Clinical trial NCT03430895
Conditions: Non-Transitional Cell Carcinoma of the Urothelial Tract Small Cell of the Bladder Adenocarcinoma of the Bladder Squamous Cell Carcinoma of the Bladder Metastatic Bladder Cancer
Keywords: Durvalumab (MEDI4736) Tremelimumab immunotherapy 17-511
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2018-01-31; Completion date: 2021-02-10
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is being done test to test the safety and effectiveness of durvalumab combined with tremelimumab in patients who have a rare form of cancer of the urinary tract.

Detailed description:

Arms: arm 1: Patients will receive durvalumab 1500 mg and tremelimumab 75 mg IV Q4W for up to 4 doses/cycles, then durvalumab 1500 mg Q4W starting at Week 16 for 9 doses (total treatment duration of 12 months).
Interventions: intervention 1: durvalumab and tremelimumab
Intervention descriptions: intervention 1: Patients will receive durvalumab 1500 mg and tremelimumab 75 mg IV Q4W for up to 4 doses/cycles, then durvalumab 1500 mg Q4W starting 4 weeks after the last combination treatment for up to 9 doses.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 17-511 A(3) 
Page 1 of 100 
Version: 2/26/16 
 
 
Approval date: 13-Nov-2018 
A Phase II Trial of Durvalumab (MEDI4736) and Tremelimumab i 
Transitional Cell Carcinoma of the Urothelial Tr 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC PROTOCO 
Principal Investigator/Department: 
Samuel Funt, MD 
n Metastatic, Non- 
act 
L 
Medicine 
Co-Principal 
Jonathan Rosenberg, MD 
Investigator(s)/Department: 
Dean Bajorin, MD 
Medicine 
Medicine 
Investigator(s)/Department: 
Robert Motzer, MD 
Yu Chen, MD, PhD 
Daniel Danila, MD 
Gopa Iyer, MD 
Lewis Kampel, MD 
Darren R. Feldman, MD 
Michael Morris, MD 
Dana Rathkopf, MD 
Susan Slovin, MD, PhD 
David Solit, MD 
Martin Voss, MD 
Karen Autio, MD 
Wassim Abida, MD, PhD 
Chung-Han Lee, MD, PhD 
Min Yuen Teo, MB, BCh 
Maria Carlo, MD 
Jedd Wolchok, MD PhD 
Magaret Callahan, MD 
Maryann Carousso, NP 
Christine Liebertz, NP 
Aaron Mitchell, MD, PhD 
Deaglan McHugh, MB BCh 
Joshua Chaim, DO 
Hikmat Al-Ahmadie, MD 
Victor Reuter, MD 
Satish Tickoo, MD 
Irina Ostrovnaya, PhD 
Han Xiao, MD 
Sree Chalasani, MD 
Afsheen Iqbal, MD 
Loren Michel, MD 
Rodrigo Erlich, MD 
Carly Osborne, APN 
Janet Cogswell, RN 
Medicine 
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Epidemiology and 
Biostatistics 
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Memorial Sloan Kettering Cancer Center 
IRB Number: 17-511 A(3) 
Approval date: 13-Nov-2018 
Jennifer Howgate-Klingaman, RN 
Lisa Sarmasti, RN 
Elizabeth Won, MD 
Alice Zervoudakis, MD 
Parisa Momtaz, MD 
Christine Anderson, NP 
Gloria Wasilewski, RN 
Sherie Mar-Chaim, RN 
Avni Desai, MD 
Stuart Lichtman, MD 
Jahan Aghalar, MD 
Juliana Eng, MD 
John Fiore, MD 
Jia Li, MD 
Wanqing Iris Zhi, MD, PhD 
Krysti O‟Keefe, RN 
Nursing 
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Medicine 
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Nursing 
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Consenting 
Professional(s)/Department: 
Dean F. Bajorin, MD 
Samuel Funt, MD 
Yu Chen, MD, PhD 
Daniel Danila, MD 
Darren R. Feldman, MD 
Gopa Iyer, MD 
Lewis Kampel, MD 
Michael Morris, MD 
Robert J. Motzer, MD 
Dana Rathkopf, MD 
Jonathan Rosenberg, MD 
Susan Slovin, MD, PhD 
David Solit, MD 
Martin Voss, MD 
Karen Autio, MD 
Wassim Abida, MD 
Chung-Han Lee, MD 
Min Yuen Teo, MB, BCh 
Maria Carlo, MD 
Maryann Carousso, NP 
Christine Liebertz, NP 
Aaron Mitchell, MD PhD 
Deaglan McHugh, MB BCh 
Han Xiao, MD 
Sree Chalasani, MD 
Afsheen Iqbal, MD 
Medicine 
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Memorial Sloan Kettering Cancer Center 
IRB Number: 17-511 A(3) 
Approval date: 13-Nov-2018 
 
 
 
 
 
Loren Michel, MD 
Medicine 
Rodrigo Erlich, MD 
Medicine 
Elizabeth Won, MD 
Medicine 
Alice Zervoudakis, MD 
Medicine 
Parisa Momtaz, MD 
Medicine 
Avni Desai, MD 
Medicine 
Stuart Lichtman, MD 
Medicine 
Jahan Aghalar, MD 
Medicine 
Juliana Eng, MD 
Medicine 
John Fiore, MD 
Medicine 
Jia Li, MD 
Medicine 
Wanqing Iris Zhi, MD, PhD 
Medicine 
 
 
Please Note: A Consenting Professional must have completed the 
mandatory Human Subjects E ducation and Certification Program . 
 
 
 
OneMSK Sites 
Manhattan 
Basking Ridge 
Westchester 
Commack 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ....................................................................................................... 5 
3.0 
BACKGROUND AND RATIONALE ............................................................................................................ 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................................. 16 
4.1 
Design ........................................................................................................................................ 16 
4.2 
Intervention ................................................................................................................................ 16 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ................................................................................................. 17 
6.0 
CRITERIA FOR SUBJECT ELIGIBIL ITY ................................................................................................... 20 
6.1 
Subject Inclusion Criteria ............................................................................................................. 20 
6.2 
Subject Exclusion Criteria ............................................................................................................. 23 
7.0 
RECRUITMENT PLA N ............................................................................................................................ 25 
8.0 
PRETREA TMENT EVALUA TION ........................................................................................................... 25 
9.0 
TREATMENT/ INTERVENTION PLA N .................................................................................................. 27 
10.0 
EVALUA TION DURING TREA TMENT/ INTERV ENTION ................................................................... 34 
11.0 
TOXICITIES/ SIDE EFFECTS ................................................................................................................. 35 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/ OUTCOME ASSESSMENT......................................... 40 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ............................................................................................ 41 
14.0 
BIOSTA TISTICS ..................................................................................................................................... 42 
15.0 
RESEARCH PARTICIPA NT REGISTRA TION A ND RA NDOMIZA TION PROCED URES ............... 45 
15.1 
Research Participant Registration ................................................................................................. 45 
15.2 
Randomization ............................................................................................................................ 45 
16.0 
DATA MA NA GEMENT ISSUES .................................................................................................................... 45 
16.1 
Quality Assurance ........................................................................................................................ 45 
16.2 
Data and Safety Monitoring .......................................................................................................... 46 
17.0 
PROTECTION OF HUMA N SUBJECTS .................................................................................................. 46 
17.1 
Privacy ....................................................................................................................................... 47 
17.2 
Serious Adverse Event (SAE) Reporting ........................................................................................ 47 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................................. 51 
19.0 
REFERENCES ........................................................................................................................................... 52 
20.0 
APPEND ICES ........................................................................................................................................... 57 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a phase II study testing durvalumab and tremelimumab in metastatic, non-transitional 
cell carcinoma of the urothelial tract. Patients with I) any component of small cell carcinoma 
(or neuroendocrine features)  II) predominant squamous cell carcinoma or III) predominant 
adenocarcinoma of the urothelial tract will be enrolled. A Simon‟s minimax two-stage design 
will be carried out. We will enroll 13 patients in the first stage. If we see 1 or more responses 
in the first stage, we continue to the second stage where we enroll an additional 14 patients 
for a total sample size of 27 patients. Patients will be treated in 4-week cycles. Patients will 
receive 4 cycles of the combination of durvalumab and tremelimumab followed by up to 9 
cycles of durvalumab maintenance or until lack of clinical benefit or unacceptable toxicity. 
Cross-sectional imaging will be performed every 8 weeks until the end of treatment. The 
best, confirmed overall response rate (ORR) by RECIST 1.1 will be  determined  as  the 
primary endpoint. 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective: 
 
• 
To determine the efficacy of the combination of durvalumab and tremelimumab in 
patients with I) carcinoma with a small-cell component (or neuroendocrine features) 
II) predominant squamous cell carcinoma or III) predominant adenocarcinoma or the 
urothelial tract as measured by best ORR, which will include the sum of  complete 
response (CR) + partial response (PR) by RECIST v 1.1. 
Secondary Objectives: 
 
• 
To assess for other parameters of clinical outcome of the combination of durvalumab 
plus tremelimumab in patients with I) carcinoma with a small-cell component (or 
neuroendocrine features) II) predominant squamous cell carcinoma or III) 
predominant adenocarcinoma or the urothelial tract including: 
o Progression Free Survival (PFS) and duration of response (DOR) rate by 
RECIST v1.1 
o Overall survival (OS) 
o Best ORR (CR + PR), PFS, and DOR by Immune-related Response Criteria in 
Solid Tumors (irRECIST) criteria 
o Clinical benefit (CR + PR + Stable Disease [SD]) rate by RECIST v1.1 and 
irRECIST 
o Rate of immune-related Adverse Events (irAE) 
o Rate of serious adverse events (SAE) 


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Figure 1 : Non-transitional cell carcinoma is 
associated with poor outcomes following radical 
cystectomy (3) 
 
Exploratory Objectives: 
• 
To determine differences in the immune microenvironment between bladder cancer 
histologies as determined by PD-L1 staining, immune related gene expression 
profiles, and multiplex immunofluorescence (IF) for multiple immune cell subsets 
• 
To determine whether bladder cancer histology and the associated immune 
microenvironment as defined above is predictive of the clinical benefit rate (CBR). 
• 
To determine if T cell clonality in tumors and blood will be associated with the CBR. 
• 
To determine whether immune suppressive cells types in the peripheral blood and in 
tumors will correlate with a decreased CBR. 
3.1 
BACKGROUND AND RATIONALE 
 
3.2 
Non-Transitional Cell Carcinoma of the Urothelial Tract 
 
Approximately 90% of malignant tumors arising from the urothelial tract are transitional cell 
carcinoma (TCC) (1). The remainder encompasses a variety of subtypes such as 
adenocarcinoma, squamous cell carcinoma, 
small cell/neuroendocrine carcinoma, 
sarcoma, paraganglioma, 
carcinosarcoma/sarcomatoid, lymphoma, or 
melanoma. Adenocarcinoma, squamous 
cell carcinoma, small cell/neuroendocrine 
carcinoma are the most common of these 
non-TCC histologies and compromise 0.5- 
2%, 3-5%,  and 0.5-1% of bladder tumors, 
respectively (1). TCC plus squamous cell 
carcinoma, adenocarcinoma, and small 
cell/neuroendocrine carcinoma are the 
recognized as distinct clinical entities (2). 
Although each of these tumors is 
characterized by unique risk factors and 
biology, a unifying feature is their 
aggressive course and dismal prognosis, including in patients with organ-confined disease 
(3) (Figure 1). For patients with metastatic disease, poor outcomes with standard, front-line 
chemotherapeutic regimes have been reported in two small prospective and a variety of 
small retrospective studies (Table 1).  For patients with metastatic disease that has 
progressed despite front-line therapy, clinicians have only case reports and a few 
retrospective studies to guide management. Outcomes are typically poor, and new 
therapeutic strategies are urgently needed. 


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Histology 
Regime 
ORR 
(% re sponse ; 95% CI) 
Median OS (Months) 
Citation 
Adeno 
TIP 
4/11 (36%; 15-59%) 
24.8 (95% CI, 10.2 to 32.2) 
(4) 
Adeno 
DMF IA/ IV 
5/8 (62.5%) 
10 (95% CI not reported) 
(5) 
Adeno 
Variable* 
3/9 (33%) 
20 (95% CI not reported) 
(6) 
Squamous 
TIP 
2/8 (25%; 3-65%) 
8.9 (95% CI, 5.4 to not reached) 
(4) 
Squamous 
Variable** 
0/5 
11 (95% CI not reported) 
(7) 
Small Cell 
IA and EP 
11/12 (92%) 
13.3 (95% CI, 8.5 to not reached) 
(8) 
Small Cell 
Variable^ 
9/12 (75%) 
15 (95% CI not reported) 
(9) 
Table 1. Frontline Chemotherapy Regimes in Non-Transitional Cell Predominant Metastatic 
Carcinoma of the Urothelial Tract. TIP=ifosfamide, paclitaxel, and cisplatin; 
IA=Ifosfamide/Doxorubicin; EP= Etoposide/Cisplatin; DMF= intra venous and/or intra -arterial 5-fluorouracil, 
doxorubicin, and mitomycin-C; *5-fluorouracil or cisplatin containing regimes; 
**methotrexate/vinblastine/doxorubicin/cisplatin or 5FU/cisplatin or gemcitabine/cisplatin; 
^cyclophosphamide/doxorubicin/vincristine or carboplatin/etoposide, or other platinum -based regime 
 
 
3.3 
Rationale for Immune Checkpoint Blockade in Non-Transitional Cell 
Carcinoma of the Urothelial Tract 
Checkpoint blockade is a transformative therapeutic approach to a broad spectrum of 
malignancies because it increases the power of antitumor immunity to obtain durable 
responses. Antibodies targeting the programmed death 1 (PD-1) pathway have  
demonstrated evidence of activity and been approved by the Federal Drug Administraion 
(FDA) in untreated and pre-treated metastatic TCC (10–15). Although these agents have not 
yet been investigated in non-TCC histologies, the promising results in small cell and 
squamous cell lung cancer (Table 2) provide strong rationale for their use in this setting. With 
regard to adenocarcinoma of the urothelial tract, a recently presented phase I expansion 
study incorporating immune checkpoint blockade reported that 1 in 4 patients had a partial 
response (16). Our group has also had success treating patients with adenocarcinoma of the 
urothelial tract with anti-PD-1 antibodies (personal communication with Dr. Dean Bajorin). 
Durvalumab is a anti-PDL1 antibody, which demonstrated a toxicity profile similar to other 
anti-PD-1/anti-PD-L1 agents, and was recently granted accelerated approval by the FDA for 
pre-treated metastatic TCC (10). 
 
Although treatment with PD-1 blockade has led to dramatic success in patients with 
previously incurable metastatic TCC, it is still only a minority of patients who benefit. This 
finding has driven the field toward developing combination therapies to increase response 
rates. Tremelimumab is an antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 
(CTLA-4), which is expressed on the surface of T cells, where it primarily suppresses their 
early stages of activation by inducing inhibitory downstream T-cell receptor (TCR) signaling 
and counteracting activity of the T-cell costimulatory receptor,  CD28  (17,18).  The 
combination of CTLA-4 and PD-1 blockade is FDA approved in melanoma and seems to be 
more efficacious than CTLA-4 blockade alone (19,20) or PD-1 blockade alone in patients 
whose tumors do not express PD-L1 (19). In patients with previously treated metastatic 
urothelial carcinoma who received anti-PD-L1 therapy, our group recently demonstrated that 
the diversity of the baseline peripheral TCR repertoire was directly correlated with overall 
survival (21). Importantly, CTLA-4 blockade has also been shown to increase the diversity 


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peripheral TCR repertoire, which may increase the likelihood that a particular anti-tumor T 
cell population is present (22,23). In addition, anti-PD-1 monotherapy and the combination of 
CTLA-4 and PD-1 blockade were evaluated in randomized phase II trial in recurrent small 
cell carcinoma of the lung (24). The combination demonstrated higher response rates over 
anti-PD-1 monotherapy is now listed in the NCCN compendium guidelines for the treatment 
of small cell carcinoma of the lung. Finally, in Checkmate 032, combined CTLA-4/PD-1 
blockade in patients with previously-treated, metastatic TCC with nivolumab 1 mg/kg and 
ipilimumab 3 mg/kg led to an ORR of 38.5%, which compares favorably with 24.4% ORR 
seen with nivolumab monotherapy (25). Although drug-related adverse events of grade 3 or 
4 are more common with the combination of PD-1 and CTLA-4 therapies, most of these 
events resolve with immunosuppressive medication. 
 
Therefore, the anti-PD-L1 antibody durvalumab in combination with the anti-CTLA-4 antibody 
tremelimumab is a logical therapeutic strategy. We hypothesize that it will demonstrate 
activity in patients with adenocarcinoma, squamous cell carcinoma, small  
cell/neuroendocrine carcinoma of the bladder. If successful, the proposed trial could change 
the standard of care for this patient population with very limited treatment options. 
 
Histology 
PD-1 Blocking Agent 
ORR 
Citation 
Small Cell (PD-L1+) 
Pembrolizumab 
7/20 (35%) 
(26) 
Small Cell 
Nivolumab 3 mg/kg 
10/98 (10%) 
(24) 
Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg 
14/61 (23%) 
Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg 
10/54 (19%) 
Squamous 
Nivolumab 
17/117 (15%) 
(27) 
Squamous 
Nivolumab 
27/135 (20%) 
(28) 
Squamous 
Durvalumab 
18/88 (21%) 
(29) 
Table 2. Immune checkpoint Blockade in Recurrent Small Cell and Squamous Cell Lung Cancer 
 
 
3.4 
Rationale for allowing chemo-naïve patients with squamous 
cell 
carcinoma and adenocarcinoma 
Atezolizumab (anti-PD-L1) and pembrolizumab (anti-PD-1) both have accelerated approval 
from the FDA for front-line use in chemo-naïve, cisplatin-ineligible patients with metastatic 
TCC. Approximately 50% of patients with metastatic TCC are cisplatin-ineligible (30). 
Pembrolizumab demonstrated a 29% ORR with the median duration of response not yet 
being reached after a median follow-up of 9.5 months (31). Atezolizumab demonstrated an 
ORR of 23% with a median overall survival of 15.9 months (14), which compares favorably to 
the 13.8-14.8 month median overall survival of cisplatin-eligible patients with metastatic TCC 
treated with a front-line cisplatin based regimens (32). These data have provided  the 
rationale for multiple, randomized, front-line clinical trials evaluating immune checkpoint 
blockade in patients with metastatic TCC. The squamous cell and adenocarcinoma 
histologies are generally believed to be chemotherapy refractory. Indeed, the NCCN 
guidelines suggest that patients with muscle-invasive squamous cell and adenocarcinoma of 


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the bladder proceed directly to cystectomy without receiving the neoadjuvant cisplatin-based 
chemotherapy that is standard of care for patients with muscle-invasive TCC. Small cell 
carcinoma, on the other hand, is well known to be chemotherapy sensitive, although it almost 
uniformly progresses after treatment. Thefore, we will allow patients with squamous cell 
carcinoma 
and 
adenocarcinoma 
to 
be 
chemo-naïve 
while 
patients 
with 
small 
cell/neuroendocrine must have been previously treated. 
 
