Clinical trial NCT03075527
Conditions: Mesothelioma
Keywords: Mesothelioma
Sponsor: Dana-Farber Cancer Institute
Start date: 2017-04-10; Completion date: 2024-12-16
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying a pair of immunotherapies as a possible treatment for malignant pleural mesothelioma.

The drugs involved in this study are:

* Durvalumab
* Tremelimumab

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved durvalumab or tremelimumab as a treatment for any disease.

In this research study, the investigators are studying if the study drug can help your cancer compared to the usual approach to treating malignant pleural mesothelioma . Durvalumab is a drug that blocks a protein often produced by cancer cells or surrounding cells to suppress immune cells from attacking cancer cells. Tremelimumab blocks a receptor on immune cells that normally suppresses immune attack. These two study drugs have been used alone for mesothelioma but the combination has not yet been tested for mesothelioma. These two drugs have been used for cancers such as melanoma and have been effective than using either drug alone.

Arms: arm 1: Subjects will receive durvalumab and tremelimumab both via intravenous infusion once per day for every 28 day cycles (+ 7 days). Participants will receive tremelimumab for up to 4 cycles (4 doses). Beginning with cycle 5 day 1, subjects will continue to receive durvalumab alone, until clinical or radiological progression.
Interventions: intervention 1: Tremelimumab intervention 2: Durvalumab
Intervention descriptions: intervention 1: Tremelimumab blocks a receptor on immune cells that normally suppresses immune attack. intervention 2: Durvalumab is a drug that blocks a protein often produced by cancer cells or surrounding cells to suppress immune cells from attacking cancer cells.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 
Version Date: May 12, 2017 
DF/HCC Protocol #: 16-549 
TITLE:  A Phase 2 Study of Durvalumab in Combination with Tremelimumab in Malignant 
Pleural Mesothelioma 
Coordinating Center: 
 
Dana-Farber Cancer Institute 
*Principal Investigator (PI): 
Mark M. Awad MD, PhD
Dana-Farber Cancer Institute 
mark_awad@dfci.harvard.edu
Statistician:
 
Susan Dahlberg 
Dana-Farber Cancer Institute 
 
dahlberg@jimmy.harvard.edu 
Responsible Data Manager: 
Bryan Marion 
Dana-Farber Cancer Institute 
450 Brookline Avenue LG-1B 
 
Tel: 617-632-3383 
 
Fax: 617-632-6485 
bryan_marion@dfci.harvard.edu 
NCI-Supplied Agents:  None 
Other Agents:  Durvalumab (MEDI4736) – AstraZeneca, Tremelimumab (CP-675,206) - 
AstraZeneca 
IND #:  132044 
IND Sponsor: Investigator-Initiated Study, Mark Awad MD, PhD 
Protocol Type / Version # / Version Date: 
Revised, Version 3, May 12, 2017 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
2 
 
SCHEMA 
 
 
 
 
 
Patient diagnosed 
with pleural 
mesothelioma 
Informed consent 
and confirmation 
of trial eligibility 
Participant receives tremelimumab + 
durvalumab therapy x4 cycles (where 1 
cycle = 28 days), followed by durvalumab 
monotherapy 
Disease progression, 
unacceptable toxicity 
Stable disease, partial or 
complete response 
Study treatment continues 
Study discontinuation 
Pre-treatment biopsy
Optional biopsy and study 
follow up 
On-treatment biopsy 


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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Study Design ............................................................................................................6 
1.2 
Primary Objective ....................................................................................................6 
1.3 
Secondary Objectives ...............................................................................................6 
1.4 
Exploratory Objectives ............................................................................................6 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Study Disease ...........................................................................................................6 
2.2 
Durvalumab..............................................................................................................7 
2.3 
Tremelimumab .......................................................................................................12 
2.4 
Durvalumab in Combination with Tremelimumab ................................................16 
2.5 
Rationale ................................................................................................................18 
2.6 
Correlative Studies Background ............................................................................20 
3. 
PARTICIPANT SELECTION ...........................................................................................22 
3.1 
Eligibility Criteria ..................................................................................................22 
3.2 
Exclusion Criteria ..................................................................................................23 
3.3 
Inclusion of Women and Minorities ......................................................................26 
4. 
REGISTRATION PROCEDURES ...................................................................................26 
4.1 
General Guidelines for DF/HCC Institutions ........................................................26 
4.2 
Registration Process for DF/HCC Institutions .......................................................26 
5. 
TREATMENT PLAN ........................................................................................................26 
5.1 
Treatment Regimen ................................................................................................26 
5.2 
Duration of Treatment and Criteria for Retreatment .............................................27 
5.3 
Pre-Treatment Criteria ...........................................................................................28 
5.4 
Agent Administration .............................................................................................28 
5.5 
General Concomitant Medication and Supportive Care Guidelines ......................29 
5.6 
Criteria for Taking a Participant Off Protocol Therapy .........................................31 
5.7 
Duration of Follow Up ...........................................................................................32 
5.8 
Criteria for Taking a Participant Off Study ...........................................................32 
6. 
DOSING DELAYS ............................................................................................................32 
6.1 
Toxicity Management Guidelines ..........................................................................33 
6.2 
Overdose ................................................................................................................60 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................61 
7.1 
Expected Toxicities ................................................................................................61 
7.2 
Definition of Adverse Events .................................................................................62 
7.3 
Adverse Event Characteristics ...............................................................................63 
7.4 
Serious Adverse Events .........................................................................................64 
7.5 
Adverse Events of Special Interest ........................ Error! Bookmark not defined. 


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Protocol Version Date: 12 May 2017 
 
4 
7.6 
Time Period for Collection of Adverse Events ......................................................64 
7.7 
Post-Study Events ..................................................................................................64 
7.8 
Follow-up of Unresolved Adverse Events .............................................................65 
7.9 
Reporting of Serious Adverse Events to AstraZeneca ...........................................65 
7.10 
Other Events Requiring Immediate Reporting ......................................................65 
7.11 
Expedited Adverse Event Reporting ......................................................................67 
7.12 
Expedited Reporting to the Food and Drug Administration (FDA) ......................67 
7.13 
Expedited Reporting to Hospital Risk Management .............................................67 
7.14 
Routine Adverse Event Reporting .........................................................................67 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................68 
8.1 
Durvalumab............................................................................................................68 
8.2 
Tremelimumab .......................................................................................................70 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................72 
9.1 
Tumor Tissue Collection........................................................................................72 
9.2 
Laboratory Correlative Studies ..............................................................................74 
10. 
STUDY CALENDAR .......................................................................................................75 
11. 
MEASUREMENT OF EFFECT........................................................................................78 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................78 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................85 
12.1 
Data Reporting .......................................................................................................86 
12.2 
Data Safety Monitoring ..........................................................................................86 
13. 
STATISTICAL CONSIDERATIONS...............................................................................86 
13.1 
Study Design/Endpoints.........................................................................................87 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................88 
13.3 
Analysis of Primary and Secondary Endpoints .....................................................88 
13.4 
Reporting and Exclusions ......................................................................................89 
14. 
PUBLICATION PLAN .....................................................................................................90 
REFERENCES ..............................................................................................................................91 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................94 
APPENDIX B 
Cockcroft-Gault equation for CREATININE CLEARANCE ...................95 
 
 
 
 
LIST OF TABLES: 
 
Table 1: Treatment Regimen Description ..................................................................................... 28 
Table 2: Highly Effectivea Methods of Contraception ................................................................. 31 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions ......................................................................................................... 34 
Table 4: Toxicity Management Guidelines for Immune-related Adverse Events not Otherwise 
Noted ............................................................................................................................................. 57 
Table 5: Dosing Modification and Toxicity Management Guidelines for Infusion-Related 
Reactions ....................................................................................................................................... 59 
Table 6: Dosing Modification and Toxicity Management Guidelines for Non-Immune Mediated 
Reactions ....................................................................................................................................... 60 
Table 7: Study Calendar................................................................................................................ 76 
Table 8: Criteria for Participants with Measurable Disease ......................................................... 84 
Table 9: Criteria for Participants with Non-Measurable Disease ................................................. 84 
Table 10: Accrual Targets ............................................................................................................. 88 


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1. OBJECTIVES 
 
The objective of this phase 2 study is to determine the antitumor activity of the CTLA-4 inhibitor 
tremelimumab in combination with the PD-L1 inhibitor durvalumab (MEDI4736) in malignant 
pleural mesothelioma.  Immunologic and genomic biomarkers of response will also be evaluated 
through correlative studies incorporated throughout this trial. 
 
1.1 
Study Design 
 
This is an open-label, single-arm, phase 2 study of tremelimumab plus durvalumab in patients 
with previously-treated unresectable malignant pleural mesothelioma. 
 
1.2 
Primary Objective 
 Examine the overall response rate (ORR) utilizing modified RECIST criteria for 
mesothelioma 
 
1.3 
Secondary Objectives 
 Determine the progression free survival (PFS) rate, defined as the time from 
registration to disease progression or death due to any cause.  Participants alive 
without disease progression will be censored at date of last disease evaluation. 
 Determine the overall survival (OS) rate, defined as the time from registration to 
death due to any cause (or censored at date last known alive). 
 Determine the duration of response (DoR), defined as the time from 
documentation of tumor response to disease progression (or censored at the date 
of last disease evaluation). 
 Evaluate the safety and tolerability of tremelimumab in combination with 
durvalumab. 
 
1.4 
Exploratory Objectives 
 Investigate the immunologic determinants of primary response and resistance to 
tremelimumab in combination with durvalumab in malignant pleural 
mesothelioma 
 Investigate the immunologic mechanisms of acquired resistance to tremelimumab 
in combination with durvalumab 
 Investigate genomic correlates of response to tremelimumab in combination with 
durvalumab 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
Malignant mesothelioma is an insidious cancer with a very poor prognosis. There are about 3300 
new cases of mesothelioma diagnosed in the United States each year, and 80% of these cases are 
pleural in origin. Mesothelioma results in significant morbidity and mortality typically through 
local invasion, and patients often experience progressive chest pain, shortness of breath, fatigue, 


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7 
and hypoxemia related to encasement of the lungs and accumulation of pleural fluid.  Extension 
into other thoracic structures can cause a number of disabling symptoms including dysphagia, 
spinal cord and brachial plexus injury, superior vena cava syndrome, and cardiac dysfunction.   
 
For patients with unresectable pleural mesothelioma, cisplatin-pemetrexed is the only FDA-
approved treatment regimen based on a 2003 randomized phase III first-line trial comparing this 
combination with cisplatin monotherapy.1  In this study, chemotherapy-naïve patients who 
received cisplatin and pemetrexed had a significantly longer median survival time (12.1 vs. 9.3 
months) and higher response rates (41.3% vs. 16.7%) compared to those receiving cisplatin 
alone. There are no effective second-line treatment options for patients with mesothelioma.  
There was a 16% response to weekly vinorelbine in a single-arm phase II trial of 63 patients with 
relapsed mesothelioma.2  A retrospective study of 66 mesothelioma patients treated with second- 
or third-line vinorelbine or gemcitabine found the response rate to be only 2%.3   
 
Immune checkpoint blockade as monotherapy was recently evaluated in a randomized, double-
blind, placebo-controlled study of tremelimumab in patients with unresectable pleural or 
peritoneal mesothelioma (Study D4880C0003, NCT01843374) and unfortunately was found not 
to extend overall survival. However, in the Keynote-028 phase Ib trial of patients with advanced 
solid tumors, among 25 PD-L1 positive mesothelioma patients treated with pembrolizumab, a 
partial response was seen in 7 patients and stable disease was seen in 12 patients4. In support of 
this finding is a growing body of evidence that a substantial number of malignant mesotheliomas 
express the immune checkpoint marker PD-L1.  In one recent study of 106 mesothelioma cases, 
PD-L1 was detected in 40% of patients by immunohistochemistry (IHC).  Furthermore, nearly 
all samples with sarcomatoid histology expressed PD-L1.  Compared to PD-L1-negative 
specimens, expression of PD-L1 was associated with a significant decrease in median overall 
survival (5 months vs. 14.5 months).5   
 
Recent pre-clinical work has suggested that targeting both PD-L1 and CTLA-4 may have 
additive or synergistic effects6. Based on these results, we hypothesize that PD-L1 inhibition 
with durvalumab and CTLA-4 inhibition with tremelimumab will result in high response rates in 
previously-treated patients with malignant pleural mesothelioma.  
 
 
2.2 
Durvalumab 
 
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.  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.  
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-L17. Based on these findings, an anti-PD-L1 antibody could be used therapeutically 


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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 activity8-10. 
 
2.2.1 Summary of Durvalumab Pre-Clinical Studies 
 
Engagement of PD-1 on T cells inhibits activation with downstream effects on cytokine 
production, proliferation, cell survival, and transcription factors associated with effector T-cell 
function11-16. 
 
Durvalumab has shown the following activity as an anti-PD-L1 molecule: 
• 
Durvalumab binds to PD-L1 and blocks its interaction with PD-1 and CD80  
• 
Durvalumab can relieve PD-L1-mediated suppression of human T-cell activation in vitro 
• 
Durvalumab inhibits tumor growth in a xenograft model via a T-cell dependent 
mechanism 
• 
A surrogate anti-mouse PD-L1 antibody resulted in improved survival in a syngeneic 
tumor model as monotherapy and resulted in complete tumor regression in > 50% of 
treated mice when given in combination with chemotherapy 
• 
In the same study, anti-mouse PD-L1 antibody-treated mice were completely tumor free 
3 months after tumor implantation and demonstrated long-term immunity during 
rechallenge 
• 
In a subsequent study in the same syngeneic model, the combination of an anti-mouse 
PD-L1 antibody and anti-CTLA-4 antibody resulted in complete tumor regression in all 
mice treated 
 
The cynomolgus monkey is considered to be the only relevant nonclinical species for evaluation 
of local and systemic toxicities of durvalumab. In addition, in vivo in cynomolgus monkeys, 
durvalumab suppresses soluble PD-L1 (sPD-L1) in serum and fully occupies membrane PD-L1 
on various leukocyte subsets at doses equal to or more than 0.1 mg/kg (lowest dose tested) with a 
dose-related duration of suppression and occupancy. 
 
In general, there were no durvalumab-related adverse effects in toxicity studies conducted in 
cynomolgus monkeys with durvalumab considered to be of relevance to humans. Adverse 
findings in the non-Good Laboratory Practice (GLP) pharmacokinetic (PK)/pharmacodynamic 
and dose range-finding study (4 doses over 5 weeks), and a GLP 4-week repeat-dose toxicity 
study were consistent with anti-drug antibody (ADA)-associated morbidity and mortality in 
individual animals. The death of a single animal in the non-GLP, PK/pharmacodynamic, and 
dose range-finding study was consistent with an ADA-associated acute anaphylactic reaction 
based on the presence of ADAs within days of the first dose, acuteness and timing (after repeated 
dosing) of the death, clinical signs consistent with an anaphylactic reaction, lack of remarkable 
effects on other study parameters, and lack of histopathologic findings consistent with any other 
cause of death. In addition, the spectrum of findings, especially the clinical signs and 
microscopic pathology, in a single animal in the GLP, 4-week, repeat-dose study was consistent 
with ADA-associated immune complex deposition. Similar effects have been observed by 
MedImmune in cynomolgus monkeys administered other unrelated human MAbs. With 
durvalumab, ADA immune-complexes were identified in the affected animal in a subsequent 


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9 
investigative immunohistochemistry study. Given that immunogenicity of human MAbs in 
nonclinical species is not generally predictive of responses in humans, the ADA-associated 
morbidity and mortality were not taken into consideration for the determination of the no-
observed-adverse-effect level (NOAEL) of durvalumab in these studies. Finally, interim audited 
data from the dosing phase of the pivotal 3-month, repeat-dose GLP toxicity study in 
cynomolgus monkeys, showed that subchronic dosing of durvalumab was not associated with 
any adverse effects. Therefore, the NOAEL of durvalumab in all the general toxicity studies was 
considered to be 100 mg/kg, the highest dose tested in these studies. 
 
2.2.2 Durvalumab Clinical Studies 
 
Durvalumab has been given to humans as part of ongoing studies as a single drug or in 
combination with other drugs.  As of the data cut-off dates (15Apr2015 to 18Sep2015, 
durvalumab IB version 9.0), a total of 1,910 subjects have been enrolled and treated in 
30 ongoing durvalumab clinical studies, including 20 sponsored and 10 collaborative studies. Of 
the 1,910 subjects, 1,279 received durvalumab monotherapy, 454 received durvalumab in 
combination with tremelimumab or other anticancer agents, 14 received other agents (1 gefitinib, 
13 MEDI6383), and 163 have been treated with blinded investigational product. No studies have 
been completed or terminated prematurely due to toxicity.  
 
2.2.2.1 
Durvalumab Pharmacokinetics 
 
As of 09 Feb 2015, pharmacokinetic (PK) data were available for 378 subjects in the dose-
escalation and dose-expansion phases of Study CD-ON-MEDI4736-1108 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 clearance 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 09 Feb 2015, 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. 
 
