Duration of Immune Checkpoint Therapy in Locally Advanced or Metastatic Urothelial Carcinoma: A Randomized Phase 3 Non-Inferiority Trial (IMAGINE)
Phase: PHASE3
Conditions: Locally Advanced Bladder Urothelial Carcinoma, Locally Advanced Renal Pelvis Urothelial Carcinoma, Locally Advanced Ureter Urothelial Carcinoma, Locally Advanced Urethral Urothelial Carcinoma, Locally Advanced Urothelial Carcinoma, Metastatic Bladder Urothelial Carcinoma, Metastatic Renal Pelvis Urothelial Carcinoma, Metastatic Ureter Urothelial Carcinoma, Metastatic Urethral Urothelial Carcinoma, Metastatic Urothelial Carcinoma
Sponsor: Alliance for Clinical Trials in Oncology

 
 
NCI Version Date 3/21/23  
1 
 
 
 
 
 
 
 
 
 
 
 
Update #03 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
___________________________________ 
PROTOCOL UPDATE FOR A031901 
___________________________________ 
 
DURATION OF IMMUNE CHECKPOINT THERAPY IN LOCALLY ADVANCED OR METASTATIC 
UROTHELIAL CARCINOMA: A RANDOMIZED PHASE 3 NON-INFERIORITY TRIAL (IMAGINE) 
Study Exempt from IND Requirements per 21 CFR 312.2(b) 
Commercial agents: Pembrolizumab (NSC #776864), Nivolumab (NSC #748726), Atezolizumab (NSC 
#783608), Avelumab (NSC #799232) 
 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
X Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
X Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
 
Data Submission / Forms changes 
 
 
 
 
 
 
 
 
 
Editorial / Administrative changes 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
The changes included in this update to A031901 have been made in response to the NCI Action Letter 
from 
 This Action Letter is posted on the A031901 study page 
on the CTSU website. A revised CAEPR for pembrolizumab with new risks has been added to the 
protocol. The model consent form has been updated, however, there are no changes to the risk/benefit 
ratio. 
 
Reconsent is not required, please follow the policy of your IRB of record regarding notifying patients 
of new information contained in this update. 
 
No recommended level of IRB review is provided by the Alliance since the CIRB is the IRB of record 
for this trial. This amendment must be implemented within 30 days after posting. Please refer to the 
CIRB amendment application and CIRB guidelines for further instructions. 
 
 
 

 
 
NCI Version Date 3/21/23  
2 
UPDATES TO THE PROTOCOL: 
Section 8.2.1 Dose Management Guidelines for Pembrolizumab  
- “Dose Modifications” and “Dose Modification and Toxicity Management for Immune-related Adverse 
Events Associated with Pembrolizumab” information has been added per NCI’s updated dose modification 
guidelines for pembrolizumab. 
-  The table “Dose Modification and Toxicity Management Guidelines for Immune-related AEs and 
Infusion Reactions Associated with Pembrolizumab” has been updated.  
- The new table, “Infusion-Related Reactions” has been added.  
-The new table, “Neurology Toxicites” has been added.  
 
UPDATES TO THE REGISTRATION MODEL CONSENT: 
Possible Side Effects of Pembrolizumab 
The word pembroluzimab was amended to Pembroluzimab (MK-3475).  
• 
Decrease in Risk Attribution: 
• 
Changed to Also Reported on Pembrolizumab (MK-3475) Trials But With Insufficient 
Evidence for Attribution from Occasional (i.e., removed from the Risk Profile): Fluid in 
the joints; Pain in chest 
• 
Deleted Risk: 
• 
Occasional: Infection 
• 
Provided Further Clarification: 
• 
Rare: Changed from “Swelling and redness of the eye” to “Swelling and redness of the 
eye which may cause blurred vision with a chance of blindness” 
 
 
  
A replacement protocol and model consent have been issued. 
 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
 
 