3.5 
Durvalumab and tremelimumab 
 
3.4.1 
Durvalumab 
 
The non-clinical and clinical experience is fully described in the current version of the 
durvalumab Investigator‟s Brochure. 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 
kappa subclass that inhibits binding of PD-L1 and is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer.  (MedImmune is a  
wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to 
as AstraZeneca throughout this document.)  As durvalumab is an engineered mAb, it 
does not induce antibody-dependent cellular cytotoxicity or complement-dependent 
cytotoxicity. The proposed mechanism of action (MOA) for durvalumab is interference 
in the interaction of PD-L1 with PD-1 and CD80 (B7.1).  Blockade of PD-L1/PD-1 and 
PD-L1/CD80 interactions releases the inhibition of immune responses, including 
those that may result in tumor elimination.  In vitro studies demonstrate that 
durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells 
resulting in the restored proliferation of IFN-γ (36).  In vivo studies have shown that 
durvalumab inhibits tumor growth in xenograft models via a T cell dependent 
mechanism (36).  Based on these data, durvalumab is expected to stimulate the 
patient‟s antitumor immune response by binding to PD L1 and shifting the balance 
toward an antitumor response. Durvalumab has been engineered to reduce antibody- 
dependent cellular cytotoxicity and complement-dependent cytotoxicity. 
Durvalumab has been given to humans as part of ongoing studies as a single drug or 
in combination with other drugs. To date durvalumab has been given to more than 
6000 patients as part of ongoing studies either as monotherapy or in combination with 
other anti-cancer agents. No studies have been completed or terminated prematurely 
due to toxicity. 
 
As of 09Feb2015, pharmacokinetic (PK) data were available for 378 subjects in the 
dose-escalation and dose-expansion phases of Study CD-ON-durvalumab-1108 
following treatment with durvalumab 0.1 to 10 mg/kg every 2 weeks (Q2W) or 15 
mg/kg every 3 weeks (Q3W). The maximum observed concentration (Cmax) increased 
in an approximately dose-proportional manner over the dose range of 0.1 to 15 
mg/kg. The area under the concentration-time curve from 0 to 14 days (AUC0- 14) 
increased in a greater than dose-proportional manner over the dose range of 0.1 to 
3 mg/kg and increased dose-proportionally at ≥ 3 mg/kg. These results suggest 


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durvalumab exhibits nonlinear PK likely due to saturable target-mediated clearance at 
doses < 3 mg/kg and approaches linearity at doses ≥ 3 mg/kg. Near complete target 
saturation (soluble programmed cell death ligand 1 [sPD-L1] and membrane bound)  
is expected with durvalumab ≥ 3 mg/kg Q2W. Exposures after multiple doses showed 
accumulation consistent with PK parameters estimated from the first dose. In  
addition, PK simulations indicate that following durvalumab 10 mg/kg Q2W dosing, 
> 90% of subjects are expected to maintain PK exposure ≥ 40 µg/mL throughout the 
dosing interval. The PK data on the 4 week dosing of durvalumab is in section 3.3.3. 
 
As of 09Feb2015, a total of 388 subjects provided samples for anti-drug antibody 
(ADA) analysis. Only 8 of 388 subjects (1 subject each in 0.1, 1, 3, and 15 mg/kg 
cohorts, and 4 subjects in 10 mg/kg cohort) were ADA positive with an impact on 
PK/pharmacodynamics (PDx) in 1 subject in the 3 mg/kg cohort. 
 
Of note, durvalumab has been granted accelerated FDA approval for treatment of 
patients with platinum-refractory urothelial bladder cancer. The designation was  
based on the results of a phase I/2 multicenter study evaluating durvalumab in 61 
patients (40 PD-L1–positive, 21 PD-L1–negative) (33). The ORR was 31.0% (95% CI, 
17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the 
PD-L1–positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1–negative 
subgroup. Responses are ongoing in 12 of 13 responding patients, with median 
duration of response not yet reached (range, 4.1+ to 49.3+ weeks). The most 
common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), 
diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs 
occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. 
One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. 
3.4.2 Tremelimumab 
 
The non-clinical and clinical experience is fully described in the current version of the 
tremelimumab Investigator‟s Brochure. 
Tremelimumab is an IgG 2 kappa isotype mAb directed against the cytotoxic T- 
lymphocyte-associated protein 4 (CTLA-4) also known as CD152 (cluster of 
differentiation 152). This is an immunomodulatory therapy (IMT) that is being 
developed by AstraZeneca for use in the treatment of cancer. 
An extensive program of non-clinical and clinical studies has been conducted for 
tremelimumab both as monotherapy and combination therapy with conventional 
anticancer agents to support various cancer indications using different dose 
schedules.  To date tremelimumab has been given to more than 1500 patients as part 
of ongoing studies either as monotherapy or in combination with other anticancer 
agents. Refer to the current tremelimumab Investigator‟s Brochure for a complete 
summary of non-clinical and clinical information including safety, efficacy and 
pharmacokinetics. 


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Tremelimumab exhibited a biphasic PK profile with a long terminal phase half-life of 
22 days. Overall, a low incidence of ADAs (<6%) was observed for treatment with 
tremelimumab. 
3.4.3 
Durvalumab in combination with tremelimumab 
 
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity 
(34) because the mechanisms of action of CTLA-4 and PD-1 are non-redundant; 
therefore, AstraZeneca is also investigating the use of durvalumab + tremelimumab 
combination therapy for the treatment of cancer. 
To date more than 3000 patients have received the combination using a number of 
doses and dosing schedules. 
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, PK/PDx, 
and preliminary anti-tumor activity of durvalumab + tremelimumab combination 
therapy in patients with advanced NSCLC (35).  The dosing schedule utilized is 
durvalumab every 2 weeks (Q2W) up to week 40 or every 4 weeks (Q4W) up to 
Week 48 (12 months), combined with tremelimumab Q4W up to Week 24 for 7 doses 
then every 12 weeks for 2 additional doses for up to 12 months.  The recently 
published results are discussed below. 
Study D4190C00006: As of 20Feb2015, durvalumab PK (n = 55) and tremelimumab 
PK (n = 26) data were available from 10 cohorts (1a, 2a, 3a, 3b, 4, 4a, 5, 5a, 8, and 
9) following durvalumab every Q4W or Q2W dosing in combination with 
tremelimumab Q4W regimens. An approximately dose-proportional increase in PK 
exposure (Cmax  and area under the concentration-time curve from 0 to 28 days 
[AUC0- 28]) of both durvalumab and tremelimumab was observed over the dose range 
of 3 to 15 mg/kg durvalumab Q4W and 1 to 10 mg/kg tremelimumab Q4W. Exposures 
following multiple doses demonstrated accumulation consistent with PK parameters 
estimated from the first dose. It is to be noted that steady state PK parameters are 
based on limited numbers of subjects. The observed PK exposures of durvalumab 
and tremelimumab following combination were consistent with respective 
monotherapy data, indicating no PK interaction between these 2 agents. 
 
As of 20Feb2015, ADA data were available from 60 subjects for durvalumab and 53 
subjects for tremelimumab in Study D4190C00006. Four of 60 subjects were ADA 
positive for anti-durvalumab antibodies post treatment. One of 53 subjects was ADA 
positive for anti-tremelimumab antibodies post treatment. There was no clear 
relationship between ADA and the dose of either durvalumab or tremelimumab, and 
no obvious association between ADA and safety or efficacy. 
An update of Study D4190C00006 was published in March of 2016 (35). Between Oct 
28, 2013, and April 1, 2015, 102 patients were enrolled into the dose-escalation  
phase and received treatment. At the time of this analysis (June 1, 2015), median 
follow-up was 18·8 weeks (IQR 11-33). The maximum tolerated dose was exceeded 


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in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 
mg/kg, with two (30%) of six patients having a dose-limiting toxicity (one grade 3 
increased aspartate aminotransferase and alanine aminotransferase and one grade 4 
increased lipase). The most frequent treatment-related grade 3 and 4 adverse events 
were diarrhea (11 [11%]), colitis (nine [9%]), and increased lipase (eight [8%]). 
Discontinuations attributable to treatment-related adverse events occurred in 29 
(28%) of 102 patients. Treatment-related serious adverse events occurred in 37 
(36%) of 102 patients. 22 patients died during the study, and three deaths were 
related to treatment. The treatment-related deaths were due to complications arising 
from myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 
mg/kg), pericardial effusion (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 
1 mg/kg), and neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus 
tremelimumab 3 mg/kg). Evidence of clinical activity was noted both in patients with 
PD-L1-positive tumors and in those with PD-L1-negative tumors. Investigator- 
reported confirmed objective responses were achieved by six (23%, 95% CI 9-44) of 
26 patients in the combined tremelimumab 1 mg/kg cohort, comprising two (22%, 
95% CI 3-60) of nine patients with PD-L1-positive tumors and four (29%, 95% CI 8- 
58) of 14 patients with PD-L1-negative tumors, including those with no PD-L1 staining 
(four [40%, 95% CI 12-74] of ten patients). 
3.4.3.1 Durvalumab  + tremelimumab combination therapy dose rationale 
 
The durvalumab + tremelimumab doses and regimen selected for this study 
are based on the goal of selecting an optimal combination dose of durvalumab 
and tremelimumab that would yield sustained target suppression (PD-L1), 
demonstrate promising efficacy, and have an acceptable safety profile. 
 
In order to reduce the dosing frequency of durvalumab to align with the Q4W 
dosing of tremelimumab, while ensuring an acceptable PK/PDx, safety, and 
efficacy profile, cohorts were narrowed to 15 and 20 mg/kg durvalumab Q4W. 
PK simulations from the durvalumab monotherapy data indicated that a similar 
area under the plasma drug concentration-time curve at steady state (AUCss; 4 
weeks) was expected following both 10 mg/kg Q2W and 20 mg/kg Q4W 
durvalumab.  The observed durvalumab PK data from the D4190C00006  
study were well in line with the predicted monotherapy PK data developed 
preclinically.  This demonstrates similar exposure of durvalumab 20 mg/kg 
Q4W and 10 mg/kg Q2W, with no alterations in PK when durvalumab and 
tremelimumab (doses ranging from 1 to 3 mg/kg) are dosed together.  While 
the median Cmax  at steady state (Cmax,ss) is expected to be higher with 
20 mg/kg Q4W (approximately 1.5 fold) and median trough concentration at 
steady state (Ctrough,ss) is expected to be higher with 10 mg/kg Q2W 
(approximately 1.25 fold), this is not expected to impact the overall safety and 
efficacy profile, based on existing preclinical and clinical data. 


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Monotonic increases in PDx activity were observed with increasing doses of 
tremelimumab relative to the activity observed in patients treated with 
durvalumab monotherapy.  There was evidence of augmented PDx activity 
relative to durvalumab monotherapy with combination doses containing 1 
mg/kg tremelimumab, inclusive of both the 15 and 20 mg/kg durvalumab plus 
1 mg/kg tremelimumab combinations. 
 
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate 
of adverse events (AEs), including discontinuations due to AEs, serious AEs 
(SAEs), and severe AEs.  Between the 10 mg/kg durvalumab + 1 mg/kg 
tremelimumab and 10 mg/kg durvalumab + 3 mg/kg tremelimumab cohorts 
treated at the Q2W schedule, the number of patients reporting any AE, Grade 
3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg 
durvalumab + 3 mg/kg tremelimumab cohort than the 10 mg/kg durvalumab + 
1 mg/kg tremelimumab cohort.  A similar pattern was noted in the Q4W 
regimens, suggesting that, as the dose of tremelimumab increased above 1 
mg/kg, a higher rate of treatment-related events may be anticipated.  Further, 
the SAEs frequently attributed to immunotherapy, pneumonitis and colitis, 
were more commonly seen in cohorts using either 3 or 10 mg/kg of 
tremelimumab compared to the 1 mg/kg dose cohorts.  Together, these data 
suggest that a combination using a tremelimumab dose of 1 mg/kg appeared 
to minimize the rate of toxicity when combined with durvalumab.  As a result, 
all combination doses utilizing either the 3 or 10 mg/kg doses of 
tremelimumab were eliminated in the final dose selection. 
 
In contrast, cohorts assessing higher doses of durvalumab with a constant 
dose of tremelimumab did not show an increase in the rate of AEs. The data 
suggested that increasing doses of durvalumab might not impact the safety of 
the combination as much as the tremelimumab dose. Further, safety data 
between the 10-mg/kg and 20-mg/kg cohorts were similar, with no change in 
safety events with increasing dose of durvalumab. 
 
In Study D4190C00006 (35), of all treatment cohorts, the cohort of 11 patients 
treated in the 20 mg/kg durvalumab + 1 mg/kg tremelimumab group had the 
fewest AEs, Grade ≥3 AEs, SAEs, and treatment discontinuations due to AEs, 
but still showed strong evidence of clinical activity. This cohort had a lower 
number of treatment-related Grade ≥3 AEs or treatment-related SAEs. No 
dose-limiting toxicities were reported. 
Preliminary clinical activity of the durvalumab and tremelimumab combination 
did not appear to change with increasing doses of tremelimumab. The 15- 
and 20-mg/kg durvalumab Q4W cohorts demonstrated objective responses at 
all doses of tremelimumab, and increasing doses of tremelimumab did not 
provide deeper or more rapid responses. 


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Efficacy data suggested that the 20 mg/kg durvalumab + 1 mg/kg 
tremelimumab dose cohort may demonstrate equivalent clinical activity to 
other dose combinations.  A total of 5 of 11 patients in the 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab cohort were evaluable for efficacy with 
at least 8 weeks of follow-up.  Of these, there were 2 patients (40%) with 
partial response (PR), 1 patient (20%) with stable disease (SD), and 1 patient 
(20%) with progressive disease (PD).  (The fifth patient had only a single 
scan, which was conducted outside the window for these evaluations.) 
 
Taken together, the efficacy and toxicity data suggested that the 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab dose combination should be selected 
for further development. 
3.4.3.2 Rationale   for  4  cycles  of  combination  therapy  followed  by 
durvalumab monotherapy 
Long-term follow up on melanoma patients treated with ipilimumab, an anti- 
CTLA-4 targeting antibody (dosed every 3 weeks [q3w] for 4 doses and then 
discontinued), shows that patients responding to ipilimumab derive long-term 
benefit, with a 3-year OS rate of approximately 22%. Furthermore, the survival 
curve in this  population reached a plateau at 3 years  and was maintained 
through 10 years of follow up (31). 
 
Data from Study D4190C00006 (Phase I trial in NSCLC patients using the 
combination of durvalumab and tremelimumab) also show an approximately 
dose-proportional increase in PK exposure for durvalumab over  the  dose 
range of 3 to 20 mg/kg durvalumab Q4W or Q2W. (For further information on 
PK observations in Study 006, please see the current IB). 
The observed durvalumab PK data from the combination study were well in 
line with the predicted monotherapy PK data (5th median and 95th 
percentiles) for a Q4W regimen. 
 
Similar data have been presented for other anti-PD-1/PD-L1 targeting 
antibodies: 
 
Nivolumab (anti-PD-1) was dosed Q2W for up to 96 weeks in a large Phase I 
dose-escalation and expansion study, and showed responses were 
maintained for a median of 22.94 months for melanoma (doses 0.1 mg/kg to 
10 mg/kg), 17 months for NSCLC (doses 1, 3, and 10 mg/kg), and 12.9 
months for renal cell carcinoma patients (doses 1 and 10 mg/kg) at the time of 
data analysis (28,37,38).  Furthermore, responses were maintained beyond 
treatment discontinuation in the majority of patients who stopped nivolumab 
treatment (either due to protocol specified end of treatment, complete 
response [CR], or toxicity) for up to 56 weeks at the time of data analysis (37). 


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MPDL3280a (anti-PD-L1) and the combination of nivolumab with ipilimumab, 
in which patients were dosed for a finite time period and responses 
maintained beyond treatment discontinuation have been reported (39,40). 
 
Similar long-term results may be expected with use of other immune-mediated 
cancer therapeutics including anti-CTLA-4 antibodies such as tremelimumab, 
anti PD-L1 antibodies such as durvalumab, or the combination of the two. 
3.4.3.3 Fixed Dosing for durvalumab and tremelimumab 
 
A population PK model was developed for durvalumab using monotherapy 
data from a Phase I study (study 1108; N=292; doses=0.1 to 10 mg/kg Q2W 
or 15 mg/kg Q3W; solid tumors). Population PK analysis indicated only minor 
impact of body weight (WT) on the PK of durvalumab (coefficient of ≤0.5). The 
impact of body WT-based (10 mg/kg Q2W or 20 mg/kg Q4W) and fixed dosing 
(750 mg Q2W or 1500 mg Q4W) of durvalumab was evaluated by comparing 
predicted steady state PK exposures (AUCss,0-28, Cmax,ss, and Cmin,ss) 
using the population PK model. A fixed dose of 750 mg Q2Wwas selected to 
approximate 10 mg/kg Q2W and a fixed dose of 1500 mg Q4W was selected 
to approximate 20 mg/kg Q4W (based on median body WT of ~75 kg). A total 
of 1000 patients were simulated using body WT distribution of 40–120 kg. 
Simulation results demonstrate that body WT-based (10 mg/kg Q2W) and 
fixed dosing (750 mg Q2W) regimens yield similar median steady state Q2W 
and a fixed dose of 1500 mg Q4W was selected to approximate 20 mg/kg 
Q4W .Similarly, a population PK model was  developed  for  tremelimumab 
using data from Phase 1 through Phase 3 (N=654; doses= 0.01 to 15 mg/kg 
Q4W or Q90D; metastatic melanoma) (42). Population PK model indicated 
minor impact of body WT on PK of tremelimumab (coefficient of ≤ 0.5). The 
WT-based (1 mg/kg Q4W) and fixed dosing (75 mg/kg Q4W; based  on 
median body WT of ~75 kg) regimens were compared using predicted PK 
concentrations (5th, median and 95th  percentiles) using population PK model in 
a simulated population of 1000 patients with body weight distribution of 40 to 
120 kg. Similar to durvalumab, simulations indicated that both body WT-based 
and fixed dosing regimens of tremelimumab yield similar median steady state 
PK concentrations with slightly less between-subject variability with fixed 
dosing regimen. 
 
