A Phase II Study of MEDI4736 (Durvalumab) Plus Tremelimumab as Therapy for Patients With Previously Treated Anti-PD-1/PD-L1 Resistant Stage IV Squamous Cell Lung Cancer (Lung-Map Non-Match Sub-Study)
Phase: PHASE2
Conditions: Recurrent Squamous Cell Lung Carcinoma, Stage IV Squamous Cell Lung Carcinoma AJCC v7
Sponsor: SWOG Cancer Research Network

Cover Page for Clinical Trials Document posting 
 
 
Official Title:  
S1400F, “A Phase II Study of MEDI4736 (Durvalumab) Plus Tremelimumab as Therapy 
for Patients with Previously Treated Anti-PD-1/PD-L1 Resistant Stage IV Squamous Cell 
Lung Cancer (Lung-MAP Non-Match Sub-Study)” 
 
 
NCT Number: 03373760 
 
 
Version Date: 
10/21/2019 
 
Description: 
S1400 [NCT 02154490] is the parent study to S1400F [NCT 03373760].  
The S1400 Lung-MAP study is considered one study under one IND consisting of: 
• 
S1400 Version Control Protocol  
• 
S1400 Main Screening Protocol Component 
• 
Multiple Sub-Studies (or sub-protocols) Components  
Each component is contained in its own separate document.   
S1400F is one of these components. Each “component” consists of the protocol 
document and its associated informed consent document(s).  Since each screening 
and sub-study component operates independently from the other components contained 
in Lung-MAP, each has its own version date and NCT number. This is due to the complexity 
of the study and how it must be entered into different computer programs.  
 

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S1400F: (Non-Match sub-study):  Anti-PD-1/PD-L1 Resistant – MEDI4736 (Durvalumab) plus 
Tremelimumab 
 
TITLE 
A BIOMARKER-DRIVEN MASTER PROTOCOL FOR PREVIOUSLY  
TREATED SQUAMOUS CELL LUNG CANCER 
 
A MASTER PROTOCOL TO EVALUATE BIOMARKER-DRIVEN THERAPIES AND 
IMMUNOTHERAPIES IN PREVIOUSLY-TREATED NON-SMALL CELL LUNG CANCER 
 
A PHASE II STUDY OF MEDI4736 (DURVALUMAB) PLUS TREMELIMUMAB AS THERAPY FOR 
PATIENTS WITH PREVIOUSLY TREATED ANTI-PD-1/PD-L1 RESISTANT STAGE IV SQUAMOUS 
CELL LUNG CANCER (LUNG-MAP NON-MATCH SUB-STUDY) 
 
NCT # 03373760 
 
This is an FDA registration study. There will be additional centralized and on-site monitoring conducted in 
addition to routine audits. Sites must also maintain a study specific Trial Master File for this study. 
 
Lung-MAP and its sub-studies are being conducted under SWOG IND 119672 and CIRB. The Lung-
MAP Study is considered a single study under one IND, consisting of the Screening Protocol and 
multiple sub-studies. Each sub-study protocol operates independently and has its own version 
date. However, for regulatory purposes, all Lung-MAP sub-study protocols should be processed 
as a single study for Continuing Review.  
 
SUB-STUDY CHAIRS: 
STUDY AGENTS: 
 
 
Natasha Leighl, BSc, MMSc, M.D. 
Available from Pharmaceutical Collaborator: 
   (Medical Oncology) 
SWOG Held IND: 
NCTN Group: CCTG 
MEDI4736 (Durvalumab) (NSC 778709) 
Univ. Health Network-Princess Margaret Hospital 
(IND-119672) 
610 University Avenue 
Tremelimumab (NSC 744483) (IND-119672) 
Toronto, Ontario, Canada M5G 2M9 
 
Phone:  416/946-4645 
BIOSTATISTICIANS: 
FAX:  416/946-6546 
 
E-mail: Natasha.leighl@uhn.ca 
Mary Redman, Ph.D. 
 
Katherine Minichiello, M.S. 
Naiyer Rizvi, M.D. 
Jieling Miao, M.S. 
   (Medical Oncology) 
James Moon, M.S. 
NCTN Group: SWOG 
SWOG Statistics & Data Management Center 
Columbia University Medical Ctr 
1100 Fairview Ave N, M3-C102 
Division of Hematology-Oncology 
P.O. Box 19024 
177 Fort Washington Ave, Ste 6GN435 
Seattle, WA 98109-1024 
New York, NY 10032 
Phone: 206/667-4623 
Phone: 646/317-6344 
FAX: 206/667-4408 
FAX: 212/305-3035 
E-mail: mredman@fredhutch.org  
E-mail: nar2144@cumc.columbia.edu 
E-mail: kgriffin@fredhutch.org  
 
E-mail: jmiao@fredhutch.org  
 
E-mail: jmoon@fredhutch.org 
 
 

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TABLE OF CONTENTS 
 
TITLE  ......................................................................................................................................................... 1 
TABLE OF CONTENTS ............................................................................................................................... 2 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 4 
SCHEMA ....................................................................................................................................................... 5 
1.0 
OBJECTIVES .................................................................................................................................. 6 
1.1 
Primary Objective ............................................................................................................................. 6 
1.2 
Secondary and Exploratory Objectives ............................................................................................ 6 
1.3 
Translational Medicine Objectives ................................................................................................... 6 
2.0 
BACKGROUND ............................................................................................................................... 6 
3.0 
DRUG INFORMATION .................................................................................................................. 11 
3.1 
MEDI4736 (Durvalumab) – Liquid (NSC 778709) (IND-119672)................................................... 11 
3.2 
Tremelimumab (NSC 744483) (IND 119672) ................................................................................ 18 
3.3 
DRUG ORDERING & ACCOUNTABILITY .................................................................................... 24 
4.0 
STAGING CRITERIA ..................................................................................................................... 25 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 25 
5.1 
Sub-Study Specific Disease Related Criteria................................................................................. 25 
5.2 
Sub-Study Specific Clinical/Laboratory Criteria ............................................................................. 26 
5.3 
Common Eligibility Criteria for all Sub-Studies .............................................................................. 27 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 29 
7.0 
TREATMENT PLAN ...................................................................................................................... 29 
7.1 
Pre-Medication and Supportive Care ............................................................................................. 30 
7.2 
Treatment – MEDI4736 (Durvalumab) plus Tremelimumab .......................................................... 30 
7.3 
Criteria for Removal from Protocol Treatment ............................................................................... 30 
7.4 
Discontinuation of Treatment ......................................................................................................... 31 
7.5 
Follow-Up Period ............................................................................................................................ 31 
8.0 
TOXICITIES TO BE MONITORED AND DOSE INTERRUPTIONS ............................................. 31 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 31 
8.2 
General Considerations ................................................................................................................. 32 
8.3 
Dose Interruptions – MEDI4736 (Durvalumab) or in Combination with Tremelimumab ................ 32 
8.4 
Dose Modification Contacts ........................................................................................................... 51 
8.5 
Adverse Event Reporting ............................................................................................................... 52 
9.0 
STUDY CALENDAR ...................................................................................................................... 53 
9.1 
MEDI4736 (Durvalumab) plus Tremelimumab .............................................................................. 53 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 56 
10.1 
Measurability of Lesions................................................................................................................. 56 
10.2 
Objective Status at Each Disease Evaluation ................................................................................ 57 
10.3 
Best Response ............................................................................................................................... 59 
10.4 
Performance Status ....................................................................................................................... 59 
10.5 
Time to Death ................................................................................................................................. 60 
10.6 
irRC-Progression ............................................................................................................................ 60 
10.7 
Investigator-Assessed Progression-Free Survival ......................................................................... 60 
10.8 
Progression-Free Survival by Central Review ............................................................................... 60 
10.9 
Duration of Response (DoR) .......................................................................................................... 60 
10.10 
irRC Investigator-Assessed Duration of Response (irRC-IA-DoR) ................................................ 61 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 61 
11.1 
Primary Objective ........................................................................................................................... 61 
11.2 
Secondary Objectives .................................................................................................................... 61 
11.3 
Sample Size with Power Justification ............................................................................................ 61 
11.4 
Analysis Plan .................................................................................................................................. 62 
11.5 
Accrual Information ........................................................................................................................ 63 
11.6 
Data and Safety Monitoring Committee ......................................................................................... 63 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 63 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 63 
13.1 
Registration Timing ........................................................................................................................ 63 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 64 
14.1 
Data Submission Requirements .................................................................................................... 64 

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14.2 
Master Forms ................................................................................................................................. 64 
14.3 
Data Submission Procedures ........................................................................................................ 64 
14.4 
Data Submission Overview and Timepoints .................................................................................. 65 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 67 
15.1 
SWOG Specimen Tracking System (STS) .................................................................................... 67 
15.2 
Correlative Studies and Banking  (Optional for Patients) .............................................................. 67 
15.3 
PD-L1 IHC Testing ......................................................................................................................... 69 
15.4 
Specimen Flow Diagram ................................................................................................................ 70 
15.5 
Radiology Review (Required) ........................................................................................................ 71 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 72 
16.1 
Adverse Event Reporting Requirements........................................................................................ 72 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 78 
18.0 
APPENDIX ..................................................................................................................................... 79 
18.1 
Background of Adverse Events of Special Interest (AESIs) .......................................................... 80 
18.2 
Biomarker Analysis of Immunotherapy Resistance ....................................................................... 81 
18.3 
PD-L1 IHC Testing ......................................................................................................................... 82 
18.4 
Instructions for the SWOG Biospecimen Bank .............................................................................. 83 
 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory 
requirements: 
For patient 
enrollments: 
 
For study data submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal: 
 (Sign in at www.ctsu.org, 
and select the Regulatory 
Submission sub-tab under 
the Regulatory tab.)  
Institutions with patients 
waiting that are unable to 
use the Portal should alert 
the CTSU Regulatory Office 
immediately at 866-651-
2878 to receive further 
instruction and support. 
Contact the CTSU 
Regulatory Help Desk at 
866-651-2878 for regulatory 
assistance. 
 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network 
(OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN
_SYSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help 
Desk with any OPEN-
related questions at 
ctsucontact@westat.com. 
 
 
 
Data collection for this study will be done 
exclusively through Medidata Rave.  Please 
see the data submission section of the 
protocol for further instructions.  
 
Other Tools and Reports: 
Institutions participating through the CTSU 
continue to have access to other tools and 
reports available on the SWOG Workbench 
via the SWOG website (www.swog.org).   
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at 
https://www.ctsu.org.  Access to the CTSU members’ website is managed through the Cancer Therapy 
and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and requires 
user log on with CTEP-IAM username and password. Permission to view and download this protocol and 
its supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS. 
 
 
For patient eligibility or data submission questions contact the SWOG Statistics and Data 
Management Center by phone or email: 
 
206/652-2267 
LUNGMAPquestion@crab.org 
 
For treatment or toxicity related questions contact the S1400FMedicalQuery@swog.org. 
 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help 
Desk by phone or e-mail: 
 
CTSU General Information Line: 
1-888-823-5923 
S1400contact@westat.com 
 
All calls and correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Web site is located at https://www.ctsu.org 

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SCHEMA 
 
Screening/Pre-Screening Registrationa 
 
 
Common Broad Platform CLIA Biomarker Profiling b 
 
 
If NOT eligible for biomarker driven sub-studies, 
Pure Squamous AND have progressed on or after an anti-PD-1/PD-L1 c 
 
 
 
S1400F Registration 
(Non-Match, Anti-PD-1/PD-L1 Resistant) 
 
 
 
Cohort 1 (acquired resistance) 
Cohort 2 (primary resistance) 
MEDI4736 (Durvalumab) plus Tremelimumab  
MEDI4736 (Durvalumab) plus Tremelimumab 
 
 
a 
Patients may have screened/pre-screened on S1400 or LUNGMAP 
NOTE: At the time of LUNGMAP activation, S1400 screening will close to accrual. Please see the 
Lung-MAP protocol training webpage for additional information (https://www.swog.org/required-
lung-map-s1400-training). 
 
b 
Archival formalin-fixed paraffin-embedded (FFPE) tumor, fresh core needle biopsy if needed 
 
c 
Notification of sub-study assignment will be provided by the SWOG Statistics and Data 
Management Center (see Section 11.0 in S1400 or LUNGMAP for details). 
 
 

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for biomarker-driven studies through non-match sub-studies, to date focusing on immune 
checkpoint inhibitors.   
 
After S1400 was developed and began accrual, the standard of care for platinum-treated advanced 
lung cancer patients with squamous carcinoma evolved from docetaxel chemotherapy to PD-1 
checkpoint inhibitor therapy. Several Phase III randomized trials have demonstrated improved 
survival, progression-free survival, response and even quality of life with the use of PD-1 checkpoint 
inhibitors compared to docetaxel in advanced pre-treated non-small cell lung cancer. Nivolumab 
improved survival (HR 0.59, 95% CI 0.44-0.79, p<0.001; median 9.2 versus 6.0 months), PFS (HR 
0.62, 95% CI 0.47 – 0.81, p<0.001, median 3.5 versus 2.8 months) and, response (20% versus 
9%, p=0.008) and quality of life compared to docetaxel in patients with advanced squamous 
carcinoma. (1) Longer duration of response (median not reached versus 8 months with 
chemotherapy) and significantly fewer Grade 3 or 4 treatment-related AEs (7 versus 55%) were 
also seen in the nivolumab arm. (2) Nivolumab has also been approved for use in non-squamous 
lung cancer based on a similar trial demonstrating improved survival, response rate and less toxicity 
compared to docetaxel. (3) Pembrolizumab, another PD-1 checkpoint inhibitor, also demonstrated 
significantly better survival, PFS and response compared to docetaxel in pretreated non-small cell 
lung cancer patients with PD-L1 tumor expression (including 21% squamous carcinoma patients). 
(4)  
 
Despite the progress of immune checkpoint inhibition in this population, a significant number of 
patients will not derive long-term benefit from second-line therapy with single agent PD-1 or PD-L1 
inhibitors. For this group, the next step in therapy is undefined. Many will receive docetaxel as 
subsequent therapy, with significant treatment-associated toxicity, response rate in the range of 
10% and median survival time of 6 months or less. Better options are needed for this newly 
emerging population, and whether this group has the potential to benefit from further immune 
targeted therapy is unknown.  
 
