Clinical trial NCT03557918
Conditions: Urothelial Carcinoma
Sponsor: Matthew Galsky
Start date: 2018-11-12; Completion date: 2023-06-07
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase II trial designed to estimate the activity of single agent tremelimumab in subjects with metastatic urothelial cancer with disease progression despite prior treatment with PD-1/PD-L1 blockade. The primary endpoint is objective response rate and the study will employ a Simon's 2-stage design.

Detailed description:

Arms: arm 1: Tremelimumab 750 mg IV Day 1 of each 28 day cycle. Up to 7 cycles.
Interventions: intervention 1: Tremelimumab
Intervention descriptions: intervention 1: Tremelimumab 750 mg IV on Day 1 of each 28 day cycle; up to 7 cycles.

Subjects that complete all initial 7 cycles but later progress during follow up may receive an additional 7 cycles of tremelimumab providing they meet eligibility criteria.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
HCRN GU17-294 
 
Phase 2 Trial of Tremelimumab in Patients with Metastatic Urothelial Cancer Previously 
Treated with PD-1/PD-L1 Blockade 
 
 
Sponsor Investigator 
Matthew D. Galsky, MD 
Icahn School of Medicine at Mount Sinai 
Tisch Cancer Institute 
 
Co-Principal Investigator 
Neeraj Agarwal, MD 
University of Utah School of Medicine 
 
Statistician 
Menggang Yu, PhD 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
500 N. Meridian, Suite 100 
Indianapolis, IN 46204 
 
 
Trial Supported by  
AstraZeneca 
ESR-17-12779 
 
 
Investigational New Drug (IND) # 138594 
 
 
 
 
Initial Protocol Version Date: 02JUL2018 
Protocol Amendment Version Date:  
28MAR2019 
 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 2 of 69 
PROTOCOL SIGNATURE PAGE 
 
Phase 2 Trial of Tremelimumab in Patients with Metastatic Urothelial Cancer Previously 
Treated with PD-1/PD-L1 Blockade 
 
VERSION DATE: 28MAR2019 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s). 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Site Investigator 
 
 
  
 Date 
 
 
____________________________________ 
 Site Investigator Name (printed) 
 
 
____________________________________ 
 Site Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
 
 
 PLEASE COMPLETE AND EMAIL A COPY TO HCRN 
 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 3 of 69 
SYNOPSIS 
TITLE 
Phase 2 Trial of Tremelimumab in Patients with Metastatic Urothelial 
Cancer Previously Treated with PD-1/PD-L1 Blockade 
SHORT TITLE 
Phase 2 Trial of Tremelimumab in previously treated urothelial cancer 
PHASE  
2 
OBJECTIVES 
Primary Objective: 
Estimate the objective response rate (according to RECIST 1.1) with 
tremelimumab in subjects with metastatic urothelial cancer previously 
treated with PD-1/PD-L1 blockade 
 
Secondary Objectives: 
 Describe the safety of treatment 
 Describe the disease control rate (objective response + stable 
disease)  
 Describe the duration of response  
 Describe the progression-free survival  
 Describe the overall survival 
 
Correlative/Exploratory Objectives: 
 Explore the relationship between PD-L1 expression and response 
to treatment 
 Explore the relationship between gene expression signatures and 
response to treatment 
 Explore the relationship between genomic alterations including 
mutational load and response to treatment 
 Explore the impact of treatment on the peripheral blood immune 
cells and other circulating biomarkers 
 Explore the relationship between the microbiome and adverse 
events and outcomes with treatment 
 
STUDY DESIGN 
This is a phase II trial designed to estimate the activity of single agent 
tremelimumab in subjects with metastatic urothelial cancer with disease 
progression despite prior treatment with PD-1/PD-L1 blockade. The 
primary endpoint is objective response rate and the study will employ a 
Simon’s 2-stage design. 
 
KEY ELIGIBILITY 
CRITERIA; See 
Section 3 for ALL 
eligibility criteria 
1. Histologically or cytologically documented urothelial cancer. Locally 
advanced (T4b, any N; or any T, N 2−3) or metastatic disease (M1, 
Stage IV) (also termed TCC or UCC of the urinary tract; including 
renal pelvis, ureters, urinary bladder, and urethra)  Subjects with 
mixed histologies are eligible provided that the predominant 
component is urothelial cancer.  Locally advanced bladder cancer 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 4 of 69 
must be inoperable on the basis of involvement of pelvic sidewall or 
adjacent viscera (clinical Stage T4b) or bulky nodal metastasis 
(N2−N3). 
 
2. Representative formalin-fixed paraffin-embedded (FFPE) tumor 
specimens in paraffin blocks (blocks preferred) or at least 15 
unstained slides. If archival tissue is not available and the subject is 
undergoing a standard of care biopsy, tissue from the biopsy is 
required to be submitted for correlative analyses. Subjects without 
adequate baseline tumor tissue may be considered for enrollment on a 
case by case basis after discussion with the sponsor-investigator.  
 
3. Measurable disease according to RECIST 1.1 within 28 days prior to 
registration. At least 1 lesion, not previously irradiated, that can be 
accurately measured at baseline as ≥10 mm in the longest diameter 
(except lymph nodes, which must have short axis ≥15 mm) with 
computed tomography (CT) (preferred) or magnetic resonance 
imaging (MRI) scans, preferably with IV contrast, and that is suitable 
for accurate repeated measurements as per RECIST 1.1 guidelines; 
lesions in a previously irradiated field can be used as a measurable 
disease provided that there has been demonstrated progression in the 
lesion 
 
4. A subject with prior brain metastasis may be considered if they have 
completed their treatment for brain metastasis at least 4 weeks prior 
to study registration, have been off of corticosteroids for ≥ 2 weeks, 
and are asymptomatic 
 
5. Subjects must have progressed despite prior treatment with anti-PD-
1/PD-L1 antibody therapy. Subjects must not have progressed within 
2 months of starting prior anti-PD-1/PD-L1 antibody therapy. 
Subjects must have received at least 1 line of prior systemic therapy. 
Subjects must not have experienced a toxicity that led to permanent 
discontinuation of prior immunotherapy. All AEs while receiving 
prior immunotherapy must have completely resolved or resolved to 
baseline prior to screening for this study with the exception of 
endocrine related AEs that are stable on replacement therapy (e.g., 
steroids, thyroid hormone) which may be considered eligible but must 
be discussed with the sponsor-investigator. 
 
6. Prior cancer treatment must be completed at least 28 days or 5 half-
lives (whichever is shorter) prior to first dose of study drug. Subjects 
must have recovered from all reversible acute toxic effects of the 
regimen (other than alopecia) to ≤ Grade 1 or baseline. 
 
7. Adequate organ function per screening labs


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 5 of 69 
8. Cannot have QT interval corrected for heart rate using Fridericia’s 
formula (QTcF) ≥470 ms calculated. Any clinically significant 
abnormalities detected require triplicate ECG results and a mean 
QTcF< 470 ms calculated from 3 ECGs obtained over a brief period 
(eg, 30 minutes) 
 
STATISTICAL 
CONSIDERATIONS 
 
A Simon’s 2-stage design will be applied. The null hypothesis that the 
true response rate is 2% will be tested against a one-sided alternative. In 
the first stage, 18 subjects will be accrued. If there are 0 responses in these 
18 subjects, enrollment will be stopped. Otherwise, 10 additional subjects 
will be accrued for a total of 28. The null hypothesis will be rejected if 3 
or more responses (complete/partial) are observed in 28 subjects and 
further investigation will be warranted. This design yields a type I error 
rate of 0.02 and power of 80% when the true response rate is 15% or 
larger. 
TOTAL  
NUMBER OF 
SUBJECTS 
N = Approximately 28  
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 12 months 
ESTIMATED STUDY 
DURATION  
Estimated 24 months 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 6 of 69 
TABLE OF CONTENTS 
 
Schema ............................................................................................................................... 7 
1. 
Background and Rationale ..................................................................................... 8 
2. 
Study Objectives and Endpoints........................................................................... 12 
3. 
Eligibility Criteria .................................................................................................. 13 
4. 
Subject Registration............................................................................................... 19 
5. 
Treatment Plan....................................................................................................... 19 
6. 
Toxicities and Dose Delays/Dose Modifications .................................................. 23 
7. 
Study Calendar & Evaluations ............................................................................. 26 
8. 
Biospecimen Studies and Procedures ................................................................... 30 
9. 
Criteria for Disease Evaluation ............................................................................ 32 
10. Drug Information ................................................................................................... 36 
11 
Adverse Events ....................................................................................................... 37 
12 
Statistical Methods ................................................................................................. 43 
13 
Trial Management ................................................................................................. 45 
14. Data Handling and Record Keeping .................................................................... 46 
15 
Ethics ....................................................................................................................... 47 
16 
References ............................................................................................................... 48 
Appendix 1 ....................................................................................................................... 50 
 
 
 
 
 


Clinical Study Protocol 
HCRN GU17-297 
Version Date: 28MAR2019 
Confidential 
Page 7 of 69 
SCHEMA 
 
 
 
 
   


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 8 of 69 
1. 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background 
Each year in the United States, over 60,000 patients succumb to metastatic urothelial cancer. 
Standard first-line treatment for metastatic urothelial cancer includes platinum-based 
chemotherapy, regimens characterized by a relatively high response proportion but for the 
majority of patients, insufficient response durations. Given that a large subset of patients with 
metastatic urothelial cancer treated with first-line platinum based chemotherapy regimens are 
candidates for further treatment, several novel therapeutic approaches have been explored over 
the last several decades. However, until 2016, there had been no treatments approved in this 
setting by the United States Food and Drug Administration. The development of immune 
checkpoint blockade has recently changed the landscape of treatment for metastatic urothelial 
cancer.      
 
1.2 
Immune checkpoint blockade in advanced urothelial cancer 
 
1.2.1 PD-1/PD-L1 blockade in advanced urothelial cancer 
Several phase 1-3 trials have now established the activity and safety of PD-1/PD-L1 blockade in 
patients with metastatic urothelial cancer (Table 1). Collectively, these trials demonstrate durable 
responses are achieved in approximately 15-25% of patients with metastatic urothelial cancer 
with grade 3-4 adverse events occurring in approximately 5-15% of patients. Based on these 
findings, as of 5/2017, five PD-1/PD-L1 inhibitors had been approved by the United States Food 
and Drug Administration for the treatment of patients with metastatic urothelial cancer and has 
been integrated into standard therapy.  
 
Table 1. Major trials exploring PD-1/PD-L1 blockade in patients with metastatic urothelial 
cancer 
 
Reference 
Drug 
Antibody 
Target 
Setting 
Phase 
N 
Response 
Rate 
Balar, 
Lancet, 20161 
Atezolizumab 
Humanized 
IgG1 
PDL-1 
First line 
cis-
ineligible
Phase II 
119 
24% 
Balar, ESMO, 
20162 
Pembrolizumab 
Human IgG4 
PD-1 
First line 
cis-
ineligible
Phase II 
100 
24% 
Rosenberg, Lancet, 
20163 
Atezolizumab 
Humanized 
IgG1 
PDL-1 
Post 
platinum 
Phase II 
310 
16% 
Sharma, Lancet 
Oncology, 20164 
Nivolumab 
Human 
IgG4 
PD-1 
Post 
platinum 
Phase II 
270 
20% 
Bellmunt, NEJM, 
20175 
Pembrolizumab 
Human IgG4 
PD-1 
Post 
platinum 
Phase II 
270 
21% 
Plimack, Lancet 
Oncology, 20176 
Pembrolizumab 
Human IgG4 
PD-1 
Post 
platinum 
Phase I 
basket 
29 
28% 
Massard, JCO, 
20167 
Durvalumab 
Human 
IgG1 
PDL-1 
Post 
platinum 
Phase I 
basket 
42 
31% 
Apolo, JCO, 20178 
Avelumab 
Human IgG1 
PD-L1 
Post 
platinum 
Phase I 
basket 
44 
16% 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 9 of 69 
1.2.2 CTLA-4 blockade in advanced urothelial cancer 
Though extensive studies have rapidly established proof of concept for immune checkpoint 
blockade with PD-1/PD-L1 blockade in advanced urothelial cancer leading to integration into 
standard treatment, CTLA-4 blockade has been understudied in this disease. Blocking the 
interaction between CTLA-4 expressed on T lymphocytes, and B7 family molecules expressed 
on antigen-presenting cells, has been shown to augment T cell activation, proliferation, and anti-
tumor immunity. In a syngeneic murine bladder cancer model, CTLA-4 blockade induced tumor 
regression, improved survival, and increased levels of tumor-reactive T cells.9   
 
A “window of opportunity” study explored the pharmacodynamic effects of the CTLA-4 
antibody, ipilimumab, administered prior to radical cystectomy in 12 patients with localized 
invasive urothelial cancer of the bladder.10 This study demonstrated infiltration of T cells in the 
post-ipilimumab cystectomy specimens. A phase II trial has explored gemcitabine, cisplatin, plus 
ipilimumab in patients with metastatic urothelial cancer.11 This study demonstrated 
pharmacodynamics effects and unusual response kinetics suggestive of benefit with the addition 
of CTLA-4 blockade. 
 