2.2.2.2 
Durvalumab Adverse Events 
 
A total of 736 subjects with advanced solid tumors have been treated in Study CD-ON-


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MEDI4736-1108. Of these subjects, 694 have received durvalumab at 10 mg/kg Q2W, either in 
the dose-escalation or dose-expansion phase of the study. The 10 mg/kg Q2W cohort represents 
combined data from subjects treated with this dosing regimen in either the dose-escalation or 
dose-expansion phase. The 10 mg/kg Q2W cohort comprises subjects with NSCLC (n = 252), 
SCCHN (n = 62), gastroesophageal cancer (n = 51), HCC (n = 40), pancreatic adenocarcinoma 
(n = 31), TNBC (n = 28), bladder cancer (n = 28), uveal melanoma (n = 24), and advanced 
cutaneous melanoma (n = 23). Subjects in the 10 mg/kg Q2W dose cohort were exposed to a 
median of 6 doses of durvalumab, ranging from 1 to 27 doses. Exposure was generally consistent 
across the tumor types, with the exception of advanced cutaneous melanoma having a higher 
median exposure of 13 doses, and gastroesophageal cancer, TNBC, and bladder cancer having 
lower median exposures of ~3 doses. 
 
In addition, safety data are presented for 42 subjects in the following dose-escalation cohorts: 
4 subjects in each of the 0.1 and 0.3 mg/kg Q2W cohorts, 3 subjects in each of the 1 and 
3 mg/kg Q2W cohorts, 2 subjects in the 10 mg/kg Q3W cohort, 7 subjects in the 15 mg/kg 
Q3W cohort, and 19 subjects in the 20 mg/kg Q4W cohort. 
 
Of the 694 subjects treated with 10 mg/kg Q2W, 668 subjects (96.3%) had at least 1 adverse 
event (AE) (regardless of causality). AEs (all grades) reported in decreasing order of frequency 
in ≥ 10% of subjects were fatigue, nausea, decreased appetite, dyspnea, cough, constipation, 
diarrhea, vomiting, back pain, pyrexia, abdominal pain, anemia, arthralgia, peripheral edema, 
headache, rash, and pruritus. Across the tumor types, the overall incidence of AEs was generally 
similar; however, differences were noted by system organ class and preferred term (PT). 
 
Grade 3 or higher AEs were reported in 379 subjects (54.6%) and were manageable by general 
treatment guidelines. Events occurring in > 2% of subjects were dyspnea (7.2%), hyponatremia 
(4.6%), NSCLC (4.5%), anemia (4.2%), increased GGT (3.9%), fatigue (3.3%), increased AST 
(3.2%), sepsis (2.7%), pneumonia (2.6%), abdominal pain (2.4%), back pain (2.3%), and 
malignant lung neoplasm (2.2%). 
 
A total of 378 subjects (54.5%) reported AEs that were considered by the investigator to be 
related to investigational product. Treatment-related AEs (all grades) reported in > 2% of 
subjects were fatigue (17.7%); nausea (8.6%); diarrhea (7.3%); decreased appetite (6.8%); 
pruritus (6.3%); rash (6.1%); vomiting (5.0%); hypothyroidism (4.8%); arthralgia (4.0%); 
increased AST (3.9%); increased ALT, myalgia (3.6% each); dyspnea (3.3%); pyrexia (2.7%); 
increased GGT, cough (2.4% each); anemia, hyperthyroidism (2.3% each); and asthenia (2.2%). 
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 AST (7 subjects, 1.0%); increased 
GGT (6 subjects, 0.9%); increased ALT (5 subjects, 0.7%); and colitis, vomiting, decreased 
appetite, hyponatremia (3 subjects, 0.4% each). Six subjects (3 NSCLC, 2 HCC, and 1 SCCHN) 
had treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, increased AST, dyspnea, 
neutropenia, colitis, diarrhea, and pneumonitis) and 1 subject (NSCLC) had a treatment-related 
Grade 5 event (pneumonia). 
 
AEs (regardless of causality) reported for ≥ 2 subjects in any of the other Q2W dose escalation 


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cohorts were as follows: pyrexia (3/4 subjects in the 0.3 mg/kg cohort); diarrhea (2/4 subjects in 
each of the 0.1 and 0.3 mg/kg cohorts); fatigue and arthralgia (2/4 subjects each in the 0.3 mg/kg 
cohort); rash (2/4 subjects in the 0.3 mg/kg cohort and 2/3 subjects in the 1 mg/kg cohort); and 
nausea and dizziness (2/3 subjects each in the 1 mg/kg cohort). AEs reported for ≥ 2 subjects in 
the Q3W cohorts (all occurring at 15 mg/kg) were cough (4/7 subjects); nausea, fatigue, pyrexia, 
dyspnea (3/7 subjects each); and abdominal pain, vomiting, asthenia, musculoskeletal pain, 
dizziness, and rhinorrhea (2/7 subjects each). In the 20 mg/kg Q4W cohort, AEs reported for ≥ 2 
subjects were fatigue, decreased appetite (3/19 subjects each); sepsis, back pain, hypoesthesia, 
and cough (2/19 subjects each). No ≥ Grade 3 events were reported for more than 1 subject in 
any of these dose-escalation cohorts. Grade 3 events considered by the investigator to be related 
to durvalumab were fatigue and peripheral motor neuropathy in 1 subject each in the 15 mg/kg 
Q3W cohort, and increased GGT in 1 subject in the 20 mg/kg Q4W cohort. No treatment-related 
Grade 4 or 5 AEs, and no DLTs have been reported. 
 
2.2.2.3 
Durvalumab Serious Adverse Events 
 
A total of 718 serious adverse events (SAEs) (regardless of causality) have been reported in 345 
of 694 subjects (49.7%) treated with 10 mg/kg durvalumab Q2W. SAEs reported for 10 or more 
subjects were dyspnea, NSCLC, pneumonia, pyrexia, sepsis, malignant lung neoplasm, 
abdominal pain, pleural effusion, general physical health deterioration, pancreatic carcinoma, 
vomiting, and dehydration. The overall rates for SAEs were generally comparable across the 
tumor types, except for a much higher rate (80.6%) in the pancreatic cancer cohort and a lower 
rate (30.4%) in the advanced cutaneous melanoma cohort. The higher frequency of SAEs in the 
pancreatic cancer cohort could be explained, in part, by the high rate of disease progressions (PT 
of pancreatic carcinoma; 32.3%) reported in these subjects. Of note, disease progressions were 
reported as SAEs in this study. 
 
Twenty-five subjects (3.6%) had SAEs considered by the investigator to be related to 
durvalumab. Treatment-related SAEs that occurred in 2 or more subjects were colitis and 
pneumonitis (3 subjects each). A majority of the treatment-related SAEs were Grade 3 or higher 
in severity and recovered with or without sequelae. One subject died due to a treatment-related 
SAE (pneumonia). Prior to the fatal event of pneumonia, the subject experienced treatment-
related SAEs of pneumonitis (Grade 4) and pneumonia (Grade 3). 
 
In addition, SAEs were reported for 5 subjects (35.7%) in the other Q2W dose-escalation 
cohorts, 3 subjects (42.9%) in the 15 mg/kg Q3W cohort, and 7 subjects (36.8%) in the 20 mg/kg 
Q4W cohort. SAEs (PTs) reported for > 1 subject were abdominal pain, sepsis, and NSCLC (2 
subjects each). The majority of the SAEs were ≥ Grade 3 in severity, and none of the events were 
considered by the investigator to be related to durvalumab. 
 
2.2.2.4 
Efficacy 
 
Partial efficacy data are available for Study CD-ON-MEDI4736-1108. Tumor assessments were 
based on RECIST v1.1. 
 
A total of 456 of 694 subjects with advanced solid tumors treated with durvalumab 10 mg/kg 


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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 overall response rate (ORR), based on 
investigator assessment per RECIST v1.1, ranged from 0% in uveal melanoma to 20% in bladder 
cancer, and disease control rate at 24 weeks (DCR-24w) ranged from 4.2% in TNBC to 39.1% in 
advanced cutaneous melanoma. PD-L1 status was known for 383 of the 456 response evaluable 
subjects. Across the PD-L1-positive tumors, ORR was highest (> 10%) for bladder cancer, 
advanced cutaneous melanoma, HCC (33.3% each), NSCLC (26.7%), and SCCHN (18.2%). 
Moreover, in the PD-L1-positive subset, DCR-24w was highest (> 10%) in advanced cutaneous 
melanoma (66.7%), NSCLC (36.0%), HCC and bladder cancer (33.3% each), and SCCHN 
(18.2%). 
 
2.2.3 Durvalumab Marketing Experience 
 
Durvalumab has not been approved for marketing purposes anywhere in the world. 
 
 
2.3 
Tremelimumab 
 
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) cultures17.  In addition, 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. Tremelimumab as monotherapy was recently evaluated in a randomized, 
double-blind, placebo-controlled study of patients with unresectable pleural or peritoneal 
mesothelioma (Study D4880C0003, NCT01843374) and unfortunately was found not to extend 
overall survival. However, when used in combination with durvalumab, it may lead to increased 
activation of the human immune system and increase anti-tumor activity in patients with 
mesothelioma.  
 
2.3.1 Summary of Tremelimumab Pre-Clinical Studies 
 
Tremelimumab selectively binds to human CTLA-4 and blocks binding of CD80 and CD86 and 
has been shown to enhance human T-cell cytokine release in response to stimulation. Both in 
vitro and in vivo preclinical data suggest that a range of anti-CTLA-4 MAb exposures have the 
potential to be efficacious, the lower end of the potentially efficacious range being a plasma 
concentration of approximately 10 μg/mL and the target plasma concentration being 30 μg/mL. 
The toxicology program conducted for tremelimumab consisted of in vivo general toxicology 


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studies in cynomolgus monkeys for up to 6-months duration, an embryo-fetal development study 
in monkeys, tissue cross-reactivity studies in both monkey and human tissues, and blood 
compatibility studies. 
 
Overall, tremelimumab non-clinical toxicities were consistent with inhibition of CTLA-4 and 
with clinical safety findings, and indicated that chronic clinical use of tremelimumab may lead to 
adverse effects on the gastrointestinal tract, skin, lymphoid organs, thyroid tissues, and 
hematological systems. Dose-limiting toxicities identified in chronic toxicity studies in monkeys 
included skin rash and gastrointestinal effects. Most toxicities were reversible or showed a trend 
toward reversibility. 
 
An embryo-fetal development study was conducted in pregnant cynomolgus monkeys during the 
period of organogenesis. Tremelimumab administered intravenously (IV) once weekly from Day 
20 to Day 50 of gestation at doses of 0, 5, 15, or 30 mg/kg did not elicit maternal toxicity, 
developmental toxicity, or teratogenicity. 
 
2.3.2 Tremelimumab Clinical Studies 
 
An extensive program of 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.  As of the data cut-off dates of 
1 November 2015 (for all monotherapy studies) or 15 April 2015 to 12 July 2015 (for 
combination therapy studies), 34 sponsored clinical studies have been conducted as part of the 
tremelimumab development program. Of these, 13 studies have been completed and 21 are 
ongoing. As of 1 November 2015, 973 patients have received tremelimumab monotherapy in 
completed monotherapy trials, and 569 patients have been treated in the ongoing blinded phase 
IIb monotherapy study D4880C0003. A third ongoing monotherapy trial (D4884C00001) has yet 
to enroll. Additionally, 59 patients have been treated with tremelimumab in monotherapy arms of 
combination studies.  
 
Five studies of tremelimumab in combination with other anticancer agents have been completed 
and 18 are ongoing. In total, 250 patients with a variety of tumor types have received 
tremelimumab in combination with other anticancer agents in these studies. 
 
2.3.2.1 
Tremelimumab Pharmacokinetics 
 
Population PK analysis of tremelimumab was performed on combined data from Phase I, 
Phase II, and Phase III studies (N=654) in patients with metastatic melanoma using nonlinear 
mixed-effects modeling in NONMEM software. A 2-compartment population PK model 
adequately described the plasma concentrations of tremelimumab following various dosing 
regimens.  
 
The population estimate for clearance (CL) and central volume of distribution (V1) was 0.26 
L/day and 3.97 L, respectively. The inter-individual variability in CL and V1 was modest (31.8% 
and 20.4%, respectively). Clearance was faster in males, patients with higher values of creatinine 
clearance and endogenous Ig, and patients with relatively poor baseline prognostic factors. 


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Central volume of distribution was higher in males and patients with higher body weight. No 
dose adjustment was needed based on the magnitude of the change in CL (< 30%)18. Preliminary 
population PK of tremelimumab was performed using data from two second-line, single-arm 
investigator-initiated Phase II studies (NCT01649024/NCT01655888) in patients with malignant 
mesothelioma. A total of 40 patients provided evaluable PK data following 15 mg/kg Q90D 
(NCT01649024) or 10 mg/kg Q4W for 6 months followed by 10 mg/kg Q12W (NCT01655888) 
dosing regimens. 
 
Tremelimumab PK exposure in mesothelioma patients was similar to previous melanoma studies 
following 15 mg/kg Q90D. Following the 15 mg/kg Q90D, PK exposure was below the target 
trough level of approximately 30 μg/mL for about half of the dosing interval with almost all 
patients below the LLOQ at the end of the 90-day dosing interval. Following more frequent 
dosing of 10 mg/kg Q4W, PK exposure was increased and maintained at or above the target level 
in the majority of patients over the entire dosing interval. Tremelimumab PK was best described 
using a 2-compartment linear model with first order elimination. Following IV dosing, the 
typical CL and V1 were 0.2 L/day and 3.5 L, respectively. The between-patient variability for 
CL and V1 were 22% and 7%, respectively. The estimated typical PK parameters were similar to 
other mAbs without target mediated elimination. The baseline body weight and Eastern 
Cooperative Oncology Group (ECOG) performance status were identified as significant 
covariates for CL, whereas only baseline body weight was significant covariate for volume of 
distribution. 
 
Tremelimumab exhibited a biphasic PK profile with a long terminal phase half-life of 22.1 days.  
Overall, a low incidence of ADAs (<6%) was observed for treatment with tremelimumab.   
 
2.3.2.2 
Absorption, Distribution, Metabolism, and Elimination of Tremelimumab 
 
Tremelimumab is administered by IV infusion. The absorption of tremelimumab upon 
extravascular administration has not been investigated. 
 
The mean VSS for tremelimumab is 81.2 mL/kg, which is typical of mAbs with limited 
distribution. No studies of human tissue distribution of tremelimumab have been conducted. 
 
The mean CL for tremelimumab is 0.132 mL/hour/kg. Similar to other mAbs without target 
mediated drug disposition, tremelimumab is likely to be cleared from circulation by endothelial 
cell uptake and proteolysis. Since mAbs are not primarily cleared via hepatic/renal pathways, no 
impact of renal/hepatic functions is expected on tremelimumab elimination. No studies have 
been conducted in patients with renal/hepatic impairment. 
 
2.3.2.3 
Tremelimumab Adverse Events 
 
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. 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%) treated with 
tremelimumab monotherapy experienced at least 1 AE. Based on integrated data from the 


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completed and rollover tremelimumab monotherapy studies (N=973), AEs (all grades, regardless 
of severity) reported in >10% of patients were: diarrhea (45.3%), fatigue (37.5%), nausea 
(32.5%), rash (28.9%), pruritus (27.4%), decreased appetite (22.8%), vomiting (22.5%), pyrexia 
(15.3%), cough (15%), constipation (14.4%), abdominal pain (13.9%), headache (13.8%), 
dyspnea (12.4%), and decreased weight (10.3%).  
 
Adverse events were considered to be treatment related in 770 of the 973 patients (79.1%). 
Treatment-related AEs were reported at similar rates in the 10 and 15 mg/kg groups (81.8% and 
80.0%, respectively), and were mostly Grade 1 or 2 in severity (≥Grade 3 treatment-related AEs 
reported in 26.1% of patients). The most frequent treatment-related AEs (in >5% of patients) 
were diarrhea (41.2%), rash (27.2%), pruritus (25.2%), fatigue (23.8%), nausea (21.9%), 
vomiting (13.5%), decreased appetite (11.3%), headache (7.2%), pyrexia (7%), abdominal pain 
(6.7%), and colitis (5.5%). 
 
Integrated data from completed studies of tremelimumab in combination with other agents 
(N=116) showed that AEs reported in >15% of patients (all grades, regardless of causality) 
included: diarrhea (54.3%), nausea (40.5%), fatigue (38.8%), rash (35.3%), pruritus and 
decreased appetite (30.2% each), vomiting (27.6%), pyrexia (26.7%), influenza-like illness 
(20.7%), arthralgia (19.8%), constipation (19%), thrombocytopenia and injection site reaction 
(18.1% each), and increased AST (15.5%). Most of these events occurred at a higher rate with 
tremelimumab plus sunitinib than with other combinations. 
 
2.3.2.4 
Tremelimumab Serious Adverse Events 
 
As of the data cutoff date of 1 November 2015, 355 patients (36.5%) had a total of 859 SAEs. 
The highest incidence of SAEs occurred in the 10 mg/kg group (42.9%), followed by the 15 
mg/kg (36%) and All Doses <10 mg/kg (30.3%) groups. Serious adverse events experienced by 
>1% of patients were diarrhea, colitis, vomiting, disease progression, dehydration, pyrexia, 
nausea, abdominal pain, dyspnea, pneumonia, and confusional state. The majority of these events 
were ≥ Grade 3 in severity and reported at a higher rate in the 15 mg/kg group. 
 
A total of 451 SAEs in 197 patients (20.2%) were assessed as related to investigational product 
by the investigator. Treatment-related SAEs were reported in more patients in the 10 mg/kg 
group compared with the 15 mg/kg group (29.9% vs. 20%, respectively), and were ≥ Grade 3 in 
severity in the majority of patients (84.8%). The most frequent treatment-related SAEs 
(occurring in >1% of patients) were: diarrhea (9.2%), colitis (3.6%), vomiting (2.3%), and 
nausea and dehydration (1.8% each). 
 