Both PD-1 and CTLA-4 checkpoint inhibitors have demonstrated clinical activity across a range of 
tumor types, including melanoma, prostate cancer and lung cancer, both small cell and non-small 
cell subtypes. While both CTLA-4 and PD-1 checkpoint receptors are negative regulators of T cell 
activation and function, they use distinct mechanisms to block T cell activity. CTLA-4 inhibition 
impairs T-cell activation, while PD-1 inhibition results in T cell effector dysfunction. Blockade of one 
T-cell checkpoint may lead to reliance on other immune mechanisms, potentially making cells more 
sensitive to alternate checkpoint inhibitors. Preclinical studies suggest synergistic anti-cancer 
activity between PD-1 and CTLA-4 receptor inhibitors.  
 
In a relevant mouse model of melanoma, single blockade of either CTLA-4 or PD-1 enhanced the 
infiltration of activated T-cells into tumors, but the T-cells accumulated high levels of unblocked 
negative co-receptors that eventually limited their expansion. Blocking CTLA-4, PD-1 and PD-L1 
simultaneously allowed T-cells to continue to survive and proliferate, and resulted in enhanced 
infiltration, activation and cytokine production, thereby reducing tumor-induced immune 
suppression and promoting tumor rejection. (5) In a study by Curran et al, vaccination with 
irradiated B16 melanoma cells expressing the Flt3-ligand (Fvax) combined with antibody blockade 
of the negative T-cell co-stimulatory receptor CTLA-4 promoted rejection of pre-implanted tumors. 
However, despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited 
by the interaction of PD-1 with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-
1. The study showed that the combination of CTLA-4 and PD-1 blockade was more than twice as 
effective as either agent alone in promoting the rejection of B16 melanomas in conjunction with 
Fvax. (6) 
 
In clinical studies, combination of PD-1 and CTLA-4 inhibitors has led to exciting response data 
although greater toxicity. Larkin et al compared combination nivolumab/ipilimumab with either 
agent alone (1:1:1 randomization) as first-line therapy in advanced melanoma. Those receiving 
combination therapy had the longest PFS (median 11.5 v. 2.9 months with ipilimumab, HR 0.42, 

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99.5% CI 0.31-0.47, p<0.001; 6.9 months with nivolumab), as well as the highest response rate 
(57.6%). Patients with PD-L1- expressing tumors had similar PFS with either nivolumab or 
combination therapy (14.0 months median), although combination therapy yielded a higher 
response rate (72.1%, 57.5% nivolumab, 21.3% ipilimumab). However in the group with PD-L1 
negative tumors, the combination yielded the best PFS (median 11.2 v. 5.3 months in the nivolumab 
arm), and response rate (54.8%, 41.3% nivolumab, 17.8% ipilimumab). Treatment-related Grade 
3 or 4 AEs occurred more commonly in the combination arm (55%) compared to nivolumab alone 
(16.3%) or ipilimumab (27.3%). The most common severe events in the combination arm were 
diarrhea (44%), fatigue (35%) and pruritus (33%). Investigators deemed the safety profile of the 
combination greater than either single agent but still manageable. (7) 
 
A recent report from a Phase I/II study of nivolumab plus ipilimumab in small cell lung cancer 
suggests higher response rates with combination therapy, 32.6% versus 18% with nivolumab 
alone. (8) Other reports of significant activity with combination therapy have also emerged from 
early phase trials in NSCLC, including a Phase I combination study of tremelimumab with 
MEDI4736 (Durvalumab) (PD-L1 inhibitor), demonstrating a 33% response rate in those with PD-
L1 expressing tumors and a 27% response rate in those with PD-L1 negative tumors. (9)   
 
Based on these data, a trial examining whether the addition of CTLA-4 blockade to PD-L1 blockade 
would improve outcome in the growing population of advanced squamous patients that progress 
on second-line PD-1 checkpoint inhibitor therapy would be appropriate. MEDI4736 (Durvalumab) 
is a human IgG1 monoclonal antibody that inhibits PD-L1 binding without induction of antibody-
dependent cellular nor complement-dependent cytotoxicity, has shown clinical activity and safety 
across a range of solid tumors, including NSCLC. Tremelimumab, an IgG2 monoclonal antibody 
targeting CTLA-4 (CD152), has also shown activity across solid tumors including mesothelioma 
with manageable toxicity. A Phase I combination study of these two agents, both being developed 
by AstraZeneca, has been completed demonstrating efficacy and manageable toxicity at the 
recommended Phase III dose. (10)  
 
Clinical Summary 
 
Study D4190C00006, a Phase Ib dose-escalation and dose-expansion study of MEDI4736 
(Durvalumab) in combination with tremelimumab in patients with advanced NSCLC, included 
patients with ECOG performance status of 0-1, and no more than three prior lines of metastic 
therapy. Two dosing schedules were evaluated using Q4W and alternative Q2W dosing. As of 
6/1/15, a total of 102 patients have been treated in the study across 5 US centers with a median 
follow-up of 18.8 weeks (range 2-68). Dosing cohorts are detailed below: 
 
D=MEDI4736 (Durvalumab); T=Tremelimumab; q#w=every # weeks; D#, T#= # mg/kg of each 
drug 
 

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As of 6/1/15, adverse events deemed related to protocol therapy led to treatment discontinuation 
in 28% of patients (29/102). Three treatment-related deaths occurred, include a case of polymositis 
(D10/T1), pericardial effusion (D20/T1) and myasthenia gravis/neuromuscular disorder (D20/T3). 
Adverse events were considered related to treatment in 82 patients (80%) and are presented in the 
table below. The majority of these events were <Grade 3 with Grade ≥3 events reported in 43 
patients (42%).  (11) Grade 1 and 2 AEs have been managed clinically without requiring dose 
modifications or delays. Grade 3 treatment-related AEs have been manageable and reversible with 
standard toxicity management guidelines, including steroids, with the exception of Patient 
2000062006 who experienced myasthenia gravis and polymyositis. 
 
 
 
  
As of 2/20/15, MEDI4736 (Durvalumab) PK (n = 55) and tremelimumab PK (n = 26) data were 
available from 10 cohorts following MEDI4736 (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 MEDI4736 (Durvalumab) and tremelimumab was observed. While steady state PK parameters 
were based on a limited number of patients, the observed PK exposures of MEDI4736 
(Durvalumab) and tremelimumab in combination were consistent with monotherapy data of each 
agent, indicating no PK interaction. 
 
As of 2/20/15, ADA data were available from 60 patients for MEDI4736 (Durvalumab) and 53 
patients for tremelimumab in Study D4190C00006. Four of 60 patients were ADA positive for 
anti-MEDI4736 (Durvalumab) antibodies and 1 of 53 for anti-tremelimumab antibodies post 
treatment. There was no clear relationship between ADA and safety, efficacy nor dose of either 
agent. 
 
Efficacy updates are available from the 2015 Annual Meeting of the Society for Immunotherapy of 
Cancer (data cut-off 6/1/15). (12) Of 84 response evaluable patients, 21 (25%) had confirmed or 
unconfirmed response to therapy. In those with PD-L1 expression in ≥ 25% of cells, responses 
were seen in 35% (7/20). In those with PD-L1 expression in 1-24% of cells, responses were seen 
in 22% and in those with PD-L1 negative tumors, responses were seen in 33% (9/27). Median time 
to response was 7.1 weeks (range 5.0 -37.4), with a median duration of 16.7 weeks (0.1-49.1). At 
data cut-off on 6/1/15, responses were ongoing in 14 of 21 patients (66%).  
 

Appended 4/12/17 
S1400F 
 
Page 10 
 
  Version Date 10/21/19 
 
The dose recommended for Phase III was MEDI4736 (Durvalumab) 20 mg/kg q4weeks plus 
tremelimumab 1 mg/kg q4weeks, based on aggregate safety, PK, PD and efficacy data. No dose-
limiting toxicities were reported.  Efficacy data suggested that the 20 mg/kg MEDI4736 
(Durvalumab) + 1 mg/kg tremelimumab dose cohort may demonstrate equivalent clinical activity to 
other dose combinations. The response rate in all patients treated with tremelimumab 1 mg/kg was 
28% (11/39), similar to the 25% overall response rate across doses. In those with ≥ 25% PD-L1+ 
tumors, responses were seen in 3/9 (33%), 1-24% PD-L1 positive tumors, the response rate was 
26% (6/23) and in those with PD-L1 negative tumors, half experienced tumor response (6/12). 
 
Fixed dosing for MEDI4736 (Durvalumab) and tremelimumab has been recommended by 
AstraZeneca for patients with >30 kg body weight. This is based on population PK models for each 
agent indicating similar steady stage PK concentrations with less inter-subject variability with fixed 
dosing regimens. Based on an average body weight of 75 kg, the fixed dose of MEDI4736 
(Durvalumab) 1500 mg q4weeks is recommended (equivalent to 20 mg/kg q4weeks). Similarly, 75 
mg q4weeks of tremelimumab (equivalent to 1 mg/kg q4 weeks) is recommended.  
 
Four cycles of combination MEDI4736 (Durvalumab)/tremelimumab are proposed, followed by 
MEDI4736 (Durvalumab) monotherapy until disease progression. This is based on melanoma data 
suggesting that patients responding to CTLA-4 inhibitor ipilimumab appear to derive long-term 
benefit with 22% of patients alive at 3 years. Other PD-1 targeting agents have been developed 
with protocol-mandated drug discontinuation after a specified treatment period. Despite stopping 
drug, ongoing prolonged responses have been described across multiple studies of multiple PD-
1/PD-L1 inhibitors, including combination nivolumab and ipilimumab. (13) 
 
Sub-study S1400I tests whether combination CTLA-4 and PD-1 checkpoint inhibition will improve 
outcomes compared to PD-1 checkpoint inhibition alone in unmatched squamous patients as 
second-line therapy. By contrast, in the current sub-study S1400F, we hypothesize that a subgroup 
of patients that do not respond to single PD-1 checkpoint inhibition may benefit from combination 
checkpoint blockade, specifically the addition of a CTLA-4 inhibitor to ongoing PD-1 inhibitor 
therapy. Given the growing population of patients that will develop cancer progression during PD-
1 checkpoint blockade monotherapy, the proposed study design of adding CTLA-4 inhibition in this 
population to ongoing PD-1 inhibition is novel and appropriate. As outlined in Section 3.1, the 
combination of MEDI4736 (Durvalumab) and tremelimumab has shown activity and manageable 
toxicity, and is worthy of further study in this setting. It will also offer an opportunity to explore 
potential markers of benefit and/or toxicity. 
 
HIV, HBV, and HCV Exclusion Rationale 
 
Patients with known HIV/HBV/HCV infection will be excluded from this study.  Immune checkpoint 
inhibition is a relatively new class of therapy.  While HIV patients have been studied with anti-CTLA-
4 therapy, the unique interactions of PD-1/PD-L1 inhibitors and HIV may be difficult to predict and 
require further study.  Since many of these patients may already be highly suppressed with 
antiretroviral therapy, standard assays may not be sensitive enough to detect a safety signal of 
increasing viral load.  Thus, these patients may need to be studied in trials with access to such 
sensitive assays to better inform drug development in this particular population.  The impact of PD-
1/PD-L1 inhibition in HIV patients may be beneficial, which is of great interest in drug development 
in the field of chronic infections generally.  We have elected not to complicate our trial with this 
added and important question at this time. 
 