Preliminary results of the first study to explore single-agent CTLA-4 blockade in patients with 
metastatic urothelial cancer were reported at the Society for Immunotherapy of Cancer 2017 
meeting. Sharma et al reported the results of a phase 2 multicenter study exploring 
tremelimumab monotherapy in patients with advanced solid tumors, including patients with 
advanced urothelial cancer (NCT02527434).12 Among 32 patients with metastatic urothelial 
cancer enrolled, the confirmed objective response rate was 18.8% (95% CI 7.2-36.4) with 2 
complete responses and 4 partial responses; the median duration of response was not estimable 
and all patients with confirmed CR or PR had disease control at 12 months.  
 
1.2.3 CLTA-4 blockade may be non-cross resistant with single agent PD-1/PD-L1 
blockade in advanced urothelial cancer 
Given non-overlapping mechanisms of action, and potential synergy, emerging data suggest that 
single agent CTLA-4 blockade may be active in patients with disease progression despite prior 
single-agent PD-1/PD-L1 blockade. Such findings are critical as only 15-25% of patients with 
metastatic urothelial cancer respond to single-agent PD-1/PD-L1 blockade and the development 
of additional regimens with the potential to induce durable responses in this disease is urgently 
needed.  
 
Preliminary results of a phase 2 study of ipilimumab added to nivolumab, in patients with 
metastatic urothelial cancer progressing despite single-agent nivolumab, were presented at the 
2017 ASCO Genitourinary Cancer Symposium.13 Ten patients who were refractory to nivolumab 
monotherapy were treated with the combination of ipilimumab (1 mg/kg) and nivolumab (3 
mg/kg). Among these 10 patients, 1 patient achieved a partial response and three additional 
patients achieved stable disease.  
 
Taken together, the findings outlined above support the need to further dissect the potential role 
of CTLA-4 blockade alone in patients with metastatic urothelial cancer progressing despite prior 
treatment with a PD-1/PD-L1 inhibitor.  
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 10 of 69 
1.3 
Tremelimumab 
Tremelimumab, a CTLA-4 mAb of the immunoglobulin G 2 kappa isotype, is an 
immunomodulatory therapy that is being developed by AstraZeneca for use in the treatment of 
cancer. CTLA-4 is a critical regulatory signal for T-cell expansion and activation following an 
immune response, and it serves as a natural braking mechanism that maintains T-cell 
homeostasis. During T-cell activation, T-cells upregulate CTLA-4, which binds to B7 ligands on 
APCs, sending an inhibitory signal that limits T-cell activation. Tremelimumab blocks the 
inhibitory signal resulting from CTLA-4 binding to B7, leading to indirect prolongation and 
enhancement of T-cell activation and expansion. Thus, the mechanism of action of 
tremelimumab is indirect and is applied through enhancing T-cell-mediated immune response. 
 
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. Details on the safety profile of tremelimumab monotherapy are 
summarized in Section. Refer to the current tremelimumab Investigator’s Brochure for a 
complete summary of non-clinical and clinical information including safety, efficacy and 
pharmacokinetics. Refer to the tremelimumab Investigator’s Brochure for a complete summary 
of non-clinical and clinical information. 
 
1.4 
Rationale 
A prospective trial to assess the activity of tremelimumab in patients with metastatic urothelial 
cancer progressive despite prior PD-1/PD-L1 blockade is supported by the following lines of 
evidence: 
 
1. Immune checkpoint blockade has changed the landscape of treatment for metastatic 
urothelial cancer, a disease without prior treatment advances in decades. 
2. Single-agent PD-1/PD-L1 blockade results in durable responses in ~15-20% of patients with 
metastatic urothelial cancer.  
3. Single-agent tremelimumab has shown similar response proportions to PD-1/PD-L1 blockade 
in metastatic urothelial cancer in a small phase 2 study. 
4. The mechanism of action of CTLA-4 blockade and PD-1/PD-L1 blockade are non-
overlapping and at least additive activity has been observed with combination therapy across 
several malignancies.  
5. Treatment of patients with metastatic urothelial cancer progressing despite prior PD-1/PD-L1 
blockade is a major unmet need. 
 
1.5 
Rationale for dose/schedule 
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. A total of 34 sponsored clinical studies 
have been conducted as part of the tremelimumab clinical development program. Of these, 13 
studies have completed and 21 are ongoing. Eight tremelimumab monotherapy studies have been 
completed and 3 are ongoing. As of the data cutoff date of 24 January 2016, 962 patients 
received tremelimumab in completed monotherapy studies and 380 patients in the Phase IIb 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 11 of 69 
monotherapy study (D4880C00003; DETERMINE). Study D4881C00024 is an ongoing rollover 
study, which provides continued access to treatment to 37 patients treated in prior completed 
studies. In the third ongoing monotherapy study (D4884C00001), 44 patients have been treated 
as of the data cutoff date. In addition, approximately 80 patients have been treated with 
tremelimumab in monotherapy arms of combination studies. Five studies of tremelimumab in 
combination with other anticancer agents have been completed and 18 are ongoing. In total, 
approximately 250 patients with a variety of tumor types have received tremelimumab in 
combination with other anticancer agents in these studies. 
 
In patients, tremelimumab exhibits linear (dose-proportional) PK following IV infusion. The 
estimate of clearance (CL), volume of distribution at steady state (Vss), and terminal-phase half-
life is 0.132 mL/h/kg, 81.2 mL/kg and 22.1 days, respectively. These values are consistent with 
those of natural IgG2. 
 
Across the clinical development program for tremelimumab, a pattern of efficacy has emerged 
that is similar to that of the related anti-CTLA-4 antibody, ipilimumab. In patients who respond, 
the responses are generally durable, lasting several months even in patients with aggressive 
tumors such as refractory metastatic melanoma. Some patients may have what is perceived to be 
progression of their disease in advance of developing disease stabilization or a tumor response.  
 
The target trough concentration of tremelimumab is estimated to be approximately 30 μg/mL, 
based on enhanced interleukin (IL)-2 release (in vitro) and antitumor activity (in vivo) in 
preclinical studies. PK simulations indicate that, following a dose of 10 mg/kg q4w for 6 months, 
approximately 90% of patients are expected to be above this target level of 30 μg/mL during the 
induction phase. Tremelimumab at a dose of 10 mg/kg q4w for 6 months followed by 10 mg/kg 
every 90 days is expected to yield PK exposures similar to those of the related anti-CTLA-4 
mAb ipilimumab, given at a dose of 10 mg/kg every 3 weeks (q3w) for 4 cycles (12 weeks) 
followed by 10 mg/kg every 3 months (beginning on Week 24), the dosing regimen that was 
tested in the pivotal first-line melanoma trial. 
 
Retrospective analyses of the Phase I and II tremelimumab melanoma studies show an 
improvement in OS for patients who were able to achieve a higher tremelimumab exposure, as 
measured by the area under the plasma drug concentration-time curve (AUC). The median OS 
was significantly longer in the high-AUC group (15.3 months; N=164) versus the low- AUC 
group (6.0 months; N=163) (based on the median value of AUC [103570 μ.h /mL]). This 
difference in OS corresponds to a hazard ratio (HR) of 0.41 (p<0.001), and the estimated survival 
rates in these 2 groups were 59% versus 29%, respectively, at 1 year. Additionally, a 
retrospective exposure and survival analysis of 293 patients treated with tremelimumab in a 
Phase III study in patients with melanoma showed better OS in patients with higher exposure. 
The median OS was 18.4 months for the high-AUC group (≥123665 μg.h /mL) compared to 9.0 
months for the low-AUC group (<123665 μ.h/mL) (HR 0.5; p<0.001). Tremelimumab 
monotherapy at a dose of 750 mg q4w for 7 doses (cycles) followed by 750 mg q12w for 2 
additional doses (cycles) is equivalent to 10 mg/kg tremelimumab monotherapy with the same 
dosing schedule. Therefore, the current study will utilize the following dosing regimen: 
Tremelimumab 750 mg once every 4 weeks for up to 7 doses. 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 12 of 69 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
Estimate the objective response rate (RECIST 1.1) with tremelimumab in subjects with 
metastatic urothelial cancer previously treated with PD-1/PD-L1 blockade 
 
2.1.2 Secondary Objectives 
 Describe the safety of the study treatment 
 Describe the disease control rate (objective response + stable disease)  
 Describe the duration of response  
 Describe the progression-free survival  
 Describe the overall survival  
 
2.1.3 Correlative/Exploratory Objectives 
 Explore the relationship between PD-L1 expression and response to treatment 
 Explore the relationship between gene expression signatures and response to treatment 
 Explore the relationship between genomic alterations including mutational load and 
response to treatment 
 Explore the impact of treatment on the peripheral blood immune cells and other 
circulating biomarkers 
 Explore the relationship between the microbiome and adverse events and outcomes with 
treatment 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
Objective Response rate as determined by RECIST 1.1 
 
2.2.2 Secondary Endpoints 
 Safety will be determined according to the NCI Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v4.03 
 The disease control rate is the rate of objective response and stable disease as determined 
by RECIST 1.1 
 Duration of response will be the time from the first documentation of response to the time 
of progression  
 Progression-free survival which is defined as the time from treatment initiation to death 
or progression, depending on which occurs first 
 Overall survival is defined as the time from treatment initiation to death  
 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 13 of 69 
3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
 
1. Written informed consent and HIPAA authorization for release of personal health 
information prior to registration. NOTE:  HIPAA authorization may be included in the 
informed consent or obtained separately. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. ECOG Performance Status of 0 or 1 within 14 days prior to registration. 
 
4. Histologically or cytologically documented urothelial cancer. Locally advanced (T4b, any N; 
or any T, N 2−3) or metastatic disease (M1, Stage IV) (also termed TCC or UCC of the 
urinary tract; including renal pelvis, ureters, urinary bladder, and urethra)  Subjects with 
mixed histologies are eligible provided that the predominant component is urothelial cancer. 
Locally advanced bladder cancer must be inoperable on the basis of involvement of pelvic 
sidewall or adjacent viscera (clinical Stage T4b) or bulky nodal metastasis (N2−N3). 
 
5. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks 
(blocks preferred) or at least 15 unstained slides. If archival tissue is not available and the 
subject is undergoing a standard of care biopsy, tissue from the biopsy is required to be 
submitted for correlative analyses. Subjects without adequate baseline tumor tissue may be 
considered for enrollment on a case by case basis after discussion with the sponsor-
investigator.  
 
6. Measurable disease according to RECIST 1.1 within 28 days prior to registration. At least 1 
lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in 
the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with 
computed tomography (CT) (preferred) or magnetic resonance imaging (MRI) scans, 
preferably with IV contrast, and that is suitable for accurate repeated measurements as per 
RECIST 1.1 guidelines; lesions in a previously irradiated field can be used as a measurable 
disease provided that there has been demonstrated progression in the lesion. 
 