2.3.2.5 
Tremelimumab Efficacy 
 
Across the clinical development program for tremelimumab, a pattern of efficacy has emerged 
that is similar to that of the related anti-CTLA-4 antibody, ipilimumab. The efficacy of 
tremelimumab appears to be consistent across tumor types. Response rates to anti-CTLA-4 
antibodies are generally low, approximately 10%. However, in patients who respond, the 
responses are generally durable, lasting several months even in those with aggressive tumors 
such as refractory metastatic melanoma. Moreover, a survival benefit was reported even in 


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patients without radiographic regression in tumor burden. In a single-arm, Phase II study (Study 
A3671008) of tremelimumab administered at 15 mg/kg Q90D to patients with refractory 
melanoma, a response rate of 7% and median OS of 10 months in the second line setting (as 
compared to approximately 6 months with BSC reported from a retrospective analysis19) was 
observed20. In a randomized, open-label, first-line Phase III study of tremelimumab 
(administered at 15 mg/kg Q90D) versus chemotherapy (DTIC or temozolomide) in advanced 
melanoma (Study A3671009), results of the final analysis showed a response rate of 11% and 
median OS of 12.58 months in this first-line setting (as compared to 10.71 months with standard 
chemotherapy)21. Additionally, in a Phase II maintenance study in NSCLC, PFS at 3 months was 
22.7% in the tremelimumab arm compared with 11.9% in the BSC arm (Study A3671015). 
 
2.3.3 Tremelimumab Marketing Experience 
 
There is no marketing experience for tremelimumab. 
 
 
2.4 
Durvalumab in Combination with Tremelimumab 
 
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity because 
the mechanisms of action of CTLA-4 and PD-1 are non-redundant22; therefore, AstraZeneca is 
also investigating the use of durvalumab and tremelimumab combination therapy for the 
treatment of cancer. 
 
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, 
PK/pharmacodynamics (PD), and preliminary anti-tumor activity of durvalumab and 
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.   
 
2.4.1 Durvalumab and Tremelimumab Pharmacokinetics 
 
As of 20 Feb 2015, durvalumab PK (n = 55) and tremelimumab PK (n = 26) data were available 
from 10 cohorts of study D4190C00006 (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 durvalumab 
and tremelimumab following combination were consistent with respective monotherapy data, 
indicating no PK interaction between these 2 agents. 
 
As of 20 Feb 2015, 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 


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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. 
 
2.4.2 Durvalumab and Tremelimumab Safety 
 
A total of 102 subjects with advanced NSCLC have been treated with durvalumab and 
tremelimumab across 10 dose cohorts in Study D4190C00006. Across all dose cohorts, 95 of 102 
subjects (93.1%) reported at least 1 AE (regardless of causality). AEs (all grades) reported in 
>10% subjects in decreasing order of frequency were diarrhea, fatigue, nausea, dyspnea, pruritus, 
rash, increased amylase, decreased appetite, pyrexia, increased ALT, cough, colitis, and 
increased lipase. 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 (14 of 18 subjects, 77.8%). 
 
Thirty-one of 102 subjects (30.4%) experienced AEs that were Grade 1 or 2 in severity. These 
events were manageable by general treatment guidelines. Grade 3 or higher AEs were reported in 
64 of 102 subjects (62.7%). These events occurring in > 5% of subjects were colitis (8.8%), 
diarrhea (8.8%), and increased lipase (5.9%). In addition, ≥ Grade 3 events that were uncoded as 
of the data cut-off date were verbatim terms (VTs) of gastrohepatic mass resection, elective 
diagnostic surgical excision of cerebral lesion, and chest pain (all Grade 3 and not related to 
study treatment); disease progression in 3 subjects (Grade 5 and not related to study treatment); 
and Grade 5 neuromuscular disorder occurring 42 days after the last dose of durvalumab and 
considered related to study treatment. 
 
Treatment-related AEs were reported in 74 of 102 subjects (73%). Of these subjects, 12 had 
Grade 1, 21 had Grade 2, 35 had Grade 3, 4 had Grade 4, and 2 had Grade 5 events as maximum 
severity. The treatment-related Grade 5 events were polymyositis and an uncoded event of 
neuromuscular disorder (VT). Treatment-related Grade 3 or higher events that occurred in 2 or 
more subjects were colitis (9 subjects); diarrhea (8 subjects); increased lipase (6 subjects); 
increased AST, and pneumonitis (4 subjects each); increased ALT and increased GGT (3 
subjects each); and increased amylase, anemia, and increased blood alkaline phosphatase (2 
subjects each). Safety data from the durvalumab 15 and 20 mg/kg Q4W cohorts demonstrated a 
numerical increase in the frequency of treatment-related AEs and AEs leading to discontinuation 
of investigational product with increasing doses (> 1 mg/kg) of tremelimumab. 
 
Grade 1 or 2 AEs have been managed clinically without requiring dose modifications or delays. 
Treatment-related Grade 3 AEs have been manageable and reversible with standard toxicity 
management guidelines including steroids with the exception of 1 subject who experienced 
Grade 4 myasthenia gravis and polymyositis (with fatal outcome). This event was reported as an 
SAE (death). 
 
Two subjects in the durvalumab 20 mg/kg plus tremelimumab 3 mg/kg Q4W cohort experienced 
DLTs. One subject had Grade 3 increased AST on Day 29 of Cycle 1; a second subject had 
Grade 3 increased amylase and Grade 4 increased lipase on Day 9 of Cycle 1. 


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A total of 56 subjects (54.9%) reported at least 1 SAE. Most commonly reported preferred terms 
(> 5%) were colitis (9.8%) and diarrhea (7.8%). SAEs that were not coded at the time of data 
cut-off were VTs of gastrohepatic mass resection, elective diagnostic surgical excision of 
cerebral lesion, neuromuscular disorder, progression of disease, progression of malignant 
neoplasm, and chest pain. The majority of subjects with SAEs (94.6%) had events of Grade 3 or 
higher severity. Thirty-six (35.3%) subjects experienced SAEs that were considered related to 
investigational products. Twenty-six subjects (25.5%) discontinued treatment due to SAEs of 
colitis (7 subjects); pneumonitis (5 subjects each); diarrhea (3 subjects); increased AST and 
dyspnea (2 subjects each); and pancreatitis, sepsis, increased ALT, arthralgia, malignant 
neoplasm progression, lung disorder, and NSCLC (1 subject each). 
 
2.4.3 Durvalumab and Tremelimumab Efficacy 
 
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 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. 
  
2.5 
Rationale 
 
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 profile23,24. Responses have been observed in patients with PD-L1-positive 
tumors and patients with PD-L1-negative tumors. In a study of an anti-PD-L1 therapy in patients 
with advanced unresectable mesothelioma, an ORR of 14.3% was observed among PD-L1 
positive subjects and an 8% ORR was observed among PD-L1 negative subjects25. In addition, 
durvalumab monotherapy has shown durable responses in NSCLC in Phase 1 study, CD-ON-
MEDI4736-1108. 
 
The mechanisms of CTLA-4 and PD-1 are non-redundant, suggesting that targeting both 
pathways may have additive or synergistic activity22.  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 durable26. Similar results have been 
observed in an ongoing study of durvalumab and tremelimumab in NSCLC27. 
 


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2.5.1 Durvalumab  and Tremelimumab Combination Therapy Dose Rationale 
 
A population PK model was developed for durvalumab using monotherapy data from the Phase 1 
study, CD-ON-MEDI4736-1108 (N = 292; doses of 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; 
solid tumors). Population PK analysis indicated only minor impact of body weight on PK of 
durvalumab (coefficient of ≤ 0.5). The impact of body weight-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 weight of ~75 kg). A 
total of 1000 subjects were simulated using body weight distribution of 40 to 120 kg. Simulation 
results demonstrate that body weight-based and fixed dosing regimens yield similar median 
steady-state PK concentrations with slightly less overall between-subject variability with fixed 
dosing regimen. 
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N = 654; doses of 0.01 to 15 mg/kg Q4W or every 90 days; metastatic 
melanoma). The population PK model indicated minor impact of body weight on PK of 
tremelimumab (coefficient of ≤ 0.5). The weight-based (1 mg/kg Q4W) and fixed dosing (75 
mg/kg Q4W; based on median body weight of ~75 kg) regimens were compared using predicted 
PK concentrations (5th, median and 95th percentiles) using population PK model in a simulated 
population of 1,000 subjects with body weight distribution of 40 to 120 kg. Similar to 
durvalumab, simulations indicated that both body weight-based and fixed dosing regimens of 
tremelimumab yield similar median steady state PK concentrations with slightly less between-
subject variability with a fixed dosing regimen. 
Similar findings have been reported by others28-31. Wang and colleagues investigated 12 mAbs 
and found that fixed and body size-based dosing perform similarly, with fixed dosing being 
better for 7 of 12 antibodies29. 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 PK/pharmacodynamics parameters30. 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, we considered 
it feasible to switch to fixed dosing regimens. Based on an average body weight of 75 kg, a fixed 
dose of 750 mg Q2W durvalumab is equivalent to 10 mg/kg Q2W, 1500 mg Q4W durvalumab is 
equivalent to 20 mg/kg Q4W, and 75 mg Q4W tremelimumab is equivalent to 1 mg/kg Q4W. 
2.5.2 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 22%.  
Furthermore, the survival curve in this population reached a plateau at 3 years and was 
maintained through 10 years of follow up32.  
 
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies:  


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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 
analysis33-35.  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 analysis36.  
 
MPDL3280A (anti-PD-L1) was evaluated in a phase I study in which patients were dosed for a 
finite time period. Responses were maintained beyond treatment discontinuation37. The same has 
been reported for combination therapy using nivolumab with ipilimumab26. 
 
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.   
 
2.6 
Correlative Studies Background 
 
Use of combination immune therapies in patients with mesothelioma presents a variety of 
confounding variables that could contribute to success or failure of the therapy.  Correlative 
studies are designed to both enable better understanding of the possible reasons that durvalumab 
in combination with tremelimumab may prove to be effective or ineffective in individual 
patients, and to enable the development of more effective targeting strategies in the future. 
 
2.6.1 Collection of Tumor Tissue 
 
In order to explore the determinants of response and resistance to combination durvalumab and 
tremelimumab therapy, archival tumor tissue will be collected at baseline from all patients 
enrolling to the trial. In addition, mandatory pre- and on-treatment fresh tumor biopsies will be 
obtained whenever clinically feasible from all patients enrolled.  An optional final biopsy will be 
offered to all patients at the time of disease progression. The genetic and immune characteristics 
identified in the tumor tissue will be correlated to clinical outcome. 
 
Analysis of tumor tissue samples taken at distinct points enables addressing of key questions 
including: (1) the genomic lesions and immune cell presence at baseline in samples studied and 
their potential impact upon response, (2) the identification of immediate gene pathways or 
immune expression programs activated by tumors following durvalumab and tremelimumab 
combination therapy, and (3) mechanisms of acquired resistance to therapy. 
 
The first correlative question relates to the genetic and immune diversity of the patients enrolled 
in this study. It is the anticipation that most patients on this study will have had their tumor 
genomically characterized by either the OncoPanel test at DFCI/BWH (a custom hybrid capture 
panel which via next-generation sequencing [NGS] will identify mutations and copy-number 
alterations in cancer associated genes) or via another CLIA-certified method at the time of 
enrollment. These approaches have enabled comprehensive cataloguing of the mutations in 
multiple cancer types, thus greatly enhancing our understanding of the genetics and 


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21 
biology of various malignancies38. The archival tissue collected will be analyzed retrospectively 
by immunohistochemistry (IHC) to examine expression of immune markers such as PD-L1 and 
CD3. The pre-treatment tumor biopsy will undergo immune profiling by flow cytometry at the 
immuno-oncology laboratory at the Belfer Center for Applied Cancer Science. The pre-treatment 
samples will be examined for immune cell subsets (including granulocytes, monocytes, 
neutrophils, lymphocytes, dendritic cells, and NK cells) as well as immune marker expression on 
those cells (e.g. PD-L1, PD-1, TIM-3, LAG-3, etc). Additional studies will include RNA analysis 
to explore gene expression changes and pathway adaptation on-treatment compared to pre-
treatment. Advances in high-throughput genomic technologies have enabled an unprecedented 
understanding of the molecular basis of human cancers39. Techniques such as RNA sequencing 
and Nanostring have enabled highly quantitative assessment of the transcriptome of each tumor 
sample, thus permitting full analysis of the expression levels of various expressed transcripts.  
 
Another key rationale for performance of biopsies in patients after initiating drug therapy is to 
address mechanisms of resistance to the combination therapy.  The emergence of resistance to 
therapy is a profound problem in oncology.  Such resistance can follow not only acquisition of 
secondary mutations but also from the ability of cancer cells to activate immediate compensatory 
mechanisms39. Identification of these compensatory reactions is a necessary step in order to 
design subsequent rational therapies that may lead to even more durable and long-lasting clinical 
benefit. As such, RNA sequencing will be repeated in the on-treatment biopsies. The expression 
of immune markers including PD-L1 is a dynamic process, as expression can be induced by 
activated tumor antigen-specific T cells and levels can also be influenced by prior treatment 
(including use of non-immune therapies such as tyrosine kinase inhibitors). Evaluation of 
immune markers at a single time point may not reflect an evolving immune response or predict 
response to PD-L1/PD-1 pathway blockades40,41. To account for these concerns, on-treatment 
biopsies will undergo repeat immune profiling to search for any changes in the tumor immune 
microenvironment from pre-treatment.    
 
Optional biopsies obtained at the time of disease progression will be used to characterize the 
change in the tumor at the time of resistance.  Such changes could stem from the acquisition of 
novel genomic alterations, from activation of compensatory signaling pathways, or the 
production of anti-inflammatory and immunosuppressive mediators. Biopsies obtained at 
progression will be submitted for NGS as well as immune profiling to again analyze for tumor 
immune cell subsets and immune marker expression by immunohistochemistry (IHC) staining. 
The information collected from these biopsies will be vital to understanding the methods of 
resistance to the combination therapy and planning subsequent treatment strategies in this 
population. 
 
2.6.2 Non-Invasive Immunoprofiling 
 
Peripheral blood mononuclear cells (PBMCs) will be collected from whole blood to assess 
immune cell populations and cytokines. Surface staining with a panel of antibodies and 
intracytoplasmatic cytokine staining followed by flow cytometry will be performed on the 
samples.  Different T cell populations, their activation status, and the production of different 
cytokines as well as other immune cell populations including myeloid-derived suppressor cells 
(MDSCs) will be characterized. MDSCs are a heterogeneous group of immature cells which are 


DF/HCC Protocol #: 16-549 
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22 
greatly expanded in experimental models of cancer. Studies in humans have reported increased 
frequencies as well as immune-suppressive properties in some of the myeloid-derived subsets of 
MDSCs present in the peripheral blood of patients with various forms of cancer, including 
mesothelioma42,43. To further explore the relationship of immune cell populations and their 
potential correlation to clinical outcomes, peripheral blood levels will be serially collected from 
patients enrolled to the trial.   
 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
Baseline evaluations are to be conducted within two weeks prior to start of protocol therapy, with 
the exception of the informed consent and baseline imaging which must be done ≤ 4 weeks prior 
to the start of therapy.   
 
3.1.1 Written informed consent obtained prior to any study-specific procedures not considered 
part of routine medical care. 
 
3.1.2 Histologically or cytologically confirmed unresectable or medically inoperable 
malignant pleural mesothelioma. 
 
3.1.3 Disease progression after treatment with at least one line of chemotherapy that included 
a platinum agent in combination with pemetrexed. 
 
3.1.4 Participants must have measurable disease in at least one dimension of at least 10 mm in 
diameter or thickness, according to modified RECIST for pleural malignant 
mesothelioma.44  Bone metastases are not considered measurable. Prior radiation to the 
only site of measurable disease will make the participant ineligible unless the lesion has 
been demonstrated to grow after completion of radiation therapy. 
 
3.1.5 Participants must be willing and able to undergo a biopsy at the start of this study and an 
on-treatment biopsy if safe and feasible. 
 
3.1.6 Participants must be ≥28 days from any major surgery. 
 
3.1.7 ECOG performance status of 0 or 1. See APPENDIX A. 
 
3.1.8 Participants must have normal organ and marrow function as defined below: 
 
 
Absolute neutrophil count 
≥ 1.5 K/uL 
 
Platelets  
 
≥ 100 K/uL 
 
Hemoglobin 
≥ 9 g/dL (with or without transfusion support) 
 
Total bilirubin 
≤ 1.5 × institutional upper limit of normal (ULN) 
 
AST(SGOT)/ALT(SGPT) 
≤ 3 × institutional ULN, unless liver metastases are 
present and then ≤ 5 × institutional ULN is acceptable 


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23 
 
Serum creatinine 
≤ 1.5 × institutional ULN 
OR 
 
Serum creatinine clearance >40 mL/min by the Cockcroft-Gault formula (Cockcroft 
and Gault 1976) or by 24-hour urine collection for determination of creatinine 
clearance (see APPENDIX B Cockcroft-Gault equation for CREATININE 
CLEARANCE). 
 