 

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Appended 4/12/17 
S1400F 
 
Page 12 
 
  Version Date 10/21/19 
 
 
Version 2.4, April 17, 20191 
 
 Adverse Events with Possible  
 Relationship to MEDI4736 (durvalumab) 
 (CTCAE 5.0 Term) 
[n= 2833] 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Blood and 
lymphatic system 
disorders - Other 
(idiopathic 
thrombocytopenic 
purpura)2 
 
 
Thrombotic 
thrombocytopenic 
purpura2 
CARDIAC DISORDERS 
 
 
Myocarditis2 
 
 
Pericarditis2 
ENDOCRINE DISORDERS 
 
 
Adrenal 
insufficiency2 
 
 
Endocrine 
disorders - Other 
(diabetes 
insipidus) 
 
 
Endocrine 
disorders - Other 
(diabetes mellitus 
type 1)2 
 
Hyperthyroidism2 
 
 
 
Hypopituitarism2 
 
Hypothyroidism2 
 
EYE DISORDERS 
 
 
Keratitis2 
 
 
Uveitis2 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
 
Colitis2 
 
Diarrhea 
 
 
 
Gastrointestinal 
disorders -Other - 
(gastrointestinal 
perforation)2,3 
 
Nausea 
 
 
 
Pancreatitis2 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Edema limbs 
 
 
Fatigue 
 
 
Fever 
 
HEPATOBILIARY DISORDERS 

Appended 4/12/17 
S1400F 
 
Page 13 
 
  Version Date 10/21/19 
 
 
 Adverse Events with Possible  
 Relationship to MEDI4736 (durvalumab) 
 (CTCAE 5.0 Term) 
[n= 2833] 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
 
Hepatobiliary 
disorders - Other 
(autoimmune 
hepatitis)2 
IMMUNE SYSTEM DISORDERS 
 
 
Immune system 
disorders - Other 
(immune related 
adverse events)2 
 
 
Immune system 
disorders - Other 
(sarcoidosis) 
INFECTIONS AND INFESTATIONS 
 
Infection4 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
Infusion related 
reaction 
INVESTIGATIONS 
 
Alanine 
aminotransferase 
increased2 
 
 
Aspartate 
aminotransferase 
increased2 
 
 
Creatinine 
increased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthritis2 
 
 
 
Musculoskeletal 
and connective 
tissue disorder - 
Other 
(polymyositis)2 
 
Myalgia 
  
 
 
Myositis2 
NERVOUS SYSTEM DISORDERS 
 
 
Guillain-Barre 
syndrome2,5 
 
 
Myasthenia 
gravis2 
 
 
Nervous system 
disorders - Other 
(aseptic 
meningitis)2 
 
 
Peripheral sensory 
neuropathy 
RENAL AND URINARY DISORDERS 

Appended 4/12/17 
S1400F 
 
Page 14 
 
  Version Date 10/21/19 
 
 
 Adverse Events with Possible  
 Relationship to MEDI4736 (durvalumab) 
 (CTCAE 5.0 Term) 
[n= 2833] 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
Dysuria 
 
 
 
Renal and urinary 
disorders - Other 
(autoimmune 
nephritis)2 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Cough 
 
 
 
Dyspnea 
 
 
Pneumonitis2 
 
 
Respiratory, 
thoracic and 
mediastinal 
disorders - Other 
(dysphonia) 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 Hyperhidrosis 
 
 
Pruritus 
 
 
Rash2,6  
 
 
 
Skin and 
subcutaneous 
tissue disorders - 
Other 
(scleroderma) 
 
 
Skin and 
subcutaneous 
tissue disorders - 
Other (severe 
dermatitis)2,7 
 
Skin 
hypopigmentation 
 
 
NOTE: Cardiomyopathy, and graft versus host disease, while not 
observed on clinical trials of MEDI4736 (durvalumab) at this time, are 
known events with this class of agent (PD-L1 antagonist). 
 
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2 Immune-mediated adverse reactions (irAEs) have been reported in 
patients receiving MEDI4736 (durvalumab).  irAEs can involve any of 
the organs or systems in the body.  Most irAEs were reversible and 
managed with interruptions of MEDI4736 (durvalumab), administration 
of corticosteroids and supportive care, however, these events can be 
serious and fatal. 
 

Appended 4/12/17 
S1400F 
 
Page 15 
 
  Version Date 10/21/19 
 
3 Gastrointestinal perforations have been observed only in patients 
receiving MEDI4736 (durvalumab) in combination with tremelimumab 
(CP-675,206). 
 
4 Infections includes infection in the lungs, upper respiratory tract, dental 
and oral soft tissues and other organs under the INFECTIONS AND 
INFESTATIONS SOC.  Infections generally are mild (Gr 1-2) but severe 
infections including sepsis, necrotizing fasciitis, and osteomyelitis have 
been reported. 
 
5 Guillain-Barre Syndrome has been reported in patients receiving 
MEDI4736 (durvalumab) in combination with tremelimumab (CP-
675,206) but can potentially occur after durvalumab monotherapy.  
 
6Rash includes the terms: rash erythematous, rash generalized, rash 
macular, rash maculopapular, rash papular, rash pruritic, rash pustular, 
erythema, and eczema. 
 
7 In rare cases, severe dermatitis has been reported to manifest as 
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rashes 
complicated by dermal ulceration or necrotic, bullous, or hemorrhagic 
manifectations. 
 
Adverse events reported on MEDI4736 (durvalumab) trials, but for 
which there is insufficient evidence to suggest that there was a 
reasonable possibility that MEDI4736 (durvalumab) caused the 
adverse event:  
 
BLOOD 
AND 
LYMPHATIC 
SYSTEM 
DISORDERS 
- 
Anemia; 
Disseminated intravascular coagulation 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders 
- Other (coronary artery disease); Pericardial effusion; Pericardial 
tamponade; Restrictive cardiomyopathy; Right ventricular dysfunction; 
Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired 
EYE DISORDERS - Eye disorders - Other (choroidal effusion with shut 
down of ciliary body) 
GASTROINTESTINAL DISORDERS - Ascites; Constipation; Dental 
caries; Gastrointestinal disorders - Other (gastrointestinal hemorrhage); 
Mucositis 
oral; 
Proctitis; 
Small 
intestinal 
obstruction; 
Upper 
gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Edema trunk; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic hemorrhage 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other 
(drug-induced liver injury); Serum sickness 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Wound 
complication 
INVESTIGATIONS - Blood bilirubin increased; CPK increased; 
Electrocardiogram T wave abnormal; GGT increased; Lipase increased; 
Lymphocyte count decreased; Neutrophil count decreased; Platelet count 
decreased; Serum amylase increased; Weight loss; White blood cell 
decreased 

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S1400F 
 
Page 19 
 
  Version Date 10/21/19 
 
2. 
Distribution: Following an IV infusion, tremelimumab exhibits a biphasic 
pharmacokinetics with the mean systemic exposure parameters 
(maximum concertation [Cmax] and area under the plasma concentration-
time curve [AUC]) increase in an approximately dose-proportional manner.  
 
Tremelimumab mean volume of distribution at steady state (Vss) is 
81.2mL/kg.  This is typical of mAbs with limited distribution.  To date, the 
human tissue distribution of tremelimumab has not been studied. 
 
3. 
Metabolism: Tremelimumab is likely to be cleared from circulation by 
endothelial cell uptake and proteolysis.  
 
4. 
Elimination: The mean clearance for tremelimumab is 0.132 mL/hour/kg 
and the terminal-phase half-life is 22.1 days. Since mAbs are not primarily 
cleared via hepatic/renal pathways, no impact of renal/hepatic functions is 
expected on tremelimumab elimination. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Adverse Effects: 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system. Frequency is provided based on 1642 patients.  Below is the 
CAEPR for tremelimumab (CP-675,206). 
 
Version 2.1, March 25, 20191 
 
 Adverse Events with Possible  
 Relationship to Tremelimumab (CP-675,206) 
 (CTCAE 5.0 Term) 
[n= 1642] 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia2 
 
CARDIAC DISORDERS 
 
 
Myocarditis3 
ENDOCRINE DISORDERS 
 
Adrenal insufficiency2  
 
Endocrine disorders - 
Other (thyroiditis)2 
 
 
Hyperthyroidism2 
 
 
Hypophysitis2 
 
 
Hypothyroidism2 
 
EYE DISORDERS 
 
Uveitis 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
Colitis2 
 
Diarrhea 
 
 
 
 
Enterocolitis2 

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Page 20 
 
  Version Date 10/21/19 
 
 
 
Gastrointestinal disorders 
- Other (intestinal 
perforation)2  
 
Nausea 
 
 
 
Pancreatitis2 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Edema limbs 
 
 
Fatigue 
 
 
Fever 
 
HEPATOBILIARY DISORDERS 
 
 
Hepatobiliary disorders - 
Other (autoimmune 
hepatitis)2  
IMMUNE SYSTEM DISORDERS 
 
 
Anaphylaxis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Infusion related 
reaction 
 
INVESTIGATIONS 
 
Alanine 
aminotransferase 
increased2 
 
 
Aspartate 
aminotransferase 
increased2 
 
 
Lipase increased2 
 
 
Lymphocyte count 
decreased2 
 
 
Neutrophil count 
decreased2 
 
 
Platelet count 
decreased2 
 
 
Serum amylase 
increased2 
 
 
White blood cell 
decreased2 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Dehydration 
 
 
Hypokalemia 
 
 
 
Metabolism and nutrition 
disorders - Other 
(diabetes mellitus) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthritis2 
 
 
 
Musculoskeletal and 
connective tissue 
disorders - Other 
(Sjogren's syndrome) 
NERVOUS SYSTEM DISORDERS 
 
 
Guillain-Barre syndrome2 
 
Headache2 
 
 
 
Myasthenia gravis2,4  

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Page 21 
 
  Version Date 10/21/19 
 
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2 Immune-related adverse events may occur in any organs including but 
not limited to the events listed in CAEPR table. 
3 Myocarditis has been reported with other anti-CTLA4 agents; however, 
it has not yet been observed in clinical trials of tremelimumab (CP-
675,206). 
4 Myasthenia gravis was observed in trials of tremelimumab in 
combination with durvalumab. 
 
Adverse events reported on tremelimumab (CP-675,206) trials, but 
for which there is insufficient evidence to suggest that there was a 
 
 
Nervous system disorders 
- Other (encephalitis)2 
 
Peripheral motor 
neuropathy2 
 
 
Peripheral sensory 
neuropathy2 
 
RENAL AND URINARY DISORDERS 
 
Acute kidney injury 
 
 
  
Nephrotic syndrome2 
 
Renal and urinary 
disorders - Other 
(autoimmune 
nephritis)2 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
 
Dyspnea 
 
 
Pneumonitis2 
 
 
Respiratory, thoracic 
and mediastinal 
disorders - Other 
(interstitial lung 
disease)2  
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Dry skin2 
 
Pruritus 
 
 
Rash maculo-papular2 
 
 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(cutaneous scleroderma-
like syndrome) 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(Grover's disease) 
 
Skin 
hypopigmentation 
 
 
Urticaria2 
 
VASCULAR DISORDERS 
 
 
Vascular disorders - 
Other (giant cell temporal 
arteritis)2 

Appended 4/12/17 
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Page 22 
 
  Version Date 10/21/19 
 
reasonable possibility that tremelimumab (CP-675,206) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Eosinophilia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Endocrine disorders - Other (Graves' 
disease with ophthalmopathy) 
GASTROINTESTINAL DISORDERS - Constipation; Dyspepsia; Gastritis; 
Gastrointestinal disorders - Other (diverticulitis); Ileus; Mucositis oral; 
Rectal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Malaise; Pain; Sudden death NOS 
INFECTIONS AND INFESTATIONS - Conjunctivitis; Infections and 
infestations - Other (oral herpes); Lung infection; Sepsis 
INVESTIGATIONS - GGT increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; 
Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Arthralgia; Generalized muscle weakness; Myalgia 
NERVOUS SYSTEM DISORDERS - Dizziness; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Depression; Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Pleural effusion; Respiratory, thoracic and mediastinal disorders - Other 
(asthma) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; 
Hyperhidrosis; Rash acneiform 
VASCULAR DISORDERS - Flushing; Hypertension; Thromboembolic 
event; Vascular disorders - Other (hemorrhage); Vasculitis 
 
Note: Tremelimumab (CP-675,206) in combination with other agents 
could cause an exacerbation of any adverse event currently known to be 
caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
2. 
Pregnancy and Lactation: In an embryo-fetal toxicity study in primates, 
tremelimumab did not result maternal toxicity, developmental toxicity, or 
teratogenicity.  
 
The effects of tremelimumab on a pregnant woman or human fetus have 
not been studied, and information on the safety for women of childbearing 
potential or for pregnant women cannot be derived from the existing 
clinical data.  Guidance on contraception and on avoidance of egg or 
sperm collection is provided in the Investigator’s Brochure. 
 
The levels of tremelimumab in breast milk have not been analyzed. Since 
tremelimumab is a mAb of the IgG2a type and it could potentially be 
secreted in breast milk, breastfeeding should be avoided. 
 
3. 
Drug Interactions: To date, no formal drug-drug interaction studies have 
been conducted with tremelimumab. In renal cell carcinoma studies, acute 
renal failure has been reported with the combination of tremelimumab and 
sunitinib. It is unknown whether a similar reaction will be observed when 
tremelimumab is combined with other tyrosine kinase inhibitors.  
 
d. 
DOSING & ADMINISTRATION 

Appended 4/12/17 
S1400F 
 
Page 23 
 
  Version Date 10/21/19 
 
 
See Section 7.0 Treatment Plan 
 
Tremelimumab is administered intravenously into a peripheral or central vein 
using an IV bag containing 0.9% sodium chloride or 5% dextrose and a 0.2 or 
0.22-μm in-line filter.  Standard infusion time is 60 minutes (± 5 minutes).  Less 
than 55 minutes is considered a deviation.  In the event that there are interruptions 
during infusion, the total allowed infusion time should not exceed 8 hours at room 
temperature.   
 
Flush the IV line at the completion of the infusion with a volume of diluent equal 
to the priming volume of the infusion set used to ensure the full dose is 
administered and document if the line was not flushed. 
 
Monitoring of Dose Administration: Patients will be monitored during and after the 
infusion with assessment of vital signs. 
  
As with any antibody, allergic reactions to dose administration are 
possible.  Appropriate drugs and medical equipment to treat acute anaphylactic 
reactions must be immediately available, and study personnel must be trained to 
recognize and treat anaphylaxis.  The study site must have immediate access to 
emergency resuscitation teams and equipment in addition to the ability to admit 
patients to an intensive care unit if necessary. 
 
e. 
HOW SUPPLIED 
 
1. 
Tremelimumab is supplied free of charge by AstraZeneca, Inc. and 
distributed by the CTEP, DCTD, NCI 
 
2. 
Tremelimumab is formulated at 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 dihydrate (EDTA), pH 5.5. It is 
provided in a 20-mL clear glass vials with an elastomeric stopper and 
aluminum seal. Each vial contains 400 mg (nominal) of active 
investigational product.  
 
f. 
STORAGE, PREPARATION & STABILITY 
 
Storage and Stability:  
 
Store unopened tremelimumab vials refrigerated at 2°C to 8°C (36°F to 46°F). 
Tremelimumab vials should be stored in original packaging.  Do not freeze. 
 