Similar findings have been reported by others (43–45). Zhang and colleagues 
investigated 12 monoclonal antibodies and found that fixed and body size- 
based dosing perform similarly, with fixed dosing being better for 7 of 12 
antibodies. In addition, they investigated 18 therapeutic proteins and peptides 
and showed that fixed dosing performed better for 12 of 18 in  terms  of 
reducing the between-subject variability in PK/PDx parameters(45). 


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A fixed dosing approach is preferred by the prescribing community due to 
ease of use and reduced dosing errors. Given expectation of similar PK 
exposure and variability, we considered it feasible to switch to fixed dosing 
regimens. Based on average body WT of 75 kg, a fixed dose of 1500 mg Q4W 
durvalumab (equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab 
(equivalent to 1 mg/kg Q4W) is included in the current study. 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a single-arm, phase II study with a Simon minimax design testing the combination of 
durvalumab and tremelimumab in patients with non-TCC of the urothelial tract. In the first 
stage, 13 patients will be accrued. If there are no responses in these 13 patients, the study 
will be stopped. Otherwise, 14 additional patients will be accrued for a total of 27. The null 
hypothesis will be rejected if 4 or more responses are observed in 27 patients. See section 
14 for more details regarding statistical design. 
4.3 
Intervention 
 
Patients will receive durvalumab 1500 mg and tremelimumab 75 mg IV Q4W for up to 4 
doses/cycles, then durvalumab 1500 mg Q4W starting at Week 16 for 9 doses (total 
treatment duration of 12 months). The rationale for this dosing schedule is explained in 
section 3.3. 
 
Tremelimumab will be administered first.  Durvalumab infusion will start approximately 1 hour 
after the end of the tremelimumab infusion.  The duration will be approximately 1 hour for 
each infusion.  A 1-hour observation period is required after the first infusion of durvalumab 
and tremelimumab.  If no clinically significant infusion reactions are observed during or after 
the first cycle, subsequent infusion observation periods can be at the Investigator‟s discretion 
(suggested 30 minutes after each durvalumab and tremelimumab infusion). The timing is 
illustrated below. 
 
DURVALUMAB/TREMELIMUMAB  COMBINATION  TREATMENT  PLAN 
TIME: 
0hr – 1hr 
1hr – 2hr 
2hr – 3hr 
3hr – 4hr 
Tremelimumab 
X 
Observation 
X* 
X* 
Durvalumab 
X 
*If no clinically significant infusion reactions are observed during or after the first cycle, 
subsequent infusion observation periods can be at the Investigator‟s discretion 
(suggested 30 minutes after each durvalumab and tremelimumab infusion). 


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5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
durvalumab and tremelimumab to the investigator as a solution for infusion after dilution. 
 
Based on average body weight of 75 kg, a fixed dose of 1500 mg Q4W durvalumab 
(equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) 
is included in the current study. 
5.2 
Durvalumab 
 
Durvalumab will be supplied by Astrazeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 50 mg/ml durvalumab, 26 mM histidine/histidine-hydrochloride, 
275 mM trehalose dehydrate, and 0.02% (weight/volume) polysorbate 80; it has a pH of 6.0. 
The normal fill volume is 10mL. Investigational product vials are stored at 2°C to 8°C (36°F to 
46°F) and must not be frozen. Durvalumab must be used within the individually assigned 
expiry date on the label. 
Preparation of durvalumab doses for administration with an IV bag 
 
The dose of durvalumab for administration must be prepared by the Investigator‟s or site‟s 
designated (investigational protocol) IP manager using aseptic technique. Total time from 
needle puncture of the durvalumab vial to the start of administration should not exceed: 
 
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
 
• 
4 hours at room temperature 
 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. 
Infusion solutions must be allowed to equilibrate to room temperature prior to 
commencement of administration. 
 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have 
been observed. Dose of 1500mg durvalumab for patients >30 kg will be administered using 
an IV bag containing 0.9% (weight per volume [w/v]) saline or 5% (w/v) dextrose, with a final 
durvalumab concentration ranging from 1 to 20 mg/mL, and delivered through an IV 
administration set with a 0.2- or 0.22-μm in-line filter.  Remove 30.0 mL of IV solution from 
the IV bag prior to addition of durvalumab.  Next, 30.0 mL of durvalumab (i.e., 1500 mg of 
durvalumab) is added to the IV bag such that final concentration is within 1 to 20 mg/mL (IV 
bag volumes 100 to 1000 mL).  Mix the bag by gently inverting to ensure homogeneity of the 
dose in the bag. 
 
A fixed dosing of Durvalumab (1500mg) will be used. Durvalumab will be administered at 
room temperature (approximately 25°C) by controlled infusion via an infusion pump into a 
peripheral or central vein. Following preparation of durvalumab, the entire contents of the IV 
bag should be administered as an IV infusion over approximately 60 minutes, using a 0.2, or 


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0.22-μm in-line filter. Longer infusions up to 8 hours are allowed if interruptions are 
necessary (see below). 
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline or  5%  [w/v] 
dextrose) equal to the priming volume of the infusion set used after the contents of the IV 
bag are fully administered, or complete the infusion according to institutional policy to ensure 
the full dose is administered and document if the line was not flushed. 
Standard infusion time is 1 hour. However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature. The table below summarizes 
time allowances and temperature. 
Durvalumab hold and infusion times 
 
Maximum 
time from needle 
puncture 
to 
start 
of 
administration 
4 hours 
at room 
temperature, 
24 hours at 2°C to 8°C 
Maximum 
time for IV bag 
infusion, including interruptions 
8 hours at room temperature 
 
 
In the event that either preparation time or infusion time exceeds the time limits outlined in 
the table, a new dose must be prepared from new vials. Durvalumab does not contain 
preservatives, and any unused portion must be discarded. 
 
5.2 
Tremelimumab 
 
Tremelimumab will be supplied by AstraZeneca as a 400-mg vial solution for infusion after 
dilution. The solution contains 20 mg/mL of tremelimumab, 20 mM histidine/histidine 
hydrochloride, 222 m M trehalose dihydrate, 0.02% (w/v) polysorbate 80, and 0.27 mM 
disodium edetate dihydrate (EDTA); it has a pH of 5.5. The nominal fill volume is 20 mL. 
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Tremelimumab must be used within the individually assigned expiry date on the label. 
Preparation of tremelimumab doses for administration with an IV bag 
 
The dose of tremelimumab for administration must be prepared by the Investigator‟s or site‟s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
tremelimumab vial to the start of administration should not exceed: 
 
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
 
It is recommended that the prepared final IV bag be stored in the dark at 2ºC-8°C (36°F- 
46°F) until needed. If storage time exceeds these limits, a new dose must be prepared from 


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new vials. The refrigerated infusion solutions in the prepared final IV bag should be 
equilibrated at room temperature for about 2 hours prior to administration. Tremelimumab 
does not contain preservatives and any unused portion must be discarded. 
 
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin IV bags have 
been observed. Doses of 75 mg tremelimumab for patients >30 kg will be administered using 
an IV bag containing 0.9% (w/v) saline, with a final tremelimumab concentration ranging from 
0.1 mg/mL to 10 mg/mL, and delivered through an IV administration set with a 0.2 μm or 0.22 
μm in-line filter. Remove 3.8 mL of IV solution from the IV bag prior to addition of 
tremelimumab.  Next, 3.8 mL of tremelimumab (i.e., 75 mg of tremelimumab) is added to the 
IV bag such that final concentration is within 0.1 mg/mL to 10 mg/mL (IV bag volumes 50 to 
500 mL).  Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
 
A fixed dose of 75mg of Tremelimumab will be used. Tremelimumab will be administered at 
room temperature (approximately 25°C) by controlled infusion via an infusion pump into a 
peripheral or central vein. Following preparation of tremelimumab, the entire contents of the 
IV bag should be administered as an IV infusion over approximately 60 minutes, using a 0.2, 
or 0.22-μm in-line filter. Longer infusions up to 8 hours are allowed if interruptions are 
necessary (see below). 
 
The IV line will be flushed with a volume of 0.9% (w/v) saline equal to the priming volume of 
the infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed. 
 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  The table below summarizes 
time allowances and temperatures. 
Tremelimuab hold and infusion times 
 
Maximum time from needle puncture to 
start of administration 
4 hours  at room  temperature, 24 hours  at 
2°C to 8°C 
Maximum   time  for   IV  bag   infusion, 
including interruptions 
8 hours at room temperature 
 
 
In the event that either preparation time or infusion time exceeds the time limits outlined in 
the table, a new dose must be prepared from new vials.  Tremelimumab does not contain 
preservatives, and any unused portion must be discarded. 
 
5.3 Monitoring of dose administration 
 
Patients will be monitored before, during and after the infusion with assessment of vital signs 
as outlined in section 10. 


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In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion.  For patients with a ≤Grade 2 infusion-related 
reaction, subsequent infusions may be administered at 50% of the initial 
rate.  Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent 
medications per institutional standard may be administered at the discretion of the 
investigator.  If the infusion-related reaction is ≥Grade 3 or higher in severity, study drug will 
be discontinued. 
 
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. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
For inclusion in the study, patients should fulfill the following criteria: 
 
1. Age > 18 years at time of informed consent 
 
2. Body weight > 30 kg 
 
3. Histologically or cytologically confirmed small cell carcinoma, squamous cell carcinoma 
or adenocarcinoma (confirmed at MSKCC) of the bladder, ureter, urethra, urachus, or 
renal pelvis. Patients with squamous cell carcinoma and adenocarcinoma are required to 
have a predominant squamous or adenocarcinoma component as reviewed by the 
pathologist at MSKCC. However, if any element of small cell or neuroendocrine 
differentiation is present, the patients will be classified as small cell/neuroendocrine. 
 
4. Confirmation of availability of sufficient tissue from a prior sugery for correlative studies is 
required prior to enrollment. Patients must have representative non-TCC or the urothelial 
tract FFPE archival tumor specimens (tumor blocks or 30 unstained slides; preference for 
tumor blocks). These samples may be submitted between the time of consent and the 
start of treatment. Patients with < 30 slides may be enrolled after discussion with the 
principal or co-principal investigators, see Section 9.5.2 for more details. 
 
5. Clinical evidence of metastatic (T4b, any N; any T, N2-3; M1) disease. 
 
6. Life expectancy of 12 weeks of greater based on assessment by the treating investigator. 
 
7. Evidence of measurable disease by RECIST 1.1. 
 
8. Patients with small cell carcinoma must have progressed after at least one prior systemic 
therapy. Patients with squamous cell carcinoma or adenocarcinoma may be previously 


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untreated or have progressed after prior systemic therapy. Chemotherapy administered 
in conjunction with primary radiation as a radio-sensitizer WILL be counted as a systemic 
chemotherapy regimen. NOTE: There is no maximum number of prior treatments 
allowed. 
 
9. Patients with brain metastases are allowed onto the study as  long as  patients have 
completed their treatment for brain metastasis, no longer require corticosteroids, and are 
asymptomatic. Subjects with neurological symptoms should undergo a head CT scan or 
brain MRI to exclude brain metastasis, at the discretion of the treating physician. 
 
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 
 
11. Adequate normal organ and marrow function as defined below: 
 
• 
Hemoglobin ≥ 9.0 g/dL 
• 
Absolute neutrophil count (ANC) ≥ 1.0 x 109/L (> 1000 per mm3) 
• 
Platelet count ≥ 100 x 109/L (>100,000 per mm3) 
• 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (≤ 3 x institutional ULN 
in patients with Gilbert‟s syndrome) 
• 
AST  (SGOT)/ALT  (SGPT)  ≤  2.5  x  institutional  ULN unless  liver  metastases  are 
present, in which case it must be ≤ 5 x ULN 
• 
Calculated creatinine clearance > 30 mL/min by the Cockcroft-Gault formula 
(Cockcroft and Gault 1976) or by 24-hour urine collection for determination of 
creatinine clearance: 
 
Males: 
Creatinine 
CL 
(mL/min) 
= 
W eight (kg) x (140 – Age) 
. 
72 x serum creatinine (mg/dL) 
Females: 
Creatinine 
CL 
(mL/min) 
= 
W eight (kg) x (140 – Age) 
 
x 0.85 
72 x serum creatinine (mg/dL) 
 
12. Evidence of post-menopausal status or negative serum pregnancy test for female pre- 
menopausal patients. Women will be considered post-menopausal if they have been 
amenorrheic for 12 months without an alternative medical cause. The following age- 
specific requirements apply: 
- 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone  and  follicle-stimulating  hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy). 


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- 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy,  bilateral  salpingectomy  or 
hysterectomy). 
13. Female patients of reproductive potential and non-sterilized males  who  are  sexually 
active with a female partner of childbearing potential must be willing to adhere to the 
following restrictions: 
- Females of reproductive potential who are sexually active with a non-sterilized 
male partner must agree to use at least 1 highly effective method of 
contraception (Table 3) from the time of screening until 180 days after the last 
dose of durvalumab + tremelimumab combination therapy or 90 days after the last 
dose of durvalumab monotherapy. Cessation of birth control after this point should 
be discussed with a responsible physician. Periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of birth control. 
It is strongly recommended that non-sterilized male partners of a female patient 
must use male condom plus spermicide throughout this period. Not engaging in 
sexual activity for the total duration of the drug treatment and the drug washout 
period is an acceptable practice. 
 
- Non-sterilized males who are sexually active with a female partner of childbearing 
potential must use a male condom plus spermicide from screening through 180 
days after receipt of the final dose of durvalumab + tremelimumab combination 
therapy or 90 days after receipt of the final dose of durvalumab monotherapy. 
Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control. Not engaging in sexual activity is an 
acceptable practice. Male patients should refrain from sperm donation throughout 
this period. It is strongly recommended that female partners (of childbearing 
potential) of male patients to also use a highly effective method of contraception 
(Table 3) throughout this period. 
 
- Highly effective methods of contraception, defined as one that results in a low 
failure rate (i.e., less than 1% per year) when used consistently and correctly are 
described in Table 3. 


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Table 3. Highly effective methods of contraception (<1% failure rate) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
This is also considered a hormonal method 
 
14. Subject is  willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow 
up. 
 
 
6.3 
Subject Exclusion Criteria 
 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. Previous enrollment in the present study 
2. Participation in another clinical study with an investigational product during the last 14 
days 
3. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using  Fredericia‟s Correction 
4. Any previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab or an anti- 
CTLA-4, including tremelimumab 
5. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal 
antibodies, other investigational agent) < 21 days prior to enrollment. 
6. Major surgery within 28 days of starting study treatment. There is no minimum time 
requirement for minor procedures such as biopsy or vascular access placement. 
7. Radiation within 14 days of starting study treatment 
Barrier/Intrauterine  methods 
Hormonal  Methods 
• 
Copper T intrauterine device 
• 
Levonorgestrel-releasing  intrauterine  system 
(e.g., Mirena®)a 
• 
Implants:  Etonogestrel-releasing implants: 
e.g. Implanon® or Norplant® 
• 
Intravaginal:   Ethinylestradiol/etonogestrel- 
releasing intravaginal devices: e.g. 
NuvaRing® 
• 
Injection: Medroxyprogesterone injection: e.g. 
Depo-Provera® 
• 
Combined Pill: Normal and low dose 
combined oral contraceptive pill 
• 
Patch:   Norelgestromin/ethinylestradiol- 
releasing transdermal system: e.g. Ortho 
E vra® 
• 
Minipillc: Progesterone based oral 
contracepti ve pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone based pill 


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8. Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab or tremelimumab. The following are exceptions to this criterion: 
- 
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection) 
 
- 
Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of 
prednisone or its equivalent 
 
- 
Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
 
9. Any unresolved toxicity from previous anti-cancer therapy must have resolved to at least 
≤ Grade 1 (or baseline) at time of enrollment. 
Patients with irreversible toxicity that is not reasonably expected to be exacerbated by 
treatment with durvalumab and tremelimumab may be included after consultation with the 
Principal Investigator or Co-Principal Investigator (e.g. alopecia, hearing loss, peripheral 
neuropathy). 
 
10. Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis, celiac disease, 
systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome 
[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, 
uveitis, etc]).  The following are exceptions to this criterion: 
- 
Patients with vitiligo or alopecia 
- 
Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 
- 
Any chronic skin condition that does not require systemic therapy 
- 
Patients without active autoimmune disease in the last 5 years may be included 
but only after consultation with the study physician 
- 
Patients with diverticulosis 
- 
Patients with celiac disease controlled by diet alone 
11. History of primary immunodeficiency 
12. History of allogeneic organ transplant 
13. History of hypersensitivity to durvalumab, tremelimumab or any excipient 
14. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal 
conditions associated with diarrhea, or psychiatric illness/social situations that would limit 
compliance with study requirement, substantially increase risk of incurring AEs or 
compromise the ability of the patient to give written informed consent. 
15. Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing in line with local practice), 


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hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human 
immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved 
HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and 
absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are 
eligible only if polymerase chain reaction is negative for HCV RNA. 
16. History of leptomeningeal carcinomatosis 
17. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days 
of receiving durvalumab or tremelimumab. Inactivated vaccines, such as the injectable 
influenza vaccine, are permitted. 
18. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results 
19. Malignancies other than the disease under study within 5 years prior to Cycle 1, Day 1, 
with the exception of those with a negligible risk of metastasis or death and with expected 
curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or 
squamous cell skin cancer, localized prostate cancer treated surgically with curative 
intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing 
active surveillance per standard-of-care management (e.g. prostate cancer with Gleason 
score  6, and prostate-specific antigen [PSA]  10 mg/mL, etc). 
20. Patients should agree to not donate blood while participating in this study or for at least 
90 days following the last infusion of durvalumab or tremelimumab 
21. Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from screening 
to 90 days after the last dose of durvalumab monotherapy or180 days after the last dose 
of durvalumab + tremelimumab combination therapy. 
 