7. A subject with prior brain metastasis may be considered if they have completed their 
treatment for brain metastasis at least 4 weeks prior to study registration, have been off of 
corticosteroids for ≥ 2 weeks, and are asymptomatic 
 
8. Subjects must have progressed despite prior treatment with anti-PD-1/PD-L1 antibody 
therapy. In addition, subjects must meet the following criteria: 
 Subjects must not have progressed within 2 months of starting prior anti-PD-1/PD-L1 
antibody therapy.  
 Subjects must have received at least 1 line of prior systemic therapy.  
 Must not have experienced a toxicity that led to permanent discontinuation of prior 
immunotherapy.  


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 14 of 69 
 All AEs while receiving prior immunotherapy must have completely resolved or 
resolved to baseline prior to screening for this study with the exception of endocrine 
related AEs that are stable on replacement therapy (e.g., steroids, thyroid hormone) 
which may be considered eligible but must be discussed with the sponsor-investigator. 
 Must not have experienced a ≥ Grade 3 immune related AE or an immune related 
neurologic (neuro-muscular) or ocular AE of any grade while receiving prior 
immunotherapy. NOTE: Subjects with endocrine AE of ≤ Grade 2 are permitted to 
enroll if they are stably maintained on appropriate replacement therapy and are 
asymptomatic. Must not have required the use of additional immunosuppression other 
than corticosteroids for the management of an AE, not have experienced recurrence of 
an AE if re-challenged, and not currently require maintenance doses of > 10 mg 
prednisone or equivalent per day. 
 Patients with Gr 3 AST/ALT elevation < 8 fold that resolved with steroids without 
additional immunosuppression can be included (Patients who experienced Hy’s law on 
PD-1/L1 therapy will be excluded) 
 
9. Prior cancer treatment must be completed at least 28 days or 5 half-lives (whichever is 
shorter) prior to first dose of study drug. Subjects must have recovered from all reversible 
acute toxic effects of the regimen (other than alopecia) to ≤ Grade 1 or baseline. 
 
10. Demonstrate adequate organ function as defined in the table below. All screening labs to be 
obtained within 14 days prior to registration.  
 
System 
Laboratory Value 
Hematological 
Absolute Neutrophil Count (ANC)
≥ 1500/mm3 
Hemoglobin (Hgb) 
≥ 9 g/dL 
Renal 
Calculated creatinine clearance1 or creatinine
≥ 30 cc/min or creatinine ≤ 1.5 
Hepatic 
Bilirubin 
≤ 1.5 × upper limit of normal (ULN) 
This will not apply to 
subjects with confirmed Gilbert’s syndrome 
(persistent or recurrent 
hyperbilirubinemia [predominantly 
unconjugated bilirubin] in the absence of 
evidence of hemolysis or hepatic pathology), 
who may be considered for enrollment after 
discussion with the Sponsor Investigator 
Aspartate aminotransferase (AST) 
≤ 2.5 × ULN (≤ 5 x ULN for subjects with 
hepatic metastases 
Alanine aminotransferase (ALT) 
≤ 2.5 × ULN (≤ 5 x ULN for subjects with 
hepatic metastases 
1 
Cockcroft-Gault formula will be used to calculate creatinine clearance or 24 urine collection for 
creatinine can be utilized 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 15 of 69 
11. Evidence of postmenopausal status or negative urinary or serum pregnancy test for female 
premenopausal subjects. Women will be considered postmenopausal 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 postmenopausal 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 postmenopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy). 
 Women ≥ 50 years of age would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced oophorectomy with last menses >1 year ago, had 
chemotherapy-induced menopause with >1 year interval since last menses, or 
underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy) 
 
12. Females of childbearing potential who are sexually active with a non-sterilized male partner 
must be willing to abstain from heterosexual activity or to use 1 highly of effective method of 
contraception from the time of informed consent until 90 days after the last dose of 
tremelimumab. Non-sterilized male partners of a female patient must use male condom plus 
spermicide throughout this period. See Table 2 for acceptable contraceptive methods.  
 
13. Non-sterilized males who are sexually active with a female partner of childbearing potential 
must use a male condom plus spermicide from screening through 90 days after receipt of the 
final dose of tremelimumab. Female partners (of childbearing potential) of male subjects 
must also use a highly effective method of contraception throughout this period. 
 
14. Must have life expectancy of ≥ 12 weeks. 
 
3.2 
Exclusion Criteria 
 
1. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study). 
 
2. Known additional malignancy that is active and/or progressive requiring treatment. Patients 
with incidental histologic findings of prostate cancer (tumor/node/metastasis stage of T1a or 
T1b or prostate-specific antigen <10) who have not received hormonal treatment may be 
included, pending a discussion with the sponsor-investigator 
 
3. Treatment with any investigational drug within 28 days prior to registration.  
 
4. Prior treatment with an anti-CTLA-4 antibody, including tremelimumab 
 
5. Any unresolved toxicity National Cancer Institute (NCI) CTCAE Version 4.03 Grade ≥ 2 
from previous anticancer therapy with the exception of alopecia, vitiligo, and laboratory 
values defined in the inclusion criteria. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 16 of 69 
 Subjects with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Sponsor Investigator 
 Subjects with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with tremelimumab (e.g., hearing loss) may be included after consultation 
with the sponsor-investigator 
 
6. Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for 
cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g., 
hormone replacement therapy) is acceptable. Note: Local treatment of isolated lesions, 
excluding target lesions, for palliative intent is acceptable (e.g., local surgery or radiotherapy) 
 
7. Radiation therapy within 14 days of first dose of study drug 
 
8. Major surgical procedure within 28 days prior to first dose of study treatment 
 
9. History of allogeneic organ transplantation that requires use of immunosuppressive agents 
 
10. Active or prior documented autoimmune of inflammatory disorders (including but not 
limited to inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome 
[granulomatosis with polyangiitis], Graves’ disease, rheumatoid arthritis, hypophysitis, 
uveitis, etc). The following are exceptions to this criterion: 
 Subjects with vitiligo 
 Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement 
 Any chronic skin condition that does not require systemic therapy 
 Subjects without active disease in the last 5 years may be considered for enrollment 
after discussion with the sponsor-investigator 
 Subjects with celiac disease controlled by diet alone may be considered for 
enrollment after discussion with the sponsor-investigator 
 
11. QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms calculated. 
Any clinically significant abnormalities detected require triplicate ECG results and a mean 
QTcF <470 ms calculated from 3 ECGs obtained over a brief period (eg, 30 minutes) 
 
12. Past medical history of Interstitial Lung Disease (ILD), drug-induced ILD, radiation 
pneumonitis which required steroid treatment, or any evidence of clinically active interstitial 
lung disease. 
 
13. History of active primary immunodeficiency 
 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 17 of 69 
14. Active infection, including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and tuberculosis testing in line with local 
practice), hepatitis B, hepatitis C, or human immunodeficiency virus (HIV, positive HIV 1 or 
2 antibodies). Active hepatitis B virus (HBV) infection is defined by a positive HBV surface 
antigen (HBsAg) result. Subjects with a past or resolved HBV infection (defined as the 
presence of hepatitis B core IgG antibody and the absence of HBsAg, deoxyribonucleic acid 
[DNA] negative) are eligible. Subjects positive for hepatitis C virus (HCV) antibody are 
eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA). 
 
15. Current or prior use of immunosuppressive medication within 14 days before the first dose of 
tremelimumab. The following are exceptions to this criterion: 
 Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection) 
 Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or its equivalent 
 Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) 
 
16. Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment. 
NOTE: Subjects, if enrolled, should not receive live vaccine during the study and up to 30 
days after the last dose of tremelimumab. 
 
17. Known allergy or hypersensitivity to tremelimumab or any investigation product excipient, 
or to other humanized mAbs 
 
18. Weight  35 kg 
 
3.3 
Re-Treatment with Tremelimumab Criteria 
 
Inclusion Criteria 
 
1. ECOG Performance Status of 0 or 1 within 14 days prior to re-treatment. 
 
2. Demonstrate adequate organ function as defined below. All labs to be obtained within 14 
days prior to re-treatment.  
 Absolute Neutrophil Count (ANC): ≥ 1500/mm3 
 Hemoglobin (Hgb): ≥ 9 g/dL 
 CrCl or creatinine: ≥ 30 cc/min or creatinine ≤ 1.5 
 AST and ALT: ≤ 2.5 × ULN (≤ 5 x ULN for subjects with hepatic metastases 
1Cockcroft-Gault formula will be used to calculate creatinine clearance or 24 urine collection for creatinine 
can be utilized 
 
3. Evidence of postmenopausal status or negative urinary or serum pregnancy test for female 
premenopausal subjects prior to re-treatment.  
 
4. Females of childbearing potential who are sexually active with a non-sterilized male partner 
must be willing to abstain from heterosexual activity or to use 1 highly of effective method of 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 18 of 69 
contraception from the time of informed consent until 90 days after the last dose of 
tremelimumab. Non-sterilized male partners of a female patient must use male condom plus 
spermicide throughout this period.  
 
5. Non-sterilized males who are sexually active with a female partner of childbearing potential 
must use a male condom plus spermicide from screening through 90 days after receipt of the 
final dose of tremelimumab. Female partners (of childbearing potential) of male subjects 
must also use a highly effective method of contraception throughout this period. 
 
6. Must have life expectancy of ≥ 12 weeks. 
 
Exclusion Criteria 
 
1. No significant, unacceptable, or irreversible toxicities that indicate re-treatment will not 
benefit the subject 
 
2. Active autoimmune or inflammatory disorders (including but not limited to inflammatory 
bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of 
diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome [granulomatosis with 
polyangiitis], Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc). The following 
are exceptions to this criterion: 
 Subjects with vitiligo 
 Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement 
 Any chronic skin condition that does not require systemic therapy 
 Subjects without active disease in the last 5 years may be considered for enrollment 
after discussion with the sponsor-investigator 
 Subjects with celiac disease controlled by diet alone may be considered for 
enrollment after discussion with the sponsor-investigator 
 
3. QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms calculated. 
Any clinically significant abnormalities detected require triplicate ECG results and a mean 
QTcF <470 ms calculated from 3 ECGs obtained over a brief period (eg, 30 minutes) 
 
4. Active infection 
 
5. Current or prior use of immunosuppressive medication within 14 days before re-treatment 
with tremelimumab. The following are exceptions to this criterion: 
 Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection) 
 Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or its equivalent 
 Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) 
 
6. Weight  35 kg 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 19 of 69 
7. Has not received an intervening systemic anticancer therapy after initial treatment 
discontinuation 
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through HCRN’s electronic data capture (EDC) system. A subject 
is considered registered when an “On Study” date is entered into the EDC system. Subjects must 
be registered prior to starting protocol therapy. Subjects must begin therapy within 7 business 
days of registration.  
 
5. 
TREATMENT PLAN 
This is a phase 2 study exploring single-agent tremelimumab in subjects with metastatic 
urothelial cancer progressive despite prior PD-1/PD-L1 blockade therapy. The study utilizes a 
Simon 2-stage design. Patients who do not receive drug or who do not complete 1 cycle of 
therapy for non-treatment related causes (e.g., traffic accidents, trauma etc.) will be replaced. 
 
 
 
5.1 
Study Drug Administration 
There are no pre-medication or hydration requirements 
Drug 
Dose1 
Route 
Schedule 
Cycle Length2 
Number of 
cycles 
Tremelimumab 
750 mg 
Intravenously (IV) 
over 1 hour 
Day 1 
Cycle 1-7 
28 days (± 3 days) 
Up to 7 
cycles 
1 Fixed dosing will be utilized. However, if a patient’s weight falls to 35kg or less, they should be 
discontinued from study treatment. 
2 A window of ± 5 minutes may be used for infusion of tremelimumab.
 