A031901 
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Update 03 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
ALLIANCE A031901 
DURATION OF IMMUNE CHECKPOINT THERAPY IN LOCALLY ADVANCED OR METASTATIC 
UROTHELIAL CARCINOMA: A RANDOMIZED PHASE 3 NON-INFERIORITY TRIAL (IMAGINE) 
Study Exempt from IND Requirements per 21 CFR 312.2(b) 
Commercial agents: Pembrolizumab (NSC #776864), Nivolumab (NSC #748726), Atezolizumab (NSC 
#783608), Avelumab (NSC #799232) 
  
ClinicalTrials.gov Identifier: NCT 04637594 
 
Study Chair 
Study Co-Chair 
 
 
 
 
 
 
 
 
 
 
 
QOL Co-chair 
Health Economics Co-chair 
Correlative Committee Chair 
 
 
 
 
 
 
 
 
 
 
NRG Oncology Champion 
ECOG-ACRIN Champion 
SWOG Champion 
 
 
 
 
 
 
 
 
 
 
Community Onc Co-chair 
Disease Committee Chair 
Modality Committee Chair 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Coordinator 
Data Manager 
 
 
 
 
 
 
 
Participating Organizations 
Alliance/Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN/ECOG-ACRIN Cancer Research Group, 
NRG/NRG Oncology, SWOG/SWOG 
Primary Statistician 
QOL Statistician 
Secondary Statistician 
 
 
 
 
 
 

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Study Resources: 
Expedited Adverse Event Reporting 
 
 Medidata Rave iMedidata portal 
 
OPEN (Oncology Patient Enrollment Network) 
 
 Biospecimen Management System 
 
 
Protocol Contacts: 
 
A031901 Nursing Contact 
 
 
 
  
 
 
 
 
 
A031901 Pharmacy Contact 
 
 
 
 
IROC 
 
 
 
 
 
 
 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data 
Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
 
Questions regarding CTEP-AERS reporting: 
Alliance Pharmacovigilance Inbox 
 
Questions regarding specimens/specimen 
submissions: 
Alliance Biorepository  
Questions regarding drug administration 
Pharmacy Contact 
 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
 (Sign in at 
, and 
select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 
 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 
 
for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
 
 
Contact the CTSU Help Desk 
with any OPEN related questions 
by phone or email : 
 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the 
protocol for further instructions.  
 
Do not submit study data or 
forms to the CTSU. Do not copy 
the CTSU on data submissions. 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website 
Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password.  
: Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
Institutions will order the following supplies from the CTSU Operations Office: the QOL booklets. 
Supplies can be ordered by downloading and completing the CTSU Supply Request Form (available on 
the protocol-specific page on the CTSU website) and submitting it as instructed on the form. 
 
For clinical questions (i.e. patient eligibility or treatment-related) see the Protocol Contacts, Page 2. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 
All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 
 

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DURATION OF IMMUNE CHECKPOINT THERAPY IN LOCALLY ADVANCED OR METASTATIC 
UROTHELIAL CARCINOMA: A RANDOMIZED PHASE 3 NON-INFERIORITY TRIAL (IMAGINE) 
Commercial agents: Pembrolizumab, Nivolumab, Atezolizumab, Avelumab 
 
Pre- registration Eligibility Criteria 
Pre-reg and Reg Required Lab Values 
Histologic or cytologic confirmed urothelial carcinoma 
Patients must have adequate bone marrow 
and organ function to continue PD-L1 ICI 
as judged by the treating physician. No 
specific parameters need to be met. 
Locally advanced or metastatic  
At least 1 cycle of active treatment with standard of care 
ICI 
At least one scan showing CR, PR or SD (no PD) 
No history of allogeneic organ transplant 
 
Registration Eligibility Criteria 
No PD per RECIST v1.1 after 12-18 months of ICI 
 
No ICI toxicity that makes treatment continuation 
unacceptable 
 
Age ≥ 18 years 
 
ECOG PS 0-2 
 
CNS disease allowed if stable 
 
No immunosuppressive medication exceeding 10 mg/day 
of prednisone or equivalent 
 
Non-pregnant and non-nursing 
 
Schema 
Cycle definition is based on ICI cycle length 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 
ICI agents include pembrolizumab, nivolumab, atezolizumab, and avelumab 
 
Patients will be followed for 5 years or until death or withdrawal of consent, whichever occurs first. 
Please refer to the full protocol text for a complete description of the eligibility criteria and 
treatment plan. 
 