3.1.9 Age ≥ 18 years. 
 
3.1.10 Female subjects of childbearing potential who are sexually active with a non-sterilized 
male partner must agree to use at least one highly effective method of contraception (see 
Table 2) from the time of screening and must agree to continue using such precautions 
for 180 days after the last dose of investigational product. Male partners of a female 
subject must also agree to use male condom plus spermicide throughout this period. 
Cessation of birth control after this point should be discussed with a responsible 
physician. Not engaging in sexual activity for the total duration of the trial and the drug 
washout period is an acceptable practice; however, occasional abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception. 
Female patients should refrain from breastfeeding throughout this period.   
 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-
menopausal (defined as ≥ 12 months with no menses without an alternative medical 
cause). 
 
3.1.11 Non-sterilized male subjects who are sexually active with a female partner of 
childbearing potential must use male condom plus spermicide from screening through 
180 days after the last dose of investigational product. Not engaging in sexual activity 
for the total duration of the trial and the drug washout period 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 a male subject must use a highly effective 
method of contraception throughout this period. Highly effective methods of 
contraception are described in Table 2. 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent document. 
 
3.1.13 Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow 
up. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Previous treatment with a CTLA-4, PD-1, or PD-L1 inhibitor, including prior treatment 
with either durvalumab or tremelimumab. 
 


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24 
3.2.2 Known central nervous system metastasis. Patients with known brain metastases, spinal 
cord compression, carcinomatous meningitis, or leptomeningeal disease may be enrolled 
if they have been treated, are no longer taking corticosteroids, and have been stable on 
imaging for at least 3 weeks.  
 
3.2.3 Subjects currently receiving systemic corticosteroids above 10 mg daily of prednisone or 
equivalentfor more than 14 days; subjects receiving other systemic immunosuppressive 
drugs greater than 10 mg prednisone or equivalent for more than 14 days. Exceptions 
include: inhaled, intranasal, ophthalmic, and topical corticosteroids, local corticosteroid 
injections (e.g., intra-articular injections), and subjects requiring corticosteroid pre-
medication for hypersensitivity reactions (e.g. CT scan premedication).  
 
3.2.4 Subjects with medical conditions that require the chronic use of systemic corticosteroids. 
Exceptions include: inhaled, intranasal, ophthalmic, and topical corticosteroids, local 
corticosteroid injections (e.g., intra-articular injections), and subjects requiring 
corticosteroid pre-medication for hypersensitivity reactions (e.g. CT scan 
premedication). 
 
3.2.5 Active or prior documented autoimmune disease within the past 2 years, including but 
not limited to systemic lupus erythematosus, sarcoidosis syndrome, or Wegener’s 
granulmatosis.  NOTE: Subjects with vitiligo, Grave’s disease, or psoriasis not requiring 
systemic treatment within the past 2 years are not excluded. 
 
3.2.6 Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis), or any other chronic, serious GI condition associated with diarrhea. 
NOTE: Subjects with known diverticulosis are permitted to enroll.  
 
3.2.7 History of interstitial lung disease or pneumonitis that has required steroid 
administration. 
 
3.2.8 History of primary immunodeficiency. 
 
3.2.9 History of allogeneic organ transplant. 
 
3.2.10 History of hypersensitivity to tremelimumab, durvalumab, or any excipient. 
 
3.2.11 Known history of active tuberculosis. 
 
3.2.12 Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 
days of receiving durvalumab or tremelimumab. 
 


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25 
3.2.13 Participants with a history of a second primary malignancy. Exceptions include: patients 
with a history of malignancies that were treated curatively and have not recurred within 
5 years prior to study entry; resected basal and squamous cell carcinomas of the skin, 
and completely resected carcinoma in situ of any type. 
 
3.2.14 Participants who have had chemotherapy, biologic therapy, or investigational therapy 
within 21 days (including bevizumab)  or radiotherapy within 7 days prior to entering 
the study or those who have not recovered to CTCAE ≤ grade 1 or baseline from adverse 
events due to agents administered. 
 
3.2.15 Any history of a prior ≥ grade 3 immune-related adverse event (irAE) while receiving 
any previous immunotherapy agent. 
 
3.2.16 Participants who are receiving any other investigational agents. 
 
3.2.17 Uncontrolled intercurrent illness including, but not limited to: 
 Ongoing or active infection 
 Gastritis 
 Symptomatic congestive heart failure 
 Severe hypertension (defined as BP ≥ 160/100 during the screening period despite 
optimal medical management) 
 Unstable angina pectoris 
 Cardiac arrhythmia 
 Active bleeding diatheses 
 Active peptic ulcer disease 
 Psychiatric illness/social situations that would limit compliance with study 
requirements 
 
3.2.18 Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Fredericia’s Correction 
 
3.2.19 Known HIV-positive participants are ineligible because these participants are at 
increased risk of lethal infections.  Appropriate studies will be undertaken in participants 
receiving combination antiretroviral therapy when indicated. 
 
3.2.20 Participants with known acute or chronic hepatitis B or hepatitis C. 
 
3.2.21 Pregnant women are excluded from this study because tremelimumab and durvalumab 
have unknown effects on the developing fetus.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with tremelimumab or durvalumab, breastfeeding women are also excluded. Female 
subjects of child bearing potential must have a negative serum pregnancy test obtained 
prior to trial registration. 
 


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26 
3.2.22 Participants who are involved in the planning and/or conduct of the study (applies to 
both AstraZeneca staff and/or staff at the study site).  
 
3.2.23 Participants who have undergone a pneumonectomy due to known potential for 
pulmonary toxicities and heightened risk for complications. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore.  Registrations must occur prior to the initiation of protocol therapy.  Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
One cycle is defined as 28 consecutive days. Participants will receive durvalumab and 
tremelimumab both via IV infusion on day 1 of each cycle. Participants will receive 
tremelimumab for up to 4 cycles (4 doses). Beginning with cycle 5 day 1, participants will 
continue to receive durvalumab alone (as monotherapy).  
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy, with the exception of palliative 


DF/HCC Protocol #: 16-549 
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27 
radiation therapy or surgical resection to non-target lesions. Bisphosphonate use is permitted. 
 
 
5.2 
Duration of Treatment and Criteria for Retreatment 
 
Participants who are tolerating durvalumab monotherapy without evidence of disease 
progression per modified RECIST criteria for mesothelioma may continue to receive durvalumab 
as monotherapy indefinitely or until other criteria for discontinuation are met (see Section 5.6).  
 
Participants experiencing either confirmed or unconfirmed PD during the durvalumab 
monotherapy portion of the trial may undergo retreatment with tremelimumab (once only) if they 
meet the retreatment criteria below.  The same treatment guidelines followed during the initial 
treatment period will be followed during the retreatment period, including the same dose and 
frequency of treatments and the same schedule of assessments, with the exception that 
participants undergoing retreatment are not required to undergo additional tumor biopsies. 
 
1. The patient has not received any other anticancer treatments for their disease (with the 
exception of palliative radiation or surgical procedures as allowed per protocol). 
2. The patient does not meet any of the other investigational product discontinuation criteria 
(Section 5.6). 
3. Absence of clinical symptoms or signs indicating clinically significant disease 
progression. 
4. No decline in ECOG performance status compared to baseline. 
5. Absence of rapid PD or threat to vital organs/critical anatomical sites (e.g., spinal cord 
compression) requiring urgent alternative medical intervention. 
6. All AEs while receiving initial therapy must have resolved to ≤ Grade 1 or baseline. Must 
not have experienced a ≥ Grade 3 AE, or pneumonitis or neurologic AE of any grade 
while receiving initial therapy. Note: Subjects with an endocrine AE of any grade are 
permitted to be retreated if they are stably maintained on appropriate replacement therapy 
and are asymptomatic. 
7. Must not have used additional immunosuppression other than corticosteroids for the 
management of an AE, must not have experienced recurrence of an AE if rechallenged, 
and not currently requiring maintenance doses > 10 mg prednisone or equivalent per day.  
8. The patient has had a tumor imaging assessment within 28 days of restarting their 
assigned treatment; all further scans should occur with the same frequency as during the 
initial treatment period (relative to the date of registration) until study treatment is 
stopped.   
 
During the retreatment period, patients may resume tremelimumab dosing at 75 mg once every 4 
weeks for 4 doses while continuing to receive durvalumab once every 4 weeks. Patients will then 
continue with durvalumab monotherapy at 1500 mg once every 4 weeks, beginning 4 weeks after 
the last dose of combination therapy.   
 
Treatment through progression is at the treating investigator’s discretion, and the treating 
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 


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28 
with a confirmed progression receiving durvalumab plus tremelimumab cannot continue therapy 
or obtain retreatment if dosing is ongoing in the combination portion of therapy and progression 
occurs in a target lesion that has previously shown a confirmed response. Patients who the 
Overall PI (in communication with AstraZeneca) and/or the treating investigator determine may 
not continue treatment will enter follow-up.   
 
Subjects should be made aware of the potential benefits and risks of continuing study regimens 
in the setting of confirmed or suspected PD leading to retreatment by providing separate written 
informed consent. Subjects will only be eligible for one retreatment opportunity. 
 
 
5.3 
Pre-Treatment Criteria 
 
5.3.1 Cycle 1, Day 1 
 
Patients who completed screening assessments >72 hours prior to cycle 1 day 1 must have cycle 
1 day 1 laboratory values that re-meet eligibility criteria. If screening assessments were 
completed ≤ 72 hours prior to cycle 1 day 1, laboratory tests do not need to be repeated on cycle 
1 day 1 and the screening laboratory values can be used as the cycle 1 day 1 values. 
 
If patients have cycle 1 day 1 labs performed, review of results by the treating investigator prior 
to dosing is required for the following tests: complete blood count with differential (CBC), blood 
urea nitrogen (BUN), serum creatinine, electrolytes, and liver function tests.  
 
5.3.2 Subsequent Cycles  
 
Management of specific toxicities considered at least possibly related to tremelimumab and/or 
durvalumab are outlined in Section 6. 
 
 
5.4 
Agent Administration 
 
Table 1: Treatment Regimen Description 
Agent 
Premedications/ 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Tremelimumab None 
75 mg 
IV over 1 hour (± 
5 min) 
 
Administer prior 
to durvalumab 
Day 1 
for 4 
cycles 
28 days 
(4 weeks)
 
 
 
Durvalumab 
None 
1500 
mg 
IV over 1 hour (± 
5 min) 
 
Begin infusion 1 
hour after 
Day 1  


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29 
completion of 
tremelimumab (± 
10 min) 
 
 
5.4.1 Tremelimumab 
 
Tremelimumab will be administered first. Participants will receive 75 mg tremelimumab via IV 
infusion on day 1 of each cycle for up to 4 cycles (once every 4 weeks for up to 4 doses). 
Tremelimumab should be infused over 1 hour; there is a ± 5 minute infusion window. 
Tremelimumab will be administered at room temperature by controlled infusion via an infusion 
pump into a peripheral or central vein. Following preparation of tremelimumab, the entire 
contents of the IV bag should be administered as an IV infusion using a 0.2 or 0.22-μm in-line 
filter.  
 
The IV line should be flushed with a volume of IV solution (0.9% saline) equal to the priming 
volume of the infusion set used after the contents of the IV bag are fully administered, or 
complete the infusion according to institutional policy to ensure the full dose is administered. 
 
 
5.4.2 Durvalumab 
 
Participants will receive 1500 mg durvalumab via IV infusion on day 1 of each cycle (once every 
4 weeks). Durvalumab infusion will start 1 hour after the end of the tremelimumab infusion (±10 
minute window). Durvalumab should be infused over 1 hour; there is a ± 5 minute infusion 
window.  Durvalumab will be administered at room temperature by controlled infusion via an 
infusion pump into a peripheral or central vein. Following preparation of durvalumab, the entire 
contents of the IV bag should be administered as an IV infusion using a 0.2 or 0.22-μm in-line 
filter. 
 
The IV line should be flushed with a volume of IV solution (0.9% saline) equal to the priming 
volume of the infusion set used after the contents of the IV bag are fully administered, or 
complete the infusion according to institutional policy to ensure the full dose is administered. 
 
 
5.4.3 Post-Infusion Observation Period 
 
A 1 hour observation period is required after the completion of the first infusions of both 
durvalumab and tremelimumab (±10 minute window).  If no clinically significant infusion 
reactions are observed during or after the first infusions, subsequent infusion observation periods 
can be at the treating investigator’s discretion (suggested 30 minutes after each durvalumab and 
tremelimumab infusion).   
 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 


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30 
The treating 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).  Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the CRF.   
 
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables.   
 
5.5.1 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 5.5.2. 
 
5.5.2 Excluded 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, other than any stated 
protocol specified therapies. Concurrent use of hormones for noncancer-related 
conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.  
Local treatment of isolated lesions for palliative intent is acceptable (e.g., by local 
surgery or radiotherapy). Bisphosphonate use is permitted. 
3. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses exceeding 10 mg per day, 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, 
topical, ophthalmic, and intranasal corticosteroids is permitted, along with local steroid 
injections.  
4. Live attenuated vaccines within 30 days of durvalumab and tremelimumab dosing (i.e., 
30 days prior to the first dose, during treatment with durvalumab and tremelimumab, and 
for 30 days post discontinuation of durvalumab and tremelimumab).  Inactivated 
vaccines, such as the injectable influenza vaccine, are permitted.   
 
5.5.3 Highly Effective Methods of Contraception 
 
Female subjects of childbearing potential who are sexually active with a non-sterilized male 
partner must agree to use at least one highly effective method of contraception from the time of 
screening and must agree to continue using such precautions for 180 days after the last dose of 
investigational product. Male partners of a female subject must also agree to use male condom 
plus spermicide throughout this period. 
 
Non-sterilized male subjects who are sexually active with a female partner of childbearing 
potential must use male condom plus spermicide from screening through 180 days after the last 
dose of investigational product. Female partners of a male subject must use a highly effective 


DF/HCC Protocol #: 16-549 
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31 
method of contraception throughout this period. 
 
A highly effective method of contraception is defined as one that results in a low failure rate (i.e. 
less than 1% per year) when used consistently and correctly. Note that some contraception 
methods are not considered highly effective (e.g. male or female condom with or without 
spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper 
containing intrauterine device; progestogen-only oral hormonal contraceptive pills where 
inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which 
is considered highly effective]; and triphasic combined oral contraceptive pills). 
 
Table 2: Highly Effectivea Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing intrauterine 
system (eg, Mirena®)b 
• 
Etonogestrel implants: e.g. Implanon or 
Norplan 
• 
Intravaginal device: e.g. 
ethinylestradiol and etonogestrel 
• 
Medroxyprogesterone injection: e.g. 
Depo-Provera  
• 
Normal and low dose combined oral 
contraceptive pill 
• 
Norelgestromin/ethinylestradiol  
transdermal system 
• 
Cerazette (desogestrel) 
a 
Highly effective (i.e. failure rate of <1% per year)  
b 
This is also considered a hormonal method 
 
5.6 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
indefinitely as described in Section 5.2 or until one of the following criteria applies: 
 
 
Disease progression (exception for allowed retreatment as described in Section 5.2). 
 
 
Intercurrent illness that prevents further administration of treatment 
 
 
Unacceptable adverse event(s) 
 
 
Participant demonstrates an inability or unwillingness to comply with the medication 
regimen and/or documentation requirements 
 
 
Participant decides to withdraw from the protocol therapy 
 
 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 


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32 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
The research team will update the relevant Off Treatment information in OnCore. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Mark Awad MD, PhD at 617-632-3468. 
 
 
5.7 
Duration of Follow Up 
 
Participants will be followed until death after removal from protocol therapy. This follow up will 
be performed by review of the medical record, contact with care providers, and/or telephone 
contact as needed every 3-4 months.  
 
5.8 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
 Lost to follow-up 
 Withdrawal of consent for data submission 
 Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
The research team will update the relevant Off Study information in OnCore.  
 
 
6. DOSING DELAYS 
 
Dose delays will be made as indicated in the following tables. The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03 will be utilized for dose delays. A copy of the CTCAE version 4.03 can be 
downloaded from the CTEP website: 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
For adverse events (AEs) that are considered at least partly due to administration of durvalumab 
or tremelimumab the following dosing guidance may be applied: 


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33 
 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 tremelimumab along with appropriate 
continuing supportive care. 
 The maximum amount of time that durvalumab and tremelimumab can be held before a 
participant is permanently withdrawn from the study is 56 days. 
 In the event that the treating investigator believes a toxicity to be related to 
tremelimumab and not to durvalumab, the treating investigator may opt to discontinue 
tremelimumab and continue with durvalumab as monotherapy once the toxicity has 
resolved to ≤ Grade 1 or baseline. If tremelimumab is discontinued prematurely due to 
toxicity, it may not be reinstated. 
 If tremelimumab dosing is held but toxicity does not necessitate discontinuation of the 
study agent, participants may receive the 4 total doses of tremelimumab (i.e. the 
tremelimumab infusion may be given upon acceptable resolution of the adverse event 
rather than omitted or skipped entirely).  
 
In addition, there are certain circumstances in which durvalumab or tremelimumab should be 
permanently discontinued. 
 
Following the first dose of durvalumab or tremelimumab, subsequent administration of 
durvalumab or tremelimumab can be delayed based on toxicities observed (see Tables 3 - 6).  
Dose reductions of either durvalumab or tremelimumab are not permitted. 
 
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 colitis, pneumonitis, 
hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, 
pancreatitis and nephritis. 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 colitis, pneumonitis, 
hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, 
pancreatitis and nephritis should be considered to be immune-related.   
 