5.1.1 
Monitoring During Study Drug Infusions 
First Infusion: On the first infusion day, subjects will be monitored, and vital signs 
collected/recorded in eCRF prior to, during and after infusion as presented in the bulleted list 
below. BP and pulse will be collected from subjects before, during, and after each infusion at the 
following times (based on a 60-minute infusion): 
 Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before beginning of the infusion) 
 Approximately 30 minutes during the infusion (halfway through infusion)  
 At the end of the infusion (approximately 60 minutes ±5 minutes) 
 
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the 
principles as described above or be taken more frequently if clinically indicated. A 1-hour 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 20 of 69 
observation period is recommended after the first infusion of tremelimumab.  
 
Subsequent infusions: BP, pulse and other vital signs should be measured, collected/recorded in 
eCRF prior to the start of the infusion. Subjects should be carefully monitored, and BP and other 
vital signs should be measured during and post infusion as per institution standard and as 
clinically indicated. Any clinically significant changes in vital signs should be entered onto an 
unscheduled vital signs eCRF page. 
 
5.1.2 Treatment Beyond RECIST 1.1 Progression 
If there is evidence of RECIST 1.1 defined disease progression within the initial 7 cycles of 
tremelimumab, subjects may continue protocol therapy provided that none of the following 
apply: 
 Absence of signs and symptoms indicating disease progression 
 No decline in ECOG performance status 
 Absence of rapid progression of disease 
 Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
 
5.1.3 Re-treatment of Subjects Progressing within 1 Year of Completing Initial 
Tremelimumab 
Patients that complete the initial 7 cycles of tremelimumab then have evidence of disease 
progression per RECIST 1.1 (with or without confirmation) during the 1-year follow-up period 
may be eligible for re-treatment with up to 7 additional cycles of tremelimumab. Such patients 
are required to meet the eligibility criteria outlined in Section 3.3. Testing done during 
progression may be used for screening prior to re-treatment. Subjects should follow the same 
schedule of events/procedures for the initial Cycles 1-7 of tremelimumab.  
 
5.2 
Concomitant Medications, Treatments, and Restrictions 
 
5.2.1 Allowed Concomitant Medications/Treatments 
Medication other than that described below that is considered necessary for the patient’s safety 
and well-being may be given at the discretion of the site investigator and recorded in the eCRF.  
 
Rescue/supportive medication/class of drug 
Usage 
Concomitant medications or treatments (eg, 
acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed above 
To be administered as prescribed by the site 
investigator 
Basic Supportive Care (BSC) including 
antibiotics, nutritional support, correction of 
metabolic disorders, optimal symptom control, 
and pain management [including palliative 
radiotherapy to non-target lesions, etc]) 
Should be used, when necessary, for all subjects 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 21 of 69 
5.2.2 Prohibited Concomitant Medications/Treatments 
Restricted and prohibited concomitant medications are described in the tables.  
 
Prohibited medication/class of drug 
Usage 
Any investigational anticancer therapy other than 
those under investigation in this study 
Should not be given concomitantly while the 
patient is on study treatment 
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study 
Should not be given concomitantly while the 
patient is on study treatment 
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal therapy 
for cancer treatment 
Should not be given during the study. (Concurrent 
use of hormones for non-cancer-related conditions 
[eg, insulin for diabetes and hormone replacement 
therapy] is acceptable. Local treatment of isolated 
lesions, excluding target lesions, for palliative 
intent is acceptable [eg, 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 tumor necrosis 
factor-alpha blockers 
Should not be given during the study. Short-term 
use of immunosuppressive medications, including 
corticosteroids for the acute management of non-
IP emergencies (eg, COPD, asthma) or IP-related 
emergent AEs, is permitted. In addition, 
immunosuppressive medication for palliative 
treatment for oncologic emergencies or prior to 
imaging procedures in subjects with contrast 
allergies is acceptable. Use of inhaled, topical, 
and intranasal corticosteroids is permitted for all 
treatment arms. 
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP 
Sunitinib 
Should not be given to subjects within 3 months 
of a dose of tremelimumab, as acute renal failure 
has been reported with combination therapy of 
tremelimumab and sunitinib 
Drugs with laxative properties 
Should be used with caution through 90 days after 
the last dose of tremelimumab during the study. In 
case of strong medical need, should be used with 
caution. 
Herbal and natural remedies 
Should be avoided during the study. 
AE adverse event; CTLA-4 cytotoxic T lymphocyte-associated antigen 4; IP investigational product; PD-1 
programmed cell death 1; PD-L1 programmed cell death ligand 1 
 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 22 of 69 
5.3 
Contraception 
 
5.3.1 Female patient of child-bearing potential 
Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Females 
of childbearing potential who are sexually active with a non-sterilized male partner must use at 
least 1 highly effective method of contraception (Table 2) from the time of screening and must 
agree to continue using such precautions for 90 days after the last dose of tremelimumab. Non-
sterilized male partners of a female patient must use male condom plus spermicide throughout 
this period. Cessation of birth control after this point should be discussed with a responsible 
physician. Not engaging in sexual activity for the total duration of the drug treatment and the 
drug washout period is an acceptable practice; however, periodic abstinence, the rhythm method, 
and the withdrawal method are not acceptable methods of birth control.  
 
Female subjects should also refrain from breastfeeding throughout this period. 
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply:  
 Women < 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone levels 
in the post-menopausal range for the institution or underwent surgical sterilization 
(bilateral oophorectomy or hysterectomy).  
 Women ≥ 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
 
5.3.2 Male subjects with a female partner of childbearing potential 
Non-sterilized males who are sexually active with a female partner of childbearing potential 
must use a male condom plus spermicide from screening through 90 days after receipt of the 
final dose of tremelimumab. Not engaging in sexual activity is an acceptable practice; however, 
occasional abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. Male subjects should refrain from sperm donation throughout this 
period. 
 
Female partners (of childbearing potential) of male subjects must also use a highly effective 
method of contraception throughout this period (Table 2).  Highly effective methods of 
contraception, defined as one that results in a low failure rate (ie, less than 1% per year) when 
used consistently and correctly are described in Table 2. Note that some contraception methods 
are not considered highly effective (eg. male or female condom with or without spermicide; 
female cap, diaphragm, or sponge with or without spermicide; non-copper containing 
intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of 
ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered 
highly effective]; and triphasic combined oral contraceptive pills). 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 23 of 69 
Table 2: Highly effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine methods 
Hormonal Methods 
 
Copper T intrauterine device 
 
Levonorgestrel-releasing intrauterine 
system (eg, Mirena®)a 
 
 
Etonogestrel implants: eg, Implanon or 
Norplan 
 
Intravaginal device: eg, ethinylestradiol 
and etonogestrel 
 
Medroxyprogesterone injection: eg, 
Depo-Provera  
 
Normal and low dose combined oral 
contraceptive pill 
 
Norelgestromin/ethinylestradiol 
transdermal system 
 
Cerazette (desogestrel) 
a 
This is also considered a hormonal method 
 
5.4 
Blood donation 
Subjects should not donate blood while participating in this study, or for at least 90 days 
following the last infusion of tremelimumab. 
 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03 will be used to 
grade adverse events.  
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Study 
Calendar & Evaluations. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring study drug interruption or discontinuation as specified in Study Calendar & 
Evaluations.   
 
6.1 
Infusion Reactions 
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 subjects with a ≤ Grade 2 infusion-related reaction, 
subsequent infusions may be administered at 50% of the initial rate. Acetaminophen and/or an 
antihistamine (eg, diphenhydramine) or equivalent medications per institutional standard may be 
administered at the discretion of the site investigator. If the infusion-related reaction is ≥ Grade 3 
or higher in severity, study drug will be discontinued. For management of subjects who 
experience an infusion reaction, please refer to the toxicity and management guidelines in 
Appendix 1.  
 
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 subjects to an intensive care unit if necessary. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 24 of 69 
6.2 
Dose Delays/Dose Modifications 
The following general guidance should be followed for management of tremelimumab-related 
toxicities. 
 Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity if required). 
 If the symptoms promptly resolve with supportive care, consideration should be 
given to continuing study drug along with appropriate continuing supportive 
care. 
 If medically appropriate, dose modifications are permitted (Appendix 1) 
 All dose modifications should be documented with clear reasoning and documentation of 
the approach taken. 
 
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions are provided in Appendix 1, Dosing Modification and Toxicity 
Management Guidelines. In addition, there are certain circumstances in which tremelimumab 
should be permanently discontinued (see Section 6.4 and Appendix 1). 
 
Following the first dose of study drug, subsequent administration tremelimumab can be modified 
based on toxicities observed as described in Appendix 1, the Dosing Modification and Toxicity 
Management Guidelines. These guidelines apply to adverse events considered by the reporting 
site investigator to be causally related to tremelimumab. In case of doubt, the site investigator 
should consult with the sponsor-investigator. 
 
6.3 
Liver Function Test Abnormalities 
If a patient shows an AST or ALT ≥ 3 x ULN together with total bilirubin ≥ 2 x ULN, refer to 
Appendix 1 for further instructions. These cases should be reported as SAEs if, after evaluation, 
they meet the criteria for a Hy’s law case or if any of the individual liver test parameters fulfill 
any of the SAE criteria.  
 
6.4 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined in Appendix 1, a 
subject will also be discontinued from protocol therapy and followed per protocol under the 
following circumstances outlined below.  The reason for discontinuation of protocol therapy will 
be documented on the electronic case report form (eCRF)   
 
Confirmed disease progression per RECIST 1.1 prior to Cycle 7 
 
Completion of scheduled treatment 
 
Site investigator determines a change of therapy would be in the best interest of the 
subject 
 
Subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons 
o In a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if he or she may still be contacted for further 
scheduled study assessments. The outcome of that discussion should be documented 
in both the medical records and in the eCRF. 
 
Female subject becomes pregnant.  
 
If subject weight falls to 35kg or less. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 25 of 69 
 
Grade  3 infusion reaction. 
 
Study therapy is interrupted for ≥ 120 days.  
 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 7, 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. 
 
6.5 
Protocol Discontinuation  
If a subject decides to discontinue from the protocol (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. A 
complete final evaluation at the time of the subject’s protocol withdrawal should be made with 
an explanation of why the subject is withdrawing from the protocol. If the reason for removal of 
a subject from the study is an adverse event, it will be recorded on the eCRF. 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 26 of 69 
7. 
STUDY CALENDAR & EVALUATIONS 
 
Study Evaluations 
Cycle = 28 days 
Screening 
Cycles 1-7  
(± 3 days)16 
Cycles 1-3  
(± 3 days)16 
Safety Follow 
Up Visit14 
Follow up15 
Progression 
of Disease 
Screening for 
Re-
Treatment17 
-28 days 
Day 1 
Day 15 
~30 days post 
last dose  
(+7 days)
Every 3 
months  
(± 14 days)
REQUIRED ASSESSMENTS 
 
Informed Consent 
X
 
Medical History1 
X
 
Physical Exam 
X
X
X
X
X
Vital signs and ECOG Performance Status2
X
X9 
X
X
X
ECG3 
X
 
X
AEs & concomitant medications 
X
X
X
X
X
X
LABORATORY ASSESSMENTS 
 
Complete Blood Cell Count with diff (CBC)
X
X
X
X
X
Comprehensive Metabolic Profile (CMP)
X
X
X
X
X
Amylase and Lipase 
X
X
 
X
GGT and Magnesium level 
X
 
X
PT/INR and aPTT 
X
 
X
Thyroid Function (TSH, T4, free T3)4 
X
X4 
 
X
Pregnancy test (serum or urine) (WOCBP)5 
X
 
X
Hepatitis B and C and HIV6 
X
 
Urinalysis7  
X
 
X
DISEASE ASSESSMENT 
 
CT of chest8 
X
X8 
X8 
Every 3 
months  
(± 7 days) 
X
CT or MRI of abdomen and pelvis8 
X
X8 
X8 
X
Bone scan in subjects with bone metastases8
X
X8 
X8 
X
TREATMENT EXPOSURE 
 
Tremelimumab9 
X9 (750 mg)
 
SPECIMEN COLLECTION  
 
Archival Tumor Tissue or Fresh Biopsy10 
X10 
 
Tumor tissue obtained for clinical purposes11 
X11 
X11 
X11 
X11 
X11 
X11
Blood samples12 
X12
X12
 
X12 
X12
Stool sample for microbiome13 
X13 
 
FOLLOW-UP 
 
Survival Status, Subsequent Therapy 
 
X
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 27 of 69 
CBC with differential and platelet to include: Hgb, Hct, WBC, ANC, absolute lymphocyte count, platelets. CMP to include sodium, potassium, 
chloride, creatinine, blood urea nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase  
 
Key to Footnotes  
1: Medical History includes: smoking history questionnaire and a question regarding how the patient heard about the study. Prior anti-cancer 
treatment should be documented including medications (chemotherapy, checkpoint inhibitors, etc) radiation or surgery. Antibiotic use for 6 
months prior to stool collection will be documented. Diagnosis and staging to include pathology report and Tumor Node Metastasis (TNM) 
staging. Prior genomic or molecular testing results are required if available. 
 