Total time from needle puncture of the tremelimumab vial to the start of 
administration should not exceed:  
4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 46°F) 
 
Infusion solution must be allowed to equilibrate to room temperature prior to 
commencement of administration. In the event that either preparation time or 
infusion time exceeds the time limits a new dose must be prepared from new vials.  
Tremelimumab does not contain preservatives, and any unused portion must be 
discarded.   
 
If a storage temperature excursion is identified, promptly return (tremelimumab or 
MEDI4736) to between 2-8°C and quarantine the supplies.  Provide a detailed 
report of the excursion (including documentation of temperature monitoring and 

Appended 4/12/17 
S1400F 
 
Page 24 
 
  Version Date 10/21/19 
 
duration of the excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability. 
 
Preparation of Tremelimumab: 
 
Sites should follow standard and local aseptic procedures and the clinical study 
protocol for all activities. All dispensing activities should be documented according 
to local procedures.  
 
Withdraw the required volume of tremelimumab from the vial(s) and further dilute 
in an IV bag containing 0.9% sodium chloride or 5% dextrose to obtain a final 
concentration of 0.10 to 10 mg/mL.  The IV bag should be administered with a 0.2 
or 0.22 μm in-line filter.  Infusion bags must be latex-free and can be made of 
polyvinyl chloride (PVC) or polyolefins (e.g., polyethylene), manufactured with bis 
(2-ethylhexyl) phthalate (DEHP) or DEHP free. 
 
3.3 
DRUG ORDERING & ACCOUNTABILITY 
 
a. 
Drug ordering: Sites may order initial agent supplies when a subject has been 
registered.  Starter supplies will not be provided.  NCI-supplied agents may be 
requested by eligible participating Investigators (or their authorized designee) at 
each participating institution.  The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents.  The eligible participating 
investigators at each participating institution must be registered with CTEP, DCTD 
through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there 
are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
participating investigator at that institution. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status.  For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to agent 
management. 
 
1. 
Drug Handling and Accountability 
 
a. 
Drug Accountability: The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of 
the receipt, disposition, and return of all drugs received from the 
PMB using the Drug Accountability Record Form available on the 
NCI home page (http://ctep.cancer.gov). 
 
b. 
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI DARF. 
 
2. 
Drug Return and/or Disposition Instruction 
 
a. 
Drug Returns: All unused drug supplies must be returned to the 
PMB. When it is necessary to return study drug (e.g., sealed 
bottles remaining when PMB sends a stock recovery letter), 
investigators should return the study drug to the PMB using the 

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Appended 4/12/17 
S1400F 
 
Page 33 
 
  Version Date 10/21/19 
 
Toxicity 
Dose Interruptions 
Toxicity Management 
> Grade 3 
Discontinue protocol 
therapy and remove 
from protocol 
therapy. 
 
severe (Grade ≥3) events promptly start prednisone PO 1-
2mg/kg/day or IV equivalent  
- If symptoms recur or worsen during corticosteroid tapering 
(> 28 days of taper), increase the corticosteroid dose 
(prednisone dose  [e.g. up to 2-4mg/kg/day PO or IV 
equivalent]) until stabilization or improvement of symptoms, 
then resume corticosteroid tapering (> 28 days) at a slower 
rate   
- More potent immunosuppressives such as TNF inhibitors 
(e.g. infliximab, also refer to the individual sections of the 
immune-related adverse event for specific type of 
immunosuppressive) should be considered for events not 
responding to systemic steroids.   
- Discontinuation of study drug is not mandated for Grade 3 / 
Grade 4 inflammatory reactions attributed to local tumor 
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 
- Patients with endocrinopathies who may require prolonged 
or continued steroid replacement can be retreated with 
study drug/study regimen on the following conditions: 1) the 
event stabilizes and is controlled, 2) the patient is clinically 
stable as per Investigator or treating physician’s clinical 
judgement, and 3) doses of prednisone are at less than or 
equal to 10mg/day or equivalent. 
 
 

Appended 4/12/17 
S1400F 
 
Page 34 
 
  Version Date 10/21/19 
 
Toxicity 
Dose Interruptions 
Toxicity Management 
Pneumonitis/ Interstitial Lung Disease (ILD) 
Any Grade 
 
- Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests including other diagnostic procedures as 
described below 
‒ Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up and high-resolution CT scan. 
Grade 1 
No dose 
modifications 
However, consider 
holding study 
drug/study regimen 
dosing as clinically 
appropriate and 
during diagnostic 
work-up for other 
etiologies. 
 (Radiographic Changes Only) 
- Monitor and closely follow up in 2-4 days for clinical 
symptoms, pulse oximetry (resting and exertion) and 
laboratory workup and then as clinically indicated 
- Consider Pulmonary and Infectious disease consult 
 
Grade 2 
Hold protocol therapy 
until resolution to ≤ 
Grade 1 and after 
completion of steroid 
taper then resume 
protocol therapy 
administration at next 
scheduled dose. 
 
- If toxicity worsens 
then treat as ≥ 
Grade 3  
 
  
- Monitor symptoms daily and consider hospitalization 
- Promptly start systemic steroids (e.g., prednisone 1-2 
mg/kg/day PO or IV equivalent) 
- Reimaging as clinically indicated 
- If no improvement within 3-5 days, additional workup should 
be considered and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started  
- If still no improvement within 3-5 days despite IV 
methylprednisolone at 2-4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors (e.g. 
infliximab at 5 mg/kg every 2 weeks). 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, antifungal or anti PCP 
treatment (refer to current NCCN guidelines for treatment of 
cancer-related infections)  
- Consider pulmonary and infectious disease consult 
- Consider as necessary after discussing with Study Chair 
> Grade 3 
Permanently 
discontinue protocol 
therapy and remove 
from protocol 
therapy. 
- Promptly initiate empiric IV methylprednisolone 1 to 4 
mg/kg/day or equivalent   
- Obtain Pulmonary and iInfectious disease consult; consider, 
as necessary, discussing with study physician. 
- Hospitalize the patient 
- Supportive Care (oxygen, etc.) 
- If no improvement within 3-5 days, additional workup should 
be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors (e.g. 
infliximab at 5 mg/kg every 2 weeks dose) started. Caution: 
rule out sepsis and refer to infliximab label for general 
guidance before using infliximab  
- Once 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 

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Toxicity 
Dose Interruptions 
Toxicity Management 
Diarrhea/ Colitis 
Any Grade 
 
 
- Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes 
in bowel habits such as increased frequency over baseline 
or blood in stool) or related to bowel perforation (such as 
sepsis, peritoneal signs and ileus) 
- Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, infections including testing for clostridium 
difficile toxin, etc.) 
- Steroids should be considered  in the absence of clear 
alternative etiology, even for low grade events, in order to 
prevent potential progression to higher grade event 
- Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis 
Grade 1 
No dose 
modifications 
- Close monitoring for worsening symptoms 
- Consider symptomatic treatment including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use of 
probiotics as per treating physician’s clinical judgment. 
Grade 2 
Hold protocol therapy 
until resolution to ≤ 
Grade 1 and after 
completion of steroid 
taper then, resume 
protocol therapy 
administration at next 
scheduled dose. 
 
- Consider symptomatic treatment including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide 
- Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent  
- If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day PO or IV equivalent, GI consult 
should be obtained for consideration of further workup such 
as imaging and/or colonoscopy to confirm colitis and rule out 
perforation, and prompt treatment with IV methylprednisolone 
2-4mg/kg/day started.  
- If still no improvement within 3-5 days despite 2-4 mg/kg IV 
methylprednisolone, promptly start immunosuppressives 
such as (infliximab at 5mg/kg once every 2 weeks).  Caution: 
Important to rule out bowel perforation and refer to infliximab 
label for general guidance before using infliximab   
- Consider consulting study physician if no resolution to ≤ 
Grade 1 in 3-4 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) 
Grade 3  
Hold protocol therapy 
until resolution to ≤ 
Grade 1 and after 
completion of steroid 
taper then, resume 
protocol therapy 
administration at next 
scheduled dose. 
If resolution to ≤ 
Grade 1 does not 
occur within 14 days, 
- Promptly initiate empiric IV methylprednisolone 2 to 4 
mg/kg/day or equivalent  
- Monitor stool frequency and volume and maintain hydration   
- Urgent GI consult and imaging and/or colonoscopy as 
appropriate 
- If still no improvement within 3-5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (e.g. infliximab at 5 mg/kg 
once every 2 weeks).   

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permanently 
discontinue protocol 
therapy. 
- Caution: Ensure GI consult to rule out bowel perforation and 
refer to infliximab label for general guidance before using 
infliximab.  
- Once improving, gradually taper steroids over ≥28 day and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current  NCCN guidelines for 
treatment of  cancer-related infections) 
> Grade 4 
Permanently 
discontinue protocol 
therapy and remove 
from protocol therapy. 
 

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Toxicity 
Dose Interruptions 
Toxicity Management 
Hepatitis (Elevated LFTs) 
Any Grade 
 
- Monitor and evaluate liver function test: AST, ALT, ALP and 
total bilirubin  
- Evaluate for alternative etiologies (e.g., viral hepatitis, 
disease progression, concomitant medications) 
Grade 1 
(Based on 
ULN 
regardless of 
baseline LFT) 
No dose 
modifications 
- Continue LFT monitoring per protocol 
Grade 2 
(Based on 
ULN 
regardless of 
baseline LFT)  
Hold protocol therapy 
until resolution to ≤ 
Grade 1 or baseline 
and after completion 
of steroid taper then 
resume protocol 
therapy 
administration at next 
scheduled dose. 
 
 
‒ 
Regular and frequent checking of LFTs (e.g. every 1-2 
days) until elevations of these are improving or resolved.   
‒ 
If no resolution to ≤ Grade 1 in 1-2 days, consider 
discussing with study physician. 
‒ 
If event is persistent (> 3-5 days) or worsens, promptly 
start prednisone 1-2 mg/kg/day PO or IV equivalent.  
‒ 
If still no improvement within 3-5 days despite 1-2 
mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and prompt treatment with IV 
methylprednisolone at 2-4 mg/kg/day started. 
‒ If still no improvement within 3-5 days despite 2-4 
mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e.mycophenolate mofetil). Discuss 
with Study Chair if mycophenolate mofetil is not available.  
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). 
Grade 3 
(Based on 
ULN 
regardless of 
baseline LFT)  
For elevated 
transaminases, ≤ 8x 
ULN or bilirubin ≤5x 
ULN, hold protocol 
therapy until 
resolution to ≤ Grade 
1 or baseline and 
after completion of 
steroid taper. 
Resume protocol 
therapy 
administration at next 
scheduled dose. 
If resolution to ≤ 
Grade 1 or baseline 
does not occur within 
14 days, permanently 
discontinue protocol 
therapy. 
For elevated 
transaminases > 8× 
ULN or bilirubin >5x 
ULN, permanently 
discontinue protocol 
therapy. Permanently 
discontinue study 
‒ 
Promptly initiate empiric IV methylprednisolone at 1 to 4 
mg/kg/day or equivalent  
‒ 
If still no improvement within 3-5 days despite 1 to 4 
mg/kg/day methylprednisolone IV or equivalent , promptly 
start treatment with immunosuppressive therapy 
(i.e.mycophenolate mofetil)  Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used. 
‒ 
Hepatology consult, abdominal workup, 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. 

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Toxicity 
Dose Interruptions 
Toxicity Management 
Hepatitis (Elevated LFTs) 
drug/study regimen 
for any case meeting 
Hy’s law criteria (AST 
and/or ALT > 3x ULN 
+ bilirubin > 2x ULN 
without initial findings 
of cholestasis (i.e. 
elevated alkaline 
P04) and in the 
absence of any 
alternative cause. 
Grade 4 
(Based on 
ULN 
regardless of 
baseline LFT)  
Permanently 
discontinue protocol 
therapy. 
 
 
Toxicity 
Dose Interruptions 
Toxicity Management 
Hepatitis (Elevated LFTs) - 
Hepatitis 
Infliximab should not be used for management of immune-
related hepatitis 
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing 
total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if >ULN at baseline) or signs 
of DILI/liver decompensation (e.g., fever, elevated INR): 
- 
Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise 
- 
Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise 
- 
Grade 3-4: Permanently discontinue study drug/study regimen 
Any 
Grade 
 
- Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 
- Evaluate for alternative etiologies (e.g., viral hepatitis, 
disease progression, concomitant medications, worsening of 
liver cirrhosis [e.g., portal vein thrombosis]). 
- For HBV+ patients: evaluate quantitative HBV viral load, 
quantitative HBsAg, or HBeAg 
- For HCV+ patients: evaluate quantitative HCV viral load 
- Consider consulting hepatologist/Infectious disease specialist 
regarding change/implementation in/of antiviral medications 
for any patient with an elevated HBV viral load >2000 IU/ml 
- Consider consulting hepatologist/Infectious disease specialist 
regarding change/implementation in/of antiviral HCV 
medications if HCV viral load increased by ≥2-fold 
For HCV+ with HBcAB+: Evaluate for both HBV and HCV as 
above 
Grade 2 
Hold protocol therapy 
until resolution to ≤ Grade 
1 or baseline and after 
completion of steroid 
taper then resume 
protocol therapy 
administration at next 
scheduled dose. 
- Regular and frequent checking of LFTs (e.g., every 1 to 3 
days) until elevations of these are improving or resolved. 
- Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver perfusion. 
- Consider, as necessary, discussing with study physician. 
- If event is persistent (>3 to 5 days) or worsens, and 
investigator suspects toxicity to be immune-mediated AE, 

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Toxicity 
Dose Interruptions 
Toxicity Management 
Hepatitis (Elevated LFTs) - 
Hepatitis 
Infliximab should not be used for management of immune-
related hepatitis 
recommend to start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
- If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and treatment with IV methylprednisolone 
2 to 4 mg/kg/day. 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, consider additional 
abdominal workup (including liver biopsy) and imaging (i.e., liver 
ultrasound), and consider starting immunosuppressives (i.e., 
mycophenolate mofetil). Discuss with study physician if 
mycophenolate mofetil is not available. Infliximab should NOT 
be used. 
Grade 3 
Hold protocol therapy 
until resolution to ≤ Grade 
1 and after completion of 
steroid taper then, 
resume protocol therapy 
administration at next 
scheduled dose. 
If resolution to ≤ Grade 1 
does not occur within 14 
days, permanently 
discontinue protocol 
therapy 
Permanently discontinue 
study drug/study regimen 
for any case meeting Hy’s 
law criteria, in the 
absence of any 
alternative cause 
- Regular and frequent checking of LFTs (e.g., every 1-2 days) 
until elevations of these are improving or resolved. 
- Consult hepatologist (unless investigator is hepatologist); 
obtain abdominal ultrasound, including Doppler assessment 
of liver perfusion; and consider liver biopsy. 
- Consider, as necessary, discussing with study physician. 
- If investigator suspects toxicity to be immune-mediated, 
promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
- If no improvement within 3 to 5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, obtain liver biopsy (if it 
has not been done already) and promptly start treatment with 
immunosuppressive therapy (mycophenolate mofetil). 
Discuss with study physician if mycophenolate is not 
available. Infliximab should NOT be used. 
- Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections 
Grade 4 
Permanently discontinue 
protocol therapy. 
 