Dose delay requirements and toxicity management guidelines for immune-mediated reactions, 
infusion-related reactions, and non-immune-mediated reactions are detailed in Tables 3 - 6. 
 
In addition, reporting guidelines for adverse events of special interest (AESIs) and serious 
adverse events (SAEs) are detailed in Sections 7.4, 7.5, 7.9, 7.10, and 7.11.   
 
6.1 
Toxicity Management Guidelines 
 


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34 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
 
Pneumonitis / 
ILD 
All participants should be monitored 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 clinically indicated. 
 
Initial work-up may include clinical evaluation, monitoring of oxygenation via 
pulse oximetry (resting and exertion), laboratory work-up and high-resolution 
CT scan as determined by the treating investigator.  
Grade 1  
 
No dose delay required.  
 
However, consider 
holding study drug/study 
regimen dosing as 
clinically appropriate and 
during diagnostic work-
up for other etiologies. 
Monitor and closely follow up in 2-4 
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  
 
Hold study drug/study 
regimen dose. 
 
• If  toxicity worsens 
then treat as Grade 3 or 
Grade 4  
• If toxicity improves to 
baseline then the 
decision to reinitiate 
study drug/regimen at 
next scheduled treatment 
date will be based upon 
treating physician’s 
clinical judgment.  
 
Study drug/study 
treatment can be 
resumed at the next 
Monitor symptoms daily and consider 
hospitalization as clinically 
appropriate. 
 
Promptly start systemic steroids (e.g., 
prednisone PO 1-2mg/kg/day [or 
equivalent] or IV equivalent). 
 
Reimage as clinically indicated. 
 
If no improvement within 5 days, 
additional work-up should be 
considered and prompt treatment with 
IV methylprednisolone 2-4mg/kg/day 
started (or equivalent). 
 
If still no improvement within 5 days 
despite IV methylprednisolone at 2-


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35 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
scheduled dose once 
event stabilizes to grade 
≤1 and at least 5 days 
have passed after 
completion of steroid 
taper. 
4/g/kg/day (or equivalent), promptly 
start immunosuppressive therapy 
such as TNF inhibitors (e.g. 
infliximab at 5mg/kg every 2 weeks 
or equivalent). Caution: Important to 
rule out sepsis and refer to infliximab 
label for general guidance before 
using infliximab.  
 
Once improving, gradually taper 
steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals 
and in particular, anti PCP treatment 
(please refer to current NCCN 
guidelines for treatment of cancer-
related infections (Category 2B 
recommendation)45.  
 
Consider pulmonary and infectious 
disease consult. 
 
Consider as necessary discussing with 
Overall PI. 
≥ Grade 
3  
Permanently discontinue 
study drug/study 
regimen. 
 
Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day 
or equivalent. 
 
Obtain pulmonary and infectious 
disease consults as clinically 
indicated. 
 
Hospitalize the patient as clinically 
appropriate. 
 
Provide supportive care (oxygen, 


DF/HCC Protocol #: 16-549 
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36 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
etc.). 
 
If no improvement within 5 days, 
additional work-up should be 
considered and prompt treatment with 
additional immunosuppressive 
therapy such as TNF inhibitors (e.g. 
infliximab at 5mg/kg every 2 weeks 
dose or equivalent) started. Caution: 
rule out sepsis and refer to infliximab 
label for general guidance before 
using infliximab.  
 
Once improving, gradually taper 
steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals 
and in particular, anti PCP treatment 
(please refer to current NCCN 
guidelines for treatment of cancer-
related infections (Category 2B 
recommendation)45. 
 
Diarrhea / 
Enterocolitis 
All participants should be monitored for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes in bowel habits 
such as increased frequency over baseline or blood in stool) or related to bowel 
perforation (such as sepsis, peritoneal signs, and ileus). 
 
Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, other medications, 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. 
 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
37 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
Use analgesics carefully; they can mask symptoms of perforation and 
peritonitis. 
Grade 1 
diarrhea 
No dose delay 
Close monitoring for worsening 
symptoms. 
 
Consider symptomatic treatment 
including hydration, electrolyte 
replacement, dietary changes (e.g., 
American Dietetic Association colitis 
diet), and loperamide or equivalent. 
Use of probiotics as per treating 
physician’s clinical judgment. 
Grade 2 
diarrhea 
Hold study drug/study 
regimen 
 
• If toxicity worsens then 
treat as Grade 3 or Grade 
4 
• If toxicity improves 
then treat at next 
scheduled treatment date 
 
Study drug/study 
regimen can be resumed 
at the next scheduled 
dose once event 
stabilizes to grade ≤ 1 
and at least 5 days have 
passed after completion 
Consider symptomatic treatment 
including hydration, electrolyte 
replacement, dietary changes (e.g., 
American Dietetic Association colitis 
diet), and loperamide and/or 
budesonide or equivalents.  
 
Promptly start prednisone 1 to 2 
mg/kg/day or equivalent. 
 
If event is not responsive within 5 
days or worsens despite prednisone at 
1-2 mg/kg/day or equivalent, 
consideration of further workup such 
as imaging and/or colonoscopy to 
confirm colitis and rule out 
perforation, and prompt treatment 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
38 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
of steroid taper.  
with IV methylprednisolone 2-
4mg/kg/day (or equivalent) started. 
 
If still no improvement within 5 days 
despite 2-4mg/kg IV 
methylprednisolone (or equivalent), 
promptly start immunosuppressives 
such as infliximab at 5mg/kg once 
every 2 weeks (or equivalent). 
Caution: Important to rule out bowel 
perforation and refer to infliximab 
label for general guidance before 
using infliximab. 
   
Consider consulting Overall PI if no 
resolution to ≤ Grade 1 in 5 days. 
 
Once improving, gradually taper 
steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals 
and anti PCP treatment (please refer 
to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation])45. 
Grade ≥ 
3 
diarrhea 
Permanently discontinue 
study drug/study regimen
Promptly initiate empiric IV 
methylprednisolone 2 to 4 mg/kg/day 
or equivalent. 
 
Monitor stool frequency and volume 
and maintain hydration. 
 
Consider urgent GI consult and 
imaging and/or colonoscopy as 
appropriate. 
 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
39 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
If no improvement within 5 days of 
IV methylprednisolone 2 to 
4mg/kg/day or equivalent, promptly 
start further immunosuppressives 
(e.g. infliximab at 5mg/kg once every 
2 weeks). Caution: Rule out bowel 
perforation and refer to infliximab 
label for general guidance before 
using infliximab.  
 
Once improving, gradually taper 
steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, 
and anti PCP treatment (please refer 
to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation])45. 
Hepatitis 
(Elevated AST 
[SGOT], ALT 
[SGPT], and/or 
total bilirubin) 
 
Note: Infliximab 
should not be used 
for management of 
Immune Related 
Hepatitis 
Grade 1 
 
 No dose delay required. 
 
If it worsens, treat as 
Grade 2 event. 
Monitor and evaluate liver function 
tests: AST, ALT, alkaline 
phosphatase (ALP) and total bilirubin 
as per protocol.  
 
Evaluate for alternative etiologies 
(e.g., viral hepatitis, disease 
progression, concomitant 
medications). 
 
Grade 2  
 
Hold study drug/study 
regimen dose. 
 
• If toxicity worsens then 
treat as Grade 3 or Grade 
4 
• If improves to baseline 
then treat at next 
Regular and frequent checking of 
LFTs (e.g. every 1-2 days) until 
elevations are improving or resolved.  
 
If no resolution to ≤ Grade 1 or 
baseline in 2 days, discuss with the 
Overall PI. 
 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
40 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
scheduled treatment date. 
 
Study drug/study 
regimen can be resumed 
at the next scheduled 
dose once event 
stabilizes to grade ≤1 or 
baseline and at least 5 
days have passed after 
completion of steroid 
taper.    
If event is persistent (>5 days) or 
worsens, promptly start prednisone 1-
2mg/kg/day or IV equivalent.  
 
If still no improvement within 5 days 
despite 1-2mg/kg/day of prednisone 
or IV equivalent, consider additional 
workup and prompt treatment with IV 
methylprednisolone 2-4mg/kg/day or 
equivalent. 
 
If still no improvement within 5 days 
despite 2-4mg/kg/day of IV 
methylprednisolone or equivalent, 
promptly start immunosuppressives 
(mycophenolate mofetil1 or 
equivalent). Infliximab should NOT 
be used. 
 
Once improving, gradually taper 
steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals 
and anti PCP treatment (please refer 
to current NCCN guidelines for 
treatment of  cancer-related infections 
[Category 2B recommendation])45. 
Grade 3 
For elevations in 
transaminases ≤ 8 × 
ULN, or elevations in 
bilirubin ≤ 5 × ULN: 
 
 Hold study 
drug/study regimen 
Promptly initiate empiric IV 
methylprednisolone at 1 to 4 
mg/kg/day or equivalent. 
 
If still no improvement within 5 days 
despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, 
                                                 
 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
41 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
dose until resolution 
to ≤ Grade 1 or 
baseline   
 Resume study 
drug/study regimen 
administration at the 
next scheduled dose 
if elevations 
downgrade ≤ Grade 1 
or baseline within 14 
days 
Permanently discontinue 
study drug/study regimen 
if the elevations do not 
downgrade to ≤ Grade 1 
or baseline within 14 
days.  
 
For elevations in 
transaminases > 8 × 
ULN or elevations in 
bilirubin > 5 × ULN, 
discontinue study 
drug/study regimen. 
 
Permanently discontinue 
study drug/study regimen 
for any case meeting 
Hy’s law criteria (ALT > 
3x ULN + bilirubin > 2x 
ULN without initial 
findings of cholestasis 
[i.e. elevated alkaline 
P04] and in the absence 
of any alternative 
cause46). 
promptly start treatment with 
immunosuppressive therapy 
(mycophenolate mofetil or 
equivalent). Infliximab should NOT 
be used. 
 
Consider hepatology consult, 
abdominal work-up, and imaging as 
appropriate. 
 
Once improving, gradually taper 
steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals 
and anti PCP treatment (please refer 
to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation])45. 
 
 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
42 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 4  
 
Permanently discontinue 
study drug/study 
regimen.  
Promptly initiate empiric IV 
methylprednisolone at 1 to 4 
mg/kg/day or equivalent. 
 
If still no improvement within 5 days 
despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, 
promptly start treatment with 
immunosuppressive therapy 
(mycophenolate mofetil or 
equivalent). Infliximab should NOT 
be used. 
 
Consider hepatology consult, 
abdominal work-up, and imaging as 
appropriate. 
 
Once improving, gradually taper 
steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals 
and anti PCP treatment (please refer 
to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation])45. 
Nephritis or 
Renal 
Dysfunction 
(Elevated 
Serum 
Creatinine)  
For elevations of serum creatinine of any grade, consider consulting with a 
nephrologist as clinically appropriate. 
 
Monitor for signs and symptoms that may be related to changes in renal 
function (e.g. elevated serum BUN and creatinine, decreased creatinine 
clearance, electrolyte imbalances, 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 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
43 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
for low grade events (Grade 2) in order to prevent potential progression to 
higher grade event. 
Grade 1  No dose delay. 
Monitor serum creatinine weekly and 
any accompanying symptom 
 
 If creatinine returns to baseline, 
resume its regular monitoring per 
study protocol. 
 If it worsens, depending on the 
severity , treat as Grade 2 or Grade 3 
or 4 
  
Consider symptomatic treatment 
including hydration, electrolyte 
replacement, diuretics, etc. 
Grade 2  
 
Hold study 
drug/study regimen. 
 
 If  toxicity worsens 
then treat as Grade 3 
or Grade 4 
 If toxicity improves 
to baseline then treat 
at next scheduled 
treatment date 
 
Study drug/study 
Consider symptomatic treatment 
including hydration, electrolyte 
replacement, diuretics, etc.  
 
Carefully monitor serum creatinine 
every 2-3 days and as clinically 
warranted. 
 
Consider consulting a nephrologist 
and consider renal biopsy if clinically 
indicated. 
 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
44 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade ≤1 and at least 
5 days have passed 
after completion of 
steroid taper. 
If event is persistent (>5 days) or 
worsens, promptly start prednisone 1 
to 2 mg/kg/day or IV equivalent. 
 
If event is not responsive within 5 
days or worsens despite prednisone at 
1-2 mg/kg/day or IV equivalent, 
additional workup should be 
considered and prompt treatment with 
IV methylprednisolone at 2-
4mg/kg/day (or equivalent) started.  
 
Once improving gradually taper 
steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals 
and anti PCP treatment (please refer 
to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation])45.  
 
When event returns to baseline or ≤ 
grade 1, resume study drug/study 
regimen and routine serum creatinine 
monitoring per study protocol. 
Grade 3 
or 4  
 
Permanently discontinue 
study drug/study regimen
Carefully monitor serum creatinine 
on a daily basis. 
 
Consider consulting a nephrologist 
and consider renal biopsy if clinically 
indicated. 
 
Promptly start prednisone 1 to 2 
mg/kg/day or IV equivalent. 
 
If event is not responsive within 3-5 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
45 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
days or worsens despite prednisone at 
1-2 mg/kg/day or IV equivalent, 
additional workup should be 
considered and prompt treatment with 
IV methylprednisolone 2-4mg/kg/day 
(or equivalent) started.  
 
Once improving, gradually taper 
steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals 
and anti PCP treatment (please refer 
to current  NCCN guidelines for 
treatment of  cancer-related infections 
[Category 2B recommendation])45.  
Rash (excluding 
bullous skin 
formations) 
All participants should be monitored for signs and symptoms of dermatitis (rash 
and pruritus). 
  
**IF THERE IS ANY BULLOUS FORMATION, THE OVERALL PI 
SHOULD BE CONTACTED AND STUDY DRUG DISCONTINUED** 
Grade 1  
No dose delay. 
Consider symptomatic treatment 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) 
and topical therapy (e.g., urea cream). 
Grade 2 
For persistent (>2 
weeks) grade 2 
events, hold 
scheduled study 
drug/study regimen 
until resolution to ≤ 
Grade 1 or baseline. 
 
 If  toxicity worsens 
then treat as Grade 3  
 If  toxicity improves 
then  resume 
Obtain dermatology consult as 
clinically indicated. 
 
Consider symptomatic treatment 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine or 
equivalents) and topical therapy (e.g., 
urea cream or equivalent). 
 
Consider moderate-strength topical 
steroid. 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
46 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
administration at next 
scheduled dose 
 
Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade ≤1 or baseline 
and 7 days have 
passed after 
completion of steroid 
taper. 
 
If no improvement of rash/skin 
lesions occurs within 5 days or is 
worsening despite symptomatic 
treatment and/or use of moderate 
strength topical steroid, discuss with 
Overall PI and promptly start 
systemic steroids prednisone 1-2 
mg/kg/day or IV equivalent. 
 
Consider skin biopsy if persistent for 
>2 weeks or recurs. 
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.  
Consult dermatology as clinically 
indicated. 
  
 Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day 
or equivalent. 
 
Consider hospitalization if clinically 
indicated. 
 
 
Consider skin biopsy (preferably 
more than 1) as clinically feasible. 
 
Once improving, gradually taper 
steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals 
and anti PCP treatment (please refer 
to current NCCN guidelines for 
treatment of  cancer-related infections 
[Category 2B recommendation])45. 
 
Grade 4 Permanently discontinue 
study drug/study regimen 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
47 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
Discuss with Overall PI. 
Endocrinopathy 
  
(e.g., 
hyperthyroidism, 
hypothyroidism, 
hypopituitarism, 
adrenal 
insufficiency, etc.) 
For patients experiencing endocrinopathy of any grade, consider consulting 
with an endocrinologist as clinically appropriate. 
 
All patients should be monitored patients for signs and symptoms of 
endocrinopathies.  Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, unusual bowel habits, 
hypotension and weakness. 
 
Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression including brain metastases, infections, etc.) 
 
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 of any grade that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, diabetes 
insipidus), the investigator should send a blood sample for appropriate 
autoimmune antibody testing. 
Grade 1 
 
(including 
those with 
asymptom
-atic TSH 
elevation) 
 
No dose delay. 
Monitor patient with appropriate 
endocrine function tests. 
 
If TSH < 0.5X LLN, or TSH >2X 
ULN or consistently out of range in 2 
subsequent measurements, include 
FT4 at subsequent cycles as clinically 
indicated and consider endocrinology 
consult. 
Grade 2  
 
 
For endocrinopathy 
other than 
hypothyroidism, 
hold study 
drug/study regimen 
dose until subject is 
Initiate hormone replacement as 
needed for management. 
 
Evaluate endocrine function, and as 
clinically indicated, consider pituitary 
scan. 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
48 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
clinically stable. 
 
 If  toxicity worsens 
then treat as Grade 3 
or Grade 4  
 If toxicity improves 
to baseline then treat 
at next scheduled 
treatment date 
 
Isolated 
hypothyroidism may 
be treated with 
replacement therapy 
without treatment 
interruption and 
without 
corticosteroids. 
 
Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade ≤1 and at least 
5 days have passed 
after completion of 
steroid taper. 
 
 Patients with 
endocrinopathies 
who may require 
prolonged or 
continued steroid 
replacement can be 
retreated with study 
drug/study regimen 
 
For patients with abnormal endocrine 
work up, except for those  with 
isolated hypothyroidism,  consider 
short-term, corticosteroids (e.g., 1-
2mg/kg/day methylprednisolone or 
IV equivalent) and prompt initiation 
of treatment with relevant hormone 
replacement (e.g. Levothyroxine, 
hydrocortisone, or sex hormones). 
 