 
 
R
A
N
D
O
M
I
Z
E 
Arm A: 
Continue immune 
checkpoint inhibitor 
(ICI)* until disease 
progression or 
unacceptable toxicity 
Arm B: 
Discontinue ICI 
treatment 
Disease 
progression 
or toxicity 
Disease 
progression 
Treat at 
physician’s 
discretion 
Option to 
restart ICI 
P
R
E
-
R
E
G
I
S
T
E
R 

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Table of Contents 
Section 
Page 
1.0 
BACKGROUND ............................................................................................................................. 7 
1.1 
Mechanism of action of immunotherapy and potential for durable benefit after treatment 
discontinuation .......................................................................................................................................... 7 
1.2 
Immune checkpoint blockade in advanced UC ............................................................................. 7 
1.3 
Clinical data evaluating early ICI discontinuation ........................................................................ 8 
2.0 
OBJECTIVES ................................................................................................................................. 9 
2.1 
Primary Objective ......................................................................................................................... 9 
2.2 
Major Secondary Objectives ....................................................................................................... 10 
2.3 
Biomarker Objectives ................................................................................................................. 10 
2.4 
Quality of Life (QOL) and Health Economics Objectives .......................................................... 10 
3.0 
PATIENT SELECTION............................................................................................................... 10 
3.1 
On-Study Guidelines ................................................................................................................... 11 
3.2 
Pre-registration Eligibility Criteria ............................................................................................. 11 
3.3 
Registration Eligibility Criteria ................................................................................................... 12 
4.0 
PATIENT REGISTRATION ....................................................................................................... 12 
4.1 
Cancer Therapy Evaluation Program Investigator Registration Procedures ............................... 12 
4.2 
CTSU Site Registration Procedures ............................................................................................ 14 
4.3 
Patient Pre-registration Requirements ........................................................................................ 15 
4.4 
Patient Registration Requirements .............................................................................................. 16 
4.5 
Patient Pre-registration and Registration Procedures .................................................................. 16 
4.6 
Registration to Substudies and Companion Studies .................................................................... 17 
4.7 
Stratification Factors and Treatment Assignments for Registered Patients ................................ 17 
5.0 
STUDY CALENDAR ................................................................................................................... 18 
5.1 
Arm A Study Calendar (For patients who are randomized to continue ICI treatment) .............. 18 
5.2 
Arm B Study Calendar (for patients who are randomized to discontinue ICI treatment) ........... 20 
6.0 
DATA AND SPECIMEN SUBMISSION ................................................................................... 23 
6.1 
Data Collection and Submission ................................................................................................. 23 
6.2 
Specimen collection and submission .......................................................................................... 24 
6.3 
Digital radiation therapy data submission using Transfer of Images and Data (TRIAD) ........... 25 
6.4 
Submission of Patient Completed Measures ............................................................................... 28 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 29 
7.1 
Protocol Therapy ......................................................................................................................... 29 
7.2 
ICI choices .................................................................................................................................. 29 
8.0 
DOSE AND TREATMENT MODIFICATIONS ....................................................................... 30 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care ......................................... 30 
8.2 
Dose Modifications ..................................................................................................................... 31 
9.0 
ADVERSE EVENTS .................................................................................................................... 48 
9.1 
Routine Adverse Event Reporting .............................................................................................. 48 
9.2 
CTCAE Routine Reporting Requirements .................................................................................. 50 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) .................................................................. 50 
9.4 
Adverse Event Lists for Commercial Agents.............................................................................. 53 
10.0 
DRUG INFORMATION .............................................................................................................. 54 
10.1 
General Considerations ............................................................................................................... 54 