7.0 
RECRUITMENT PLAN 
 
Eligible patients with non-TCC of the urothelial tract will be recruited from the Genitourinary 
Oncology and Urology Services at MSKCC. Every attempt will be made to recruit women and 
minorities to participate in this study. Participation is voluntary. The consenting physician will 
inform patients of their diagnosis, current treatment options including standard treatment, and 
the risks, benefits, and experimental nature of this treatment program. 
 
 
8.1 
PRETREATMENT EVALUATION 
 
The following studies must be completed within 14 days prior to study registration/ enrollment 
(unless otherwise indicated): 
• 
Informed consent (within 28 days) 
• 
Review of eligibility criteria 
• 
Medical history and demographics, including tobacco and alcohol use 


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• 
Complete physical exam (with height measured at screening only) 
• 
ECOG Performance Status 
• 
Vitals signs including temperature, blood pressure, respiratory rate, heart rate, weight, and 
height 
• 
12-lead ECG (in triplicate [2-5 minutes apart]) 
• 
Submission of archival tumor tissue. Patients without archival tumor tissue may be 
enrolled after discussion with the principal investigator. Repeat biopsies purely for 
investigational purposes for this study will not be performed. See section 9.5.2 for 
additional details. 
• 
Review of prior/concomitant medications 
• 
Appropriate radiographic diagnostic procedures (for example CT scan of chest and CT or 
MRI of the abdomen & pelvis) for evaluation of measurable disease at baseline within 28 
days of registration. 
• 
Clinical laboratory tests for: 
o CBC (see Table 4) 
o Clinical chemistry panel (see Table 5) 
o TSH (free T3 and free T4 only if TSH is abnormal) 
o Coagulation (PT, PTT, INR) 
o Estimated Creatinine Clearance using the Cockcroft-Gault formula 
o Serum pregnancy test (for women of childbearing potential only) 
o Hepatitis serologies (Hepatitis B surface antigen, hepatitis B core antibody, 
hepatitis C antibody) and HIV antibody screen within 28 days 
o Urinalysis (see Table 6) 
 
• 
Research bloods as outlined in section 9 and per MSKCC standard operating procedures 
 
Table 4. Complete blood count (CBC) 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
Mean corpuscular haemoglobin 
Total white cell count 
Mean corpuscular haemoglobin concentration 
 
 
 


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Table 5. Clinical chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Creatinine 
Alkaline phosphatase 
Glucose 
Alanine aminotransferase 
Lipase* 
Magnesium * 
Amylase* 
Potassium 
Aspartate aminotransferase 
Sodium 
Bicarbonate 
Total bilirubina 
Calcium 
Total protein 
Chloride 
Urea or blood urea nitrogen, depending on local practice 
 
 
a    If Total bilirubin is ≥1.5xULN (and no evidence of Gilbert‟s syndrome) then fractionate into 
direct and indirect bilirubin 
*These tests are not part of the standard MSKCC comprehensive metabolic panel and will need 
to be ordered separately. 
 
 
 
 
 
 
 
 
 
 
a   Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red 
blood cells 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
Intervention 
 
This is a single-arm, phase II study with a Simon minimax design testing the combination of 
durvalumab and tremelimumab in patients with non-TCC of the urothelial tract. 
 
Patients will receive durvalumab 1500 mg and tremelimumab 75 mg IV Q4W for up to 4 
doses/cycles, then durvalumab 1500 mg Q4W starting 4 weeks after the last combination 
treatment for up to 9 doses. The rationale for this dosing schedule is explained in section 3.3. 
Table 6. 
Urinalysis Testsa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 


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9.2 
Duration of treatment, treatment beyond progression, and criteria  for 
retreatment 
Patients will continue study treatment until lack of clinical benefit, development of 
unacceptable toxicity, or completion of planned study treatment. Patients may be treated 
beyond RECIST progression if the investigator deems them to be continuing to derive clinical 
benefit and if they meet all of the following criteria: 
 
• 
Absence of symptoms and signs (including worsening of laboratory values [e.g. 
new or worsening hypercalcemia]) indicating unequivocal progression of disease 
• 
No decline in ECOG performance status from baseline 
• 
Absence of tumor growth at critical anatomic sites (e.g. leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions 
• 
Evidence of clinical benefit (defined as the stabilization or improvement of 
disease-related symptoms) as assessed by the investigator. 
 
Patients for whom radiographic disease progression is confirmed at subsequent tumor 
assessments may be considered for continued study treatment at the discretion of the 
investigator if they continue to meet the criteria above and have evidence of clinical benefit. 
Other immunotherapy studies have demonstrated that patients who initially derive clinical 
benefit from treatment and have progression while off treatment can derive clinical benefit 
again if they are retreated (40,46,47). Retreatment is allowed (once only) for patients 
meeting the retreatment criteria below.  The same treatment guidelines followed during the 
initial 12-month treatment period will be followed during the retreatment period, including the 
same dose and frequency of treatments and the same schedule of assessments. 
 
Patients may undergo retreatment in 2 clinical scenarios, described below: 
 
• 
Patients who achieve and maintain disease control (i.e., CR, PR, or SD) up until 
the end of the treatment period may restart treatment with durvalumab 1500 mg 
and tremelimumab 75 mg IV Q4W for up to 4 doses/cycles, then durvalumab 
1500 mg Q4W beginning 4 weeks after the last dose of combination therapy for 
up to 9 doses of durvalumab monotherapy upon evidence of PD (with or without 
confirmation according to RECIST 1.1) during follow-up provided the study is still 
on-going. If patients experienced unacceptable toxicity with the combination, they 
may resume durvalumab 1500 mg Q4W alone. 
• 
Patients who complete the 4 dosing cycles of the combination durvalumab plus 
tremelimumab with clinical benefit per Investigator judgment  but  subsequently 
have evidence of PD during the durvalumab monotherapy portion, with or without 
confirmation according to RECIST 1.1, may restart treatment with the durvalumab 
dosing at 1500 mg Q4W with 75 mg of tremelimumab Q4W for 4 doses each 
followed by durvalumab monotherapy 1500mg Q4W (for 9 additional doses) at the 
investigator‟s discretion. 
 
For  patients   who  restart  combination   durvalumab  +   tremelimumab  treatment,  before 
restarting their assigned treatment, the Investigator should ensure that the patient: 


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a. Does not have any significant, unacceptable, or irreversible toxicities that indicate 
continuing treatment will not further benefit the patient 
b. Still fulfills the eligibility criteria for this study, including re-consenting to restart 
durvalumab 
and 
tremelimumab 
and excluding previous treatment  
with 
durvalumab and tremelimumab. 
 
c. Has not have received an intervening systemic anticancer therapy after their 
assigned treatment discontinuation. 
 
d. Has had a baseline tumor assessment within 28 days of restarting their assigned 
treatment; all further scans should occur with the same frequency as during the 
initial 13 cycles of treatment until study treatment is stopped (maximum of 13 
cycles of further treatment). 
 
During the retreatment period, patients receiving durvalumab + tremelimumab may resume 
durvalumab dosing at 1500 mg Q4W with 75 mg of tremelimumab Q4W for 4 doses each. 
Patients will then continue with durvalumab monotherapy at 1500 mg Q4W beginning 4 
weeks after the last dose of combination therapy for up to 9 doses of durvalumab 
monotherapy. 
 
Treatment through progression is at the Investigator‟s discretion, and the Investigator should 
ensure that patients do not have any significant, unacceptable, or irreversible toxicities that 
indicate that continuing treatment will not further benefit the patient. 
 
Patients must resign the informed consent form to be treated through progression. 
Patients who the Investigator determines may not continue treatment will enter follow-up. 
9.3 
Concomitant Treatment 
 
Patients must inform the treating investigator about any medication taken from the time of 
screening until the end of the clinical phase of the study (final study visit). Any concomitant 
medication(s), including herbal preparations, taken during the study will be recorded. 
 
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables. 
Permitted concomitant medications 
 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” as listed in the section below. 
 
Local therapy (palliative radiotherapy, surgery, radiofrequency ablation) is allowed. 


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Excluded Concomitant Medications 
 
The following medications are considered exclusionary during the study. 
 
• 
Any investigational anticancer therapy (other than the protocol specified therapies) 
• 
Any 
concurrent chemotherapy, radiotherapy 
(except palliative 
radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of 
hormones for noncancer-related conditions (e.g., insulin for diabetes and hormone 
replacement therapy) is acceptable. NOTE: Treatment of isolated lesions for palliative 
intent is acceptable (e.g., by local surgery or radiotherapy). 
• 
Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses exceeding 10 mg/day of prednisone or equivalent,  methotrexate, 
azathioprine, and TNF-α blockers, except when required to treat investigational 
product-related AEs. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. 
In addition, use of inhaled and intranasal corticosteroids is permitted. A temporary 
period of steroids will be allowed for different indications, at the discretion of the 
principal investigator (e.g., chronic obstructive pulmonary disease, radiation, nausea, 
etc). 
• 
Live attenuated vaccines within 30 days of durvalumab and tremelimumab dosing 
(i.e., 30 days prior to the first dose, during treatment with durvalumab and 
tremelimumab for 30 days post discontinuation of durvalumab and tremelimumab) are 
not permitted. Inactivated vaccines, such as the injectable influenza vaccine, are 
permitted. 
Table 7. Prohibited and Rescue Medications 
 
Prohibited medication/class of 
drug: 
Usage: 
Additional investigational 
anticancer therapy concurrent with 
those under investigation in this 
study 
Should not be given whilst the patient is 
on investigational protocol (IP) treatment 
mAbs against CTLA-4, PD-1, or 
PD-L1 
Should not be given whilst the patient is 
on IP treatment through 90 days after the 
last dose of IP. 
Any concurrent chemotherapy, 
biologic therapy, or hormonal 
therapy for cancer treatment. Local 
therapy (palliative radiotherapy, 
surgery, radiofrequency ablation) is 
allowed. 
Should not be given whilst the patient is 
on IP treatment.  (Concurrent use of 
hormones for non-cancer-related 
conditions [e.g., insulin for diabetes and 
hormone replacement therapy] is 
acceptable.) 


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Prohibited medication/class of 
drug: 
Usage: 
Immunosuppressive medications, 
including, but not limited to, 
systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone 
or its equivalent, methotrexate, 
azathioprine, and tumor necrosis 
factor α blockers. Herbal and 
natural remedies which may have 
immune-modulating effects should 
not be given concomitantly unless 
agreed by the sponsor. 
Should not be given whilst the patient is 
on IP treatment. Use of 
immunosuppressive medications for the 
management of IP-related AEs or in 
patients with contrast allergies is 
acceptable.  In addition, use of inhaled, 
topical, and intranasal corticosteroids is 
permitted. 
Live attenuated vaccines 
Should not be given through 30 days 
after the last dose of IP during the study 
 
 
Rescue/supportive 
medication/class of drug: 
Usage: 
Concomitant medications or 
treatments (e.g., acetaminophen or 
diphenhydramine) deemed 
necessary by the Investigator to 
provide adequate prophylactic or 
supportive care, except for those 
medications identified as 
“prohibited” as listed above 
To be administered as prescribed by the 
Investigator 
Best supportive care (including 
antibiotics, nutritional support, 
growth factor support, correction of 
metabolic disorders, optimal 
symptom control, and pain 
management [including palliative 
radiotherapy, etc]) 
Should be used when necessary for all 
patients 


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Rescue/supportive 
medication/class of drug: 
Usage: 
Best supportive care (including 
antibiotics, nutritional support, 
growth factor support, correction of 
metabolic disorders, optimal 
symptom control, and pain 
management [including palliative 
radiotherapy, etc]) 
Should be used when necessary for all 
patients 
 
 
Blood donation 
Subjects should not donate blood while participating in this study, or for at least 90 days 
following the last infusion of durvalumab or tremelimumab. 
 
9.4 
End of treatment 
 
The end of treatment is considered the last visit where the decision is made to discontinue 
treatment. All required procedures might be completed within ± 28 days of the end of 
treatment visit. Repeat disease assessment is not required if performed within 28 days prior 
to the end of treatment visit. 
 
Every effort should be made to complete the end of treatment visit and all required 
procedures. However, if the subject is unfit or unwilling to return to clinic during the specified 
time frame, the assessments can be skipped with permission from the Principal Investigator. 
Assessments for subjects who have completed protocol therapy and achieved  disease 
control, or have discontinued durvalumab or tremelimumab due to toxicity in the absence of 
confirmed progressive disease are provided in Appendix 2. 
 
Assessments for subjects who have discontinued durvalumab or  tremelimumab treatment 
due to confirmed PD are presented in Appendix 3. 
 
9.5 Research blood and tumor specimens 
 
For an explanation of the immune related hypotheses and the exploratory analysis plan, see 
section 14.3. Please see the clinical laboratory manual (Appendix 6) for further details 
regarding research blood and archival tissue collection. 
9.5.1 
Research blood 
 
Blood specimens will be obtained for research purposes on cycle 1 day 1, cycle 1 day 14, 
and cycle 2 day 1 (+ 4 days). An additional two blood draws at two different time points after 
cycle 2 day 1 and the last protocol clinic visit are recommended when feasible (as 
determined by investigator discretion). 


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Specimens should be collected prior to drug administration. Four (4) tubes of blood are to be 
collected in BD Vacutainer® CPT™ Cell Preparation Tubes with Sodium Heparin (BD order # 
362761 or equivalent) at each research blood draw. Peripheral blood mononuclear cells and 
plasma will be isolated per institutional practice in the MSK Immune Monitoring Facility (IMF). 
One EDTA tube should be collected at every research time point for purification of RNA/DNA 
for TCR analysis and collection of genomic data. 
9.5.2 Tumor specimens 
 
For the requirement of submission of pre-treatment tumor tissue, samples collected from 
fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases without a 
soft tissue component, and lavage are not acceptable. Acceptable samples include 
transurethral resection of bladder tumor specimens, radical cystectomy specimens, core-
needle or excisional biopsies for deep tumor tissue or excisional, incisional, punch, or 
forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Representative non-TCC 
of the urothelial tract FFPE archival tumor specimens (tumor blocks or 30 unstained slides; 
preference for tumor blocks) must be provided. Patients with < 30 slides may be enrolled 
after discussion with the principal or co-principal investigators. Biopsy purely for research 
purposes for this study will not be allowed. Sections should be stored at ambient temperature 
and protected from light until use or shipment to testing lab by courier at ambient 
temperature. Samples can be submitted during screening any time after the patient signs the 
informed consent form up until cycle 1, day 1. Exceptions can be provided by the principal 
investigator or co-principal investigators. 


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10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
A cycle is defined as 4 weeks and includes treatment on day 1 followed by 27 days until the 
start of the next cycle. 
 
Assessments to be performed at the 
times stipulated in the table and as 
clinically required in the management 
of the patient. 
Screening 
All assessment to be performed pre-infusion unless 
stated otherwise 
Within 
28 days 
Within 
14 days 
Cycle 1-4, Day 1 
(+/- 4 days) 
Cycle 1-4, Day 15 
(+/- 4 days) 
Day 1 of Cycle 
5 onward (+/- 4 
days) 
Written informed consent 
X 
Demography and history of tobacco and 
alcohol use 
X 
Previous treatments 
X 
Archival tumor tissue collection1 
X 
Formal verification of eligibility criteria 
X 
Medical and surgical history 
X 
Serum pregnancy test2 
X 
As clinically indicated 
Durvalumab and trememlimumab co- 
administration 
X 
Durvalumab monotherapy administration 
X 
Physical examination3 
X 
X 
X 
X 
Vital signs (blood pressure, heart rate, 
respiratory rate, and temperature; pre-, 
during and post-infusion)4 
X 
X 
X 
X 
Oxygen saturation (pulse oximetry) 
X 
X 
X 
X 
Weight 
X 
X 
X 
Electrocardiogram (ECG)5 
X 
X 
X 
Adverse event/serious adverse event 
assessment6 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
ECOG Perf ormance Status 
X 
X 
X 
X 
CBC (Table 4) 
X 
X 
X 
X 
Comprehensive chemistry panel (Table 
5)10 
X 
X 
X 
X 
TSH7 
X 
X 
X 
Coagulation parameters ( PTT/ PT/ INR) 
X 
As clinically indicated 
Hepatitis B and C; HIV screening 
X 
As clinically indicated 
Urinalysis (Table 6) 
X 
As clinically indicated 
Research blood collection8 
X (C 1 & 2 only) 
X (C1 only) 
X 
Chest CT9 
X 
X 
CT or MRI of Ab/Pelvis9 
X 
X 9 
1. 
See section 9.5.2 for tumor collection details 
2. 
Pre-menopausal female subjects of childbearing potential only. 
3. 
Full physical examination at baseline; targeted physical examination at other time points 
4. 
Vital signs should be collected before, during, and after the infusion according to the treating investigator‟s discretion and 
institutional guidelines and w hen clinically indicated. Patients w ill be informed about the possibility of delayed post-infusion 
symptoms and instructed to contact their study physician if they develop such symptoms. 
5. 
3 ECG during screening then 1 ECG w ith prior to each dose. 
6. 
For AE‟s/SAEs reported during the prescreening additional information such as medical history and concomitant medications 
may be needed. 
7. 
Free T3 and free T4 w ill only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an 
adverse event related to the endocrine system. 


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8. 
See section 9.5.1 for research blood collection details. Blood specimens w ill be obtained for research purposes on cycle 1 day 
1, cycle 1 day 14, and cycle 2 day 1 (+ 4 days). An additional two blood draws at two diff erent time points after cycle 2 day 1 
and the last protocol clinic visit are recommended w hen feasible ( as determined by investigator discretion). 
9. 
Scans to be performed every 2 cycles (+/- 7 days). See section 10.4 for post-treatment follow up. CT chest may be with or 
without contrast. MRI of the chest may be performed if patients refuse CT. Abdomen/Pelvis imaging should include IV contrast 
unless there is an extenuating circumstance approved by the PI or co-PI. 
10. It is acceptable to proceedw ith treatment prior to receipt of amylase and/or lipase results for asymptomatic patients. For 
subsequently noted grade >3 amylase or lipase levels, study drug/study regimen may be continued at the date of the next 
scheduled treatment if complete w orkup shows no evidence of pancreatitis. 
 