 

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Toxicity 
Dose Interruptions 
Toxicity Management 
Nephritis or Renal Dysfunction (Elevated Serum Creatinine) 
Any Grade 
 
- Consult with Nephrologist 
- Monitor for signs and symptoms that may be related to 
changes in renal function (e.g. routine urinalysis,  elevated 
serum BUN and creatinine, decreased creatinine 
clearance, electrolyte imbalance, decrease in urine output, 
proteinuria, etc.)  
- Thoroughly evaluate to rule out any alternative etiology 
(e.g., disease progression, infections etc.) 
‒ Steroids should be considered in the absence of clear 
alternative etiology even for low grade events (Grade 2), in 
order to prevent potential progression to higher grade 
event 
Grade 1 
No dose 
modifications 
‒ 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 protocol therapy 
until resolution to ≤ 
Grade 1 or baseline 
and after completion 
of steroid taper then 
resume protocol 
therapy 
administration at next 
scheduled dose. 
‒ Consider symptomatic treatment including hydration, 
electrolyte replacement, diuretics, etc.  
‒ Carefully monitor serum creatinine  every 2-3 days and as 
clinically warranted 
‒ Consult Nephrologist and consider renal biopsy if clinically 
indicated 
‒ If event is persistent (> 3-5 days) or worsens,  promptly 
start  prednisone 1 to 2 mg/kg/day PO or IV equivalent  
‒ If event is not responsive within 3-5 days or worsens 
despite prednisone at 1-2 mg/kg/day or PO IV equivalent, 
additional workup should be considered and prompt 
treatment with IV methylprednisolone at 2-4 mg/kg/day 
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. 
‒ When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
 
 

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> Grade 3 
Permanently 
discontinue protocol 
therapy and remove 
from protocol therapy. 
- Carefully monitor serum creatinine  on  daily basis 
- Consult Nephrologist and consider renal biopsy if clinically 
indicated 
- Promptly  start  prednisone 1 to 2 mg/kg/day PO or IV 
equivalent  
- If event is not responsive within 3-5 days or worsens 
despite prednisone at 1-2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt 
treatment with IV methylprednisolone 2-4 mg/kg/day 
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). 
 
 
Toxicity 
Dose Interruptions 
Toxicity Management 
Rash (excluding Bullous skin formations) 
Any Grade 
 
Monitor for signs and symptoms of dermatitis (rash and 
pruritus)  
**IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
CHAIR SHOULD BE CONTACTED AND STUDY DRUG 
DISCONTINUED** 
Grade 1 
No dose 
modifications 
Consider symptomatic treatment including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream) 
Grade 2 
For persistent (> 1- 2 
weeks) Grade 2 
events, hold protocol 
therapy until 
resolution to ≤ Grade 
1 or baseline and 
after completion of 
steroid taper, resume 
protocol therapy 
administration at next 
scheduled dose. 
 
 
‒ Obtain dermatology consult  
‒ Consider symptomatic treatment including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream) 
‒ Consider moderate-strength topical steroid  
‒ If no improvement of rash/skin lesions occurs within 3-5 
days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid, consider 
discussing with study physician and promptly start systemic 
steroids prednisone 1-2 mg/kg/day PO or IV equivalent   
‒ Consider skin biopsy if persistent for >1-2 weeks or recurs 
Grade 3 
Hold protocol therapy 
until resolution to ≤ 
Grade 1 or baseline; 
resume protocol 
therapy 
administration at next 
scheduled dose. 
‒ Consult dermatology  
‒  Promptly initiate empiric IV methylprednisolone 1 to 4 
mg/kg/day or equivalent  
‒ Consider hospitalization 
‒ Monitor extent of rash [Rule of Nines] 
‒ Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
‒ Once 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) 
 
Grade 4 
 
Permanently 
discontinue protocol 
therapy and remove 
from protocol therapy. 
 

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Toxicity 
Dose Interruptions 
Toxicity Management 
Endocrinopathy (e.g., hyper-thyroidism, hypo-thyroidism, hypo-pituitarism, Type 1 diabetes 
mellitus hypophysitis, adrenal insufficiency, etc.)  
Any Grade 
 
‒ Consider consult an Endocrinologist for endocrine events 
‒ Consider discussing with study physician  
‒ Monitor patients for signs and symptoms of 
endocrinopathies. Non-specific symptoms include 
headache, fatigue, behavior changes, changed mental 
status, vertigo, abdominal pain, unusual bowel habits, 
polydipsia, polyuria, hypotension and weakness. 
‒ Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including 
brain metastases, infections, etc.) 
‒ Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, free T3 and free T4 
and other relevant endocrine and related labs (e.g., blood 
glucose and ketone levels, HgA1c). 
‒ For modest asymptomatic elevations in serum amylase 
and lipase, corticosteroid treatment is not indicated as long 
as there are no other signs or symptoms of pancreatic 
inflammation. 
‒ 
If a patient experiences an AE that is thought to be 
possibly of autoimmune nature (e.g., thyroiditis, 
pancreatitis, hypophysitis, diabetes insipidus), the 
investigator should send a blood sample for appropriate 
autoimmune antibody testing 
Grade 1 
No dose 
modifications 
(including those with asymptomatic TSH elevation) 
- Monitor patient with appropriate endocrine function tests 
- For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment of 
early-morning ACTH, cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, and prolactin 
levels, as well as cosyntropin stimulation test (though it 
may not be useful in diagnosing early secondary adrenal 
insufficiency). 
- If TSH < 0.5X 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 Grade 2 
endocinopathy other 
than hypothyroidism 
and Type 1 diabetes 
mellitus, hold protocol 
therapy until patient is 
clinically stable, and 
after completion of 
steroid taper, resume 
protocol therapy 
administration at next 
scheduled dose. 
 
Patients with 
endocrinopathies who 
may require 
prolonged or 
continued steroid 
(including those with symptomatic endocrinopathy) 
- EvaluateConsult endocrinologist to guide evaluation of 
endocrine function, and, as indicated by suspected 
endocrinopathy and as clinically indicated, consider 
pituitary scan. 
- For all patients with abnormal endocrine work up, except 
for those with isolated hypothyroidism or Type 1 DM, and 
as guided by an  endocrinologist, consider short term 
corticosteroids (e.g., 1 to 2 mg/kg/day methylprednisolone 
or IV equivalent) and prompt initiation of treatment with 
relevant hormone replacement (e.g., levothyroxine, 
hydrocortisone, or sex hormones). - 
- Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
- Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids. 

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Toxicity 
Dose Interruptions 
Toxicity Management 
Endocrinopathy (e.g., hyper-thyroidism, hypo-thyroidism, hypo-pituitarism, Type 1 diabetes 
mellitus hypophysitis, adrenal insufficiency, etc.)  
replacement can be 
retreated with 
protocol therapy on 
the following 
conditions: 1) the 
event stabilizes and is 
controlled, 2) the 
patient is clinically 
stable as per 
Investigator or 
treating physician’s 
clinical judgement, 
and 3) doses of 
prednisone are at 
less than or equal to 
10mg/day or 
equivalent. 
- Once the patient ispatients on steroids are improving, 
gradually taper steroids immunosuppressive steroids (as 
appropriate and with guidance of endocrinologist) over ≥28 
days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]). 
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory 
assessments/MRI as clinically indicated. 
> Grade 3 
For Grade 3/4 
endocrinopathy other 
than hypothyroidism 
and Type 1 diabetes 
mellitus, hold protocol  
patient is clinically 
stable and after 
completion of steroid 
taper, resume 
protocol therapy 
administration at next 
scheduled dose. 
Patients with 
endocrinopathies 
who may require 
prolonged or 
continued steroid 
replacement (e.g., 
adrenal insufficiency) 
can be retreated with 
study drug/study 
regimen on the 
following conditions: 
1. The event 
stabilizes and is 
controlled. 
2. The patient is 
clinically stable as 
per investigator or 
treating physician’s 
clinical judgement. 
 
- Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy 
and as clinically indicated, consider pituitary scan. 
Hospitalization recommended. 
- For all patients with abnormal endocrine work up, except 
those with isolated hypothyroidism or Type 1 DM, and as 
guided by an endocrinologist, promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or equivalent, as well 
as relevant hormone replacement (e.g., hydrocortisone, 
sex hormones). 
- For adrenal crisis, severe dehydration, hypotension, or 
shock, immediately initiate IV corticosteroids with 
mineralocorticoid activity. 
- Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
- Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids. 
- Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN guidelines for treatment 
of cancer-related infections). 
 

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Toxicity 
Dose Interruptions 
Toxicity Management 
Immune Mediated Neurotoxicity (except Myasthenia Gravis and Guillain-Barre) 
Any Grade 
- Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes and medications, etc.)  
- Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness) 
- Consider appropriate diagnostic testing (e.g. 
electromyogram and nerve conduction investigations) 
- Symptomatic treatment with neurological consult as 
appropriate 
Grade 1 
No dose 
modifications 
 
Grade 2  
Hold protocol therapy 
until resolution to ≤ 
Grade 1 and after 
completion of steroid 
taper then resume 
protocol therapy 
administration at next 
scheduled dose. 
 
  
- Consider discussing with the study chair  
- Consider Neurology Consult  
- Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin, duloxetine, etc.) 
- Promptly start systemic prednisone 1-2 mg/kg/day PO or IV 
equivalent  
- If no improvement within 3-5 days despite 1-2 mg/kg/day 
prednisone PO or IV equivalent consider additional workup 
and promptly treat with additional immunosuppressive 
therapy (e.g. IVIG)  
Grade 3 
Hold protocol therapy 
until resolution to ≤ 
Grade 1 and after 
completion of steroid 
taper then resume 
protocol therapy 
administration at next 
scheduled dose. 
- Consider, as necessary, discussing with study physician. 
- Obtain neurology consult. 
- Consider hospitalization. 
- Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
- If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressants (e.g., IV IG). 
- Once stable, gradually taper steroids over ≥28 days. 
Grade 4 
Permanently 
discontinue protocol 
therapy and remove 
from protocol therapy. 
 
 
 

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Toxicity 
Dose Interruptions 
Toxicity Management 
Immune Mediated Peripheral Neuromotor Syndromes, such as Guillain-Barre and Myasthenia 
Gravis 
Any Grade 
 
‒ The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain subjects 
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 
progressive weakness, and signs of respiratory 
insufficiency or autonomic instability 
‒ Evaluate patients 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 subjects 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 
modifications 
- Consider discussing with the study chair 
- Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above 
- Obtain  neurology consult  
Grade 2 
Hold protocol 
therapy until 
resolution to ≤ 
Grade 1; resume 
protocol therapy 
administration at 
next scheduled 
dose. 
 
If there are signs of 
respiratory 
insufficiency or 
autonomic instability 
permanently 
discontinue protocol 
therapy and remove 
from protocol 
therapy. 
‒ Consider discussing with the study chair  
‒ Monitor patients for sentinel symptoms of a potential 
decompensation as described above 
‒ Obtain a Neurology Consult 
‒ Manage sensory neuropathy/neuropathic pain with 
appropriate medications (e.g., gabapentin, duloxetine, etc.) 
MYASTHENIA GRAVIS 
o 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. 
o 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. 
o If Myasthenia Gravis-like neurotoxicity present, consider 

Appended 4/12/17 
S1400F 
 
Page 46 
 
  Version Date 10/21/19 
 
Toxicity 
Dose Interruptions 
Toxicity Management 
Immune Mediated Peripheral Neuromotor Syndromes, such as Guillain-Barre and Myasthenia 
Gravis 
starting acetylcholine esterase (AChE) inhibitor therapy 
in addition to steroids. Such therapy, if successful, can 
also serve to reinforce the diagnosis. 
GUILLAIN-BARRE:  
o Importantly 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 protocol 
therapy until 
resolution to ≤ 
Grade 1; resume 
protocol therapy 
administration at 
next scheduled 
dose. 
 