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10.2 
Pembrolizumab (NSC #7766864, MK-3475) ............................................................................. 54 
10.3 
Nivolumab (NSC #748726, BMS-936558, MDX1106) ............................................................. 55 
10.4 
Atezolizumab (NSC #783608, MPDL3280A) ............................................................................ 55 
10.6 
Avelumab (NSC #799232).......................................................................................................... 56 
11.0 
MEASUREMENT OF EFFECT ................................................................................................. 57 
11.1 
RECIST 1.1 and iRECIST Criteria ............................................................................................. 57 
12.0 
END OF TREATMENT/INTERVENTION .............................................................................. 60 
12.1 
Duration of Protocol Treatment .................................................................................................. 60 
12.2 
Criteria for Discontinuation of Protocol Treatment .................................................................... 60 
12.3 
Follow-up .................................................................................................................................... 60 
12.4 
Extraordinary Medical Circumstances ........................................................................................ 61 
12.5 
Managing ineligible patients and registered patients who never receive protocol intervention . 61 
13.0 
STATISTICAL CONSIDERATIONS ........................................................................................ 62 
13.1 
Study Design ............................................................................................................................... 62 
13.2  Study Endpoints .......................................................................................................................... 62 
13.3 
Subgroup Analysis ...................................................................................................................... 62 
13.4 
Sample Size Calculation ............................................................................................................. 63 
13.5 
Accrual time and study duration ................................................................................................. 63 
13.6 
Primary Analysis Plan ................................................................................................................. 63 
13.7 
Secondary Analysis Plans ........................................................................................................... 64 
13.8 
Data and Safety Monitoring ........................................................................................................ 64 
13.9 
Inclusion of Women and Minorities ........................................................................................... 64 
14.0 
CORRELATIVE AND COMPANION STUDIES ..................................................................... 66 
14.1 
Quality of Life and Health Economics (Alliance A031901-HO1) ............................................. 66 
14.2 
Correlative Science (Alliance A031901-ST1) ............................................................................ 72 
15.0 
REFERENCES .............................................................................................................................. 75 
APPENDIX I 
REGISTRATION FATIGUE/UNISCALE ASSESSMENT ..................................... 78 
APPENDIX II: QOL AND HEALTH ECONOMICS FORMS ........................................................... 79 
APPENDIX III:  PATIENT CLINICAL TRIAL WALLET CARD .................................................... 94 
 
 
 

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1.0 
BACKGROUND 
Immune checkpoint inhibitors that target negative regulators of the immune system, particularly the 
PD1/PD-L1 axis, have changed the paradigm of treatment for multiple advanced malignancies, 
including locally advanced or metastatic urothelial carcinoma (UC). The current standard of care is 
to administer PD-1 and PD-L1 blocking antibodies until disease progression or intolerable toxicity, 
with consideration of stopping treatment at 24 months in patients without disease progression. The 
optimal duration of therapy remains undefined. This is a prospective multicenter, randomized, open-
label, phase 3 non-inferiority trial comparing PD-1/L1 ICI continuation (Arm A) versus 
discontinuation (Arm B) in patients with locally advanced or metastatic UC. Eligible patients must 
have investigator-assessed radiographic response, defined as any % decrease in target lesion(s) by 
RECIST 1.1 criteria (confirmed), without evidence of disease progression 12-18 months after 
initiating a standard of care PD1-/L1 containing regimen. The primary endpoint is overall survival. 
1.1 
Mechanism of action of immunotherapy and potential for durable benefit after treatment 
discontinuation 
Immunotherapies have a different mechanism of action compared to traditional cytotoxic or 
targeted biological agents. The goal of immunotherapy is to harness long-term memory of the 
adaptive anti-tumor immune response to achieve durable tumor regression and potential cure. 
In preclinical models, successful immunotherapy given in a finite number of treatments leads to 
tumor rejection, and mice are protected from tumor re-challenge, consistent with the 
development of immunologic memory (1-4). Lymphocyte depletion experiments have 
demonstrated that protection from tumor re-challenge are T-cell dependent (3,4). In the clinic, 
immunotherapy strategies including high-dose interleukin 2 (IL-2) in advanced renal cell 
carcinoma (RCC) and chimeric antigen receptor (CAR)-modified T cells targeting CD19 in 
advanced B-cell hematologic malignancies, are administered in a finite number of doses and 
lead to durable survival benefit in the subgroup of patients who achieve deep objective responses 
(5,6). Emerging data indicates that patients who stop anti-PD-1 or anti-PD-L1 inhibitors early 
may still derive benefit beyond treatment discontinuation (See below).  
1.2 
Immune checkpoint blockade in advanced UC 
Urothelial carcinoma (UC) is the most common malignancy in the urinary tract, and accounts 
for approximately 16,000 deaths annually in the U.S. (7). Approximately 10%-15% of patients 
initially diagnosed with non-muscle invasive bladder cancer (NMIBC) later develop invasive, 
locally advanced, and metastatic disease, and approximately 10% of patients present with locally 
advanced or metastatic disease at initial diagnosis. The standard of care for patients with locally 
advanced or metastatic UC is cisplatin-containing chemotherapy; however, many patients are 
cisplatin-ineligible due to comorbidities, including renal dysfunction, hearing impairment, and 
peripheral neuropathy. Since May 2016, monoclonal antibodies that disrupt the interaction of 
PD-1 and PD-L1 are rapidly approved for the management of locally advanced and metastatic 
UC. 
PD-1 and PD-L1 inhibitors approved for locally advanced or metastatic UC include 
pembrolizumab, atezolizumab, nivolumab, and avelumab in patients whose disease progressed 
during or after platinum-containing chemotherapy (8-11). There is level 1 evidence 
demonstrating OS benefit for pembrolizumab in the post-platinum setting compared to 
investigator’s choice of chemotherapy of paclitaxel, docetaxel, or vinflunine (8).  
In May 2017, pembrolizumab and atezolizumab were granted accelerated approval for the first-
line treatment of cisplatin-ineligible locally advanced or metastatic UC based on single-arm 
phase 2 studies demonstrating objective response rate (ORR) of 20%-25% and favorable toxicity 
profile (13,14). In August 2018, based on early reviews of two ongoing phase 3 randomized 