10.1 Physical examinations 
Physical examinations will be performed according to the assessment schedule. A  full 
physical examination will be performed at screening. Height will be measured at screening 
only. While on treatment, targeted physical examinations are to be utilized by the 
Investigator on the basis of clinical observations and symptomatology. Vital signs are to be 
performed at each assessment. All clinical assessments should occur within +/- 4 days of the 
intended cycle start date. 
 
10.2 Laboratory Studies During Treatment 
Complete blood count (CBC) with differential and platelets and comprehensive panel (Na, K, 
Cl, CO2, BUN, Cr, Ca, magnesium, glucose, AST, ALT, total protein, Albumin, ALP, total 
bilirubin) must be performed on day 1 of each cycle. TSH, LDH, amylase, and lipase will be 
performed at baseline and on day 1 of each cycle. 
 
10.3 Radiographic Studies During Treatment 
Patients will undergo cross-sectional imaging every 2 cycles (+/- 7 days) until lack of clinical 
benefit. CT chest may be with or without contrast. MRI chest may be performed if patients 
refuse CT. Abdomen/Pelvis imaging should include IV contrast unless there is an 
extenuating circumstance approved by the PI. CT scans of the abdomen/pelvis and MRI 
abdomen/pelvis are both acceptable. Imaging will be evaluated using RECIST v1.1. 
 
10.4 Post-Treatment Follow-Up 
Assessments for subjects who have completed durvalumab and tremelimumab treatment 
and achieved disease control, or have discontinued durvalumab or tremelimumab due to 
toxicity in the absence of confirmed progressive disease are provided in Appendix 2. 
 
Assessments for subjects who have discontinued durvalumab or  tremelimumab treatment 
due to confirmed PD are presented in Appendix 3. 
 
 
11.1 TOXICITIES/SIDE EFFECTS 
 
The common terminology criteria for adverse events version 4.0 (CTCAE v4.0) will be used 
to grade the severity of adverse events. 
11.1 
Schedule modification and toxicity management 


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For adverse events (AEs) that are considered at least possibly due to administration of 
durvalumab or tremelimumab the following adjustment guidance may be applied: 
• 
Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity where required). 
• 
If the symptoms promptly resolve with supportive care, consideration should be given 
to continuing durvalumab or tremelimumab along with appropriate continuing 
supportive care.  If medically appropriate, modifications to the schedule are permitted 
for durvalumab and tremelimumab (see Appendix 1). 
• 
All schedule modifications should be documented with clear reasoning and 
documentation of the approach taken. 
• 
Dose reductions are not permitted. 
In addition, there are certain circumstances in which durvalumab or tremelimumab should be 
permanently discontinued. 
 
Following the first dose of durvalumab or tremelimumab, subsequent administration of 
durvalumab or tremelimumab can be modified based on toxicities observed (see Appendix 
1).  Dose reductions are not permitted. 
 
Based on the mechanism of action of durvalumab or tremelimumab leading to T-cell 
activation and proliferation, there is the possibility of observing immune related Adverse 
Events (irAEs) during the conduct of this study. Potential irAEs include immune-mediated 
enterocolitis, dermatitis, hepatitis, and endocrinopathies. Subjects should be monitored for 
signs and symptoms of irAEs. In the absence of an alternate etiology (e.g., infection or PD) 
signs or symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy should be 
considered to be immune-related. 
 
Schedule modification recommendations and toxicity management guidelines for immune- 
mediated reactions, for infusion-related reactions, and for non-immune-mediated reactions 
are detailed in Appendix 1. As outlined in Appendix 1, patients may temporarily suspend 
study treatment for up to 12 weeks beyond the scheduled date of delayed infusion if study 
drug-related toxicity requiring dose suspension is experienced.  If study drug is held because 
of AEs for  12 weeks beyond the scheduled date of infusion, the patient will be discontinued 
from study therapy. Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per 
day (or equivalent) within 12 weeks after last dose of study drug/regimen will result in study 
discontinuation. Recurrence of a previously experienced Grade 3 treatment-related AE 
following resumption of dosing will result in study discontinuation. Patients who discontinue 
study therapy due to toxicity will be followed as outlined in Appendix 2 or 3. Dose 
interruptions for reasons other than toxicity, such as surgical procedures, may be allowed. 
The acceptable length of interruption will be at the discretion of the Sponsor. 
11.2 
Definition of adverse events 


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The International Conference on Harmonization (ICH) Guideline for  Good Clinical Practice 
(GCP) E6 (R1) defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
 
An AE includes but is not limited to any clinically significant worsening of a subject‟s 
pre-existing condition. An abnormal laboratory finding (including ECG finding) that requires 
an action or intervention by the investigator, or a finding judged by the investigator to 
represent a change beyond the range of normal physiologic fluctuation, should be reported 
as an AE. 
 
Adverse events may be treatment emergent (i.e., occurring after initial receipt of 
investigational product) or nontreatment emergent. A nontreatment-emergent AE is any new 
sign or symptom, disease, or other untoward medical event that begins after written informed 
consent has been obtained but before the subject has received investigational product. 
 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition, that did  
not worsen from baseline, is not considered an AE (serious or nonserious). An untoward 
medical event occurring during the prescheduled elective procedure or routinely scheduled 
treatment should be recorded as an AE or SAE. The term AE is used to include both serious 
and non-serious AEs. 
 
The description and reporting of serious adverse events (SAEs) are outlined in section 17.2. 
 
11.3 
Durvalumab + tremelimumab adverse events of special interest 
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product. 
AESIs for durvalumab ±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 


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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 Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Principal Investigator or Co-Principal Investigator. 
AESIs observed with durvalumab ± tremelimumab include: 
 
• 
Diarrhea / Colitis and intestinal perforation 
 
• 
Pneumonitis / ILD 
 
• 
Hepatitis / Transaminase increases 
 
• 
Endocrinopathies  (i.e.  events  of  hypophysitis/hypopituitarism,  adrenal  insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus) 
• 
Rash / Dermatitis 
 
• 
Nephritis / Blood creatinine increases 
 
• 
Pancreatitis  / serum lipase and amylase increases 
 
• 
Myocarditis 
 
• 
Myositis / Polymyositis 
 
• 
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
 
• 
Other inflammatory responses that are rare / less frequent with a potential immune- 
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and 
other events involving the eye, skin, haematological and rheumatological events. 
In  addition,  infusion-related  reactions  and  hypersensitivity/anaphylactic  reactions  with  a 
different underlying pharmacological aetiology 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 detail in the Dosing 
Modification and Toxicity Management Guidelines (please see Appendix 1). These 
guidelines have been prepared by the Sponsor to assist the Investigator in the exercise of 
his/her clinical judgment in treating these types of toxicities.  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 detail in the Dosing Modification and Toxicity Management Guidelines (see 
Appendix 1) will be applied. The results of the full diagnostic workup (including high- 


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resolution computed tomography (HRCT), blood and sputum culture, hematological 
parameters etc) will be captured in the eCRF. 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 and the Dosing Modification and 
Toxicity Management Guidelines should be followed. 
Pneumonitis (ILD) investigation 
 
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis. The results of the 
assessment will be collected. 
 
• 
Physical examination 
 
− 
Signs and symptoms (cough, shortness of breath and pyrexia, etc.) including 
auscultation for lung field will be assessed. 
 
• 
SpO2 
 
− 
Saturation of peripheral oxygen (SpO2) 
 
• 
Other items 
 
− 
When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible and deemed appropriate by the 
treating physician: 
 
(i) 
ILD Markers (KL-6, SP-D) and β-D-glucan 
 
(ii) 
Additional Clinical chemistry: CRP, LDH 
 
11.4 Immune-related adverse events 
 
Based on the mechanism of action of durvalumab and tremelimumab leading to T-cell 
activation and proliferation, there is a possibility of observing irAEs during the conduct of this 
study.  Potential irAEs may be similar to those seen with the use of ipilimumab, BMS-936558 
(anti-PD-1 mAb), and BMS-936559 (anti-PD-L1 mAb) and may include immune-mediated 
enterocolitis, dermatitis, hepatitis (hepatotoxicity), pneumonitis, and endocrinopathies (49– 
51). These AEs are inflammatory in nature and can affect any organ.  With anti-PD-L1 and 
anti-CTLA-4 combination therapy, the occurrence of overlapping or increasing cumulative 
toxicities that include irAEs could potentially occur at higher frequencies than with either 
durvalumab or tremelimumab monotherapy.  Patients should be monitored for signs and 
symptoms of irAEs.  In the absence of an alternate etiology (e.g., infection or PD), an 
immune-related etiology should be considered for signs or symptoms of enterocolitis, 
dermatitis, pneumonitis, hepatitis, and endocrinopathy.  In addition to the dose modification 


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guidelines provided in Appendix 1, it is recommended that irAEs are managed according to 
the general treatment guidelines outlined for ipilimumab (52). These guidelines recommend 
the following: 
 
• 
Patients should be evaluated to identify any alternative etiology. 
• 
In the absence of a clear alternative etiology, all events of an inflammatory nature should 
be considered immune related. 
• 
Symptomatic and topical therapy should be considered for low-grade events. 
• 
Systemic corticosteroids should be considered for a persistent low-grade event or for a 
severe event. 
• 
More potent immunosuppressives should be considered for events not responding to 
systemic steroids (e.g., infliximab or mycophenolate). 
• 
If the Investigator has any questions in regards to an AE being an irAE, the Investigator 
should immediately contact the Study Physician. 
11.5 Criteria for Hy’s Law (FDA Guidance 2009) 
 
• 
The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo 
 
• 
Among trial subjects showing such aminotransferase elevations, often with 
aminotransferases much greater than 3 x ULN, one or more also show elevation of 
serum total bilirubin to >2 x ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
 
• 
No other reason can be found to explain the combination of increased aminotransferases 
and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or 
another drug capable of causing the observed injury. 
 
 
12.1 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Patients will be assessed every cycle by physical examination for response for disease 
progression. Patients will have appropriate radiographic diagnostic procedures (CT scan of 
chest and CT or MRI of abdomen and pelvis) for evaluation of  measurable  disease  at 
baseline within 28 days of initiation of the study. Imaging will be repeated to evaluate the 
disease every 2 cycles while patients are on study. 
12.2 Response Criteria 
 
The response evaluation criteria in solid tumors (RECIST 1.1) will be used as presented in 
Appendix 4. The immune-related RECIST (irRECIST) criteria will also be used as a response 


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assessment as described in Appendix 5. 
 
 
 
12.3 Confirmation 
 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made 
clear when reporting the outcome of such studies that the responses are not confirmed. 
 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met. Longer intervals as determined by the study protocol may also be 
appropriate. 
 
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the 
study protocol. 
 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
An individual subject will not receive any further investigational product if any of the following 
occur in the subject in question: 
- Withdrawal of consent or lost to follow-up. If consent is withdrawn, the subject will not 
receive any further investigational product or further study observation. Note that patients 
may withdraw from treatment without withdrawing consent for the study. Such patients 
will receive no further investigational treatment but can be followed for progression and 
survival. Documentation distinguishing these two outcomes should be placed in the 
patient‟s chart. 
- Adverse event that, in the opinion of the investigator or the sponsor, contraindicates 
further dosing 
- Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy  might  constitute  a 
safety risk 
- Pregnancy or intent to become pregnant 
- Any AE that meets criteria for discontinuation as defined in Section 11.0 
- Grade ≥ 3 infusion reaction 
- Subject noncompliance that, in the opinion of the investigator, warrants withdrawal; e.g., 
refusal to adhere to scheduled visits 
- Initiation of alternative anticancer therapy including another investigational agent 


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- Prolonged duration of therapy-related toxicity as defined in section 11.2. 
- Patients  may  be  permitted  to  continue  study  treatment  after  RECIST  v1.1-defined 
progressive disease if they meet all of the following criteria: 
• 
Absence of symptoms and signs (including worsening of laboratory values [e.g. 
new or worsening hypercalcemia]) indicating unequivocal progression of disease 
• 
No decline in ECOG performance status from baseline 
• 
Absence of tumor growth at critical anatomic sites (e.g. leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions 
• 
Evidence  of  clinical  benefit  (defined  as  the  stabilization  or  improvement  of 
disease-related symptoms) as assessed by the investigator. 
Patients for whom radiographic disease progression is confirmed at subsequent tumor 
assessments may be considered for continued study treatment at the discretion of the 
investigator if they continue to meet the criteria above and have evidence of clinical 
benefit. 
 
Subjects who are permanently discontinued from further receipt of investigational 
product, regardless of the reason (withdrawal of consent, due to an AE, other), will be 
identified as having permanently discontinued treatment. 
 
Subjects who are permanently discontinued from receiving investigational product will be 
followed per section 9.4 for safety, including the collection of any protocol-specified blood 
specimens, unless consent is withdrawn or the subject is lost to follow-up or enrolled in 
another clinical study. All subjects will be followed for survival. Subjects who decline to 
return to the site for evaluations will be offered follow-up by phone every 3 months as an 
alternative. 
 
 
14.1 
BIOSTATISTICS 
 
14.2 
Primary Endpoint and Sample Size Justification 
 
The three histologic groups (Small-Cell, Squamous Cell Carcinoma, and Adenocarcinoma) 
will be part of the same cohort given they are expected to have similar response rates. With 
an unacceptable rate of 5% and acceptable rate of 20%, and setting type I error to 5% and 
power to 80%, with Simon‟s minimax two-stage design, we will enroll 13 patients in the first 
stage. Non-transitional cell carcinoma of the urothelial tract is  a rare entity. Single, arm 
phase II studies have been published, but only in the front-line setting and only in small 
cohorts of patients (summarized in table 1). To our knowledge, there is no published data on 
response rates to second-line chemotherapy in patients with non-transitional cell carcinoma 
of the urothelial tract. The patient population under study has no standard treatment options 
and, in our group‟s clinical experience, rarely experiences a meaningful clinical benefit from 
chemotherapy. Therefore, we have elected to set the null hypothesis at an ORR of 5%.  If no 


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patients in the first 13 have achieved a response, enrollment for stage 2 will be halted until 
the 13 subjects in the first stage have been assessed for response (window of 2 disease 
assessment scans following initiation of treatment). If we see 1 or more responses in any of 
the histologies in the first stage, we continue to the second stage where we will enroll 
additional 14 patients. If, at the end of the study, we see 4 or more responses out of the total 
of 27 patients, we will consider the therapy promising. As an exploratory analysis, we will 
also estimate the response rate of the small cell/neuroendocrine, predominant squamous, 
and predominant adenocarcinoma cohorts separately as a proportion of responders with the 
corresponding confidence interval, although formal comparisons between the three cohorts 
are not planned. 
The response evaluable population is defined as all patients with a baseline disease 
assessment who have received at leat one treatment with durvalumab and tremelimumab on 
study and have had either at least one post-baseline disease assessment or withdrawn from 
study treatment prior to post-baseline disease assessment due to clinical progression or 
death. 
 
As described in section 9.2, patients may undergo retreatment after disease progression. 
The primary endpoint of best overall response is based on the best response from the first 
round of treatment. 
Patients who discontinue protocol therapy for toxicity will be followed for response per 
Appendix 2. Patient who come off study for withdrawal of consent prior to having one post- 
baseline disease assessment will be considered inevaluable and will be replaced. All treated 
patients will remain evaluable for toxicity. 
 
With an estimated patient accrual of 1 patient every month, it would take approximately 13- 
30 months to complete accrual to the trial. 
14.3 
Secondary Endpoint Justification 
 
1. Safety and tolerability: Adverse events and immune-related adverse events by  the 
current version of Common Terminology Criteria for Adverse Events version 4 (CTCAE 
v4.03) will be tabulated in order to assess the safety profile and tolerability therapy in 
treated patients. 
 
2. Progression-free survival (PFS): PFS will be defined as the duration of time from start of 
treatment to time of recurrence, progression, or death due  to  any  cause,  whichever 
occurs first. Patients will be censored at last follow up date. The Kap lan Meier estimate of 
median PFS will be reported, as well as the PFS rate at 24 weeks (+/- 1 week). 
 
3. Overall survival (OS): Overall survival will be evaluated using the Kaplan Mei er Method. 
 
4. Duration of response (DOR): Duration of response will be determined for each patient 
with time origin at the first occurrence of confirmed response (CR, PR) until the first 
occurrence of progression or date of death if the patient dies due to any cause before 
progression. Duration of response will be evaluated using the Kaplan Meier Method. 


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5. Clinical benefit rate (CBR): Clinical benefit rate will be defined as the percentage of 
patients with complete response (CR) + partial response (PR) + stable disease (SD) by 
24 weeks from the start of treatment will be reported and the 90% confidence interval will 
be estimated using exact binomial proportions. 
 
6. Best confirmed ORR, PFS, CBR, and DOR according to immune-related RECIST 
(irRECIST) as presented by Bohnsack et al.(53) and as proposed in Appendix 5. The 
methodology is the same as described for RECIST 1.1 except for new lesions do not 
automatically denote disease progression and the measurement of longest diameter of 
new measurable lesions are included in the sum of the measurement of the original 
target lesions. This method accounts for some of the delayed response patterns seen 
with immune checkpoint blockade.  The efficacy endpoints based on irRECIST will be 
estimated using the same methods for these endpoints based on RECIST. 
14.4 
Exploratory analyses 
 
Listed below are immune related hypotheses and the plan for exploratory analyses. 
Additional or different investigational methods will be used to characterize and measure 
components of the immune response based upon the latest available technology at the time 
of analysis. Specimens will also be stored for future studies related to non-TCC of the 
urothelial tract immunity for those patients who have consented to an institutional biobanking 
protocol (e.g. 06-107, 12-245, etc). If tissue availability or funding is limited, assay priority will 
be determined at the investigators discretion. 
The exploratory hypotheses listed below are hypothesis generating.  As such, all four of the 
exploratory analyses will be descriptive and graphical in nature.  To test the associations 
between binary CBR or subtypes and biomarkers we will use Fisher‟s exact or Wilcoxon rank 
sum tests for binary or continous variables respectively. 
Immune Hypothesis 1: The tumor microenvironment will vary based on the histologic subtype 
of non-TCC of urothelial tract. 
Proposed biomarker evaluation: Analysis of immune infiltrate will be performed using 
immunohistochemistry (IHC), immunofluorescence (IF), and computational approaches 
based upon RNA sequencing data. Immune regulatory molecules and populations of cells 
analyzed may include, but will not be limited to PD-L1, CD4, CD8, Tregs, B cells, 
macrophages, and dendritic cells and expression of biologically relevant/phenotypic markers 
thereof. The Ventana SP263 assay (performed in accordance with the package insert on the 
Ventana Benchmark platform (Ultra or XT) should be used to measure PD-L1. 
 