2: Vital signs to include: blood pressure, pulse, temperature, respiration rate, weight, height (screening only) and ECOG performance status.  
Please see Section 5 for guidelines regarding vital signs during study drug infusion. 
 
3: Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the study. ECGs should be obtained after the patient 
has been in a supine position for 5 minutes and recorded while the patient remains in that position. In case of clinically significant ECG 
abnormalities, including a QTcF value >470 ms, 2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm. 
 
4: Thyroid Function (TSH, T4 and T3) will be done prior to treatment C1D1 then C3D1, C5D1, and C7D1 or more often if clinically indicated per 
site investigator discretion. For T4 and T3, free versus total is at the discretion of the site investigator. 
 
5: For women of childbearing potential (WOCBP): urine or serum βhCG if clinically appropriate. If a urine test is done and it is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required.   
 
6: Active infection, including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and 
tuberculosis testing in line with local practice), hepatitis B, hepatitis C, or human immunodeficiency virus (HIV, positive HIV 1 or 2 antibodies). 
Active hepatitis B virus (HBV) infection is defined by a positive HBV surface antigen (HBsAg) result. Subjects with a past or resolved HBV 
infection (defined as the presence of hepatitis B core IgG antibody and the absence of HBsAg, deoxyribonucleic acid [DNA] negative) are eligible. 
Subjects positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA). 
 
7: Urinalysis for bilirubin, blood, glucose, ketones, pH, protein, specific gravity to be performed at screening and as clinically indicated throughout 
the study per site investigator’s discretion. 
 
8: Radiology imaging to include: CT of the chest, CT or MRI of the abdomen/pelvis and bone scan (in subjects with bone metastasis). Scans 
should be performed at screening then every 2 months (± 7 days) during Cycles 1-7 (e.g., after C2, C4, etc.) and then every 3 months (± 7 days) 
until the time of progression. Imaging for the D30 safety visit may be omitted if already performed within 2 past months. 
 
9: Tremelimumab will be given approximately every month for up to 7 cycles in the absence of disease progression or prohibitive toxicity. Refer 
to Section 5 for information regarding monitoring of subjects during infusion. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 28 of 69 
10: Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks preferred) or at least 15 unstained slides 
will be identified prior to subject registration and shipped prior to C1D1. If archival tissue is not available and the subject is undergoing a standard 
of care biopsy, tissue from the biopsy is required to be submitted for correlative analyses. Subjects without adequate baseline tumor tissue may be 
considered for enrollment on a case by case basis after discussion with the sponsor-investigator. See Correlative Laboratory Manual (CLM) for 
additional details. 
 
11: Surplus tissue remaining after routine standard of care procedures (e.g., metastatic biopsies) during and after treatment will be collected during 
this study. Subjects may have tumor tissue obtained during the course of the study or at the time of disease progression for clinical purposes (e.g., 
confirmation of disease progression, management of complication of disease progression, etc.). Subjects will have the option of whether samples 
obtained during standard of care procedures may be used for research purposes. Samples for correlative analysis are required if a standard of care 
biopsy is performed at screening for the first 7 cycles of treatment. See CLM for additional details. 
 
12: Blood samples for research will be drawn pre-treatment C1D1 (may be done during screening if subject is found eligible), C2D1, C3D1, C6D1 
and at time of progression. See Table 3 and CLM for additional information. Blood samples for research will be collected for subjects receiving re-
treatment after progression. If samples are collected at progression after the initial 7 cycles of tremelimumab, samples at screening prior to re-
treatment C1D1 do not need to be repeated. Samples will also be done prior to treatment C2D1, C3D1, C6D1 and at progression after re-treatment. 
 
13. Stool for microbiome analysis will be collected prior to treatment prior to C1D1 of initial treatment. Subjects will be provided a kit with 
detailed instructions regarding collection of the sample prior to the timepoint. Samples will not be collected during re-treatment. Please see the 
CLM for additional details. 
 
14: The safety follow-up visit should only occur when subjects stop study treatment for whatever reasons (toxicity, progression, or at discretion of 
site investigator) and should be performed ~30 days (+7 days) after the last dose of treatment. Subjects who have an ongoing Grade ≥ 2 or serious 
AE (SAE) at this visit will continue to be followed until the AE resolves to ≤ Grade 1 or baseline, deemed clinically insignificant, and/or until a 
new anti-cancer treatment starts, whichever is earlier. 
 
15: Subjects completing study treatment without evidence of disease progression will be followed every 3 months for progression. Subjects with 
disease progression within 1 year of completing initial treatment with tremelimumab may be eligible for re-treatment with tremelimumab. After 
progression for subjects who are not candidates for tremelimumab retreatment or who initiate other anticancer therapies, patients will be followed 
for survival which may be accomplished via clinic visit, phone call, or other avenues as appropriate. Subjects who decline to return to the site for 
evaluations will be offered follow-up by phone every 3 months as an alternative. 
 
16: Results for LFTs, electrolytes and creatinine MUST BE REVIEWED by the treating physician or site investigator within 3 days prior to 
administration of study drug. For Day 15 Cycles 1-3, subjects will be contacted via phone call or other avenues as appropriate on Day 15 (± 3 
days) for AE assessment. If issues are identified during communication with the subject, appropriate assessment will be performed based on 
discretion of research staff. This may include a clinic visit, lab work or additional communication. 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 29 of 69 
17: Patients that complete the initial 7 cycles of tremelimumab then have evidence of disease progression per RECIST 1.1 (with or without 
confirmation) during the 1-year follow-up period may be eligible for re-treatment with up to 7 additional cycles of tremelimumab. Such patients 
are required to meet the eligibility criteria outlined in Section 3.3. Testing done during progression may be used for screening prior to re-treatment. 
Subjects should follow the same schedule of events/procedures for the initial Cycles 1-7 of tremelimumab. Baseline tumor assessment will be 
within 28 days of starting retreatment. Subjects should follow the same schedule of events/procedures for the initial cycles 1-7 of tremelimumab. 
Re-treatment should start within 28 days of documented progression.  
 
 
 
 
 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 30 of 69 
Table 3:  Schedule for correlative blood sample collections 
 
Timepoint 
Correlative blood samples 
Pre-Treatment Cycle 1 Day 1 
5 purple top tubes (50 ml total) 
2 ACD tubes (17 ml total) 
1 PAXgene tube (8.5 ml total)
Pre-Treatment Cycle 2 Day 1 
2 purple top tube (20 ml total) 
2 ACD tubes (17 ml total) 
1 PAXgene tube (8.5 ml total)
Pre-Treatment Cycle 3 Day 1 
2 purple top tubes (20 ml total) 
5 ACD tubes (42.5 ml total) 
1 PAXgene tube (8.5 ml total)
Pre-Treatment Cycle 6 Day 1 
2 purple top tubes (20 ml total) 
5 ACD tubes (42.5 ml total) 
1 PAXgene tube (8.5 ml total)
Time of progression  
5 purple top tubes (50 ml total) 
2 ACD tubes (17 ml total) 
1 PAXgene tube (8.5 ml total)
 
 
8. 
BIOSPECIMEN STUDIES AND PROCEDURES  
Tumor tissue, peripheral blood, and possibly normal urothelium will be used for biospecimen-
based research in this study. Full details of specimen collection and processing can be found in 
the CLM. 
 
Correlative studies may include genomic sequencing of tumor tissue and/or peripheral blood and 
immune monitoring studies including T cell receptor sequencing and flow cytometry and/or mass 
cytometry on tissue and/or peripheral blood, antigen-specific T cell assays, HLA typing, and 
gene expression.  
 
8.1 
Tissue 
Analysis of tumor tissue will include assessment for changes in the composition of immune cells, 
tumor cells, and tumor microenvironment. Immune cell composition and changes in the tumor 
microenvironment will be analyzed by platforms including but not limited to 
immunohistochemistry, flow cytometry, and mass cytometry. Tumor cells will be analyzed by 
immunohistochemistry, DNA, and RNA sequencing. Normal tissue or blood will be used for the 
germline genome. An effort will be made to identify tumor antigens for each subject using 
strategies including, but not limited to, collating the “antigenome” using immunohistochemistry 
data as well as identifying mutation-derived tumor antigens through genome sequencing and 
computational biology approaches to predict epitope: MHC binding affinity. Subject HLA typing 
will be done by sequence specific oligonucleotide probing and sequence specific priming of 
genomic DNA using standard procedures. T-cell responses will be detected using standard 
ELISPOT and intracellular cytokine assays or other emerging technologies. Tumor tissue will 
also be utilized for PD-L1 expression as determined by immunohistochemistry.    
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 31 of 69 
8.1.1 Archival Tissue 
Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks 
(blocks preferred) or at least 15 unstained slides will be identified prior to subject registration 
and shipped after registration but prior to C1D1. Representative formalin-fixed paraffin-
embedded (FFPE) tumor specimens in paraffin blocks (blocks preferred) or at least 15 unstained 
slides. If archival tissue is not available and the subject is undergoing a standard of care biopsy, 
tissue from the biopsy is required to be submitted for correlative analyses. Subjects without 
adequate baseline tumor tissue may be considered for enrollment on a case by case basis after 
discussion with the sponsor-investigator. Specimens will be utilized for cellular and molecular 
analyses including but not limited to DNA sequencing, RNA sequencing, and tissue 
imaging/multiplex staining. 
 
8.1.2 Tissue collected during routine clinical procedures 
Surplus tissue remaining after routine standard of care procedures (e.g., metastatic biopsies) will 
be collected during this study. Subjects may have tumor tissue obtained during the course of the 
study or at the time of disease progression for clinical purposes (e.g., confirmation of disease 
progression, management of complication of disease progression, etc.). Specimens obtained in 
these settings may be accessed by the research team to facilitate an understanding of the 
pharmacodynamic effects of treatment at the level of the tumor and microenvironment including 
mechanisms of treatment resistance.  Subjects will have the option of whether samples obtained 
during standard of care procedures may be used for research purposes. 
 
8.2 
Blood Samples 
For blood samples, the volume of blood and type of tube to be used for each collection is 
specified in Table 3 and CLM.  Collection of whole blood samples is mandatory for participation 
in this study. Blood samples for research will also be collected for subjects receiving re-
treatment after progression. 
 
8.2.1 Blood for Immune cell subsets 
The quantity and composition of immune cells in the peripheral blood will be analyzed by flow 
cytometry or mass cytometry. Antigen specific T cell responses will be detected as described 
above.   
 
8.2.2 Peripheral blood for DNA and RNA 
Plasma will be stored for future ctDNA isolation and quantitative expression using sequence 
specific primers and/or for exome sequencing. DNA from whole blood may be used to germline 
sequencing to facilitate analysis of somatic tumor DNA sequencing. Whole blood will be stored 
for gene expression profiling from RNA.  
 