If there are signs of 
respiratory 
insufficiency or 
autonomic instability 
permanently 
discontinue protocol 
therapy and remove 
from protocol 
therapy. 
- Consider discussing with study chair 
- Recommend hospitalization 
- Monitor symptoms and obtain neurological consult 
MYASTHENIA GRAVIS 
o Steroids may be successfully used to treat Myasthenia 
Gravis.  It should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist. 
o Patients unable to tolerate steroids may be candidates 
for treatment with plasmapharesis or IVIG. 
o 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:  
o Important to consider here that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should 
be started with IVIG and followed by plasmapheresis if 
not responsive to IVIG. 
Grade 4 
Permanently 
discontinue protocol 
therapy and remove 
from protocol 
therapy. 
 

Appended 4/12/17 
S1400F 
 
Page 47 
 
  Version Date 10/21/19 
 
Toxicity 
Dose Modification 
Toxicity Management 
Cardiac toxicities (including arrhythmia, conduction disorder heart failure, IV dysfunction, Myocarditis) 
Any Grade 
General Guidance for Any Grade: 
− The prompt diagnosis of immune-mediated myocarditis is important, particularly in patients 
with baseline cardiopulmonary disease and reduced cardiac function.  
− Consider, as necessary, discussing with the study physician. 
− Monitor patients for signs and symptoms of myocarditis (new onset or worsening chest pain, 
arrhythmia, shortness of breath, peripheral edema). As some symptoms can overlap with 
lung toxicities, simultaneously evaluate for and rule out pulmonary toxicity as well as other 
causes (e.g., pulmonary embolism, congestive heart failure, malignant pericardial effusion). 
A Cardiology consultation should be obtained early, with prompt assessment of whether and 
when to complete a cardiac biopsy, including any other diagnostic procedures. 
− Initial workup should include clinical evaluation, BNP, cardiac enzymes, ECG, 
echocardiogram (ECHO), monitoring of oxygenation via pulse oximetry (resting and 
exertion), and additional laboratory workup as indicated. Spiral CT or cardiac MRI can 
complement ECHO to assess wall motion abnormalities when needed. 
− Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, other medications, or infections) 
− Discontinue protocol therapy permanently upon diagnosis of myocarditis, regardless 
of grade 
Grade 1 
(asymptoma
tic with 
laboratory 
(e.g., BNP, 
EKG, 
Troponin) 
and etiology 
is unclear) 
No dose modifications 
required unless 
clinical suspicion for 
myocarditis is high in 
which case 
suspected, hold 
protocol therapy 
during workup.  
 
− If myocarditis is 
excluded, resume 
after complete 
resolution to 
Grade 0. 
− If myocarditis is 
diagnosed, 
permanently 
discontinue 
protocol therapy. 
For Grade 1 (no definitive findings): 
− Monitor and closely follow up in 2 to 4 days for clinical symptoms, 
BNP, cardiac enzymes, ECG, ECHO, pulse oximetry (resting and 
exertion), and laboratory workup as clinically indicated. 
− Consider using steroids if clinical suspicion is high. 

Appended 4/12/17 
S1400F 
 
Page 48 
 
  Version Date 10/21/19 
 
Toxicity 
Dose Modification 
Toxicity Management 
Cardiac toxicities (including arrhythmia, conduction disorder heart failure, IV dysfunction, Myocarditis) 
≥ Grade 2 
(Grade 2: 
Symptoms 
with mild to 
moderate 
activity or 
exertion) 
 
 (Grade 3: 
Severe with 
symptoms at 
rest or with 
minimal 
activity or 
exertion; 
intervention 
indicated) 
 
(Grade 4: 
Life-
threatening 
consequenc
es; urgent 
intervention 
indicated 
(e.g., 
continuous 
IV therapy or 
mechanical 
hemodynami
c support) 
If Grade 2 - Hold 
protocol therapy. 
− If toxicity rapidly 
improves to Grade 
0 AND myocarditis 
is excluded, then 
the decision to 
reinitiate protocol 
therapy will be 
based upon 
treating 
physician’s clinical 
judgment and after 
completion of 
steroid taper. 
− If toxicity does not 
rapidly improve. 
permanently 
discontinue 
protocol therapy 
− If myocarditis is 
diagnosed, 
permanently 
discontinue 
protocol therapy 
 
If Grade 3-4, 
permanently 
discontinue protocol 
therapy. 
For Grade 2-4: 
− Monitor symptoms daily, hospitalize. 
− Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined whether 
and when to complete diagnostic procedures including a cardiac 
biopsy. 
− Supportive care (e.g., oxygen). 
− If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− Once the patient is improving, gradually taper steroids over ≥28 
days and consider prophylactic antibiotics, antifungals, or anti-
PJP treatment (refer to current NCCN guidelines for treatment of 
cancer-related infections [Category 2B recommendation]).a 
 
Toxicity 
Dose Interruptions 
Toxicity Management 
Myositis/Polymyositis (“Poly/myositis”) 
Any Grade 
- Monitor patients for signs and symptoms of 
poly/myositis. Typically, muscle weakness/pain occurs 
in proximal muscles including upper arms, thighs, 
shoulders, hips, neck and back, but rarely affects the 
extremities including hands and fingers; also difficulty 
breathing and/or trouble swallowing can occur and 
progress rapidly. Increased general feelings of 
tiredness and fatigue may occur, and there can be 
new-onset falling, difficulty getting up from a fall, and 
trouble climbing stairs, standing up from a seated 
position, and/or reaching up. 
- If poly/myositis is suspected, a Neurology consultation 
should be obtained early, with prompt guidance on 
diagnostic procedures. Myocarditis may co-occur with 
poly/myositis; refer to guidance under Myocarditis. 
Given breathing complications, refer to guidance 
under Pneumonitis/ILD.  
Given possibility of an existent (but previously 
unknown) autoimmune disorder, consider 
Rheumatology consultation. 

Appended 4/12/17 
S1400F 
 
Page 49 
 
  Version Date 10/21/19 
 
Toxicity 
Dose Interruptions 
Toxicity Management 
Myositis/Polymyositis (“Poly/myositis”) 
- Consider, as necessary, discussing with the study 
physician. 
- Initial work-up should include clinical evaluation, 
creatine kinase, aldolase, LDH, BUN/creatinine, 
erythrocyte sedimentation rate or C-reactive protein 
level, urine myoglobin, and additional laboratory work-
up as indicated, including a number of possible 
rheumatological/antibody tests (i.e., consider whether 
a rheumatologist consultation is indicated and could 
guide need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase [such as 
anti-Jo-1], and/or signal-recognition particle 
antibodies). Confirmatory testing may include 
electromyography, nerve conduction studies, MRI of 
the muscles, and/or a muscle biopsy. Consider 
Barium swallow for evaluation of dysphagia or 
dysphonia. 
- Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 
other medications, or infections). 
Grade 1 
No dose modifications 
- Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically 
indicated. 
- Consider Neurology consult. 
- Consider, as necessary, discussing with the study 
physician. 
Grade 2 
Hold protocol therapy until resolution 
to ≤ Grade 1; resume protocol 
therapy administration at next 
scheduled dose. 
 
- Monitor symptoms daily and consider hospitalization. 
- Obtain Neurology consult, and initiate evaluation. 
- Consider, as necessary, discussing with the study 
physician. 
- If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), 
promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from 
Neurology consultant  
- If clinical course is not rapidly progressive, start 
systemic steroids (e.g., prednisone 1 to 2 mg/kg/day 
PO or IV equivalent); if no improvement within 3 to 5 
days, continue additional work up and start treatment 
with IV methylprednisolone 2 to 4 mg/kg/day 
- If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 3 to 5 
days, consider start of immunosuppressive therapy 
such as TNF inhibitors (e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is important to rule out 
sepsis and refer to infliximab label for general 
guidance before using infliximab. 
- Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections 

Appended 4/12/17 
S1400F 
 
Page 50 
 
  Version Date 10/21/19 
 
Toxicity 
Dose Interruptions 
Toxicity Management 
Myositis/Polymyositis (“Poly/myositis”) 
Grade 3 
Hold protocol therapy until resolution 
to ≤ Grade 1; resume protocol 
therapy administration at next 
scheduled dose. 
 
 
- Monitor symptoms closely; recommend 
hospitalization. 
- Obtain Neurology consult, and complete full 
evaluation. 
- Consider, as necessary, discussing with the study 
physician. 
- Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from 
Neurology consultant. 
- If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 3 to 5 
days, consider start of immunosuppressive therapy 
such as TNF inhibitors (e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is important to rule out 
sepsis and refer to infliximab label for general 
guidance before using infliximab. 
- Consider whether patient may require IV IG, 
plasmapheresis. 
- Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections 
Grade 4 
Permanently discontinue protocol 
therapy and remove from protocol 
therapy. 
 
 

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Appended 4/12/17 
S1400F 
 
Page 52 
 
  Version Date 10/21/19 
 
 
For treatment or dose modification questions, please contact Drs. Natasha Leighl and 
Naiyer Rizvi at S1400FMedicalQuery@swog.org.  For dosing principles or questions, 
please consult the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" at 
https://www.swog.org/sites/default/files/docs/2017-11/Policy38. 
 
8.5 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Coordinator and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 
 

Appended 4/12/17 
S1400F 
 
Page 53 
 
  Version Date 10/21/19 
 
 
9.0 
STUDY CALENDAR 
 
9.1 
MEDI4736 (Durvalumab) plus Tremelimumab 
 
Cycle 
1 
Cycle 2 
Cycle 
3 
Cycle 
4 
Cycle 5 
Cycle 
6  
Cycle 
7 
Subsequent 
Cycles β 
At Off 
TX 
Off Tx 
FU Prior 
to Prog ∆ 
Off Tx FU 
After Prog √ 
REQUIRED STUDIES 
PRE-
STUDY 
Wk 
1 
Wk 
5 
Wk 
7 
Wk 
9 
Wk 
13 
Wk 
17 
Wk 
19 
Wk 
21 
Wk 
25 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History & Physical Exam 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Weight & Performance Status 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Vital Signs £ 
X£ 
X£ 
X£ 
 
X£ 
X£ 
X£ 
 
X£ 
X£ 
X£ 
 
 
 
Disease Assessment  Ω 
X 
 
 
XΩ 
 
XΩ 
 
XΩ 
 
XΩ 
XΩ 
 
XΩ 
 
Toxicity Notation 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Xȸ 
Xȸ 
Smoking Status Assessment 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Diff/Platelets/Hgb 
X 
X€ 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Xȸ 
Xȸ 
Serum Bilirubin 
X 
X€ 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Xȸ 
Xȸ 
ALT or AST 
X 
X€ 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Xȸ 
Xȸ 
Serum Creatinine/Calc CrCl 
X 
X€ 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Xȸ 
Xȸ 
Lipase π 
X 
X€ 
X 
 
X 
X 
X 
 
X 
X 
Xπ 
X 
Xπ 
Xȸ 
Amylase π 
X 
X€ 
X 
 
X 
X 
X 
 
X 
X 
Xπ  
X 
Xπ 
Xȸ 
TSH w/ reflex Free T3/Free T4 π 
X 
X€ 
X 
 
X 
X 
X 
 
X 
X 
Xπ 
X 
Xπ 
Xȸ 
Albumin  ¥ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI for Disease 
Assessment  Ω 
X 
 
 
XΩ 
 
XΩ 
 
XΩ 
 
XΩ 
XΩ 
 
XΩ 
 
Brain CT/MRI 
X 
 
 
 
 
X♦ 
 
 
 
X♦ 
X♦ 
 
X♦ 
 
EKG © 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Image Submission  Σ 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue for Banking  
Xǂ 
 
 
 
 
 
 
 
 
 
 
 
 
X§ 
Blood for Banking  ƒ 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Xð 
Calendar continued on next page.  Click here for footnotes. 
 

Appended 4/12/17 
S1400F 
 
Page 54 
 
  Version Date 10/21/19 
 
 
 
Cycle 
1 
Cycle 2 
Cycle 
3 
Cycle 
4 
Cycle 5 
Cycle 
6  
Cycle 
7 
Subsequent 
Cycles β 
At Off 
TX 
Off Tx 
FU Prior 
to Prog ∆ 
Off Tx FU 
After Prog √ 
REQUIRED STUDIES 
PRE-
STUDY 
Wk 
1 
Wk 
5 
Wk 
7 
Wk 
9 
Wk 
13 
Wk 
17 
Wk 
19 
Wk 
21 
Wlk
25 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
28 day cycle 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tremelimumab * 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
MEDI4736 (Durvalumab) * 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
NOTE:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Forms submission guidelines are found in 
Section 14.0. 
 
NOTE:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
Click here for footnotes. 
 