Immune Hypothesis 2: The composition and phenotype of the tumor microenvironment at 
baseline will correlate with the clinical benefit rate (CBR). 
 
Proposed Biomarker Evaluation: See immune hypothesis 1. 
 
Immune Hypothesis 3: High T cell clonality in the tumor plus peripheral expansion of 
dominant tumor-resident T cell receptor clones will be associated with the CBR. 


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Proposed Biomarker Evaluation: We will perform high throughput DNA sequencing of the 
CDR3 region of the TCR beta chain in baseline tumors and pre- and post-treatment 
peripheral blood. 
 
Immune Hypothesis 4: High levels of myeloid derived suppressor cells (MDSCs) and T 
regulatory cells (Tregs) in the peripheral blood and high levels of immunosuppressive tumor 
associated myeloid cells and T regulatory cells in will correlate with a decreased CBR. 
Proposed Biomarker Evaluation: We will perform a whole blood flow cytometry based assay 
to determine the MDSC and Treg percentage in pre- and post-treatment blood samples. We 
will analyze tumor associated myeloid cells and T regulatory cells in the tumor using 
immunohistochemistry (IHC), immunofluorescence (IF), and computational approaches 
based upon RNA sequencing data. 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist 
is confirming whether or not the participant is eligible to enroll in the study. Study staff are 
responsible for ensuring that all institutional requirements necessary to enroll a participant to 
the study have been completed. See related Clinical Research Policy and Procedure #401 
(Protocol Participant Registration). 
15.3 
Randomization 
 
N/A 
 
 
 
16.0 
DAT A M ANAGEMENT ISSUES 
 
A MSKCC Research Study Assistant (RSA) will be assigned to the study. The 
responsibilities of the RSA include project compliance, data collection, abstraction and entry, 
data reporting, regulatory monitoring, problem resolution and prioritization, and coordinate 
the activities of the protocol study team. 
 
The data collected for this study will be entered into a  MSKCC secure database (CRDB). 
Source documentation will be available to support the computerized patient record. 
 
16.1 
Quality Assurance 


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Weekly registration reports may be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates, accuracy of evaluations, and follow-up will be monitored 
periodically throughout the study period. Potential problems will be brought to the attention of 
the study team. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety  Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
(MSKCC) were approved by the National Cancer Institute in September 2001.   The plans 
address the new policies set forth by the NCI in the document entitled “Policy of the National 
Cancer  Institute  for  Data  and  Safety  Monitoring  of  Clinical  Trials”  which  can  be  found 
at:   http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at 
MSKCC  were  established  and  are  monitored  by  the  Office  of  Clinical  Research. 
The 
MSKCC  Data  and  Safety  Monitoring  Plans  can  be  found  on  the  MSKCC  Intranet  at:  
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitoring%   
20Plans.pdf 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials report to the Center‟s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Subject data protection. 
 
Potential risks to human subjects include drug-related toxicity, pain and discomfort 
associated with durvalumab and tremelimumab, placement of IV catheters, phlebotomy, and 
possible psychological discomfort from the stresses associated with obtaining imaging 
studies (e.g., CT scan). The side effects and potential toxicities of durvalumab and 
tremelimumab are listed in the informed consent form. All efforts will be made to avoid any 
complication by completely reviewing patients‟ symptoms, providing appropriate 
management, and monitoring blood tests. If an adverse medical event occurs, the patient will 
first contact the primary oncologist or the principal investigator. At nights and weekends, 
there is an oncology physician on call at all times. Patients may either call or come directly to 


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the urgent care center at Memorial Hospital (or to their local emergency room) to be seen. 
Patients suffering serious adverse reactions must be carefully followed and all follow-up 
information recorded. 
Alternatives/Options for treatment 
 
Patients can elect to receive chemotherapy or supportive/hospice care. They can also elect 
to participate in another clinical trial. Participation in a clinical trial is voluntary. 
Costs 
 
The patient will be responsible for all costs related to treatment and complications of 
treatment. Durvalumab and tremelimumab will be provided without charge.  Costs  to  the 
patient (or third party insurer) will include the cost of hospitalizations, routine blood tests and 
diagnostic studies, office visits, baseline EKG, other medications such as antibiotics and 
doctor‟s fees. Tests done solely for research purposes will not be billed to the patient. 
17.2 
Privacy 
 
MSK‟s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death,  be  life  threatening,  or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE  reporting  is  required  as  soon  as  the  participant  signs  consent. 
SAE  reporting  is 
required for 30-days after the participant‟s last investigational treatment or intervention. Any 


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events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 „Reporting of Serious 
Adverse Events‟, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‟s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject‟s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
The PI or Co-PI‟s signature and the date it was signed are required on the completed report. 
 
The CRDB SAE report should be completed as per above instructions.  If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office. 
 
17.3.1 
Requirement SAE Reporting to AstraZeneca/MedImmune 


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17.2.1.1 
Serious adverse events 
 
* Send deidentified SAE report and accompanying cover page by way of email 
to AstraZeneca’s designated mailbox: 
AE MailboxClinicalTrialTCS@astrazeneca.com 
 
If a non-serious AE becomes serious, this and other relevant follow-up information 
must also be provided to AstraZeneca and the FDA. 
The study PI will request additional information for any subject with ongoing AE(s) / 
SAE(s) at the end of the study, if judged necessary 
 
Serious adverse events that do not require expedited reporting to the FDA still need 
to be reported to AstraZeneca preferably using the MedDRA coding language for 
serious adverse events.  This information should be reported on a monthly basis and 
under no circumstance less frequently than quarterly. 
 
AstraZeneca/MedImmune retains the right to request additional information for any 
subject with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
17.2.1.2 
Reporting of deaths to AstraZeneca 
 
All deaths that occur during the study, or within the protocol-defined 90-day post-last 
dose of durvalumab + tremelimumab safety follow-up period must be reported to 
AstraZeneca as follows: 
 
• 
Death that is clearly the result of disease progression should be documented but 
should not be reported as an SAE. 
 
• 
Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to AstraZeneca as a SAE within 
24 hours. The report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign main and contributory 
causes of death. 
• 
Deaths with an unknown cause should always be reported as a SAE. 
 
17.2.1.3 
Overdose 
 
An overdose is defined as a subject receiving a dose of durvalumab + tremelimumab 
in excess of that specified in the Investigator‟s Brochure, unless otherwise specified 
in this protocol. 
Any overdose of a study subject with durvalumab + tremelimumab, with or without 
associated AEs/SAEs, is required to be reported within 24 hours of knowledge of the 
event to the sponsor and AstraZeneca/MedImmune Patient Safety or designee using 
the designated Safety  e-mailbox  (AE MailboxClinicalTrialTCS@astrazeneca.com).  If 
the overdose results in an AE, the AE must also be recorded as an AE. Overdose 


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does not automatically make an AE serious, but if the consequences of the overdose 
are serious, for example death or hospitalization, the event is serious and must be 
recorded and reported as an SAE (see Section 17.2). There is currently no specific 
treatment in the event of an overdose of durvalumab or tremelimumab. 
 
The investigator will use clinical judgment to treat any overd ose. 
 
17.2.1.4 
Hepatic function abnormality 
 
Hepatic function abnormality (as defined per Hy‟s law in Section 11.5) in a study 
subject, with or without associated clinical manifestations, is required to be reported 
as “hepatic function abnormal” within 24 hours of knowledge of the event to the 
sponsor and AstraZeneca/MedImmune Patient Safety using the designated Safety e- 
mailbox (AE MailboxClinicalTrialTCS@astrazeneca.com), unless a definitive 
underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) 
that is unrelated to investigational product has been confirmed. 
 
• 
If the definitive underlying diagnosis for the abnormality has been established 
and is unrelated to investigational product, the decision to continue dosing of 
the study subject will be based on the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing 
of the study subject must be interrupted immediately. Follow-up investigations 
and inquiries must be initiated by the investigational site without delay. 
Each  reported  event  of  hepatic   function  abnormality  will  be  followed  by  the 
investigator and evaluated by the sponsor and AstraZeneca/MedIm mune. 
17.2.1.5 
Maternal Exposure 
 
If  a patient becomes  pregnant during the  course of the study, the  IPs should be 
discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP  
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities or birth defects and spontaneous miscarriages should be 
reported and handled as SAEs.  Elective abortions without complications should not 
be handled as AEs.  The outcome of all pregnancies (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth, or congenital abnormality) 
should be followed up and documented even if the patient was discontinued from the 
study. 
 
If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel should inform the appropriate AstraZeneca representatives within 1 day, 
i.e., immediately, but no later than 24 hours of when he or she becomes aware of it. 


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The designated AstraZeneca representative will work with the Investigator to ensure 
that all relevant information is provided to the AstraZeneca Patient Safety data entry 
site within 1 to 5 calendar days for SAEs and within 30 days for all other pregnancies. 
 
The same timelines apply when outcome information is available. 
 
It is the MSK IRB stance that pregnant partners are out of our human subject 
protection (HSP) purview since the pregnant partners are not our patients. If notified, 
MSK will provide the external sponsor the information for their further action, but MSK 
will not be involved in the consent or data oversight of that pregnant individual. 
 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning  research  specific  information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 


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19.0 
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16. Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 
in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065–8. 
 
17. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T 
cells to stimulation. J Exp Med. 1995 Aug 1;182(2):459–65. 
 
18. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined 
Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 
2015 Jul 2;373(1):23–34. 
 
19. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. 
Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. N Engl J Med. 
2015 May 21;372(21):2006–17. 
 
20. Funt S, Charen AS, Yusko E, Vignali M, Benzeno S, Boyd ME, et al. Correlation of 
peripheral and intratumoral T-cell receptor (TCR) clonality with clinical outcomes in 
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[Internet]. 2016 [cited 2016 Oct 5];34(suppl; abstr 3005). Available from: 
http://meetinglibrary.asco.org/content/167312-176 
 
21. Robert L, Tsoi J, Wang X, Emerson R, Homet B, Chodon T, et al. CTLA4 blockade 
broadens the peripheral T-cell receptor repertoire. Clin Cancer Res Off J Am Assoc 
Cancer Res. 2014 May 1;20(9):2424–32. 
 
22. Cha E, Klinger M, Hou Y, Cummings C, Ribas A, Faham M, et al. Improved Survival 
with T Cell Clonotype Stability After Anti–CTLA-4 Treatment in Cancer Patients. Sci 
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23. Antonia SJ, López-Martin JA, Bendell J, Ott PA, Taylor M, Eder JP, et al. Nivolumab 
alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 
032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016 Jul;17(7):883–95. 
 
24. Ott PA, Fernandez ME, Hiret S. Pembrolizumab (MK-3475) in patients (pts) with 
extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results 
from KEYNOTE-028. J Clin Oncol [Internet]. [cited 2015 Dec 3]; Available from: 
http://meetinglibrary.asco.org/content/148558-156 
 
25. Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity 
and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with 
advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 
2, single-arm trial. Lancet Oncol. 2015 Mar;16(3):257–65. 
 
26. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, et al. 
Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung 
Cancer. N Engl J Med. 2015 Jul 9;373(2):123–35. 
 
27. Rizvi NA, Brahmer JR, Ou S-HI, Segal NH, Khleif S, Hwu W-J, et al. Safety and clinical 
activity of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in 
patients with non-small cell lung cancer (NSCLC). J Clin Oncol [Internet]. [cited 2015 
Dec 13]; Available from: http://meetinglibrary.asco.org/content/147607-156 
 
28. Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. Safety and 
Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune 
Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. J Clin Oncol 
Off J Am Soc Clin Oncol. 2016 Sep 10;34(26):3119–25. 
 
29. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer. 2012 Apr;12(4):252–64. 
 
30. Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, et al. Safety 
and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: 
a multicentre, phase 1b study. Lancet Oncol. 2016 Mar;17(3):299 –308. 
 
31. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, et al. Pooled 
Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab 
in Unresectable or Metastatic Melanoma. J Clin Oncol. 2015 Feb 9;JCO.2014.56.2736. 
 
32. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. 
Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced 
Melanoma Receiving Nivolumab. J Clin Oncol. 2014 Apr 1;32(10):1020–30. 
 
33. Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, et al. 
Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II 
Trial. J Clin Oncol. 2014 Dec 1;JCO.2014.59.0703. 
 
34. Herbst RS, Soria J-C, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive 
correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. 
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35. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. 
Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 
11;369(2):122–33. 
 
36. Stewart R, Morrow M, Hammond SA, Mulgrew K, Marcus D, Poon E,  et al.  
Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal 
antibody. Cancer Immunol Res. 2015 Sep;3(9):1052-62. 
 
37. Wang E, Kang D, Bae K-S, Marshall MA, Pavlov D, Parivar K. Population 
pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with 
metastatic melanoma. J Clin Pharmacol. 2014 Oct;54(10):1108–16. 
 
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pertuzumab in cancer patients based on population pharmacokinetic analysis. Pharm 
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39. Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based 
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40. Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing 
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Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer. N Engl J Med. 2012 
Jun 28;366(26):2455–65. 
 
45. Hodi FS, O‟Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. 
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med. 
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48. Pawel J von, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, et al. 
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Resources/ESMO-2014/Immunotherapy-of-Cancer/Adaptation-of-the-immune-related- 
response-criteria-irRECIST 


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20.1 
APPENDICES 
 
Appendix 1 
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, 
Infusion-Related, and Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or 
Combination Therapy With Tremelimumab or Tremelimumab Monotherapy) - 
(1 November 2017 Version) 
General Considerations 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions: 
• 
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per 
day (or equivalent) within 12 weeks after last dose of study drug/study 
regimen 
• 
Recurrence of a previously experienced Grade 3 treatment-related AE 
following resumption of dosing 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
Study drug/study regimen can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid taper. 
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study 
drug/study regimen on the following conditions: 
1. 
The event stabilizes and is controlled. 
2. 
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are at ≤10 mg/day or equivalent. 
It is recommended that management of immune-mediated adverse events (imAEs) 
follows the guidelines presented in this table: 
− 
It is possible that events with an inflammatory or immune mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines. 
− 
Whether specific immune-mediated events (and/or laboratory indicators of 
such events) are noted in these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, and infections) to a possible immune- 
mediated event. In the absence of a clear alternative etiology, all such events 
should be managed as if they were immune related. General 
recommendations follow. 
− 
Symptomatic and topical therapy should be considered for low-grade (Grade 
1 or 2, unless otherwise specified) events. 
− 
For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) 
events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
Some events with high likelihood for morbidity and/or mortality – e.g., myo- 
carditis, or other similar events even if they are not currently noted in the 
guidelines – should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if 
clinical suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the study physician, and promptly 
pursue specialist consultation. 
− 
If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [e.g., up to 2 to 
4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a slower rate (>28 days of 
taper). 
− 
More potent immunosuppressives such as TNF inhibitors (e.g., infliximab) 
(also refer to the individual sections of the imAEs for specific type of 


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Appendix 1 
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, 
Infusion-Related, and Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or 
Combination Therapy With Tremelimumab or Tremelimumab Monotherapy) - 
(1 November 2017 Version) 
 
 
General Considerations 
 
Dose Modifications 
Toxicity Management 
Grade 3 
Depending on the individual toxicity, study drug/study regimen 
may be permanently discontinued. Please refer to guidelines below. 
Grade 4 
Permanently discontinue study drug/study regimen. 
Note: For Grade ≥3 asymptomatic amylase or lipase levels, hold study drug/study 
regimen, and if complete work up shows no evidence of pancreatitis, study 
drug/study regimen may be continued or resumed. 
Note: Study drug/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines. 
Similarly, consider whether study drug/study regimen should be permanently 
discontinued in Grade 2 events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they are not currently noted in 
the guidelines – when they do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper 
Note: There are some exceptions to permanent discontinuation of study drug for 
Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus). 
immunosuppressive) should be considered for events not responding to 
systemic steroids. Progression to use of more potent immunosuppressives 
should proceed more rapidly in events with high likelihood for morbidity 
and/or mortality – e.g., myocarditis, or other similar events even if they are 
not currently noted in the guidelines – when these events are not responding 
to systemic steroids. 
− 
With long-term steroid and other immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis 
carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose 
monitoring. 
− 
Discontinuation of study drug/study regimen is not mandated for Grade 
3/Grade 4 inflammatory reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study drug/study regimen in this situation should be based 
upon a benefit-risk analysis for that patient. 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI National Cancer 
Institute; PO By mouth. 


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Pediatric Considerations 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study drug/study regimen based on 
CTC grade/severity is the same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤ a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks after last dose of study drug/study regimen 
− 
All recommendations for specialist consultation should occur with a 
pediatric specialist in the specialty recommended. 
− 
The recommendations for dosing of steroids (i.e., mg/kg/day) and for IV IG 
and plasmapheresis that are provided for adult patients should also be used 
for pediatric patients. 
− 
The infliximab 5 mg/kg IV dose recommended for adults is the same as 
recommended for pediatric patients ≥ 6 years old. For dosing in children 
younger than 6 years old, consult with a pediatric specialist. 
− 
For pediatric dosing of mycophenolate mofetil, consult with a pediatric 
specialist. 
− 
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring. 