8.3 
Stool for microbiome analysis 
Prior to treatment, patients will provide a stool sample from a single bowel movement for 
microbiome analysis as per the CLM. Stool samples will be analyzed to assess microbiome 
diversity and composition. Exploratory analyses correlating clinical outcomes and 
diversity/composition as well as assessment of metabolomics and metagenomic whole genome 
sequencing may be performed. Stool samples will not be collected during re-treatment with 
tremelimumab. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 32 of 69 
8.4 
Storage of Biospecimens 
Excess biospecimens not completely utilized in these experiments will be stored indefinitely at 
HCRN for future use in research focused on GU malignant diseases that are yet to be 
determined.  All specimens collected will maintain the assigned sequence ID number of the 
corresponding patient.  Deidentified samples may be shared with other research institutions.  We 
believe that allowing for storage and usage of the remaining samples for future research is 
ethically justified and a preferred option to discarding these materials given the potential impact 
on improving clinical outcomes for subjects with bladder cancer.  Subjects will be given the 
option to store excess specimens during the informed consent process. 
 
8.5 
Confidentiality of Biospecimens 
Samples that are collected will be identified by a subject’s sequence ID assigned at the time of 
registration to the trial. Any material issued to collaborating researchers will be anonymized and 
only identified by the subject’s sequence ID. 
 
9. 
CRITERIA FOR DISEASE EVALUATION 
See section 5.1.3 and 5.1.4 for criteria for continuing treatment past RECIST 1.1 disease 
progression. 
 
9.1 
RECIST 1.1 
 
9.1.1 Measurable disease  
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
 
9.1.1.1 
Measurable lesions 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
9.1.1.2 
Non- Measurable lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 33 of 69 
9.1.1.3 
Malignant lymph nodes  
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
 
9.1.1.4 Baseline documentation of “Target” and “Non-Target” lesions 
 
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions  
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
9.2 
Response Criteria 
 
Evaluation of target lesions 
Complete Response (CR) 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm.
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.  (Note:  the appearance of one or more 
new lesions is also considered progressions). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference 
the smallest sum diameters while on study. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 34 of 69 
Evaluation of non-target lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
NOTE:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
subject to be considered in complete clinical 
response.
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not 
a single lesion increase.
*Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the site physician should prevail. 
 
9.3 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Target Lesions 
Non-Target lesion
New Lesion
Overall response
CR 
CR 
No
CR 
CR 
Non-CR/ Non-PD
No
PR 
 
Not evaluated
No
PR 
PR 
Non-CR/ Non-PD/ not 
evaluated 
No 
PR 
SD 
Non-CR/ Non-PD/ not 
evaluated 
No 
SD 
PD 
Any 
Yes or No
PD 
Any 
PD* 
Yes or No
PD 
Any 
Any 
Yes
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. In some circumstances it may be difficult to 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 35 of 69 
distinguish residual disease from normal tissue.  When the evaluation of complete response 
depends on this determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) to confirm the complete response status. 
 
9.4 
Definitions for Response Evaluation – RECIST 1.1 
 
9.4.1 First documentation of response 
The time between initiation of therapy and first documentation of PR or CR. 
 
9.4.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for response 
are first met. 
 
9.4.3 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented, taking as reference the smallest 
measurements recorded since treatment started. 
 
9.4.4 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response until 
the first date that recurrent disease is objectively documented. 
 
9.4.5 Objective response rate 
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST, from the start of treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the start of treatment). 
 
9.4.6 Progression Free Survival 
A measurement from the start of the treatment until the criteria for disease progression is met or 
death occurs, taking as reference the smallest measurements recorded since the treatment started.   
 
Progression free survival will be measured from the date of initial treatment to the earliest date of 
disease progression, resection of measurable tumor or death for subjects who fail; and to the date 
of last contact for subjects who remain at risk for failure. 
 
 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 36 of 69 
10. 
DRUG INFORMATION 
 
10.1 
Tremelimumab 
Tremelimumab is an anti-CTLA-4 antibody being explored as a single-agent, and in combination 
with durvalumab, for the treatment of several malignancies.  
 
10.1.1 Supplier/How Supplied 
Tremelimumab will be supplied by AstraZeneca. Tremelimumab is formulated at 20 mg/mL in 
20 mM histidine/histidine-HCl, 22 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, and 
0.27 mM disodium edetate dihydrate, pH 5.5. The investigational product is supplied as a sterile 
liquid solution containing either 400 mg (nominal) tremelimumab per vial or 25 mg (nominal) 
per vial. The nominal fill volume for the 400 mg presentation is 20.0 mL and the nominal fill 
volume for the 25 mg presentation is 1.25 mL. Investigational product vials are stored at 2°C to 
8°C (36°F to 46°F) and must not be frozen. Drug product should be kept in secondary container 
until use to prevent excessive light exposure. 
 
10.1.2 Preparation  
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 
 
Tremelimumab will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose, with a final tremelimumab concentration ranging from 0.10 to 10 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. The IV bag size 
should be selected such that the final concentration is within 0.10 to 10 mg/mL. Mix the bag by 
gently inverting to ensure homogeneity of the dose in the bag.  
 
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. Do not co-administer other drugs 
through the same infusion line. 
 
In the event that either preparation time or infusion time exceeds the time limits a new dose must 
be prepared from new vials. Tremelimumab does not contain preservatives, and any unused 
portion must be discarded.  
 
10.1.3 Dispensing 
Tremelimumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Tremelimumab should be stored in a secure area according to 
local regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects.   
 
10.1.4 Adverse Events 
Risks with tremelimumab monotherapy include, but are not limited to, GI effects (colitis, 
diarrhea, enterocolitis and intestinal perforation), endocrine disorders (hypo and 
hyperthyroidism, hypophysitis and adrenal insufficiency), skin effects (rash, and pruritus), 
elevations in lipase and amylase and clinical manifestations of pancreatitis, other gastrointestinal 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 37 of 69 
events e.g. ulcerative colitis, dehydration, nausea and vomiting; hepatic events including 
hepatitis, and liver enzyme elevations; pneumonitis and ILD; nervous system events including 
encephalitis, peripheral motor and sensory neuropathies, Guillain-Barre and proximal muscle 
weakness; cytopenias including thrombocytopenia, anemia and neutropenia; infusion-related 
reactions, anaphylaxis, and allergic reactions; renal events including renal failure, acute kidney 
injury, nephritis, nephrotic syndrome, autoimmune nephritis and electrolyte abnormalities such 
as hypokalemia; autoimmune diseases including autoimmune arthritis, Sjogren's syndrome and 
giant cell temporal arteritis; hyperglycemia and diabetes mellitus; and pyrexia. For information 
on all identified and potential risks with tremelimumab please always refer to the current version 
of the tremelimumab IB. Using pooled data from monotherapy clinical studies AEs (all grades) 
reported very commonly (≥ 10% of patients) were diarrhea, nausea, fatigue, pruritus, decreased 
appetite, rash, vomiting, dyspnea, constipation, cough, pyrexia, abdominal pain, decreased 
weight, headache, asthenia, and anemia. Approximately 16% of patients experienced an AE that 
resulted in permanent discontinuation of tremelimumab and approximately 45% of patients 
experienced an SAE. 
 
11 
ADVERSE EVENTS 
The descriptions and grading scales found in the NCI CTCAE v4.03 will be utilized for AE 
assessment. A copy of the CTCAE v4.03 can be downloaded from the CTEP website at 
http://ctep.cancer.gov. All forms for AE/SAE recording and reporting can be found in the Study 
Procedure Manual or in the EDC system (Documents and Information Tab). 
 
11.1 
Definitions 
 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 38 of 69 
11.1.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
 Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
 Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 
11.1.3 Adverse Events of Special Interest  
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the study drug(s) and may require close monitoring and rapid communication 
by the site investigator to the sponsor-investigator. 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 the study drug(s). If any AESI occurs in the 
course of the study, then the site investigators or other site personnel should report to Hoosier 
Cancer Research Network (HCRN) within 1 business day of becoming aware of the event. 
HCRN will report to AstraZeneca within 1 business day of becoming aware of the event. AESIs 
for tremelimumab include, but are not limited to, events with a potential inflammatory or 
immune-mediated mechanism and that 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 tremelimumab therapy.  
 
An imAE is defined as an AE that is associated with drug exposure and is consistent with an 
immune-mediated mechanism of action and where there is no clear alternate etiology. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, 
or other etiologic causes of the imAE. In the event of imAE or suspected imAE, the sponsor-
investigator may request relevant clinical information (including images) for those subjects who 
demonstrate the event and may request the independent review by external experts based on the 
acquired clinical information. 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 39 of 69 
If the site investigator has any questions with regards to an AE being an imAE, the site 
investigator should immediately contact the sponsor-investigator. 
AESIs observed with tremelimumab include the following: 
 Diarrhea/Colitis and intestinal perforation 
 Pneumonitis/Interstitial Lung Disease (ILD) 
 Hepatitis/transaminase increases  
 Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
 Endocrinopathy (ie, events of hypophysitis, adrenal insufficiency, and hyperthyroidism 
and hypothyroidism, Type I diabetes) 
 Rash/Dermatitis 
 Nephritis/Blood creatinine increases 
 Pancreatitis/ serum lipase and amylase increases 
 Myocarditis 
 Myositis/Polymyositis 
 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 etiology are also considered AESIs. Further information on these 
risks (e.g. presenting symptoms) can be found in the current version of the tremelimumab 
Investigator’s Brochure. 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 Funder to assist the investigators 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) 
 
11.1.4 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.   
 
11.1.5 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 40 of 69 
11.2 
Reporting 
 
11.2.1 Adverse Events  
AEs will be recorded from time of signed informed consent until 30 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
 AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
 All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
 AEs considered related to study drug(s) will be followed until resolution to        
 ≤ Grade 1 or baseline, deemed clinically insignificant, and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
 Asymptomatic laboratory abnormalities that do not require treatment will not be collected 
as adverse events. 
 
11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1 
Site Requirements for Reporting SAEs to HCRN 
 SAEs will be reported from time of signed informed consent until 90 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
 SAEs will be reported on the SAE Submission Form within 1 business day of discovery 
of the event.   
 SAEs include events related and unrelated to the study drug(s).  
 All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
 All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 
1 or baseline and/or deemed clinically insignificant and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
 
The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form may be submitted to HCRN electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements.   
 
The original copy of the SAE Submission Form and the email correspondence must be kept 
within the study file at the study site. 
 
Once the SAE has resolved (see resolution guidelines listed above), sites must submit a follow-
up SAE Submission Form within a reasonable timeframe to HCRN electronically to 
safety@hoosiercancer.org.   
 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 41 of 69 
11.2.2.2 
HCRN Requirements for Reporting SAEs to AstraZeneca  
HCRN will report all SAEs to AstraZeneca as stipulated by company within 1 business day of 
receipt of the SAE Submission Form from a site. Follow-up information will be provided to 
AstraZeneca as it is received from site. Send SAE report and accompanying cover page by way 
of email to AstraZeneca’s designated mailbox:  AEMailboxClinicalTrialTCS@astrazeneca.com 
11.3 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 
11.4 
HCRN Responsibilities to FDA 
HCRN will manage the Investigational New Drug Application (IND) associated with this 
protocol on behalf of the sponsor-investigator. HCRN will cross-reference this submission to the 
AstraZeneca’s parent IND at the time of submission. Additionally, HCRN will submit a copy of 
these documents to AstraZeneca at the time of submission to FDA. 
 
For protocols conducted under an IND, HCRN will be responsible for all communication with 
the FDA in accordance with 21CFR312 including but not limited to the 7 and 15 Day Reports, as 
well as an Annual Progress Report. Additionally, HCRN will submit a copy of these reports to 
AstraZeneca at the time of submission to FDA. 
 