 
Once improving, gradually taper 
steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals 
and anti PCP treatment (please refer 
to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation])45. 
 
For patients with normal endocrine 
work-up (lab or MRI scans), repeat 
labs/MRI as clinically indicated. 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
49 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
on the following 
conditions:  
1) The event 
stabilizes and is 
controlled 
2) The patient is 
clinically stable 
as per treating 
physician’s 
clinical 
judgement 
3) Doses of 
prednisone are at 
less than or equal 
to 10mg/day or 
equivalent. 
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. 
 
Isolated 
hypothyroidism may 
be treated with 
replacement therapy 
without treatment 
interruption and 
without 
corticosteroids. 
 
Consult endocrinologist as clinically 
appropriate. 
 
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 intravenous corticosteroids 
with mineralocorticoid activity. 
 
Once improving, gradually taper 
immunosuppressive steroids over ≥4 
weeks and consider prophylactic 
antibiotics, antifungals and anti PCP 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
50 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
Resume study 
drug/study regimen 
administration if 
controlled at the next 
scheduled dose. 
 
Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade ≤1 and at least 
5 days have passed 
after completion of 
steroid taper. 
 
treatment (please refer to current 
NCCN guidelines for treatment of  
cancer-related infections [Category 
2B recommendation])45. 
 
Discuss with Overall PI. 
Immune- 
mediated  
Neurotoxicity  
(to include but not 
limited to limbic 
encephalitis. 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-Barre)   
 
All patients with suspected immune-mediated neurotoxicity of any grade should 
be evaluated to rule out any alternative etiology (e.g., disease progression, 
infections, metabolic syndromes and medications, etc.). Consider appropriate 
diagnostic testing (e.g. electromyogram and nerve conduction investigations). 
Utilize appropriate symptomatic treatment with neurological consult as 
indicated. 
 
All patients should be monitored for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness). 
Grade 1 
 No dose delay. 
See recommendations above. 
Grade 2 
For acute motor 
neuropathies or 
neurotoxicity, hold 
study drug/study 
regimen dose until 
resolution to ≤ Grade 
1. 
 
For sensory 
Discuss with the Overall PI. 
 
Obtain Neurology Consult as 
indicated. 
 
Sensory neuropathy/neuropathic pain 
may be managed by appropriate 
medications (e.g., gabapentin, 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
51 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
neuropathy/ 
neuropathic pain, 
consider holding 
study drug/study 
regimen dose until 
resolution to ≤ Grade 
1. 
 If toxicity worsens 
then treat as Grade 3 
or Grade 4  
 If  toxicity improves 
to baseline then treat 
at next scheduled 
treatment date 
 
Study drug/study 
regimen can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
grade ≤1 and at least 
5 days have passed 
after completion of 
steroid taper.   
duloxetine, etc.). 
 
Promptly start systemic steroids 
prednisone 1-2mg/kg/day or IV 
equivalent. 
 
If no improvement within 5 days 
despite 1-2mg/kg/day prednisone or 
IV equivalent consider additional 
work-up and promptly treat with 
additional immunosuppressive 
therapy (e.g. IVIG or equivalent). 
 
 
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. 
Discuss with Overall PI. 
 
Obtain Neurology Consult as 
indicated. 
 
Consider hospitalization as clinically 
appropriate. 
 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day 
or equivalent. 


DF/HCC Protocol #: 16-549 
Protocol Version Date: 12 May 2017 
 
52 
Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
 
If no improvement within 5 days 
despite IV corticosteroids, consider 
additional workup and promptly treat 
with additional immunosuppressants 
(e.g. IVIG or equivalent). 
 
Once stable, gradually taper steroids 
over ≥4 weeks. 
Grade 4 
 
Permanently 
discontinue study 
drug/study regimen 
Discuss with Overall PI. 
 
Obtain Neurology Consult as 
indicated. 
 
Consider hospitalization as clinically 
appropriate. 
 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day 
or equivalent. 
 
If no improvement within 5 days 
despite IV corticosteroids, consider 
additional workup and promptly treat 
with additional immunosuppressants 
(e.g. IVIG or equivalent). 
 
Once stable, gradually taper steroids 
over ≥4 weeks. 
Immune-
mediated 
peripheral 
neuromotor 
The prompt diagnosis of immune-mediated peripheral neuromotor syndromes is 
important, since certain patients may unpredictably experience acute 
decompensations which can result in substantial morbidity or in the worst case, 
death. Special care should be taken for certain sentinel symptoms which may 
predict a more severe outcome, such as prominent dysphagia, rapidly 


DF/HCC Protocol #: 16-549 
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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
syndromes such 
as Guillain-
Barre and 
Myasthenia 
Gravis 
progressive weakness, and signs of respiratory insufficiency or autonomic 
instability. 
 
All patients experiencing signs or symptoms should be evaluated to rule out any 
alternative etiology (e.g., disease progression, infections, metabolic syndromes 
and medications, etc.). It should be noted that the diagnosis of immune-
mediated peripheral neuromotor syndromes can be particularly challenging in 
patients with underlying cancer, due to the multiple potential confounding 
effects of cancer (and its treatments) throughout the neuraxis. Given the 
importance of prompt and accurate diagnosis, it is essential to have a low 
threshold to obtain a neurological consult. 
 
Neurophysiologic diagnostic testing (e.g., electromyogram and nerve 
conduction investigations, and “repetitive stimulation” if myasthenia is 
suspected) are routinely indicated upon suspicion of such conditions and may 
be best facilitated by means of a neurology consultation. 
 
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 IVIG and followed by plasmapheresis if not responsive 
to IVIG. 
Grade 1 
No dose delay. 
Discuss with the Overall PI. 
 
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. 
Discuss with the Overall PI. 
 
Care should be taken to monitor 
patients for sentinel symptoms of a 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
 
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.
 
potential decompensation as 
described above. 
 
Obtain a Neurology Consult as 
clinically indicated. 
 
Sensory neuropathy/neuropathic pain 
may be managed by appropriate 
medications (e.g., gabapentin, 
duloxetine, etc.). 
 
MYASTHENIA GRAVIS: 
 
Steroids may be successfully used to 
treat Myasthenia Gravis. Important to 
consider that steroid therapy 
(especially with high doses) may 
result in transient worsening of 
myasthenia and should typically be 
administered in a monitored setting 
under supervision of a consulting 
neurologist. 
 
Patients unable to tolerate steroids 
may be candidates for treatment with 
plasmapheresis or IVIG. Such 
decisions are best made in 
consultation with a neurologist, 
taking into account the unique needs 
of each patient. 
 
If Myasthenia Gravis-like 
neurotoxicity present, consider 
starting acetylcholine esterase 
(AChE) inhibitor therapy in addition 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
to steroids. Such therapy, if 
successful, can also serve to reinforce 
the diagnosis. 
 
GUILLAIN-BARRE:  
 
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 IVIG and followed by 
plasmapheresis if not responsive to 
IVIG. 
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 severe or life threatening 
events:  
 
Discuss with Overall PI. 
 
Recommend hospitalization. 
 
Monitor symptoms and obtain 
neurological consult as indicated. 
 
MYASTHENIA GRAVIS: 
 
Steroids may be successfully used to 


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Table 3: Dosing Modification and Toxicity Management Guidelines for Specific Immune-
mediated Adverse Reactions 
Toxicity 
Grade of 
the 
Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 4 Permanently discontinue 
study drug/study regimen 
treat Myasthenia Gravis.  It should 
typically be administered in a 
monitored setting under supervision 
of a consulting neurologist. 
 
Patients unable to tolerate steroids 
may be candidates for treatment with 
plasmapheresis or IVIG. 
 
If Myasthenia Gravis-like 
neurotoxicity present, consider 
starting acetylcholine esterase 
(AChE) inhibitor therapy in addition 
to steroids. Such therapy, if 
successful, can also serve to reinforce 
the diagnosis. 
 
GUILLAIN-BARRE:  
 
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 IVIG and followed by 
plasmapheresis if not responsive to 
IVIG. 
 
 
 


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Table 4: Toxicity Management Guidelines for Immune-related Adverse Events not Otherwise 
Noted 
Adverse 
Event 
Dose Modifications 
Toxicity Guidance 
Immune-
related 
Adverse Events 
not Otherwise 
Noted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In addition to the above criteria for 
permanent discontinuation of study 
drug/regimen based on CTC 
grade/severity (Table 3), 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 56 days after 
last dose of study drug/regimen 
 Recurrence of a previously 
experienced Grade 3 treatment-
related AE following 
resumption of dosing. 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression, 
concomitant medications, infections, 
etc.). 
 
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 
events (Grade 1 or 2, unless 
otherwise specified). 
 
For persistent (greater than 5 days) 
low-grade (Grade 2) or severe 
(Grade ≥3) events  promptly start 
prednisone PO (or equivalent) 1-
2mg/kg/day or IV equivalent.  
 
If symptoms recur or worsen during 
corticosteroid tapering (<28 days of 
taper), increase the corticosteroid 
dose until stabilization or 
improvement of symptoms, then 
resume corticosteroid tapering at a 
slower rate (> 28 days of taper) 
 
More potent immunosuppressives 
such as TNF inhibitors (e.g. 
infliximab) should be considered for 
events not responding to systemic 
steroids (also refer to the individual 
sections of the immune related 
adverse event for specific type of 
immunosuppressive).   
 
Grade 1: No dose delay. 
Grade 2: Hold study drug/study 
regimen dose until 
resolution to ≤ Grade 1 or 
baseline. 
• If toxicity worsens then 
treat as Grade 3 or Grade 
4 
• If toxicity improves to 
baseline then treat at next 
scheduled treatment date 
 
Study drug/study treatment 
can be resumed at the next 
scheduled dose once event 
stabilizes to grade ≤1 or 
baseline and at least 5 days 
have passed after 
completion of steroid taper. 
 
Patients with 
endocrinopathies who may 
require prolonged or 
continued steroid 


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Table 4: Toxicity Management Guidelines for Immune-related Adverse Events not Otherwise 
Noted 
Adverse 
Event 
Dose Modifications 
Toxicity Guidance 
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 treating 
physician’s clinical 
judgment 
3) Doses of prednisone are 
at less than or equal to 
10mg/day or equivalent. 
Note: Discontinuation of study drug 
is not mandated for Grade 3 / Grade 
4 inflammatory reactions attributed 
to local tumour response (e.g. 
inflammatory reaction at sites of 
metastatic disease, lymph nodes 
etc.). Continuation of study drug in 
this situation should be based upon a 
benefit/risk analysis for that patient 
made by the treating investigator.  
 
 
 
 
Grade 3 
Hold study drug/study 
regimen until resolution to 
≤ Grade 1 or baseline. 
 
For Grade 3 and above 
asymptomatic amylase or 
lipase levels hold study 
drug/regimen. If complete 
work up shows no evidence 
of pancreatitis, may 
continue or resume study 
drug/regimen. 
 
Study drug/study regimen 
can be resumed at the next 
scheduled dose once event 
stabilizes to grade ≤ 1 or 
baseline and at least 5 days 
have passed after 
completion of steroid taper.   
 
Grade 4 
Permanently discontinue 
study drug/study regimen. 
 
For Grade 3 and above 


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Table 4: Toxicity Management Guidelines for Immune-related Adverse Events not Otherwise 
Noted 
Adverse 
Event 
Dose Modifications 
Toxicity Guidance 
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.  
 
 
Table 5: Dosing Modification and Toxicity Management Guidelines for Infusion-Related 
Reactions 
Severity 
Grade 
Dose Modifications 
Toxicity Management 
Management of any infusion-related reaction should be per institutional standard at the 
discretion of the treating investigator. 
 
Monitor all patients for signs and symptoms of infusion-related reactions (e.g., fever and/or shaking 
chills, flushing and/or itching, alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, skin rashes etc.) and anaphylaxis (e.g., generalized urticaria, angioedema, wheezing, 
hypotension, tachycardia, etc.). 
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 1 or Grade 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. 
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. 
Grade ≥ 3 
Permanently discontinue study 
drug/study regimen. 
Manage severe infusion-related reactions per 
institutional standards (e.g., IM epinephrine, 
followed by IV diphenhydramine and 
ranitidine, and IV glucocorticoid). 
 


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Table 6: Dosing Modification and Toxicity Management Guidelines for Non-Immune 
Mediated Reactions 
CTC 
Grade/Severity 
Dose Modification  
Toxicity Management  
Note: dose delays are not required for adverse events not deemed to be related to study treatment 
(i.e. events due to underlying disease) or for laboratory abnormalities not deemed to be clinically 
significant. At the treating investigator’s discretion, study medication dosing may be held for 
toxicity considered unlikely related or unrelated to study treatment. In the event of a dosing delay 
for unrelated adverse events, the maximum amount of time either study medication may be held 
is 28 days. 
Grade 1 
No dose adjustment  
Treat accordingly as per 
institutional standard. 
Grade 2 
At the treating investigator’s discretion, study 
drug/regimen may be held 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 at 
next scheduled dose. Otherwise, discontinue study 
drug/study regimen. 
Treat accordingly as per 
institutional standard  
 
 
Grade 4 
Discontinue Study drug/study regimen. 
 
Note for grade 4 laboratory abnormalities, decision to 
discontinue would be based on accompanying clinical 
signs/symptoms and as per treating investigator’s 
clinical judgment and in consultation with the Overall 
PI. 
Treat accordingly as per 
institutional standard  
 
Abbreviations: 
AChE = acetylcholine esterase; ADA = American Dietetic Association; AE = adverse event; ALP = alkaline 
phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT = computed tomography; GI = 
gastrointestinal; IDS=Infectious Disease Service; ILD = interstitial lung disease; IM = intramuscular; irAE = 
immune-related adverse event; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events; PO = by mouth; TNF = tumor necrosis factor; TSH = thyroid stimulating hormone; 
ULN = upper limit of normal. 
 
6.2 
Overdose 
 
There are no known antidotes for over-dosage of tremelimumab or durvalumab. In the case of 
suspected overdose, monitor hematologic parameters, serum chemistries, vital signs, cardiac and 
pulmonary function, and provide supportive care as necessary. See reporting requirements in 


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Section 7.9. 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Sections 7.3, 7.4, 7.5, and 7.10) will determine whether the event requires 
expedited reporting in addition to routine reporting. 
 
7.1 
Expected Toxicities 
 
7.1.1 Adverse Event List for Durvalumab 
 
Potential risks, based on the mechanism of action of durvalumab and related molecules, include 
immune-mediated reactions, such as colitis, pneumonitis, hepatitis/hepatotoxicity (elevations in 
ALT, AST, ALP, and/or total bilirubin), neuropathy/neuromuscular toxicity, endocrinopathy, 
dermatitis, pancreatitis and nephritis.  Additional important potential risks include infusion-
related reactions, hypersensitivity, anaphylaxis or serious allergic reactions, serious infections, 
and immune complex disease.   
 
AEs that have occurred in durvalumab monotherapy trials and have been assessed to have at 
least a reasonable possibility of a causal relationship to durvalumab include: 
 
• 
Very common ( > 10/100) 
o Diarrhea 
• 
Common (> 1/100 and <10/100) 
o ALT increased 
o AST increased 
o Pneumonitis 
• 
Uncommon (> 1/1,000 to <1/100) 
o Colitis 
 
The majority of diarrhea, ALT increased, AST increased, and pneumonitis events were reported 
to be mild to moderate in severity (CTCAE Grades 1/2), while for colitis the majority of events 
were reported to be moderate to severe (Grades 2/3). Please also refer to the Investigator’s 
Brochure (IB). 
 
7.1.2 Adverse Event List for Tremelimumab 
 
Immune-mediated reactions, also considered to be adverse events of special interest or immune 
related adverse events (irAEs), are important risks of immune checkpoint inhibitors such as 
tremelimumab that can result in an inflammatory response in any organ or tissue including the 
liver, gastrointestinal tract, thyroid glands, pancreas, skin, nervous system, hematopoietic 
system, respiratory tract, kidney, and adrenal glands. 
 


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Potential immune-mediated reactions associated with tremelimumab include the following: 
• 
Gastrointestinal events including colitis, 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 hyper- and 
hypothyroidism 
• 
Hepatitis including autoimmune hepatitis, and increased serum ALT and AST 
• 
Pancreatitis including autoimmune pancreatitis, and lipase and amylase elevation 
• 
Respiratory tract events including pneumonitis and interstitial lung disease (ILD) 
• 
Nervous system events including encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barre and myasthenia gravis (the latter reported with combination 
of tremelimumab and durvalumab) 
• 
Cytopenias including thrombocytopenia, anemia and neutropenia 
 
Additional risks that are common to any immunoglobulin include infusion-related reactions, 
anaphylaxis, and serious acute IgE-mediated allergic reactions. These reactions may occur, may 
be severe, and may result in death. 
 
Other potential risks identified with tremelimumab include headache, fatigue, and pyrexia. 
Please also refer to the IB. 
 