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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below. 
− 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution CT scan. 
Grade 1 
(asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated) 
No dose modifications required. However, 
consider holding study drug/study 
regimen dose as clinically appropriate and 
during diagnostic work-up for other 
etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated. 
− 
Consider Pulmonary and Infectious disease consult. 
Grade 2 
(symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL) 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. 
For Grade 2 (mild to moderate new symptoms): 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Promptly start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started 
− 
If still no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 


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anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])a 
− 
Consider pulmonary and infectious disease consult. 
− 
Consider, as necessary, discussing with study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; limiting 
self-care ADL; oxygen 
indicated) 
(Grade 4: life- 
threatening respiratory 
compromise; urgent 
intervention indicated 
[e.g., tracheostomy or 
intubation]) 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, 
life-threatening): 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Obtain Pulmonary and Infectious disease consult; consider, as 
necessary, discussing with study physician. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks’ dose) started. 
Caution: rule out sepsis and refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and, in particular, anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections [Category 
2B recommendation]).a 
Diarrhea/Colitis 
 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes in 
bowel habits such as increased frequency over baseline or 
blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections), including testing for clostridium 
difficile toxin, etc. 
− 
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 
prevent potential progression to higher grade event. 
− 
Use anal gesics c areful ly ; t hey can mask sy mpt oms of  


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Grade 1 
(Diarrhea: stool 
frequency of <4 over 
baseline per day) 
(Colitis: asymptomatic; 
clinical or diagnostic 
observations only) 
No dose modifications. 
−
Grade 2 
(Diarrhea: stool 
frequency of 4 to 6 over 
baseline per day) 
(Colitis: abdominal 
pain; mucus or blood in 
stool) 
Hold study drug/study regimen until 
resolution to Grade ≤1 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then study drug/study regimen can be 
resumed after completion of steroid 
taper. 
−
−
−
−
−
Grade 3 or 4 
(Grade 3 diarrhea: stool 
frequency of ≥7 over 
Grade 3 
Permanently discontinue study drug/study 
regimen for Grade 3 if toxicity does not 
−


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baseline per day; 
Grade 4 diarrhea: life 
threatening 
consequences) 
(Grade 3 colitis: severe 
abdominal pain, change 
in bowel habits, medi- 
cal intervention indi- 
cated, peritoneal signs; 
Grade 4 colitis: life- 
threatening 
consequences, urgent 
intervention indicated) 
improve to Grade ≤1 within 14 days; 
study drug/study regimen can be resumed 
after completion of steroid taper. 
Grade 4 
Permanently discontinue 
study drug/study regimen. 
− 
Monitor stool frequency and volume and maintain hydration. 
− 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (e.g., infliximab at 5 mg/kg 
once every 2 weeks). Caution: Ensure GI consult to rule out 
bowel perforation and refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Hepatitis 
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications). 
PLEASE SEE 
shaded area 
immediately 
below this 
section to find 
Grade 1 
(AST or ALT >ULN 
and ≤3.0×ULN and/or 
TB > ULN and 
≤1.5×ULN) 
• 
No dose modifications. 
• 
If it worsens, then treat as Grade 2 
event. 
For Grade 1: 
− 
Continue LFT monitoring per protocol. 
guidance for 
management of 
“Hepatitis 
(elevated LFTS)” 
in HCC patients 
Grade 2 
(AST or 
ALT >3.0×ULN and 
≤5.0×ULN and/or 
TB >1.5×ULN and 
≤3.0×ULN) 
• 
Hold study drug/study regimen dose 
until Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper. 
For Grade 2: 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 2 days) 
until elevations of these are improving or resolved. 
− 
If no resolution to Grade ≤1 in 1 to 2 days, consider, as 
necessary, discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 


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additional work up and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e., mycophenolate mofetil).a Discuss 
with study physician if mycophenolate mofetil is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3: AST or 
ALT >5.0×ULN and 
≤20.0×ULN and/or 
TB >3.0×ULN and 
≤10.0×ULN) 
(Grade 4: AST or 
ALT >20×ULN and/or 
TB >10×ULN) 
For Grade 3: 
For elevations in transaminases 
≤8 × ULN, or elevations in bilirubin 
≤5 × ULN: 
• Hold study drug/study regimen dose 
until resolution to Grade ≤1 or 
baseline 
• Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 or 
baseline within 14 days and after 
completion of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days 
For elevations in transaminases >8 × ULN 
or elevations in bilirubin >5 × ULN, 
discontinue study drug/study regimen. 
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria (AST and/or ALT >3 × ULN + 
bilirubin >2 × ULN without initial 
findings of cholestasis (i.e., elevated 
alkaline P04) and in the absence of any 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy (i.e., 
mycophenolate mofetil). Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used. 
− 
Perform hepatology consult, abdominal workup, and imaging 
as appropriate. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 


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alternative cause.b 
 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
 
 
Hepatitis 
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
 
 
See instructions at 
bottom of shaded area 
if transaminase rise is 
 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications, worsening of liver 
cirrhosis [e.g., portal vein thrombosis]). 
− 
For HBV+ patients: evaluate quantitative HBV viral load, 
quantitative HBsAg, or HBeAg 
− 
For HCV+ patients: evaluate quantitative HCV viral load 
− 
Consider consulting hepatologist/Infectious disease specialist 
regarding change/implementation in/of antiviral medications 
for any patient with an elevated HBV viral load >2000 IU/ml 
− 
Consider consulting hepatologist/Infectious disease specialist 
regarding change/implementation in/of antiviral HCV 
medications if HCV viral load increased by ≥2-fold 
− 
For HCV+ with HBcAB+: Evaluate for both HBV and HCV as 
above 
 
• 
No dose modifications. 
not isolated but (at any 
time) occurs in setting 
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation 
Grade 1 
(Isolated AST or ALT 
>ULN and ≤5.0×ULN, 
whether normal or 
elevated at baseline) 
• 
If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat as 
Grade 2 event. 
For all grades, see instructions at bottom 
of shaded area if transaminase rise is not 
isolated but (at any time) occurs in setting 
of either increasing bilirubin or signs of 
DILI/liver decompensation 
THIS shaded area 
is guidance only 
for management 
of “Hepatitis 
(elevated LFTs)” 
in HCC patients 


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Grade 2 
(Isolated AST or ALT 
>5.0×ULN and 
≤8.0×ULN, if normal at 
baseline) 
(Isolated AST or ALT 
>2.0×baseline and 
≤12.5×ULN, if elevated 
>ULN at baseline) 
• 
Hold study drug/study regimen dose 
until Grade 2 resolution to Grade ≤1 
or baseline. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid taper. 
− 
− 
− 
− 
− 
− 
For Grade 2: 
Regular and frequent checking of LFTs (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, 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).a Discuss with study physician if 
mycophenolate mofetil is not available. Infliximab should 
NOT be used. 
Grade 3 
(Isolated AST or ALT 
>8.0×ULN and 
≤20.0×ULN, if normal 
at baseline) 
(Isolated AST or ALT 
>12.5×ULN and 
≤20.0×ULN, if 
elevated >ULN at 
baseline) 
• Hold study drug/study regimen dose 
until resolution to Grade ≤1 or 
baseline 
• Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 or 
baseline within 14 days and after 
completion of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days 
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria, in the absence of any alternative 
cause.b 
− 
− 
− 
− 
− 
− 
For Grade 3: 
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 


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≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Grade 4 
(Isolated AST or ALT 
>20×ULN, whether 
normal or elevated at 
baseline) 
Permanently discontinue study drug/study 
regimen. 
For Grade 4: 
Same as above 
(except would recommend obtaining liver biopsy early) 
If transaminase rise is not 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 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms that may be related to changes 
in renal function (e.g., routine urinalysis, elevated serum BUN 
and creatinine, decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, or proteinuria). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression or infections). 
− 
Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2), in 
order to prevent potential progression to higher grade event. 
Grade 1 
(Serum creatinine > 1 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and any accompanying 


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to 1.5 × baseline; > 
ULN to 1.5 × ULN) 
symptoms. 
• 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
• 
If creatinine worsens, depending on the severity, treat 
as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
Grade 2 
(serum creatinine >1.5 
to 3.0 × baseline; >1.5 
to 3.0 × ULN) 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume study 
drug/study regimen after completion 
of steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone at 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
(Grade 3: serum 
creatinine 
>3.0 × baseline; >3.0 to 
6.0 × ULN; 
Grade 4: serum 
creatinine >6.0 × ULN) 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine on daily basis. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 


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− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI CTCAE 
v 4.03 for definition of 
severity/grade 
depending on type of 
skin rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of dermatitis (rash and 
pruritus). 
− 
IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED AND STUDY 
DRUG DISCONTINUED. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream). 
Grade 2 
For persistent (>1 to 2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, then treat as 
Grade 3. 
• 
If toxicity improves to Grade ≤1 
or baseline, then resume 
drug/study regimen after 
completion of steroid taper. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream). 
− 
Consider moderate-strength topical steroid. 
− 
If no improvement of rash/skin lesions occurs within 3 to 
5 days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid, consider, as necessary, 
discussing with study physician and promptly start systemic 
steroids such as prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
Consider skin biopsy if the event is persistent for >1 to 2 weeks 
or recurs. 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen until 
For Grade 3 or 4: 
− 
Consult dermatology. 


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resolution to Grade ≤1 or baseline. 
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, then 
permanently discontinue study drug/study 
regimen. 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
Consider, as necessary, discussing with study physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
hypothyroidism,  Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
Any Grade 
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
v4.03 for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an endocrinologist for endocrine events. 
− 
Consider, as necessary, discussing with study physician. 
− 
Monitor patients for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, polydipsia, polyuria, hypotension, and 
weakness. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, or infections). 
− 
Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine and related labs (e.g., blood glucose 
and ketone levels, HgA1c). 
− 
For modest asymptomatic elevations in serum amylase and 
lipase, corticosteroid treatment is not indicated as long as there 
are no other signs or symptoms of pancreatic inflammation. 
− 
If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, 
or diabetes insipidus), the investigator should send a blood 
sample for appropriate autoimmune antibody testing. 


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Grade 1 
No dose modifications. 
Grade 2 
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until patient is clinically stable. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement. 
3. 
Doses of prednisone are ≤10 mg/day 
or equivalent. 
Grade 3 or 4 
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism and Type 1 diabetes 


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mellitus, hold study drug/study regimen 
dose until endocrinopathy symptom(s) are 
controlled. 
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement. 
3. 
Doses of prednisone are ≤10 mg/day 
or equivalent. 
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 
[Category 2B recommendation]).a 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain- 
Barre) 
Any Grade 
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v4.03 
for defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes, or 
medications). 
− 
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness). 
− 
Consider appropriate diagnostic testing (e.g., electromyogram 
and nerve conduction investigations). 
− 
Perform symptomatic treatment with neurological consult as 
appropriate. 
− 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations above. 


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Grade 2 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade ≤1. 
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to Grade ≤1. 
If toxicity worsens, then treat as 
Grade 3 or 4. 
Study drug/study regimen can be resumed 
once event improves to Grade ≤1 and 
after completion of steroid taper. 
For Grade 2: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine). 
− 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, consider additional workup 
and promptly treat with additional immunosuppressive therapy 
(e.g., IV IG). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days. 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
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. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients may 
unpredictably experience acute decompensations that can result 
in substantial morbidity or in the worst case, death. Special care 
should be taken for certain sentinel symptoms that may predict 
a more severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory insufficiency or 
autonomic instability. 
− 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes or 


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


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decisions are best made in consultation with a 
neurologist, taking into account the unique needs of 
each patient. 
o 
If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. 
o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG. 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency or 
autonomic instability. 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Consider, as necessary, discussing with study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain neurological consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. They should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG. 
o 
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. 
o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG. 


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Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently if biopsy- 
proven immune-mediated myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Monitor patients for signs and symptoms of myocarditis (new 
onset or worsening chest pain, arrhythmia, shortness of breath, 
peripheral edema). As some symptoms can overlap with lung 
toxicities, simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary embolism, 
congestive heart failure, malignant pericardial effusion). A 
Cardiology consultation should be obtained early, with prompt 
assessment of whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
− 
Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), monitoring 
of oxygenation via pulse oximetry (resting and exertion), and 
additional laboratory work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO to assess wall motion 
abnormalities when needed. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections) 
Grade 1 
(asymptomatic with 
laboratory (e.g., BNP) 
or cardiac imaging 
abnormalities) 
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0. 
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 work-up as 
clinically indicated. 
- 
Consider using steroids if clinical suspicion is high. 
Grade 2, 3 or 4 
(Grade 2: Symptoms 
with mild to moderate 
activity or exertion) 
(Grade 3: Severe with 
symptoms at rest or 
-  If Grade 2 -- Hold study drug/study 
regimen dose until resolution to 
Grade 0. If toxicity rapidly improves to 
Grade 0, then the decision to reinitiate 
study drug/study regimen will be based 
upon treating physician’s clinical 
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). 


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


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may include electromyography, nerve conduction studies, MRI 
of the muscles, and/or a muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia or dysphonia. 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections). 
Grade 1 
(mild pain) 
-  No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing with the study physician. 
Grade 2 
(moderate pain 
associated with 
weakness; pain limiting 
instrumental activities 
of daily living [ADLs]) 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
-  Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency. 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly start 
IV methylprednisolone 2 to 4 mg/kg/day systemic steroids 
alon g wit h receiv in g inp ut from Neurology consultant 
− 
If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 3 to 5 days, continue 
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(pain associated with 
severe weakness; 
For Grade 3: 
Hold study drug/study regimen dose until 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult, and complete full evaluation. 


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limiting self-care 
ADLs) 
 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency. 
 
 
For Grade 4: 
-  Permanently discontinue study 
drug/study regimen. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along wit h rece ivin g inp ut from Neurology 
consultant. 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Consider whether patient may require IV IG, plasmapheresis. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 
 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; BUN 
Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstit ial lung disease; imAE immune-mediated adverse event; IG 
Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI Magnetic resonance imaging; NCI National Cancer Institute; NCCN 
National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO  By mouth; T3  Triiodothyronine; T4 
Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 


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Infusion-Related Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the discretion of investigator. 
− 
Monitor patients for signs and symptoms of infusion-related 
reactions (e.g., fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (e.g., generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event. 
For Grade 2: 
The infusion rate of study drug/study regimen may be decreased 
50% or temporarily interrupted until resolution of the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
− 
Consider premedication per institutional standard prior to 
subsequent doses. 
− 
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per institutional 
standards (e.g., IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute. 


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Non–Immune-Mediated Reactions 
Severity Grade of the Event 
(NCI CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration. Otherwise, discontinue study drug/study 
regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 17-511 A(3) 
Approval date: 13-Nov-2018 
 
 
 
Appendix 2 
Schedule of study procedures: follow-up for subjects who have completed 
durvalumab and tremelimumab treatment and achieved disease control 
(no confirmed progression of disease) or subjects who have discontinued 
durvalumab or tremelimumab due to toxicity in the absence of confirmed 
progression of disease 
 
 
Evaluation 
Time Since Last Dose of Durvalumab 


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Day (±3) 
Months (±1 week) 
12 
Months 
and 
Every 
6 Months 
30 
2 
3 
4 
6 
8 
10 
Full physical examination 
X 
X 
X 
(±2 weeks) 
Vital signs (temperature, respiratory rate, 
blood pressure, pulse) 
X 
 
Oxygen saturation (pulse oximetry) 
X 
Weight 
X 
Urine hCG or serum βhCG 
X 
AE/SAE assessmenta, b 
X 
X 
X 
Concomitant medicationsa 
X 
X 
X 
 
Palliative radiotherapy 
As clinically indicated 
 
 
ECOG performance status 
X 
X 
X 
At time points consistent with tumor assessments until loss of clinical 
benefit 
Subsequent anti-cancer therapya 
X 
X 
X 
X 
X 
X 
X 
X 
Survival statusa 
X 
X 
X 
X 
X (every 2 months) 
CBC 
X 
X 
X 
Serum chemistry 
X 
X 
X 
 
Research blood tests 
A total of 2 additional research blood draws after the first 3 research blood draws may be 
performed at the discretion of the study physician 
 
Thyroid function tests (TSH, and fT3 and 
fT4 if TSH is abnormal)c 
X 
X 
X 
Tumour assessment (CT or MRI) 
For subjects who achie ve disease control following 48 weeks of treatment, tumour assessments should 
be performed every 12 weeks (+/- 14 days) relativeto the date of first infusion thereafter unt il confirmed 
PD by RECIST 1.1 by investigational site review. Please refer to section 10 and 12 for timings of 
confirmatory scans. 
For subjects who discontinue treatment due to toxicity (or symptomatic deterioration), t umour 
assessments should be performed relative to the date of first infusion as follows: every 8 weeks for the 
first 48 weeks , then every 12 weeks until confirmed PD by RECIST 1.1 by investigational site review. 
Please refer to Section 10 and 12 for timings of confirmatory scans. 
 
a 
Can be collected by phone. 
b 
 Patients w ith ongoing ≥ grade 2 or serious AEs w ill continue to be followed until the event is resolved to baseline or deemed 
irreversible or clinically insignif icant by the site investigator, or start of new therapy. 
c 
Free T3 and free T4 w ill only be measured if TSH is abnormal or if there is clinical suspicion of an endocrine related AE. 


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Appendix 3 
Schedule of study procedures: follow-up for subjects who have discontinued 
durvalumab and tremelimumab treatment due loss of clinical benefit at the 
investigator discretion 
 
 
 
Evaluation 
Time Since Last Dose of durvalumab 
 
Day (±3) 
Months (±1 week) 
12 Months  and Every 6 Months 
30 
2 
3 
4 
6 
8 
10 
Full physical examination 
X 
 
Vital signs (temperature, respiratory rate, 
blood pressure, pulse) 
X 
Oxygen saturation (pulse oximetry) 
X 
(±2 weeks) 
Weight 
X 
AE/SAE assessmenta,b 
X 
X 
X 
Concomitant medicationsa 
X 
 
Palliative radiotherapy 
As clinically indicated 
 
ECOG performance status 
X 
Subsequent anti-cancer therapya 
X 
X 
X 
X 
X 
X 
X 
X 
Survival statusa 
X 
X 
X 
X 
X 
X 
X (every 2 months) 
Urine hCG or serum βhCG 
X 
CBC 
X 
 
Serum chemistry 
X 
Thyroid function tests (TSH, and fT3 and 
fT4 if TSH is abnormal)c 
X 
Pharmacokinetic assessment, if applicable 
Research blood test 
A  total of 2 additional research blood draws  after the first  3 research blood draws  may  be 
performed at the discretion of the study physician 
 
 
 
Tumour assessment (CT or MRI) 
For subjects who continue treatment post-confirmed progression at the investigator’s discretion, 
tumour assessments should be performed relative to the date of first infusion per section 10 until 
durvalumab is stopped. For subjects who discontinue durvalumab following loss of clinical 
benefit, scans should be conducted according to local clinical practice and submitted for central 
review until a new treatment is started (these scans are optional). 
a 
Can be collected by phone. 
b 
 Patients w ith ongoing ≥ grade 2 or serious AEs will continue to be follow ed until the event is resolved to baseline or deemed 
irreversible or clinically insignif icant by the site investigator, or start of new therapy. 
c 
Free T3 and free T4 w ill only be measured if TSH is abnormal or if there is clinical suspicion of an endocrine related AE. 