 

Appended 4/12/17 
S1400F 
 
Page 55 
 
  Version Date 10/21/19 
 
 
Footnotes for Calendar (Durvalumab [MEDI4736] plus Tremelimumab): 
Ω CT or MRI (the same method used at prestudy to meet the eligibility criteria in Section 5.3 of S1400F) must be repeated every 6 weeks (± 
7 day window) until disease progression, regardless of treatment delays. The 6 weeks should start from Cycle 1 Day 1. If the patient remains 
on treatment following RECIST 1.1 progression, irRC disease progression is to be confirmed by a second consecutive determination of 
progression at least 28 days from the date of initial documentation of progression (see Section 10.0). 
♦   Only if patient has brain metastases at baseline.  Scans must use the same modality as baseline and be repeated every 12 weeks (+/- 7 days) 
until disease progression. 
Σ Submit scans as outlined in Section 14.0 and Section 15.0 of S1400F. 
£  Vital signs (Temperature, Blood Pressure, Pulse, and Respiratory Rate) are to be performed pre-study and at three timepoints at every 
cycle: pre-infusion, between tremelimumab and MEDI4736 (Durvalumab) dosing, and post-infusion. Vital signs are to be reported on the 
S1400F Onstudy and S1400F Treatment forms. 
©  EKG to be performed at pre-study within 7 days prior to sub-study registration, then as clinically required throughout treatment. 
β During continued treatment, items marked under physical and laboratory should be performed at the beginning of every subsequent cycle 
unless otherwise noted.  Disease assessments and image submission are to take place every 6 weeks (± 7 days). 
∆ After off treatment prior to progression, patients should be followed by repeating indicated studies every 3 months or more often as clinically 
indicated for the first year, then every 6 months for up to 3 years from date of sub-study registration.  Disease assessment should continue 
every 6 weeks until progression. 
√ After off treatment after progression, follow-up will occur (with lab tests and scans performed at the discretion of the treating physician) every 
6 months for 2 years then at end of year 3 from date of sub-study registration.  
ǂ  With patient’s consent, an additional research biopsy prior to treatment must be collected. Patients who provided fresh biopsy during 
screening may use that leftover tissue if they received no intervening treatment (see Section 15.0 of S1400F). 
§ With patient’s consent, an additional research biopsy within 1 month after the time of first progression (irRC-Progression defined in Section 
10 of S1400F) among patients who had a response to treatment (in the opinion of the treating physician) must be collected (see Section 
15.0 of S1400F). 
ƒ With patient's consent, additional research blood draws will be collected (see Section 15.0 of S1400F). 
π Lipase, Amylase, and TSH/Reflex T3/T4 are required at pre-study within 7 days prior to sub-study registration. TSH/Reflex T3/T4 must be 
repeated every 4 weeks throughout treatment, then as clinically required until disease progression, as defined in Section 10.0 of S1400F. 
Lipase and Amylase must be repeated every 4 weeks throughout treatment, if clinically indicated, then as clinically required until disease 
progression, as defined in Section 10.0 of S1400F. 
¥ Results of these tests do not determine eligibility but are recommended prior to sub-study registration. 
€ If the pre-study tests are obtained within 14 days prior to treatment, tests need not be repeated on Cycle 1 Day 1. 
* MEDI4736 (Durvalumab) and Tremelimumab will be administered on Day 1 of Cycles 1-4. Note that tremelimumab must be administered first. 
MEDI4736 (Durvalumab) only will be administered on Day 1 of Cycle 5 and subsequent cycles until one of the criterion from Section 7.3 is met. 
ȸ Assessments should continue until resolution of all acute adverse events. 
ð  Blood for Banking specimen must be collected at first progression (irRC-Progression defined in Section 10.0 of S1400F) after study treatment 
(see Section 15.0 of S1400F). 

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Appended 4/12/17 
S1400F 
 
Page 60 
 
  Version Date 10/21/19 
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light 
housework, office work. 
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 
 
10.5 
Time to Death 
 
From date of sub-study registration to date of death due to any cause.  Patients last known 
to be alive are censored at date of last contact. 
 
10.6 
irRC-Progression  
 
irRC-progression is defined by progression per RECIST 1.1 except that progression 
determined by appearance of new lesions or by a 20% increase in the sum of diameters 
must be confirmed by a second consecutive determination of progression at least 28 days 
from the date of initial documentation of progression. 
 
10.7 
Investigator-Assessed Progression-Free Survival 
 
From date of sub-study registration to date of first documentation of progression assessed 
by local review or symptomatic deterioration (as defined above), or death due to any cause.  
Patients last known to be alive without report of progression are censored at date of last 
disease assessment. For patients with a missing scan (or consecutive missing scans) 
whose subsequent scan determines progression, the expected date of the first missing 
scan (as defined by the disease assessment schedule) will be used as the date of 
progression.  
 
10.8 
Progression-Free Survival by Central Review 
 
From date of sub-study registration to date of first documentation of progression assessed 
by central review or symptomatic deterioration (as defined above), or death due to any 
cause.  Patients last known to be alive without report of progression are censored at date 
of last disease assessment. For patients with a missing scan (or consecutive missing 
scans) whose subsequent scan determines progression, the expected date of the first 
missing scan (as defined by the disease assessment schedule) will be used as the date of 
progression.  
 
10.9 
Duration of Response (DoR) 
 
From date of first documentation of response (CR or PR) to date of first documentation of 
progression assessed by local review or symptomatic deterioration (as defined above), or 
death due to any cause among patients who achieve a response (CR or PR).  Patients last 
known to be alive without report of progression are censored at date of last disease 

Appended 4/12/17 
S1400F 
 
Page 61 
 
  Version Date 10/21/19 
 
assessment. For patients with a missing scan (or consecutive missing scans) whose 
subsequent scan determines progression, the expected date of the first missing scan (as 
defined by the disease assessment schedule) will be used as the date of progression. 
 
10.10 
irRC Investigator-Assessed Duration of Response (irRC-IA-DoR)  
 
From date of first documentation of response (CR or PR) to date of first documentation of 
irRC-progression assessed by local review or symptomatic deterioration, or death due to 
any cause. Patients last known to be alive without report of irRC-progression are censored 
at date of last disease assessment. For patients with a missing scan (or consecutive 
missing scans) whose subsequent scan(s) determine irRC-progression, the date of irRC-
progression will be the expected date of the first missing scan (as defined by the disease 
assessment schedule) or the date of the first scan documenting potential irRC-progression, 
whichever is earliest. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
This study will enroll patients into two parallel and independently evaluated cohorts; 
patients will be defined as either acquired (Cohort 1) or primary (Cohort 2) resistance.  See 
Section 6.0 for the definition of the cohorts. Both cohorts have separate accrual goals and 
analysis plans.  This study is employing Design #2 for non-match therapies. A complete 
description of the statistical design and analysis plan is included this section and in Section 
11.2a of S1400. This section includes details specific to S1400F. 
 
The objectives will be addressed in each cohort separately. 
 
11.1 
Primary Objective 
 
The primary objective within each cohort is to assess the response rate (confirmed and 
unconfirmed, complete and partial) among patients treated with MEDI4736 (Durvalumab) 
plus tremelimumab. 
 
11.2 
Secondary Objectives 
 
Secondary objectives include an evaluation of IA-PFS, OS, DoR, and toxicities. 
 
11.3 
Sample Size with Power Justification 
 
The accrual goals for this study are to accrue up to 60 eligible patients per cohort and the 
same design assumptions apply to both cohorts. A design with 82% power and 1-sided 
0.05 level type I error would require 60 patients to rule out an ORR of 5% or less if the true 
ORR is 15% or greater.  If the true ORR is 20%, this design has 96% power. The 
observation of at least 6 responses of the 60 patients (10%) would be considered evidence 
to rule out an ORR of 5%. Assuming 90% of accrued patients will satisfy eligibility, the total 
accrual goal is 66 patients/cohort (132 total). 
 
 

Appended 4/12/17 
S1400F 
 
Page 62 
 
  Version Date 10/21/19 
 
 
11.4 
Analysis Plan  
 
The evaluation within each cohort will include two interim analyses.  The interim analyses 
within each cohort are as follows: 
 
Interim 1: The first interim analysis will take place when 20 patients are evaluable for 
response.  This interim analysis will only evaluate early stopping for futility.  If no responses 
are observed, this will be considered evidence of futility and the recommendation will be to 
close the cohort for lack of evidence of efficacy of the regimen.  
 
In addition to evaluating early stopping for futility, this analysis will evaluate the 
safety/tolerability of the regimen.  All grade 4 hematologic and grade 3 or worse non-
hematologic will be evaluated with a particular focus on diarrhea, colitis, transaminitis and 
lipase levels, and other immune-related adverse events (pneumonitis and other immune 
events).  These toxicities will be evaluated by the S1400F Study Chairs, the S1400 Study 
Chairs, and the study pharmaceutical collaborator. With 20 patients evaluable for toxicities, 
any toxicity with at least 10% prevalence has at least an 88% chance of being observed.   
 
Interim 2: The second interim analysis will take place when 40 patients are evaluable for 
response.  This interim analysis will also only evaluate early stopping for futility.  If 3 or 
fewer responses are observed, this will be considered evidence of futility and the 
recommendation will be to close the cohort for lack of evidence of efficacy of the regimen.  
 
Final Analysis: If a cohort is not closed to accrual at the first or second interim analysis, the 
cohort will proceed to full accrual of 60 evaluable patients. If the cohort continues to full 
accrual, the observation of at least 6 responses will be considered evidence to rule out the 
null hypothesis of a 5% response rate.  
 
Summary of analyses: 
Analysis 
Sample Size 
Futility 
Continue/Positive 
1st interim 
20 patients 
No responses 
1+ response ( 5% RR) 
2nd interim 
40 patients 
≤3 responses 
4+ responses (10% RR) 
Final 
60 patients  
≤5 responses 
6+ responses (10% RR) 
 
Evaluability for response:  Evaluability for response is defined based on RECIST 1.1 and 
accrual to each cohort is to remain open while patients are being evaluated for response.  
However, within a cohort, if 20 or more eligible patients for the first interim analysis or 40 
or more eligible patients for the second interim analysis, have made it to their second 
disease assessment and the required number of responses to continue past that interim 
analysis has not been observed, then the accrual to the cohort will be placed in temporary 
closure until the response status for all patients in the interim analysis set is known. 
 
The following table describes the likelihood of stopping at the interim analyses under a 
response rate of 5%, 10%, 15%, and 20% and the probability of a rejecting the null.  
 
 
Probability of stopping 
Average 
sample 
size 
Expected 
number of 
responses 
 
RR 
Interim 1 
Interim 
2 
Probability 
reject null  
5% 
36% 
51% 
36 
2 
5.6% 
10% 
12% 
31% 
49 
5 
46.8% 
15% 
4% 
11% 
56 
8 
82.2% 
20% 
1% 
2% 
59 
12 
96.5% 
 

Appended 4/12/17 
S1400F 
 
Page 63 
 
  Version Date 10/21/19 
 
Response rates and associated confidence intervals will be calculated.  Survival, IA-PFS, 
irRC-IA-PFS, and DoR will be estimated using the method of Kaplan-Meier. The 
Brookmeyer-Crowley method will be used to calculate confidence intervals for median OS, 
IA-PFS, and DoR. With 60 patients, ORR and toxicity rates can be estimated within 13% 
with 95% confidence.  Any toxicity with at least 5% prevalence has at least a 95% chance 
of being observed. 
 
With 60 patients, OS and PFS rates at landmark times can be estimated within 13% with 
95% confidence. The analysis of PFS and OS will occur approximately 6 months after 
completion of accrual when at least 41 OS events have been observed (but not prior to 6 
months after completion of accrual). It is estimated that the null rate (with docetaxel) in the 
population would be a median of 5 months (or a 6-month OS of 44%) for OS and of interest 
would be an improvement to a median of 9 months (a 6-month OS rate of 63%). With 60 
patients accrued over 18-22 months and an additional 6 months of follow-up, the expected 
number of OS events is 41 events (under the alternative).  The estimated number of PFS 
events at this time is at least 50 (under an alternative median PFS of 5 months). With 41 
OS events, this study has 90% power to rule out a median OS of 5 months if the true 
median OS is 9 months or greater at the 1-sided 5% level.  The observation of a 6-month 
OS rate of 55% or greater would be considered evidence to rule out the null rate.  
 
The null median OS of 5 months was estimated by simulation under the assumption of 
exponential survival post progression on nivolumab and based on the data presented on 
the Checkmate 017 study which had a median PFS of 3.5 months with nivolumab and 
median OS of 9.2 months with nivolumab. 
 
11.5 
Accrual Information 
 
The estimated average monthly accrual rate to S1400F is 3-4 patients with acquired 
resistance (Cohort 1) and 4-6 patients with primary resistance (Cohort 2). The estimated 
duration of accrual for Cohort 1 is 16-23 months and for Cohort 2 is 11-16 months, provided 
there are no halts in accrual. The accrual duration within a cohort may be different if accrual 
is temporarily halted for an interim analysis or closed for futility at an interim analysis. See 
the S1400 main protocol for a description of the accrual rate assumptions/justification. 
 
11.6 
Data and Safety Monitoring Committee 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study. The 
Committee consists of four members from outside of SWOG. Group members, 3 non-
voting representatives from the National Cancer Institute (NCI), and the Group Statistician 
(non-voting). The members of this Committee will receive confidential reports every 6 
months from the SWOG Statistics and Data Management Center, and will meet at the 
Group's bi-annual meetings as necessary.  
 
 
12.0 
DISCIPLINE REVIEW 
 
This section does not apply to this sub-study. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
See Section 13.0 of S1400 or LUNGMAP for registration guidelines. NOTE: At the time of 
LUNGMAP activation, S1400 screening will close to accrual. Please see the Lung-MAP protocol 
training webpage for additional information (https://www.swog.org/required-lung-map-s1400-
training). 
 
 
13.1 
Registration Timing 

Appended 4/12/17 
S1400F 
 
Page 64 
 
  Version Date 10/21/19 
 
 
Patients must plan to begin treatment within 10 calendar days after sub-study registration. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirements 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3 for details. 
 
14.3 
Data Submission Procedures 
 
a. 
Data collection for this study will be done exclusively through the Medidata Rave 
clinical data management system.  Access to the trial in Rave is granted through 
the iMedidata application to all persons with the appropriate roles assigned in 
Regulatory Support System (RSS).  To access Rave via iMedidata, the site user 
must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and the appropriate Rave role (Rave CRA, Read-
Only, Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. To hold the Rave CRA role or CRA Lab Admin role, the user must 
hold a minimum of an AP registration type.  To hold the Rave Site Investigator role, 
the individual must be registered as an NPIVR or IVR.  Associates can hold read-
only roles in Rave.  If the study has a DTL, individuals requiring write access to 
Rave must also be assigned the appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster ill be sent a study invitation e-mail from 
iMedidata.  To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page.  Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial site registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account.  Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance).  Additional 
information on iMedidata/Rave is available on the CTSU members’ website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
b. 
You may also access Rave® via the SWOG CRA Workbench via the SWOG 
website (www.swog.org).    
 