7.1.3 Adverse Event List for Durvalumab and Tremelimumab Combined 
 
Common (>10 % of subjects) treatment-related AEs of any grade occurring among subjects 
treated with the combination of durvalumab and tremelimumab include: 
 
• 
Diarrhea 
• 
Fatigue  
• 
Increased amylase and pruritus  
• 
Rash  
• 
Colitis  
• 
Increased lipase 
 
7.2 
Definition of Adverse Events 
 
The International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP) E6(R1) defines an adverse event (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-


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existing condition. The term disease progression should not be reported as an AE or serious 
adverse event (SAE), however, medically significant individual events and/or laboratory 
abnormalities associated with disease progression (see definition of disease progression below) 
that fulfill the AE or SAE definition should be reported. An abnormal laboratory finding 
(including ECG finding) that requires medical intervention by the investigator, or a finding 
judged by the investigator as medically significant should be reported as an AE. If clinical 
sequelae are associated with a laboratory abnormality, the diagnosis or medical condition should 
be reported (e.g., renal failure, hematuria) not the laboratory abnormality (e.g., elevated 
creatinine, urine red blood cell increased). 
 
AEs may be treatment emergent (i.e., occurring after initial receipt of investigational product) or 
non-treatment emergent. A non-treatment-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 non-serious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE. 
 
Adverse Events Associated with Disease Progression 
 
Disease progression can be considered as a worsening of a subject’s condition attributable to the 
disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of a new metastasis or progression of existing metastasis related to the primary 
cancer under study should not be considered an AE. Death clearly resulting from disease 
progression should NOT be reported as an SAE (see reporting guidelines in Section 7.4). 
 
New Cancers 
 
The development of a new cancer should be regarded as an SAE. New cancers are those that are 
not the primary reason for the administration of the investigational product and have been 
identified after the subject’s inclusion in the study. New metastatic lesion(s) of the subject’s 
known cancer should NOT be reported as a new cancer. 
 
7.3 
Adverse Event Characteristics 
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.03.  A copy of the CTCAE version 4.03 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 


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 For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.4 
Serious Adverse Events 
 
A serious adverse event (SAE) is any AE that: 
• Results in death 
• Is immediately life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect in offspring of the subject 
• Is an important medical event that may jeopardize the subject 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. 
 
 
7.5 
Time Period for Collection of Adverse Events 
 
Adverse events will be collected from the time treatment, , throughout the treatment period and 
including the follow-up period of 30 days after the last dose of durvalumab and tremelimumab, 
or at the start of a new treatment 
 
Serious adverse events will be recorded from the time treatment through30 days after the last 
dose of durvalumab and tremelimumab or the start of new treatment. 
 
7.6 
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 AEs or SAEs occurring in former study 
subjects after the 90-day safety follow-up period. 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 the 
investigational product, the investigator should notify the Overall PI and AstraZeneca or its 


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representative. 
 
7.7 
Follow-up of Unresolved Adverse Events 
 
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are to be followed by the investigator for as long as medically indicated, 
but without further recording in the eCRF. AstraZeneca 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. After 90 days, only subjects with ongoing investigational product-related SAEs will 
continue to be followed for safety. 
 
7.8 
Reporting of Serious Adverse Events to AstraZeneca 
 
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the 
initial dose of study treatment. 
 
The Overall PI is responsible for reporting certain SAEs as expedited safety reports to applicable 
regulatory authorities, ethics committees, and participating investigators, in accordance with ICH 
guidelines and/or local regulatory requirements. The Overall PI may be required to report certain 
SAEs to regulatory authorities within 7 calendar days of being notified about the event; 
therefore, it is important that investigators submit additional information requested by the 
Overall PI or AstraZeneca/MedImmune as soon as it becomes available. 
 
Investigators should provide all available information at the time of SAE Report Form 
completion. Investigators should not wait to collect additional information to fully document the 
event before notifying the Overall PI and MedImmune Patient Safety of an SAE. When 
additional information becomes available, investigators should submit a follow-up SAE Report 
Form (separate from the initial report form) with the new information. Any follow-up 
information to an SAE also needs to be provided to both the Overall PI and MedImmune Patient 
Safety within 24 hours of learning of the new information. 
 
7.9 
Other Events Requiring Immediate Reporting 
 
7.9.1 Overdose 
 
An overdose is defined as a subject receiving a dose of investigational product in excess of that 
specified in the Investigator’s Brochure (IB), unless otherwise specified in this protocol. 
 
Any overdose of a study subject with the investigational product, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to 
AstraZeneca/MedImmune Patient Safety or designee using the Safety Fax Notification Form (see 
Section 7.8 for contact information). If the overdose results in an AE, the AE must also be 
recorded on the AE eCRF. 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 7.4 and Section 7.9). 
 


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7.9.2 Hepatic Function Abnormality 
 
Adverse events of hepatic function abnormality of special interest to AstraZeneca/MedImmune 
are defined as any increase in ALT or AST to greater than 3 × institutional ULN and concurrent 
increase in bilirubin to greater than 2 × ULN (i.e., Hy’s law cases). Concurrent findings are those 
that derive from a single blood draw or from separate blood draws taken within 8 days of each 
other. In the event of hepatic function abnormality where the etiology is unknown, timely follow-
up investigations and inquiries should be initiated by the investigational site, based on medical 
judgment, to make an informed decision regarding the etiology of the event. 
 
If the underlying diagnosis for the hepatic function abnormality is known (including progression 
of pre-existing disease such as metastatic malignancy), the diagnosis should be recorded as an 
AE/SAE. 
 
If the underlying diagnosis for the hepatic function abnormality remains unknown, the term 
“hepatic function abnormal” should be used to report the AE/SAE. Hepatic function abnormality 
of unknown etiology, or which is considered attributable to investigational product, is required to 
be reported as “hepatic function abnormal” within 24 hours of knowledge of the event to the 
Overall PI and AstraZeneca/MedImmune representative(s) as an SAE (see Section 7.9). The 
investigator will review the data with AstraZeneca/MedImmune. The investigator should then 
use clinical judgment to establish the cause based on local standard of care and follow the subject 
by conducting testing as clinically indicated. 
 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by AstraZeneca/MedImmune. If the etiology of the event remains unconfirmed and/or 
is considered related to investigational product, a prompt cumulative review of safety data and 
the circumstances of the event in question will be conducted and assessed by the MedImmune 
safety review committee (or equivalent) to determine whether continued dosing of current study 
subjects and/or study entry should be interrupted, whether the protocol will be modified, or 
whether the study will be discontinued permanently. Review and approval by the MedImmune 
safety review committee (or equivalent) is required for resumption of subject dosing or study 
entry in the event that the study is interrupted. Where applicable, regulatory authorities including 
IRBs/IECs will be notified of any actions taken with the study. 
  
7.9.3 Pregnancy 
 
If pregnancy occurs in a female subject who has received investigational product, the 
investigator or other site personnel must inform the Overall PI as well as the appropriate 
AstraZeneca/MedImmune study representative(s) within 24 hours of when he or she becomes 
aware of it. 
 
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product but will not be withdrawn from the study. The pregnancy will be 
followed for outcome of the mother and child (including any premature terminations) and should 
be reported to MedImmune Patient Safety or designee after outcome.  
 


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Should the investigator become aware of a pregnancy in the partner of a male study subject who 
has received investigational product this should be reported within 24 hours of knowledge of 
the event to MedImmune Patient Safety or designee using the Safety Fax Notification Form (see 
Section 7.8 for contact information). The sponsor will endeavor to collect follow-up information 
on such pregnancies provided the partner of the study subject provides consent. 
 
7.9.4 Pneumonitis 
 
Adverse events of pneumonitis are required to be reported within 24 hours of knowledge of the 
event to the Overall PI and MedImmune Patient Safety or designee using the Safety Fax 
Notification Form (see Section 7.9 for contact information). 
 
7.10 
Expedited Adverse Event Reporting  
 
7.10.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after informed consent, during treatment, or within 90 days of the last dose of treatment 
on the local institutional SAE form.  
 
7.10.2 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.11 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
Any reports filed with the FDA should also be sent to AstraZeneca/MedImmune (see Section 7.9 
for contact information). 
 
7.12 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.13 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 


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68 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1. 
 
8.1 
Durvalumab 
 
8.1.1 Description 
 
Durvalumab (laboratory code MEDI4736) is a human IgG1κ monoclonal antibody (mAb) 
selected from a panel of hybridomas secreting human antibodies recognizing human PD-
L1. The antibody-coding deoxyribonucleic acid (DNA) sequence was recovered from a 
selected hybridoma and engineered by recombinant DNA technology to introduce a triple 
mutation in the constant domain of the IgG1 heavy chain that reduces binding to 
complement protein C1q and the Fcγ receptors involved in triggering effect or function. 
Functional binding properties of the modified antibody were confirmed. An expression 
plasmid was prepared for durvalumab production in Chinese hamster ovary (CHO) cells. 
Durvalumab is selective for human PD-L1 and blocks the binding of human PD-L1 to the 
human PD-1 and CD80 receptors. 
 
8.1.2 Form 
 
Durvalumab is formulated at 50 mg/mL. The investigational product is supplied as a 
liquid solution in clear 10R glass vials closed with an elastomeric stopper and a flip-off 
cap overseal. Each vial contains 500 mg (nominal) of active investigational product at a 
concentration of 50 mg/mL. The solution contains 50 mg/mL durvalumab, 26 
mMhistidine / histidine-hydrochloride, 275 mM trehalose dihydrate, and 
0.02% (weight/volume) polysorbate 80; it has a pH of 6.0.The nominal fill volume is 
10 mL.  
 
8.1.3 Storage and Stability 
 
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 expiration date on the 
label. 
 
8.1.4 Compatibility 
 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags 
have been observed. 
 
8.1.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment.  


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69 
 
8.1.6 Availability 
 
Durvalumab is an investigational product that will be provided by AstraZeneca.  
 
8.1.7 Preparation 
 
The dose of durvalumab for administration must be prepared by the Investigator’s or 
site’s designated investigational product (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.  
 
A dose of 1500 mg durvalumab 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.  Remove 30 mL of IV solution from the IV bag prior to addition of 
durvalumab.  Next, 30 mL of durvalumab (i.e., 1500 mg of durvalumab) is added to the 
IV bag such that final concentration is within 1 to 20 mg/mL (IV bag volumes 100 to 
1000 mL).  Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
 
8.1.8 Administration 
 
Durvalumab infusion will start 1 hour after the end of the tremelimumab infusion (±10 
minute window). Durvalumab should be infused over 1 hour; there is a ± 5 minute 
infusion window.  Durvalumab will be administered at room temperature by controlled 
infusion via an infusion pump into a peripheral or central vein. Following preparation of 
durvalumab, the entire contents of the IV bag should be administered as an IV infusion 
using a 0.2 or 0.22-μm in-line filter. 
 
The IV line should be flushed with a volume of IV solution (0.9% saline) equal to the 
priming volume of the infusion set used after the contents of the IV bag are fully 
administered, or complete the infusion according to institutional policy to ensure the full 
dose is administered. Please see Section 5. 
 
8.1.9 Ordering 
 
Drug supply will be ordered from AstraZeneca or its designee by site pharmacy 
personnel. 
 


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70 
8.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.1.11 Destruction and Return 
 
Expired supplies of durvalumab should be destroyed according to institutional policies. 
Destruction will be documented in the Drug Accountability Record Form. At the end of 
the study, unused supplies of durvalumab should be destroyed according to institutional 
policies. Destruction will be documented in the Drug Accountability Record Form. 
 
8.2 
Tremelimumab 
 
8.2.1 Description 
 
Tremelimumab is a human IgG2 mAb directed against CTLA-4. Tremelimumab has an 
overall molecular weight of approximately 149 kDa including oligosaccharides. CTLA-4 
is a critical regulatory signal for T-cell expansion and activation following an immune 
response, and it serves as a natural braking mechanism that maintains T-cell homeostasis. 
During T-cell activation, T cells upregulate CTLA-4, which binds to CD80 and CD86 
ligands on antigen-presenting cells, sending an inhibitory signal that limits T-cell 
activation. Tremelimumab blocks the inhibitory signal resulting from CTLA-4 binding to 
CD80/86, leading to prolongation and enhancement of T-cell activation and expansion.  
 
Tremelimumab is produced in accordance with current Good Manufacturing Practices. 
Tremelimumab is expressed in a NS0 (murine myeloma) cell line. It is purified using 3 
chromatography steps, a virus inactivation step, and a virus reduction filtration step. 
 
8.2.2 Form 
 
Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 
20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% 
(weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dehydrate, pH 5.5. 
 
The Drug Product is supplied as a sterile liquid solution containing 400 mg (nominal) 
tremelimumab per vial. The nominal fill volume is 20.0 mL.  
 
8.2.3 Storage and Stability 
 
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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71 
 
8.2.4 Compatibility 
 
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin IV bags 
have been observed. 
 
8.2.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment.  
 
 
8.2.6 Availability 
 
Tremelimumab is an investigational product provided by AstraZeneca. 
 
8.2.7 Preparation 
 
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 
 
It is recommended that the prepared final IV bag be stored in the dark at 2ºC-8°C (36°F-
46°F) until needed. If storage time exceeds these limits, a new dose must be prepared 
from new vials. The refrigerated infusion solutions in the prepared final IV bag should 
be equilibrated at room temperature for about 30 minutes prior to administration.  
 
Tremelimumab does not contain preservatives and any unused portion must be discarded. 
 
Doses of 75 mg tremelimumab 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 
0.1 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. Remove 3.8 mL of IV solution from the IV bag prior to addition of 
tremelimumab.  Next, 3.8 mL of tremelimumab (i.e., 75 mg of tremelimumab) is added to 
the IV bag such that final concentration is within 0.1 mg/mL to 10 mg/mL (IV bag 
volumes 50 to 500 mL).  Mix the bag by gently inverting to ensure homogeneity of the 
dose in the bag.  
 
8.2.8 Administration 
 
Tremelimumab should be infused over 1 hour; there is a ± 5 minute infusion window. 
Tremelimumab will be administered at room temperature by controlled infusion via an 
infusion pump into a peripheral or central vein. Following preparation of tremelimumab, 


DF/HCC Protocol #: 16-549 
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72 
the entire contents of the IV bag should be administered as an IV infusion using a 0.2 or 
0.22-μm in-line filter.  
 
The IV line should be flushed with a volume of IV solution (0.9% saline) equal to the 
priming volume of the infusion set used after the contents of the IV bag are fully 
administered, or complete the infusion according to institutional policy to ensure the full 
dose is administered. Please see Section 5. 
 
8.2.9 Ordering 
 
Drug supply will be ordered from AstraZeneca or its designee by site pharmacy 
personnel. 
 
8.2.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.2.11 Destruction and Return 
 
Expired supplies of tremelimumab should be destroyed according to institutional policies. 
Destruction will be documented in the Drug Accountability Record Form. At the end of 
the study, unused supplies of tremelimumab should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record 
Form. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Tumor Tissue Collection 
 
9.1.1 Archival Tissue 
 
Baseline archival tissue will be collected from all patients enrolling to the trial. Patients who do 
not have archival tissue available or who do not have sufficient tissue for analysis may be 
enrolled at the treating investigator’s discretion.  
 
A minimum of 10 unstained slides should be obtained for analysis. Slides should be labeled with 
the protocol number and study subject number and sent to: 
 
Belfer Center for Applied Cancer Science 
Dana-Farber Cancer Institute 
360 Longwood Ave, LC4210 


DF/HCC Protocol #: 16-549 
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73 
Boston, MA 02215 
 
 
9.1.2 Fresh Tumor Biopsies 
 
Mandatory pre- and on-treatment fresh tumor biopsies will be obtained from patients enrolling to 
the trial. In the event the biopsy is not clinically feasible in the opinion of the treating 
investigator or interventionalist performing the procedure, exceptions to one or both fresh biopsy 
requirements are possible after discussion with the principal investigator. 
 
The pre-treatment biopsy should be obtained following consent and prior to the first dose of any 
study medication (prior to Cycle 1 Day 1). The on-treatment biopsy may be obtained anytime 
between Cycle 2 Day 1 (after completion of the study medication infusions) to Cycle 2 Day 8. 
 
An additional optional biopsy at the time of disease progression will also be offered to patients if 
deemed clinically feasible by the treating investigator. In patients undergoing re-treatment with 
tremelimumab, the time of progression biopsy may be obtained either prior to the initiation of re-
treatment or upon progression following re-treatment. Preferably, time of progression biopsies 
should be obtained prior to the initiation of another cancer treatment. However, in the event that 
it is not possible to perform the biopsy before another treatment is begun, the biopsy can be 
obtained up to 60 days after the last dose of study medication. 
 
Pre- and on-treatment core biopsy samples a minimum of 2 cores should be collected, if 
clinically feasible. A 16-18 gauge needle are preferable, but a 20 gauge core needle biopsy is 
also acceptable.  For more information, please refer to the Thoracic Oncology Program 16-549 
Biopsy Collection Guidelines. In the event that not enough tissue is obtained, priority should go 
to immune profiling. 
 
 
If a core biopsy is judged to be too unsafe or difficult for the participant in the opinion of the 
treating investigator, a fine needle aspirate (FNA) or cytology sample can also be collected. The 
goal for a thoracentesis or paracentesis procedure will be 500 – 1000 mL collected in a standard 
collection tube. The goal for an FNA will be three distinct passes. Less than the goal amount of 
tissue is acceptable for any of the biopsy collection methods, and should be based upon the 
clinical judgment of the treating investigator and the clinician performing the procedure. 
 
All tumor biopsy samples should be labeled with the protocol number, study subject number, 
date of collection, and identified as either “pre-treatment,” “on-treatment,” or “time of 
progression.”  
 