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Appendix 4 The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
 
Modified Excerpt from Original Publication 
 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.11 
are presented below, with slight modifications and the addition of explanatory text as needed for 
clarity.2 
I. 
Measurability of Tumor at Baseline 
 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
 
A. 
Measurable Tumor Lesions 
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
o 10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater than 5 mm) 
o 10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as non-measurable) 
o 20 mm by chest X-ray 
 
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be  15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be 
measured and followed.  See also notes below on “Baseline Documentation of Target and Non- 
Target Lesions” for information on lymph node measurement. 
 
B. 
Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or pathological 
lymph nodes with  10 to  15 mm short axis), as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include:  leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, peritoneal spread, 
 
 
 
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: Revised 
2 RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47. 
For consistency within this document, the section numbers and cross-references to other sections within the 
article have been deleted and minor formatting changes have been made. 


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and abdominal masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques. 
 
C. 
Special Considerations Regarding Lesion Measurability 
 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below. 
 
Bone lesions: Bone scan, positron emission tomography (PET) scan, or plain films are 
not considered adequate imaging techniques to measure bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions. 
o Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can 
be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
o Blastic bone lesions are non-measurable. 
 
Cystic lesions: Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
o Cystic lesions thought to represent cystic metastases can be considered measurable lesions if 
they meet the definition of measurability described above.  However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Lesions with prior local treatment: Tumor lesions situated in a previously irradiated area, or in an 
area subjected to other loco-regional therapy, are usually not considered measurable unless there 
has been demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
 
II. 
Target Lesions: Specifications by Methods of Measurements 
 
A. 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 


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B. 
Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during study.  Imaging-based evaluation should always 
be the preferred option. 
 
Clinical Lesions.  Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
suggested. 
 
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  However, 
lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
 
CT, MRI.  CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable. 
 
If prior to enrollment it is known that a patient is unable to undergo CT scans with intravenous 
(IV) contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or 
MRI (without IV contrast) will be used to evaluate the patient at baseline and during the study should 
be guided by the tumor type under investigation and the anatomic location of the disease.  For 
patients who develop contraindications to contrast after baseline contrast CT is done, the decision 
as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should also  
be based on the tumor type and the anatomic location of the disease and should be optimized to 
allow for comparison with the prior studies if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, the patient 
should be considered not evaluable from that point forward.  Care must be taken in measurement of 
target lesions on a different modality and interpretation of non-target disease or new lesions since 
the same lesion may appear to have a different size using a new modality. 
 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. 
 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of these 
techniques for objective tumor evaluation cannot generally be advised. 


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III. 
Tumor Response Evaluation 
 
A. 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and to use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion, as detailed above. 
 
B. 
Baseline Documentation of Target and Non-Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline.  This means in 
instances where patients have only one or two organ sites involved, a maximum of two lesions (one 
site) and four lesions (two sites), respectively, will be recorded.  Other lesions (albeit measurable) in 
those organs will be recorded as non-measurable lesions (even if the size is  10 mm by CT scan). 
 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and  
be representative of all involved organs, but additionally, should lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement, in which circumstance the next largest lesion that can be measured 
reproducibly should be selected. 
 
Lymph nodes merit special mention since they are normal anatomical structures that may be visible 
by imaging even if not involved by tumor.  As noted above, pathological nodes that are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of  15 
mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  The short 
axis of the node is the diameter normally used by radiologists to judge if a node is involved by solid 
tumor.  Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan, this is almost always the axial plane; for MRI the plane of acquisition may be 
axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm  30 mm has a short axis of 20 mm and qualifies as 
a malignant, measurable node.  In this example, 20 mm should be recorded as the node 
measurement.  All other pathological nodes (those with short axis  10 mm but  15 mm) should be 
considered non-target lesions.  Nodes that have a short axis  10 mm are considered 
non-pathological and should not be recorded or followed. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum of diameters.  If lymph nodes are to be 
included in the sum, then, as noted above, only the short axis is added into the sum.  The baseline 


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sum of diameters will be used as a reference to further characterize any objective tumor regression 
in the measurable dimension of the disease. 
 
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as 
non-target lesions and should also be recorded at baseline.  Meas urements are not required and 
 thes e les ions s hould be follow ed as “pres ent,” “abs ent,” or in rare c as es “unequivoc al progres s ion.”  
 
In addition, it is possible to record multiple non-target lesions involving the same organ as a single 
item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver 
metastases”). 
 
IV. 
Response Criteria 
 
A. 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor response for 
target lesions. 
o Complete response (CR): disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to  10 mm. 
o Partial response (PR):  at least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters 
o Progressive disease (PD):  at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline 
 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. 
The appearance of one or more new lesions is also considered progression. 
Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum on study. 
 
 
B. 
Special Notes on the Assessment of Target Lesions 
 
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to  10 mm on study.  This means that when lymph nodes are included as target 
lesions, the sum of lesions may not be zero even if CR criteria are met since a normal lymph node is 
defined as having a short axis  10 mm. 


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Target Lesions That Become Too Small to Measure.  While on study, all lesions (nodal and non- 
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph nodes that 
are recorded as target lesions at baseline become so faint on CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being too small to measure. 
When this occurs, it is important that a value be recorded on the CRF as follows: 
 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. 
• 
If the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned and BML (below measurable limit) should be ticked. 
(Note:  It is less likely that this rule will be used for lymph nodes since they usually have a 
definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but 
too small to measure, a default value of 5 mm should be assigned in this circumstance as 
well and BML should also be ticked.) 
 
To reiterate, however, if the radiologist is able to pr ovide an actual measure, that should be recorded, 
even if it is below 5 mm, and, in that case, BML should not be ticked. 
 
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the coalesced lesion. 
 
C. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they need 
not be measured and, instead, should be assessed only qualitatively at the timepoints specified in 
the protocol. 
o Complete Response (CR):  disappearance of all non-target lesions and (if applicable) 
normalization of tumor marker level) 
 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
o Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or (if applicable) 
maintenance of tumor marker level above the normal limits 


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o Progressive Disease (PD):  unequivocal progression of existing non-target lesions. The 
appearance of one or more new lesions is also considered progression. 
o 
 
D. 
Special Notes on Assessment of Progression of Non-Target Disease 
 
When the Patient Also Has Measurable Disease.  In this setting, to achieve unequivocal 
progression on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease in a magnitude that, even in the presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A 
modest increase in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
 
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in some Phase 
III trials when it is not a criterion of study entry to have measurable disease.  The same general 
concepts apply here as noted above; however, in this instance, there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition:  if all lesions are 
truly non-measurable), a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease, that is, an increase in tumor burden representing an additional 
73% increase in volume (which is equivalent to a 20% increase in diameter in a measurable lesion). 
Examples include an increase in a pleural effusion from “trace” to “large” or an increase in 
lymphangitic disease from localized to widespread or may be described in protocols as “sufficient to 
require a change in therapy.”  If unequivocal progression is seen, the patient should be considered 
to have had overall PD at that point.  While it would be ideal to have objective criteria to apply to 
non-measurable disease, the very nature of that disease makes it impossible to do so; therefore, 
the increase must be substantial. 
E. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important.  There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal, that is, not 
attributable to differences in scanning technique, change in imaging modality, or findings thought to 
represent something other than tumor (for example, some “new” bone lesions may be simply healing 
or flare of pre-existing lesions).  This is particularly important when the patient‟s baseline lesions 


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show partial or complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan report as a “new” cystic lesion, which it is not. 
 
A lesion identified dur ing the study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. 
 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is definitely a 
new lesion, then progression should be declared using the date of the initial scan. 
 
V. 
Evaluation of Response 
 
A. 
Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each timepoint for patients who 
have measurable disease at baseline. 
 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
 
Table 1. 
Timepoint Response :  Patients with Target Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target  Lesions 
New Lesions 
Overall  Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not 
all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR =complete response; NE = not evaluable; PD =progressive disease; PR = partial response; 
SD =stable disease. 


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Table 2.  Timepoint Response :  Patients with Non-Target Lesions Only 
Non-Target  Lesions 
New Lesions 
Overall  Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
a
 
Not all evaluated 
No 
NE 
Unequivocal PD  
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a    “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised. 
 
 
B. 
Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not evaluable at 
that timepoint.  If only a subset of lesion measurements are made at an assessment, usually the 
case is also considered not evaluable at that timepoint, unless a convincing argument can be made 
that the contribution of the individual missing lesion(s) would not change the assigned timepoint 
response.  This would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and, during the study, only two lesions were 
assessed, but those gave a sum of 80 mm; the patient will have achieved PD status, regardless of 
the contribution of the missing lesion. 
 
If one or more target lesions were not assessed either because the scan was not done or the scan 
could not be assessed because of poor image quality or obstructed view, the response for target 
lesions should be “unable to assess” since the patient is not evaluable.  Similarly, if one or more 
non-target lesions are not assessed, the response for non-target lesions should be “unable to 
assess” except where there is clear progression.  Overall response would be “unable to assess” if 
either the target response or the non-target response is “unable to assess,” except where this is 
clear evidence of progression as this equates with the case being not evaluable at that timepoint. 


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Table 3.  Best Overall Response When Confirmation Is Required 
Overall Response at 
First Timepoint 
Overall Response at 
Subsequent  Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
a    If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relati ve to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
the minimum duration for SD was met.  However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first timepoint.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
 
C. 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” size 
( 10 mm), they may still have a measurement reported on scans.  This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on increase in size of the nodes.  As noted earlier, this means that patients with CR may not have a 
total sum of “zero” on the CRF. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document objective progression even after 


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discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an objective response; 
it is a reason for stopping study therapy.  The objective response status of such patients is to be 
determined by evaluation of target and non-target disease as shown in Tables 1 − 3. 
 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at the 
next scheduled assessment progression is confirmed, the date of progression should be the earlier 
date when progression was suspected. 
 
In studies for which patients with advanced disease are eligible (i.e., primary disease still or partially 
present), the primary tumor should also be captured as a target or non-target lesion, as appropriate. 
This is to avoid an incorrect assessment of complete response if the primary tumor is still present 
but not evaluated as a target or non-target lesion. 


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Appendix 5 Immune-Related RECIST Criteria 
 
Immune-related RECIST (irRECIST) is derived from RECIST 1.1 conventions (Eisenhauer et al, 
2009). The implementation of irRECIST (Perrone, 2016) is identical to RECIST 1.1 until progressive 
disease (PD) is identified. Upon demonstration of PD per RECIST 1.1, patients may remain on study 
per Investigator discretion, assuming the patient remains clinically stable, as defined in the protocol. 
Patients that remain on study will have an imaging disease assessment performed at least 4 weeks 
after the initial PD is demonstrated in order to confirm PD. 
 
EVALUATION OF LESIONS 
 
1.1 Evaluation of Target Lesions 
 
• 
Immune-related Complete Response (irCR): Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm. 
 
• 
Immune-related Partial Response (irPR): At least a 30% decrease in the sum of diameters 
of target lesions (i.e., Percentage Change in Tumor Burden), taking as reference the 
baseline sum diameters. 
 
• 
Immune-related Progressive Disease (irPD): Same requirements for PD as standard RECIST 
1.1, with exception that progressive disease must be confirmed. After demonstration of PD  
by standard RECIST 1.1 criteria, patients remain on study and are re-imaged after >4 weeks. 
Confirmation of target lesion PD is constituted by the following: 
 
o Sum of linear diameters (SLD) reaches PD threshold of ≥ 20% increase from nadir 
OR 
o SLD remains ≥ 20% increased above baseline (if already ≥ 20% increased at initial 
PD) 
 
• 
Immune-related Stable Disease (irSD): Neither sufficient shrinkage to qualify for irPR nor 
sufficient increase to qualify for irPD, taking as reference the smallest sum diameters while 
on study. 
1.2 Special Notes on the Assessment of Target Lesions 
 
Lymph Nodes 
 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of ≥ 15 
mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. Nodes that 
have a short axis < 10 mm are considered non-pathological and should not be recorded or followed. 


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Target Lesions that Become “Too Small to Measure” 
 
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm). If the radiologist is able 
to provide an actual measurement, that should be recorded, even if it is below 5 mm. However,  
when such a lesion becomes difficult to assign an exact measure to then: 
 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. 
 
• 
If the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned (note: in case of a lymph node believed to be present and 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). 
 
Target Lesions that Split or Coalesce on Treatment 
 
When non-nodal lesions „fragment,‟ the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. As lesions coalesce, a plane between them may 
be maintained that would aid in obtaining maximal diameter measurements of each individual lesion. 
If the lesions have truly coalesced such that they are no longer separable, the vector of the longest 
diameter in this instance should be the maximal longest diameter for the “coalesced lesion.” 
1.3 Evaluation of Non-target Lesions 
 
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol. 
 
• 
Immune-related Complete Response (irCR): Disappearance of all non-target lesions. All 
lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Immune-related Non-CR/Non-PD (ir-Non-CR/Non-PD): Persistence of one or more non- 
target lesion(s). This also includes non-target lesions that demonstrated unequivocal 
progression at the initial demonstration of PD but then stabilized or regressed on subsequent 
scans. 
 
• 
Immune-related Progressive Disease (irPD): Unequivocal progression of existing non-target 
lesions on a disease assessment subsequent to initial demonstration of PD. Therefore, irPD 
by non-target lesions requires one of the following on a disease assessment >4 weeks after 
the initial demonstration of PD: 
 
o New unequivocal progression 
OR 


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o Further unequivocal progression (if unequivocal progression present at initial PD) 
1.4 New Lesions 
 
Recording of New Target Lesions 
 
The longest diameters of new non-nodal measurable lesions and short axes of new nodal 
measurable lesions will be recorded. They will be added into the sum of diameters of target lesions 
(i.e. incorporated into the total Tumor Burden) for this and all subsequent follow-up assessments. 
 
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, per time 
point), new lesions must meet criteria as defined for baseline target lesion selection and meet the 
same minimum size requirements of 10 mm in long diameter and minimum 15 mm in short axis for 
new measurable lymph nodes. New measurable lesions shall be prioritized according to size, and 
the largest lesions shall be selected as new measured lesions. 
 
Recording of New Non-Target Lesions 
 
All new lesions not selected as new measurable lesions are considered new non-target lesions and 
are followed qualitatively. Only a massive and unequivocal progression of new non-measurable 
lesions leads to an overall assessment of irPD for the time point. Persisting  new nonmeasurable 
lesions prevent irCR. 
 
Progression by New Lesions 
 
irPD by new lesions requires one of the following on a disease assessment >4 weeks after the initial 
demonstration of PD: 
 
• 
New lesions appear 
 
OR 
 
• 
Additional new lesions appear 
OR 
• 
Prior new lesions grow (if new lesions were present at initial PD) 
 
1.5 Confirmation of Progressive Disease 
 
As described above, irPD requires that an initial demonstration of PD is confirmed in a subsequent 
disease assessment performed >4 weeks after the initial demonstration of PD. The above section 
describes what constitutes irPD with respect to Target Lesions, Non-target Lesions and New 
Lesions. For the sake of clarity, the presence of ALL of the following >4 weeks after initial PD means 
that PD IS NOT confirmed: 
• 
Target lesions 


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o SLD is <20% increased from nadir 
 
• 
Non-target lesions 
 
o No additional unequivocal progression from prior scan 
• 
New lesions 
 
o No additional new lesions 
 
o Any prior new lesions are stable or shrinking (qualitatively) 
 
• 
Clinical status 
 
o Patient remains clinically stable 
RESPONSE CRITERIA 
 
2.1 Time Point Response 
 
A response assessment should occur at each time point specified in the protocol. 
 
• 
Immune-related Complete Response (irCR): Complete disappearance of all tumor lesions 
(target and non-target), together with no new measurable or unmeasurable lesions, for at 
least 4 weeks from the date of documentation of irCR. All lymph nodes short axes must be < 
10 mm. 
• 
Immune-related Partial Response (irPR): The sum of the linear diameters (SLD) of all 
target lesions is measured and captured as the sum of diameters at baseline. At each 
subsequent tumor assessment, the SLD of all target lesions is calculated. A decrease in 
SLD, relative to baseline SLD, of 30% or greater is considered an irPR, in the absence of 
irCR or irPD. 
• 
Immune-related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
irCR, irPR or irPD. 
• 
Immune-related Progressive Disease (irPD): It is recommended for patients that are 
clinically stable to confirm PD at the following tumor assessment. Any of the following will 
constitute progressive disease: 
 
o Overall ir-response of irPD (per Table 1) after confirmation of PD with disease 
assessment >4 weeks after initial demonstration of PD 
 
o PD per RECIST 1.1 in a patient that is not clinically stable enough to remain on study 
for confirmation 
Table 1: irRECIST 1.1 Definitions 


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Approval date: 13-Nov-2018 
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Target Lesion 
Response per 
RECIST 1.1 
Non-target Lesion 
Response 
New Lesions 
Overall ir-response 
CR 
CR 
None OR completely 
resolved 
irCR 
PR 
Ir-Non-CR/Non-PD 
None OR 
stable/shrinking 
relative to first PD 
scan 
irPR 
SD 
Ir-Non-CR/Non-PD 
None OR 
stable/shrinking 
relative to first PD 
scan 
irSD 
PD (with confirmation) 
Any 
Any 
irPD 
Any 
Presence of 
unequivocal 
progression ≥ 4 
weeks after initial PD 
scan 
Any 
irPD 
Any 
Any 
Appearance of new 
lesions after initial PD 
scan 
irPD 
 
 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, ir= 
Immune-related 
2.2 
Best Overall Response: All Time Points 
 
Best Overall Response and Date of Progression Using irRECIST 1.1 (irBOR): The investigator will 
be asked to provide all responses on study and date(s) of progression, if applicable, and the best 
overall response will be calculated based on the time point responses and tumor measurements 
provided by the investigator.