11.5 
IND Safety Reports Unrelated to this Trial 
AstraZeneca will provide to HCRN IND safety reports from external studies that involve the 
study drug(s) per their guidelines.  HCRN will forward safety reports to the sponsor-investigator 
who will review these reports and determine if revisions are needed to the protocol or consent. 
HCRN will forward these reports to participating sites within 1 business day of receiving the 
sponsor-investigator’s review.  Based on the sponsor-investigator’s review, applicable changes 
will be made to the protocol and informed consent document (if required).  All IND safety 
reports will also be made available to sites via the EDC system.    
 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
11.6 
Other events requiring reporting 
 
11.6.1 Overdose 
Use of tremelimumab in doses in excess of that specified in the protocol is considered to be an 
overdose. There is currently no specific treatment in the event of overdose of tremelimumab, and 
possible symptoms of overdose are not established. An overdose with associated AEs will be 
recorded as the AE diagnosis or symptoms in the relevant eCRF. 
 
If an overdose of a study drug(s) occurs in the course of the study, then the site investigator or 
other site personnel will inform HCRN within 1 business day of becoming aware of the event. 
HCRN will report the event to AstraZeneca within 1 business day of becoming aware of the 
event. 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 42 of 69 
11.6.2 Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for: 
 Pregnancy discovered before the study subject has received any study drugs. 
 Pregnancy of a female partner of male subject, providing there is no restriction of male 
subject fathering a child. 
 
11.6.3 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study drug(s) should be 
discontinued immediately. Pregnancy itself is not regarded as an AE unless there is a suspicion 
that the study drug(s) 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 site investigator or other site 
personnel will inform HCRN within 1 business day of becoming aware of the event. HCRN will 
report the event to AstraZeneca within 1 business day of becoming aware of the event.  
 
11.6.4 Paternal exposure  
Male subjects should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of tremelimumab.  Pregnancy of the patient’s partner is not considered 
to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date 
of the first dose until 90 days after the last dose of tremelimumab therapy should, if possible, be 
followed up and documented.  
 
11.6.5 Reporting of deaths to AstraZeneca 
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of 
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 HCRN within 24 hours and HCRN will report 
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.  
 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 43 of 69 
12 
STATISTICAL METHODS 
 
12.1 
Study Design 
This is a phase II trial designed to estimate the activity of single agent tremelimumab in subjects 
with metastatic urothelial cancer with disease progression despite prior treatment with PD-1/PD-
L1 blockade. There is currently no standard treatment for such subjects. Therefore, given the 
durability of responses observed with immune checkpoint blockade, even a relatively low 
response proportion could be clinically meaningful. A Simon’s 2-stage design will be applied.    
 
12.2 
Endpoints 
 
12.2.1 Definition of Primary Endpoint 
The primary endpoint is to determine the response rate by RECIST 1.1 
 
12.2.2 Definition of Secondary Endpoints 
 Safety will be determined according to the NCI Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v4.03 
 Duration of response will be the time from the first documentation of response to the time 
of progression as per RECIST 1.1 or death  
 Progression-free survival which is defined as the time from treatment initiation to death 
or progression, depending on which occurs first 
 Overall survival is defined as the time from treatment initiation to death  
 
12.3 
Sample Size and Accrual 
A Simon’s 2-stage design14 will be applied. Patients who do not receive drug or who do not 
complete 1 cycle of therapy for non-treatment related causes (eg, traffic accidents, trauma etc) 
will be replaced.  
 
The null hypothesis that the true response rate is 2% will be tested against a one-sided 
alternative. In the first stage, 18 subjects will be accrued. If there are 0 responses in these 18 
subjects, enrollment will be stopped. Otherwise, 10 additional subjects will be accrued for a total 
of 28. The null hypothesis will be rejected if 3 or more responses are observed in 28 subjects. 
This design yields a type I error rate of 0.02 and power of 80% when the true response rate is 
15% or larger. 
 
12.4 
Assessment of Safety 
The safety population will be defined as any patients that receive at least one dose of 
tremelimumab and will be used in the assessment of toxicity. Safety will be determined 
according to the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. 
All subjects will be evaluable for adverse event evaluation from the time of their first dose of 
study treatment.   
 
12.5 
Assessment of Efficacy 
All subjects who have received at least one cycle of therapy and have had their disease re-
evaluated will be considered evaluable for response (exceptions will be those who exhibit 
objective disease progression prior to the end of Cycle 1 who will also be considered evaluable). 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 44 of 69 
Patients who do not receive drug or who do not complete 1 cycle of therapy for non-treatment 
related causes will be replaced. 
 
12.6 
Data Analysis Plans 
 
12.6.1 Analysis Plans for Primary Objective 
All subjects with measurable disease who have received at least one cycle of treatment and have 
their disease re-evaluated will be evaluable for assessment of objective response. The objective 
response rates as determined by RECIST 1.1 and their associated 95% confidence intervals will 
be constructed based on the exact binomial test.  
 
12.6.2 Analysis Plans for Secondary Objectives 
Any subject who receives at least one dose of treatment on this protocol is evaluable for toxicity. 
Toxicity rates will be summarized using frequency tables. Disease control rates will be analyzed 
based on the exact binomial test. Duration of response will be the time from the first 
documentation of response to the time of progression or death will be summarized using 
frequency tables. Progression free survival and overall survival curves will be based on the 
Kaplan-Meier method.  
 
12.6.3 Analysis Plans for Exploratory Objectives 
To explore the relationship between PD-L1 expression and response to treatment, Fisher's exact 
test will be used. To explore the relationship between molecular subtype of bladder cancer and 
response to treatment, frequency tables will be constructed and Fisher's exact test will be used.  
To explore the relationship between genomic alterations, including mutational load, and changes 
in circulating immune biomarkers and response to treatment both Fisher's exact test and T-test 
will be used. Exploratory analyses correlating clinical outcomes and adverse events with stool 
microbiome diversity/composition as well as assessment of metabolomics and metagenomic 
whole genome sequencing may also be performed.  
 
12.7 
Interim Analysis/Criteria for Stopping Study 
Though there has been limited experience with single agent CTLA-4 blockade in metastatic 
urothelial cancer, prior studies exploring combination PD-1/PD-L1 plus CTLA-4 blockade in 
metastatic urothelial cancer have reported a treatment-related Grade ≥ 3 adverse event rate of 
approximately 30%.15 A stopping rule for excessive toxicity will be employed after 6, 12, 18, 
and 24 subjects finish at least one cycle of treatment. This safety stopping rule will be performed 
with respect to all treatment-related Grade ≥ 3 adverse events. Two-sided 95% exact binomial 
confidence intervals (CIs) of these treatment-related Grade ≥ 3 adverse event rates will be 
constructed. If their lower bounds exceed 33%, the study drug will be considered unacceptably 
toxic for this patient population and enrollment will be halted. This corresponds to ≥ 5 out of 6 
patients with grade ≥ 3 adverse events, ≥ 8 out of 12 patients with grade ≥ 3 adverse events, ≥ 10 
out of 18 patients with grade ≥ 3 adverse events , and ≥ 13 out of 24 subjects with grade ≥ 3 
adverse events. 
 
There is a possibility of stopping at the 1st stage if no patients respond to treatment. In addition, 
the study accrual may be suspended in the case when none of the first 17 patients respond and 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 45 of 69 
the decision to move onto the 2nd stage hinges on the response of the 18th patient. Otherwise, 
during these safety analyses, enrollment will continue. 
 
13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted with guidance from the Tisch Cancer Institute Cancer Center’s 
DSMP.  
 
HCRN oversight activities include: 
 Review and process all adverse events requiring expedited reporting as defined in the 
protocol 
 Provide trial accrual progress, safety information, and data summary reports to the 
sponsor-investigator  
 Submit data summary reports at least every 6 months to the DSMC for review according 
to the Tisch Cancer Institute Cancer Center’s DSMP 
 
13.2 
Tisch Cancer Institute Cancer Center Data Safety Monitoring Committee 
HCRN will provide the following for the DSMC to review: 
 Adverse event summary report 
 Audit results, if applicable 
 Data related to stopping/decision rules described in study design 
 Study accrual patterns  
 Protocol deviations 
 
The DSMC will review study data at least every 6 months. Documentation of DSMC reviews 
will be provided to sponsor-investigator and HCRN.  Issues of immediate concern by the DSMC 
will brought to the attention of the sponsor-investigator and other regulatory bodies as 
appropriate.  The sponsor-investigator will work with HCRN to address the DSMC’s concerns.   
 
13.3 
Data Quality Oversight Activities 
Remote validation of EDC system data will be completed on a continual basis throughout the life 
cycle of the study. Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel.  
 
Participating sites may also be subject to quality assurance audits by AstraZeneca-MedImmune 
or its designee as well as inspection by appropriate regulatory agencies. 
 
13.3.1 Onsite Monitoring 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. Selected source documents will be reviewed for verification of 
agreement with data entered into the EDC system.  It is important for the site investigator and 
their relevant personnel to be available for a sufficient amount of time during the monitoring 
visits or audit, if applicable. The site investigator and institution guarantee access to source 
documents by HCRN or its designee. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 46 of 69 
13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information.   
 
14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform, a system compliant with Good Clinical Practices 
and Federal Rules and Regulations.  HCRN personnel will coordinate and manage data for 
quality control assurance and integrity. Select data will be collected and entered into the EDC 
system  by study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in the EDC system or other secure database(s). If procedures on the study 
calendar are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel. Subjects will 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 47 of 69 
be informed in writing that some organizations including the sponsor-investigator and his/her 
research associates, HCRN, AstraZeneca, IRB, or government agencies, like the FDA, may 
inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
15 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require.  
 
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject.  
 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 48 of 69 
16 REFERENCES 
 
1.  
Balar A V, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in 
cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a 
single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76. 
doi:10.1016/S0140-6736(16)32455-2. 
2.  
Balar A, Bellmunt J, O’Donnell PH, et al. Pembrolizumab (pembro) as first-line therapy 
for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the 
phase 2 KEYNOTE-052 study. Ann Oncol. 2016;27(suppl_6). 
doi:10.1093/annonc/mdw435.25. 
3.  
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following treatment 
with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 
(London, England). March 2016. doi:10.1016/S0140-6736(16)00561-4. 
4.  
Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma 
after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet 
Oncol. January 2017. doi:10.1016/S1470-2045(17)30065-7. 
5.  
Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for 
Advanced Urothelial Carcinoma. N Engl J Med. February 2017:NEJMoa1613683. 
doi:10.1056/NEJMoa1613683. 
6.  
Plimack ER, Bellmunt J, Gupta S, et al. Safety and activity of pembrolizumab in patients 
with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-
randomised, open-label, phase 1b study. Lancet Oncol. 2017;18(2):212-220. 
doi:10.1016/S1470-2045(17)30007-4. 
7.  
Massard C, Gordon MS, Sharma S, 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. June 2016. 
doi:10.1200/JCO.2016.67.9761. 
8.  
Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an Anti-Programmed Death-
Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results 
From a Multicenter, Phase Ib Study. J Clin Oncol. April 2017:JCO2016716795. 
doi:10.1200/JCO.2016.71.6795. 
9.  
Mangsbo SM, Sandin LC, Anger K, et al. Enhanced tumor eradication by combining 
CTLA-4 or PD-1 blockade with CpG therapy. J Immunother. 2010;33(3):225-235. 
doi:10.1097/CJI.0b013e3181c01fcb00002371-201004000-00001 [pii]. 
10.  
Carthon BC, Wolchok JD, Yuan J, et al. Preoperative CTLA-4 blockade: tolerability and 
immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res. 
2010;16(10):2861-2871. doi:1078-0432.CCR-10-0569 [pii]10.1158/1078-0432.CCR-10-
0569. 
11.  
Galsky MD, Hahn NM, Albany C, et al. Phase II trial of gemcitabine + cisplatin + 
ipilimumab in patients with metastatic urothelial cancer. ASCO Meet Abstr . 
2016;34(2_suppl):357. http://meeting.ascopubs.org/cgi/content/abstract/34/2_suppl/357. 
12.  
Sharma P, Callahan MK, Calvo E, et al. Efficacy and safety of nivolumab plus ipilimumab 
in previously treated metastatic urothelial cancer. In: SITC. ; 2016. 
13.  
Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of 
durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 49 of 69 
study. Lancet Oncol. 2016;17(3):299-308. doi:10.1016/S1470-2045(15)00544-6. 
14.  
Callahan MK, Kania BE, Iyer G, et al. Evaluation of the clinical activity of ipilimumab 
(IPI) plus nivolumab (NIVO) in patients (pts) with NIVO-refractory metastatic urothelial 
cancer (UC). J Clin Oncol. 2017;35(6_suppl):384-384. 
doi:10.1200/JCO.2017.35.6_suppl.384. 
15.  
Ascierto PA, Del Vecchio M, Robert C, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 
mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, 
multicentre, phase 3 trial. Lancet Oncol. March 2017. doi:10.1016/S1470-2045(17)30231-
0. 
16.  
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use 
in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152. 
doi:10.1016/S1470-2045(17)30074-8. 
17.  
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 
1989;10(1):1-10. doi:0197-2456(89)90015-9 [pii]. 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 50 of 69 
APPENDIX 1 
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and  
Non-Immune–Mediated Reactions  
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 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. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 51 of 69 
Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and  
Non-Immune–Mediated Reactions  
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).  
 