 
Samples should be sent to: 
 
Belfer Center for Applied Cancer Science 
Dana-Farber Cancer Institute 
360 Longwood Ave, LC4210 


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74 
Boston, MA 02215 
 
For time of progression core biopsy samples: 
 
 Two (2) biopsy samples should be formalin-fixed and paraffin embedded per institutional 
standards for NGS. 
 Two (2) should be placed in media (DMEM + 10% FBS) on wet ice (4°C) and delivered 
to the immuno-oncology laboratory at the Belfer Center for Applied Cancer Science for 
immune profiling.   
 
In the event that not enough tissue is obtained, priority should go to providing the samples for 
NGS.  
 
Immune samples should be sent to: 
 
Belfer Center for Applied Cancer Science 
Dana-Farber Cancer Institute 
360 Longwood Ave, LC4210 
Boston, MA 02215 
 
Samples for NGS should be sent to the Center for Advanced Molecular Diagnostics (CAMD) at 
Brigham and Women’s Hospital. 
 
For cytology samples: 
 Cytology samples should be made into paraffin blocks per institutional standards. 
 
 
9.2 
Laboratory Correlative Studies 
 
Peripheral blood mononuclear cell (PBMC) samples will be collected at baseline (on Cycle 1 
Day 1 prior to the first dose of study medication), on Cycle 2 Day 1, at visits following restaging 
scans, and at the off study visit. Samples collected on days where study medication dosing will 
occur can be collected anytime pre-dosing. 
 
Collection and Shipping Procedure: 
 
1. Blood samples should be labeled with the protocol number, study subject 
number, date of the draw, visit day (i.e. “C1D1” or “C2D1”), and labeled as 
“PBMC.” 
2. Draw venous blood into four 10 mL EDTA tubes and immediately gently 
invert the tube 3-4 times. 
3. Send tubes to the CIO lab for processing within 6 hours of blood draw (tubes 
sent outside of this window due to shipping or scheduling difficulties will not 
be considered protocol violations but every effort should be made to get the 
samples to the laboratory within 6 hours of draw time): 
 


DF/HCC Protocol #: 16-549 
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75 
ATTN: CIO Laboratory Manager 
Center for Immuno-Oncology Laboratory 
Jimmy Fund Building Room 406 
1 Jimmy Fund Way 
Boston, MA 02115 
 
 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within two weeks prior to start of protocol therapy, with 
the exception of the informed consent and baseline imaging which must be done ≤4 weeks prior 
to the start of therapy. 
 
Assessments must be performed prior to administration of any study agent.


 
 
Page 76 
 
 
 
Table 7: Study Calendar 
 
 
Pre- 
Study 
Cycle 1 
Day 1 
Cycle 1 
Day 15H 
Cycle 2 Day 
1I 
Cycle 3 Day 
1I 
Cycle 4 Day 
1I 
Day 1 of Each Subsequent Cycle (after 
Cycle 4)I 
Off 
TreatmentJ 
Every 3 Months after 
DiscontinuingK 
TremelimumabA 
 
X 
 
X 
X 
X 
 
 
 
DurvalumabA 
 
X 
 
X 
X 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
X 
 
Tumor BiopsyB 
X 
 
 
X 
 
 
 
X 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signsC 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance status 
X 
 
X 
X 
X 
X 
X 
X 
 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistryD 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis (with 
microscopy) 
X 
 
 
 
 
 
 
 
 
EKGE 
X 
 
 
 
 
 
 
 
 
Serum β-hCGF 
X 
 
 
 
 
 
 
 
 
Adverse event evaluation 
X 
X---------------------------------------------------------------------------------------------X 
X 
 
Tumor measurements 
X 
Tumor measurements are repeated every 8 weeks, there is a ± 7 day window.  Documentation (radiologic) must be 
provided for participants removed from study for progressive disease. 
X 
 
Radiologic evaluation 
X 
CT or MRI imaging of any disease-involved site. Radiologic measurements should be performed every 8 weeks, 
there is a ± 7 day window. 
X 
 
Blood immune analysisG 
 
X 
 
X 
X 
 
As indicated in footnote G. 
X 
 


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77 
 
Table 7: Study Calendar 
 
 
Pre- 
Study 
Cycle 1 
Day 1 
Cycle 1 
Day 15H 
Cycle 2 Day 
1I 
Cycle 3 Day 
1I 
Cycle 4 Day 
1I 
Day 1 of Each Subsequent Cycle (after 
Cycle 4)I 
Off 
TreatmentJ 
Every 3 Months after 
DiscontinuingK 
Telephone or Care Provider 
Contact 
 
 
 
 
 
 
 
 
X 
A. 
As described in Section 5. 
B. 
Fresh tumor biopsy to be performed at baseline, anytime between cycle 2 day 1 (following study medication administration) and cycle 2 day 8, and at the off study visit as described in 
Section 9.1. Off study biopsy should be collected prior to the initiation of another anticancer treatment whenever feasible, or within 60 days of the last dose of study medication.  Biopsy time 
points should be followed from C1D1 regardless of drug holds or delays. 
C. 
Vital signs to consist of heart rate, respiratory rate, blood pressure, temperature, and oxygen saturation (O2 sat). On infusion days, vital signs are to be collected anytime pre-infusion (exact 
time of vital signs should be recorded). May be repeated as clinically indicated. 
D. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, 
amylase, lipase, and TSH. 
E. 
Triplicate EKG to be performed at baseline. EKGs should be obtained after participant has been resting for a minimum of 5 minutes. Each EKG of the triplicate should be separated by at 
least one minute and not more than 5 minutes. Subsequent EKGs to be performed as clinically indicated. 
F. 
Serum pregnancy test for women of childbearing potential. Childbearing potential defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or 
complete hysterectomy) or post-menopausal (defined as ≥ 12 months with no menses without an alternative medical cause). 
G. 
Blood immune analysis as described in Section 9.2. Samples to be collected prior to the administration of either of the study medications on Cycle 1 Day 1, Cycle 2 Day 1, at visits following 
restaging scans (e.g. cycle Cycle 3 Day 1, Cycle 5 Day 1, and so on), and at the Off Study visit. 
H. 
A ± 3 day scheduling window exists for Cycle 1 Day 15 to accommodate adverse weather, vacations, clinic schedule, or holidays. 
I. 
A +7 day window exists for day 1 of each subsequent cycle following cycle 1 to accommodate adverse weather, vacations, clinic schedule, or holidays. 
J. 
Off-treatment evaluation. Note: follow-up visits or other contact are required in order to identify SAEs during the 90 days following the end of study treatment.  
K. 
Participants will be followed until death or withdrawal of consent after removal from protocol therapy. This follow up will be performed by review of the medical record, contact with care 
providers, and/or telephone contact as needed every 3-4 months.   


 
 
Page 78 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 8 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained 8 weeks following 
initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the modified Response 
Evaluation Criteria in Solid Tumors (RECIST) guidelines for mesothelioma (version 1.1).44   
 
Tumor thickness perpendicular to the chest wall or mediastinum is measured in two positions at 
three separate levels on transverse cuts of a CT scan. The sum of the six measurements defines a 
pleural unidimensional measure. Transverse cuts at least 1 cm apart and related to anatomical 
landmarks in the thorax are chosen to allow reproducible assessment at later time points. If 
measureable tumor is present, transverse cuts in the upper thorax, above the level of division of 
the main bronchi are preferred. At reassessment, pleural thickness is measured at the same 
position at the same level. This is not necessarily the greatest tumor thickness at that level. 
Nodal, subcutaneous and other bidimensionally measurable lesions are measured 
unidimensionally as per the RECIST 1.1 criteria. Unidimensional measurements are added to 
obtain the total tumor measurement. 
 
11.1.1 Definitions 
 
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension of at least 10 mm in diameter or thickness with CT 
scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 


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79 
considered measurable. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 


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or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 


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81 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
MIBG (meta-iodobenzylguanidine).The following is recommended, to assure high 
quality images are obtained.  
Patient preparation: Iodides, usually SSKI (saturated solution of potassium iodide), 
are administered to reduce thyroidal accumulation of free radioiodine, preferably 
beginning the day prior to injection and continuing for 3 additional days (4 days 
total). For infants and children, one drop t.i.d. is sufficient, for adolescents 2 drops 
t.i.d., and for adults 3 drops t.i.d. Participants and/or parents are asked about exposure 
to potential interfering agents. If none is noted, an indwelling intravenous line is 
established. The dose of MIBG is administered by slow intravenous injection over 90 
seconds.  
Images from the head to the distal lower extremities should be obtained.  
I-123MIBG scintigraphy is performed to obtain both planar and tomographic images.  
Planar: Anterior and posterior views from the top of the head to the proximal lower 
extremities are obtained for 10 minutes at 24 hours and occasionally at 48 hours 
following injection of 10 mCi/1.7 square meters of body surface area (~150 μCi/kg, 
maximum 10 mCi). Anterior views of the distal lower extremities are adequate. A 
large field of view dual head gamma camera with low energy collimators is preferred.  
 


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SPECT: Most participants receiving I-123 MIBG also undergo SPECT at 24 hours, 
using a single or multi-headed camera with a low energy collimator. The camera is 
rotated through 360 degrees, 120 projections at 25 seconds per stop. Data are 
reconstructed using filtered back projections with a Butterworth filter and a cut off 
frequency of 0.2-0.5. SPECT/CT may be performed at institutions with this capacity. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
from CT, MRI may be used instead of CT in selected instances.  
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in total tumor measurement. 


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Progressive Disease (PD):  At least a 20% increase in the total tumor measurement, 
taking as reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. Timing of the follow up evaluation should be performed at the 
discretion of the treating investigator and no more than 8 weeks following the date of 
the imaging that identified the potential new lesion. 


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84 
 
11.1.4.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Table 8: Criteria for Participants with Measurable Disease 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required 
CR 
CR 
No 
CR 
>4 wks Confirmation* 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*        Only for non-randomized trials with response as primary endpoint. 
**      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Table 9: Criteria for Participants with Non-Measurable Disease 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 


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85 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported. 
 
11.1.7 Response Review 
 
Evaluation of scans will be done centrally at the DFCI using the Tumor Imaging Metrics 
Core.  
 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 


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86 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the ODQ according to the schedule set by the ODQ. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
 
13. STATISTICAL CONSIDERATIONS 
 
We will employ a Simon's 2-stage design to test the hypothesis that durvalumab and 
tremelimumab improve response rates in this patient population to 35%, compared to a historical 
control rate of 16%.  In the first stage we will enroll 19 patients, and if 4 or more patients among 
those 19 respond to therapy (with either a complete or partial response), we will open the 2nd 
stage of accrual to enroll an additional 21 patients, making a total sample size of 40 patients. If 
fewer than 4 patients experience a response in the first stage then the study will be stopped. In 
order to declare study success, a total of 10 or more responses must be observed among all 40 
study participants. This design has a 0.64 probability of stopping early under the null, and has 
90% power while maintaining an overall one-sided type I error rate of 0.08. 
 
Statistical Analysis Plan for Correlative Studies: 
 
Data from correlative studies will be summarized using descriptive statistics. Associations 


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between immune cell subsets, immune marker expression, and the characteristics of the PBMCs 
will be compared to clinical outcome, will be summarized by descriptive methods, and may be 
explored graphically. 
 
We assume that 80% of patients (n=32) will be successfully biopsied at multiple time points and 
have tumors that yield valid results from the laboratory.  
 
When comparing baseline, on-treatment, and time of progression genomic and immune results, it 
is of interest to identify new alterations that were not present at baseline. Initial analyses of these 
data will utilize tests for association comparing the frequency of a particular genomic or immune 
aberration at baseline, on-treatment, and at progression (for example, using McNemar’s test) and 
association between alterations and baseline characteristics (for example, using Fisher’s exact 
test). For non-normal distributions (% T-cell infiltrate), we will explore associations with the 
presence or absence of a genomic or immune feature using non-parametric analysis for subgroup 
comparisons (Wilcoxon rank-sum or Kruskall-Wallis). Fisher’s exact test will be used for 
discrete comparisons of categorical immune and clinical variables (such as PD-L1 positive vs. 
negative). More sophisticated analyses may include multivariable logistic regression modeling 
and/or competing risks analysis, however it is expected that analyzable results will not be 
obtained from all patients (either due to things like assay failure, inability to biopsy at 
progression due to poor patient health, etc).   
 
With at least 32 patients included in the correlative analysis, this sample size provides 84% 
power to detect differences in the rate of another binary variable (such as baseline characteristics 
or abnormality) with frequencies of 8% and 60%, respectively, while testing with a one-sided 
0.10-level Fisher’s exact test; this also assumes that the underlying prevalence of the genomic 
marker is 50%, thus splitting the cohort into two groups with 16 patients in each. It is worth 
noting that the Fisher’s test for association between the presence/absence of baseline samples 
and resistant samples assumes independence between those samples. Given what is known about 
tumor heterogeneity, the likelihood that the cancer may be altered genomically over time and due 
to therapy, and the low chance that the same area of a patient’s tumor will be biopsied at both 
time points, this seems like a reasonable assumption.  
 
 
13.1 
Study Design/Endpoints 
 
Primary Efficacy Measure: 
 
Investigate the ORR in patients with malignant pleural mesothelioma. 
 
Secondary Efficacy Measures: 
 
Evaluate the safety and tolerability of tremelimumab in combination with durvalumab. 
 
Determine the OS, PFS, and DoR in patients with malignant pleural mesothelioma. 
 
Exploratory Endpoints: 
 
Investigate the immunologic determinants of primary response and resistance to 
tremelimumab in combination with durvalumab in malignant pleural mesothelioma 
 
Investigate the immunologic mechanisms of acquired resistance to tremelimumab in 


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combination with durvalumab 
 
Investigate genomic correlates of response to tremelimumab in combination with 
durvalumab 
 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
The planned total sample size is 40 patients in this single-arm, phase 2 study of durvalumab and 
tremelimumab in patients with malignant pleural mesothelioma.  The planned accrual rate is 
approximately 5 patients per quarter.  Up to an additional year of follow-up will be required on 
the last participant accrued to observe the patient’s response and survival following study 
therapy, for a total study length of approximately three years.  
 
Table 10: Accrual Targets 
Ethnic Category 
Sex/Gender
Females
Males
 
Total
Hispanic or Latino 
1 
+
3 
= 
4 
Not Hispanic or Latino 
9 
+
27 
= 
36 
Ethnic Category: Total of all subjects 
10 
(A1) +
30 
(B1) = 
40 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+
0 
= 
0 
Asian 
1 
+
2 
= 
3 
Black or African American 
1 
+
2 
= 
3 
Native Hawaiian or other Pacific 
Islander 
0 
+
0 
= 
0 
White 
8 
+
26 
= 
34 
Racial Category: Total of all subjects 
10 
(A2) +
30 
(B2) = 
40 
(C2) 
 
(A1 = A2) 
(B1 = B2) 
 
(C1 = C2) 
 
 
13.3 
Analysis of Primary and Secondary Endpoints 
 
The primary and secondary analyses will include all eligible patients who started assigned 
therapy. The exception to this includes the planned analysis of toxicity data, which will include 
all patients who received study drug regardless of eligibility. Response will be assessed using the 
modified RECIST criteria for mesothelioma; toxicity will be graded using CTCAE v. 4.03. 
 
For the analysis of the response efficacy measures, participants will be censored if they are alive 
and without disease progression at the date of the last disease evaluation. In the case of OS, 
participants will be censored if they are living at the date last known alive. 
 
Time-to-event data, such as PFS and OS, will be estimated using the Kaplan-Meier method, and 
Cox proportional hazards models will be used to estimate hazard ratios. Comparisons of groups 
will be made using the logrank test and Cox modeling. 


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89 
 
Categorical data, such as response rates (CR+PR) and toxicity, will be compared using Fisher’s 
exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling 
will be used to adjust for the effect of any covariates that are associated with these categorical 
outcomes. Though none are currently planned, any continuous outcomes will be analyzed using 
Wilcoxon rank sum test, and multivariable linear regression models may be used to adjust for 
multiple associations with outcome.  
 
Modeling procedures will implement backward selection; variables significant at the 0.10 level 
in the univariate setting will be chosen for inclusion in an initial full model, and at each step the 
least significant variable will be removed from the model. Only those covariates with p<0.05 will 
remain in any final models, unless there are factors identified by the study team as crucial to 
model interpretation.  
 
Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% 
confidence intervals. The method of Atkinson and Brown will be used for the estimation of the 
confidence interval for response. 
 
In the event that there are missing data, no imputation of the missing data will be conducted. We 
will assume that data are missing at random and will conduct all analyses as originally planned 
because we do not anticipate an excess of missing data.  
 
Subset analyses are planned for all known prognostic factors, such as performance status, age, 
sites of metastases, gender, etc. Subset analyses of all variables, including correlatives, are 
considered to be exploratory in nature.  
 
 
13.4 
Reporting and Exclusions 
 
13.4.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of study 
medication. 
 
13.4.2 Evaluation of the Primary Efficacy Endpoint 
 
All eligible participants included in the study will be assessed for response, even if there 
are major protocol therapy deviations. Each participant should be assigned one of the 
following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 
7) early death because of other cause, or 9) unknown (not assessable, insufficient data). 
By arbitrary convention, category 9 usually designates the "unknown" status of any type 
of data in a clinical database. 
 
 


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14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work.
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
COCKCROFT-GAULT EQUATION FOR 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)      
72 x serum creatinine (mg/dL)       x      0.85