to 
obtain a neurological consult. 
− 
Neurophysiologic diagnostic 
testing (eg, 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: 
− 
Discuss 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 
unless the symptoms are very 
minor and stable. 
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: 
− 
Discuss 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 (eg, gabapentin or 
duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be 
successfully used to 

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Dose Modifications 
Toxicity Management 
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. 

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the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
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 irAE does not 
resolve to Grade ≤1 within 
30 days or if there are signs 
of respiratory insufficiency 
or autonomic instability. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4 (severe or life-
threatening events): 
− 
Discuss with study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain 
neurological consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be 
successfully used to 
treat myasthenia 
gravis. They 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. 

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(ii) 
a 
ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael 
Postow MD. 
(iii) 
b 
FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical 
Evaluation. 
(iv) 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; 
irAE  Immune-related 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; PCP ; PO  By mouth; T3  Triiodothyronine; T4  Thyroxine; 
TB  Total bilirubin; TNF  Tumor necrosis factor; TSH  Thyroid-stimulating hormone; ULN  Upper limit of normal. 

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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 (eg, 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 (eg, 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 (eg, IM 
epinephrine, followed by IV 
diphenhydramine and ranitidine, and IV 
glucocorticoid). 
(v) 
CTCAE  Common Terminology Criteria for Adverse Events; IM  Intramuscular; IV  Intravenous; NCI  National Cancer 
Institute. 

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140 
 
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 (ie, events due to underlying 
disease) or for laboratory abnormalities not 
deemed to be clinically significant. 
Treat accordingly, as per institutional 
standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional 
standard. 
Grade 2 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
Treat accordingly, as per institutional 
standard. 
Grade 3 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
For AEs that downgrade to ≤Grade 2 within 7 
days or resolve to ≤Grade 1 or baseline 
within 14 days, resume study drug/study 
regimen administration.  Otherwise, 
discontinue study drug/study regimen. 
Treat accordingly, as per institutional 
standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: 
For Grade 4 labs, decision to discontinue 
should be based on accompanying clinical 
signs/symptoms, the Investigator’s clinical 
judgment, and consultation with the 
Sponsor.). 
Treat accordingly, as per institutional 
standard. 
(vi) 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.” 
(vii) AE  Adverse event; CTCAE  Common Terminology Criteria for Adverse Events; NCI  National Cancer Institute. 
 
 
 
 
 
 
 
 
 

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Appendix 2 
Schedule of study procedures: follow-up for subjects 
who have completed durvalumab and tremelimumab 
treatment and achieved disease control (until 
confirmed progression of disease) and subjects who 
have discontinued durvalumab or tremelimumab due 
to toxicity in the absence of confirmed progression of 
disease 
Evaluation 
Time Since Last Dose of MEDI4736 
Day (±3) 
Months (±1 week) 
12 Months and Every 
6 Months  
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Physical examination 
X 
 
 
 
 
 
 
 
Vital signs (temperature, respiratory rate, 
blood pressure, pulse) 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
Subsequent anti-cancer therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with 
subjects who refuse to return for 
evaluations and agree to be contacted 
 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Hematology 
X 
 
 
 
 
 
 
X 
Serum chemistry  
X 
 
 
 
 
 
 
 
Tumour assessment (CT or MRI) 
For subjects who achieve disease control following 12 months of treatment, 
tumour assessments should be performed every 8-12 weeks relative to the date 
of first infusion thereafter until confirmed PD by RECIST 1.1 by 
investigational site review.   
For subjects who discontinue MEDI4736 due to toxicity (or symptomatic 
deterioration), tumour assessments should be performed relative to the relative 
to the date of first infusion as follows: every 8-12 weeks until confirmed PD 
by RECIST 1.1 by investigational site review.  
Upon confirmed PD, scans should be conducted according to local standard 
clinical practice  
 
 
 

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Appendix 3 
Schedule of study procedures: follow-up for subjects 
who have discontinue durvalumab and tremelimumab 
treatment due to confirmed progression of disease at 
the investigator discretion 
Evaluation 
Time Since Last Dose of MEDI4736 
Day (±3) 
Months (±1 week) 
12 Months and Every 
6 Months  
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Physical examination 
X 
 
 
 
 
 
 
 
Vital signs (temperature, respiratory rate, 
blood pressure, pulse) 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
 
ECOG performance status 
X 
X 
X 
 
 
 
 
 
Survival status: phone contact with 
subjects 
who 
refuse 
to 
return 
for 
evaluations and agree to be contacted 
 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Hematology 
X 
 
 
 
 
 
 
 
Serum chemistry  
X 
 
 
 
 
 
 
 
Tumour assessment (CT or MRI) 
For subjects who continue on MEDI4736 post-confirmed progression at the 
investigator’s discretion (following consultation with the sponsor), tumour 
assessments should be performed relative to the date of first infusion until 
MEDI4736 
is 
stopped. 
For subjects who discontinue MEDI4736 following confirmed progression, 
scans should be conducted according to local clinical practice.