For difficulties with the CRA Workbench, please email  

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Appended 4/12/17 
S1400F 
 
Page 70 
 
  Version Date 10/21/19 
 
15.4 
Specimen Flow Diagram 
 
Specimen Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site 
Screening/Pre-
Screening Tumor 
Tissue 
(Required) 
See S1400 or 
LUNGMAP 
Section 5.1. 
Tumor Tissue 
prior to Tx 
(Optional a) 
 
See Sub-Study 
Section 15.0. 
Peripheral Blood  
(Optional a) 
 
See Sub-Study 
Section 15.0. 
Re-biopsy Tumor 
Tissue at 
Progression 
(Optional a, b) 
See Sub-Study 
Section 15.0. 
Lab #211: 
Foundation 
Medicine, Inc. 
(FMI) 
Test: Biomarker 
Profiling 
(Required)* 
 
See S1400 or 
LUNGMAP 
Section 15.2 
 
For Patients 
registered to 
S1400F, SWOG 
Biospecimen Bank 
will forward 2-4 
slides to 
Lab #214: Clarient 
 
Test: PD-L1 IHC 
Testing 
 
See S1400F 
Section 15.0. 
Lab #201: SWOG 
Biospecimen Bank – 
Solid Tissue 
 
Banking 
(c) 
 
See Sub-Study Section 
15.0. 
Lab 201: SWOG 
Biospeciment 
Bank – Solid 
Tissue 
 
Test: Exploratory 
Testing 
 
See S1400F 
Section 15.0 

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Expedited reporting is required if the patient has received at least one dose of the 
investigational agent(s) as part of the trial. Reporting requirements are provided in 
Table 16.1.  The investigational agent(s) used in this study MEDI4736 
(Durvalumab) and tremelimumab.  [Please note – For this sub-study the post 
dosage expedited reporting requirement window has been extended to 90 days 
rather than the normal 30 day requirement or until the initiation of alternative 
anticancer therapy].  If there is any question about the reportability of an adverse 
event or if on-line CTEP-AERS cannot be used, please telephone or email the SAE 
Specialist at the Operations Office, 210/614-8808 or adr@swog.org, before 
preparing the report. 

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Table 16.1: 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under a Non-CTEP IND within 90 Days of the Last Administration of the 
Investigational Agent/Intervention1 MEDI4736 (Durvalumab) and tremelimumab: 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events (if applicable) are 
found in the Section 16.1f. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report. 
 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
 
 
May 5, 2011 
 
 
 

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recognizes this event as a patient death. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 301-897-7404.  The potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
 
The 
Pregnancy 
Information 
Form 
is 
available 
at:  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm   
 
 

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17.0 
BIBLIOGRAPHY 
 
1  
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell 
non–small-cell lung cancer. N Engl J Med 373:123-135, 2015. [PMID: 26028407]. 
 
2  
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell 
non–small-cell lung cancer. N Engl J Med 373:123-135, 2015. [PMID: 26028407]. 
 
3  
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous 
non–small-cell lung cancer. N Engl J Med, 373:1627-1639, 2015. [PMID: 26412456]. 
 
4  
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-
L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): randomized controlled trial. 
Lancet Oncol 2015. [PMID: 26712084]. 
 
5  
Drake CG. Combination immunotherapy approaches. Annals of Oncology;23 (Supplement 8): 41-
46, 2012. [PMCID: PMC3845488]. 
 
6. 
Curran MA, Montalvo W, Yagita H et al. PD-1 and CTLA-4 combination blockade expands 
infiltrating T-cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc 
Natl Acad Sci USA; 107: 4275–4280, 2010. [PMID: 20160101]. 
 
7 
Larkin et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl 
J Med; 373:23-34, DOI: 10.1056/NEJMoa1504030, 2015. [PMID: 26398076]. 
8  
Antonia SJ, Bendell JC, Taylor MH, et al. Phase I/II study of nivolumab with or without ipilimumab 
for treatment of recurrent small cell lung cancer (SCLC): CA209-032. J Clin Oncol 33, 2015. [(suppl, 
abstr 7503) http://meetinglibrary.asco.org/content/146138-156]. 
9  
Antonia S, Goldberg S, Balmanoukian A, et al. A Phase 1 open-label study to evaluate the safety 
and tolerability of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in 
combination with tremelimumab in patients with advanced non-small cell lung cancer (NSCLC). 
Presented at ESMO 2014. Poster 1327P, Abstract 5924.  
http://annonc.oxfordjournals.org/content/25/suppl_4/iv466.3. 
 
10  
Rizvi N, Chaft J, Balmanoukian A, et al. Tumor Response from Durvalumab (MEDI4736) + 
Tremelimumab Treatment in Patients with Advanced Non-small Cell Lung Cancer is observed 
regardless of PD-L1 Status. Journal for ImmunoTherapy of Cancer, 3(Suppl 2):P193, 2015. 
Abstract, http://www.immunotherapyofcancer.org/content/3/S2/P193. 
 
11  
Antonia Goldberg, balmanoukian et al. Phase Ib study of MEDI4736, a programmed cell death 
ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-
associated protein-4 (CTLA-4) antibody, in patients (pts) with advanced NSCLC.  2015 asco 
annual 
meeting 
abstr 
3014; 
J 
Clin 
Oncol 
33, 
2015. 
[(suppl 
abstr 
3014) 
http://meetinglibrary.asco.org/content/147703-156]. 
 
12  
Rizvi N, Chaft J, Balmanoukian A, et al. Tumor Response from Durvalumab (MEDI4736) + 
Tremelimumab Treatment in Patients with Advanced Non-small Cell Lung Cancer is observed 
regardless of PD-L1 Status. Journal for ImmunoTherapy of Cancer, 3(Suppl 2):P193, 2015. 
Abstract, http://www.immunotherapyofcancer.org/content/3/S2/P193. 
 
13  
Herbst RS, Gordon MS, Fine GD, et al. A study of MPDL3280A, an engineered PD-L1 antibody in 
patients with locally advance or metastatic tumors. J Clin Oncol., 2013. [(suppl; abstr 3000), 
http://meetinglibrary.asco.org/content/115865-132]. 
 
 
 

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18.0 
APPENDIX 
 
18.1 
Background of Adverse Events of Special Interest (AESIs) 
 
18.2  
Biomarker Analysis of Immunotherapy Resistance 
 
18.3 
PD-L1 IHC Testing 
 
18.4 
Instructions for the SWOG Biospecimen Bank 
 
  
 

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18.1 
Background of Adverse Events of Special Interest (AESIs) 
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific 
to understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational 
product. 
 
AESIs for MEDI4736 (durvalumab) in combination with tremelimumab include but are not 
limited to events with a potential inflammatory or immune-mediated mechanism and which 
may require more frequent monitoring and/or interventions such as steroids, 
immunosuppressants and/or hormone replacement therapy. These AESIs are being 
closely monitored in clinical studies with durvalumab monotherapy and combination 
therapy. An immune-mediated adverse event (imAE) is defined as an AESI that is 
associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate etiology. Serologic, immunologic, and 
histologic (biopsy) data, as appropriate, should be used to support an imAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or 
other etiologic causes of the imAE.  
 
If the treating Investigator has any questions in regards to an event being an imAE, the 
Investigator should promptly contact the Study Chair. 
AESIs observed with MEDI4736 (durvalumab) and tremelimumab are listed in Section 
16.1f2. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs. 
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab and tremelimumab Investigator’s Brochures. More specific 
guidelines for their evaluation and treatment are described in Section 8.3.  These 
guidelines apply to AEs considered causally related to the study drug/study regimen by the 
reporting investigator. 
 
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality 
suggestive of pneumonitis/interstitial lung disease is observed, toxicity management as 
described in Section 8.3. It is strongly recommended to perform a full diagnostic workup, 
to exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, 
cardiogenic edema, or pulmonary hemorrhage. In the presence of confirmatory HRCT 
scans where other causes of respiratory symptoms have been excluded, a diagnosis of 
pneumonitis (ILD) should be considered.  
 
 

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18.2 
Biomarker Analysis of Immunotherapy Resistance 
 
Background: Although immunotherapies have proven efficacy in NSCLC patients, the 
majority of patients do not respond or relapse after an initial response. Obtaining biopsies 
prior to the start of the combination of durvalumab and tremelimumab will allow possible 
mechanisms of resistance to be identified.  Such identification could provide rationale for 
development of novel combinations to overcome resistance to immunotherapies. 
 
Objective: To obtain fresh biopsies prior to the start of MEDI4736 (Durvalumab) and 
tremelimumab in patients that previously received immunotherapies. 
 
Laboratory: Specimens will be shipped to the SWOG Biospecimen Bank – Solid Tissue, 
Myeloma and Lymphoma Division, Lab #201 and stored until a laboratory has been 
identified to perform the analysis. 
 
Specimen Requirements: 
 
A new biopsy is required from patients who consent to have an optional biopsy to collect a 
sample of tissue prior to starting protocol treatment.  The biopsy will be used to identify 
possible mechanism of resistance to immunotherapies to develop future novel 
combinations. The new biopsy should be either bronchoscopy/surgical biopsy or CT guided 
biopsy. The biopsy should be performed prior to the start of protocol treatment and should 
be processed as FFPE material.  The minimum requirement is a 5-10 unstained, charged, 
and unbaked 4-5 micron sections. 
 
Specimen collection kits are not being provided for this submission; sites must use 
institutional supplies. 
 
 

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18.3 
PD-L1 IHC Testing 
        
PD-L1 expression localization within the tumor microenvironment will be assessed in 
patients registered to S1400F.  Tumor specimens will be shipped from the SWOG 
Biospecimen Bank at Nationwide Children’s Hospital to Clarient about every 3 months. The 
SWOG Statistics and Data Mangaement Center will provide the SWOG Biospecimen Bank 
with the list of patient specimens to ship to Clarient.   
 
Objective 
To identify PD-L1 status in tumor samples from patients who have progressed on an anti-
PD-1/PD-L1 and enrolled onto the S1400F sub-study.  
 
Assay Description 
AstraZeneca has developed a technically validated immunohistochemistry (IHC)-based 
assay for PD-L1 determination in partnership with Ventana Medical Systems Inc. a CAP-
accredited/CLIA-certified laboratory (Tucson, AZ).  
  
Laboratory 
Clarient will serve as the central laboratory for testing PD-L1 expression in patients who 
register to S1400F.  
 
Lab #214: Clarient 
 
Specimen Requirements 
For the PD-L1 IHC testing, no on-site processing of specimens will be required prior to 
shipment to the SWOG Biospecimen Bank.  Tissue sample collected for S1400 or 
LUNGMAP  biomarker profiling will be used.  The preferred thickness is 4 micron unstained 
tissue sections; although 5 micron unstained tissue sections are allowable.  For patients 
with tumor blocks at SWOG Biospecimen Bank, SWOG Biospecimen Bank will prepare 4 
micron, unstained slides. At least 100 tumor cells are defined to be sufficient viable tumor 
tissue for PD-L1 IHC testing. Fine needle aspirates are not acceptable. A minimum of 2 
(preferably 4) unstained tissue sections along with a hematoxylin-eosin (H&E)-stained slide 
or Aperio H&E-stained image will be sent to Clarient for PD-L1 IHC testing from consented 
patients with sufficient tissue. 
 
 
 

Appended 4/12/17 
S1400F 
 
Page 83 
 
  Version Date 10/21/19 
 
18.4 
Instructions for the SWOG Biospecimen Bank 
 
Frozen Plasma and Buffy Coat 
The SWOG Biospecimen Bank will receive frozen plasma and buffy coat at up to 5 time 
points per patient. Upon receipt, the Bank will accession, barcode, and bank specimens in 
a -80°C freezer. 
 
Formalin-fixed Paraffin-Embedded (FFPE) Tissue 
The SWOG Biospecimen Bank will receive FFPE specimens as either blocks or 
slides/sections at up to 2 time points per patient. Upon receipt, the Bank will accession, 
barcode, and bank specimens at ambient temperature.   
 
At the end of the study, the Bank will receive notification from the SWOG Statistics and 
Data Management Center (SDMC) to distribute specimens for testing. The SDMC will 
create three pull lists for Nationwide informing them which samples are: 
• 
leftover tissue from patients biopsied at screening  
• 
patients who consented to a biopsy prior to treatment 
• 
patients who consented to a biopsy at progression 
 
Tumor Tissue for PD-L1 IHC Testing 
The SWOG Biospecimen Bank will send FFPE slides from consented patients for PD-L1 
IHC testing at Clarient. About every 3 months, the Bank will receive notification from the 
SWOG Statistics and Data Management Center to distribute specimens for testing. 
 
The Bank will send 2-4 unstained slides. If an FFPE tissue block was received, then the 
SWOG Biospecimen Bank will process 2-4 unstained slides (4 micron, charged) and an 
H&E-stained slide. The unstained slides will be shipped to Clarient for testing, and the H&E 
slides will be scanned to a 40x digital image.  
 
Tumor Tissue for Immunotherapy Resistance Analysis 
The SWOG Biospecimen Bank will send FFPE slides from consented patients for 
immunotherapy resistance analysis.  
 
The Bank will send 5-10 unstained slides. If an FFPE tissue block was received, then the 
SWOG Biospecimen Bank will process up to 10 unstained slides (4 micron, charged, 
unbaked) to send for testing.