− 
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. 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 52 of 69 
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 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 53 of 69 
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. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 54 of 69 
 
 
− 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
(Diarrhea: stool 
frequency of <4 over 
baseline per day) 
(Colitis: asymptomatic; 
clinical or diagnostic 
observations only) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment. 
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. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, GI consult 
should be obtained for consideration of further workup, such as 
imaging and/or colonoscopy, to confirm colitis and rule out 
perforation, and prompt treatment with IV methylprednisolone 
2 to 4 mg/kg/day started. 
− 
If still no improvement within 3 to 5 days despite 2 to 4 mg/kg 
IV methylprednisolone, promptly start immunosuppressives 
such as infliximab at 5 mg/kg once every 2 weeksa. Caution: it 
is important to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab. 
− 
Consider, as necessary, discussing with study physician if no 
resolution to Grade ≤1 in 3 to 4 days. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 55 of 69 
 
Grade 3 or 4 
(Grade 3 diarrhea: stool 
frequency of ≥7 over baseline 
per day; 
Grade 4 diarrhea: life 
threatening consequences) 
(Grade 3 colitis: severe 
abdominal pain, change in 
bowel habits, medi-cal 
intervention indi-cated, 
peritoneal signs; 
Grade 4 colitis: life-
threatening consequences, 
urgent intervention indicated) 
 
Grade 3 
Permanently discontinue study 
drug/study regimen for Grade 3 if 
toxicity does not improve to Grade 
≤1 within 14 days; study 
drug/study regimen can be resumed 
after completion of steroid taper. 
 
Grade 4 
Permanently discontinue  
study drug/study regimen.  
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and volume and maintain hydration. 
− 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 to 5 days of IV 
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). 
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. 
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 
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. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 56 of 69 
drug/study regimen after 
completion of steroid taper. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional work up and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e., mycophenolate mofetil).a Discuss 
with study physician if mycophenolate mofetil is not available. 
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 
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 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 57 of 69 
meeting Hy’s law criteria (AST 
and/or ALT >3 × ULN + bilirubin 
>2 × ULN without initial findings 
of cholestasis (i.e., elevated 
alkaline P04) and in the absence of 
any alternative cause.b 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
 
 
 
 
 
 
 
 
 
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 to 1.5 × 
baseline; > ULN to 1.5 × 
ULN) 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and any accompanying 
symptoms. 
 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
 
If creatinine worsens, depending on the severity, treat 
as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 58 of 69 
Grade 2 
(serum creatinine >1.5 to 3.0 × 
baseline; >1.5 to 3.0 × ULN) 
Hold study drug/study regimen 
until resolution to Grade ≤1 or 
baseline.  
 
If toxicity worsens, then treat 
as Grade 3 or 4. 
 
If toxicity improves to Grade 
≤1 or baseline, then resume 
study drug/study regimen after 
completion of steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone at 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
(Grade 3: serum creatinine 
>3.0 × baseline; >3.0 to 
6.0 × ULN; 
 
Grade 4: serum creatinine >6.0 
× ULN) 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine on daily basis. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 59 of 69 
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 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 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 60 of 69 
discontinue study drug/study 
regimen. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
 
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. 
 
Grade 1 
No dose modifications. 
For Grade 1 (including those with asymptomatic TSH elevation): 
− 
Monitor patient with appropriate endocrine function tests. 
− 
For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment of early-
morning ACTH, cortisol, TSH and free T4; also consider 
gonadotropins, sex hormones, and prolactin levels, as well as 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 61 of 69 
cosyntropin stimulation test (though it may not be useful in 
diagnosing early secondary adrenal insufficiency). 
− 
If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out of 
range in 2 subsequent measurements, include free T4 at 
subsequent cycles as clinically indicated and consider 
consultation of an endocrinologist. 
Grade 2 
For Grade 2 endocrinopathy other 
than hypothyroidism and Type 1 
diabetes mellitus, hold study 
drug/study regimen dose until 
patient is clinically stable. 
 
If toxicity worsens, then treat 
as Grade 3 or Grade 4. 
Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper. 
Patients with endocrinopathies who 
may require prolonged or 
continued steroid replacement 
(e.g., adrenal insufficiency) can be 
retreated with study drug/study 
regimen on the following 
conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable 
as per investigator or treating 
physician’s clinical 
judgement. 
3. 
Doses of prednisone are 
≤10 mg/day or equivalent. 
For Grade 2 (including those with symptomatic endocrinopathy): 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. 
− 
For all patients with abnormal endocrine work up, except those 
with isolated hypothyroidism or Type 1 DM, and as guided by 
an  endocrinologist, consider short-term corticosteroids (e.g., 1 
to 2 mg/kg/day methylprednisolone or IV equivalent) and 
prompt initiation of treatment with relevant hormone 
replacement (e.g., hydrocortisone, sex hormones). 
− 
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually taper  
immunosuppressive steroids (as appropriate and with guidance 
of endocrinologist) over ≥28 days and consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]).a 
− 
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory assessments/MRI 
as clinically indicated. 
Grade 3 or 4 
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism and 
Type 1 diabetes mellitus, hold 
For Grade 3 or 4: 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 62 of 69 
 
 
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. 
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. 
− 
 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 63 of 69 
 
 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations above. 
Grade 2 
For acute motor neuropathies or 
neurotoxicity, hold study 
drug/study regimen dose until 
resolution to Grade ≤1. 
For sensory 
neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to 
Grade ≤1. 
If toxicity worsens, then treat 
as Grade 3 or 4. 
Study drug/study regimen can be 
resumed once event improves to 
Grade ≤1 and after completion of 
steroid taper. 
For Grade 2: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine). 
− 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, consider additional workup 
and promptly treat with additional immunosuppressive therapy 
(e.g., IV IG). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen 
dose until resolution to Grade ≤1. 
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. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 64 of 69 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients may 
unpredictably experience acute decompensations that can result 
in substantial morbidity or in the worst case, death. Special care 
should be taken for certain sentinel symptoms that may predict 
a more severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory insufficiency or 
autonomic instability. 
− 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes or 
medications). It should be noted that the diagnosis of immune-
mediated peripheral neuromotor syndromes can be particularly 
challenging in patients with underlying cancer, due to the 
multiple potential confounding effects of cancer (and its 
treatments) throughout the neuraxis. Given the importance of 
prompt and accurate diagnosis, it is essential to have a low 
threshold to obtain a neurological consult. 
− 
Neurophysiologic diagnostic testing (e.g., electromyogram and 
nerve conduction investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated upon suspicion 
of such conditions and may be best facilitated by means of a 
neurology consultation. 
− 
It is important to consider that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered 
effective. Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive to IV IG. 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above. 
− 
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 
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 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 65 of 69 
or if there are signs of respiratory 
insufficiency or autonomic 
instability. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. It is important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision 
of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG. Such 
decisions are best made in consultation with a 
neurologist, taking into account the unique needs of 
each patient. 
o 
If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. 
o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG. 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen 
dose until resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 
imAE does not resolve to Grade ≤1 
within 30 days or if there are signs 
of respiratory insufficiency or 
autonomic instability. 
 
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. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 66 of 69 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
o 
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. 
o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG. 
 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently if 
biopsy-proven immune-mediated 
myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function.  
− 
Consider, as necessary, discussing with the study physician. 
− 
Monitor patients for signs and symptoms of myocarditis (new 
onset or worsening chest pain, arrhythmia, shortness of breath, 
peripheral edema). As some symptoms can overlap with lung 
toxicities, simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary embolism, 
congestive heart failure, malignant pericardial effusion). A 
Cardiology consultation should be obtained early, with prompt 
assessment of whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
− 
Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), monitoring 
of oxygenation via pulse oximetry (resting and exertion), and 
additional laboratory work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO to assess wall motion 
abnormalities when needed. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections) 
 
Grade 1 
No dose modifications required 
unless clinical suspicion is high, in 
which case hold study drug/study 
regimen dose during diagnostic 
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 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 67 of 69 
(asymptomatic with laboratory 
(e.g., BNP) or cardiac imaging 
abnormalities) 
work-up for other etiologies. If 
study drug/study regimen is held, 
resume after complete resolution to 
Grade 0. 
(resting and exertion), and laboratory work-up as clinically 
indicated. 
- 
Consider using steroids if clinical suspicion is high. 
 
Grade 2, 3 or 4 
(Grade 2: Symptoms with 
mild to moderate activity or 
exertion) 
 
 (Grade 3: Severe with 
symptoms at rest or with 
minimal activity or exertion; 
intervention indicated) 
 
(Grade 4: Life-threatening 
consequences; urgent 
intervention indicated (e.g., 
continuous IV therapy or 
mechanical hemodynamic 
support)) 
 
- If Grade 2 -- Hold study 
drug/study regimen dose until 
resolution to Grade 0. If toxicity 
rapidly improves to Grade 0, 
then the decision to reinitiate 
study drug/study regimen will 
be based upon treating 
physician’s clinical judgment 
and after completion of steroid 
taper. If toxicity does not 
rapidly improve, permanently. 
discontinue study drug/study 
regimen. 
If Grade 3-4, permanently 
discontinue study drug/study 
regimen. 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined 
whether and when to complete diagnostic procedures including 
a cardiac biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
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. 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 68 of 69 
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine myoglobin, 
and additional laboratory work-up as indicated, including a 
number of possible rheumatological/antibody tests (i.e., 
consider whether a rheumatologist consultation is indicated and 
could guide need for rheumatoid factor, antinuclear antibody, 
anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or 
signal-recognition particle antibodies). Confirmatory testing 
may include electromyography, nerve conduction studies, MRI 
of the muscles, and/or a muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia or dysphonia. 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections). 
 
Grade 1 
(mild pain) 
- No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing with the study physician. 
 
Grade 2 
(moderate pain associated with 
weakness; pain limiting 
instrumental activities of daily 
living [ADLs]) 
Hold study drug/study regimen 
dose until resolution to Grade ≤1. 
- Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 
days or if there are signs of 
respiratory insufficiency. 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly start 
IV methylprednisolone 2 to 4 mg/kg/day systemic steroids 
along with receiving input from Neurology consultant  
− 
If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 3 to 5 days, continue 
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 


Clinical Study Protocol 
HCRN GU17-294 
Version Date: 28MAR2019 
Confidential 
Page 69 of 69 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; 
BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated 
adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic resonance imaging; NCI  
National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); 
PO  By mouth; T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 
 
 
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; limiting self-care 
ADLs) 
For Grade 3: 
Hold study drug/study regimen 
dose until resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 
imAE does not resolve to Grade ≤1 
within 30 days or if there are signs 
of respiratory insufficiency. 
 
For Grade 4: 
- Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult, and complete full evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from Neurology 
consultant. 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Consider whether patient may require IV IG, plasmapheresis. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a