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clinical trials (KEYNOTE-361 and IMvigor130), the FDA revised the first-line indications for 
pembrolizumab and atezolizumab, which are now indicated for patients who are ineligible for 
any platinum-containing chemotherapy, and patients who are cisplatin-ineligible and whose 
tumors express PD-L1. Importantly, studies to date consistently demonstrated durability of 
response and plateaus in the tails of survival curves (Table 1). In all of the above studies, PD-1 
or PD-L1 inhibitors were administered until progressive disease or unacceptable toxicity. 
Table 1: Summary of ICI response data in locally advanced or metastatic UC 
 
Phase 
Objective 
response rate 
Disease 
control rate 
Median  
follow-up  
Median duration of 
response 
Reference 
Pembrolizumab in 2L UC 
(KEYNOTE 045) 
3 
21% 
38.5% 
14 mo 
Not reached  
(68%  1 year) 
8 
Pembrolizumab in 1L UC 
(KEYNOTE 052) 
2 
24% 
34.0% 
5 mo 
Not reached 
(95% CI: 9mo – NR) 
9 
Atezolizumab in 1L UC 
2 
23% 
30.0% 
17.2 mo 
Not reached  
(95% CI: 14.1mo – NR) 
13 
Avelumab in maintenance UC 
(JAVELIN Bladder 100) 
3 
9.7% 
41.1% 
>19 mo 
Not reported 
16 
 
The phase 3 randomized clinical trials KEYNOTE-361 and IMvigor130 are exploring the 
upfront combination of platinum-containing chemotherapy with anti-PD-1 or anti-PD-L1 
inhibition. Final PFS analysis of IMvigor130 reported that atezolizumab plus 
platinum/gemcitabine chemotherapy significantly improved PFS compared to placebo plus 
platinum/gemcitabine chemotherapy. Interim OS analysis favored atezolizumab plus 
platinum/gemcitabine chemotherapy over placebo plus platinum/gemcitabine chemotherapy; 
however, mature OS data are being awaited (14). In contrast, the addition of pembrolizumab to 
platinum-containing chemotherapy for first-line treatment of advanced UC did not lead to 
statistically significant improvement in PFS or OS compared to chemotherapy alone in 
KEYNOTE-361 (15) It remains to be determined whether concurrent platinum-based 
chemotherapy plus immune checkpoint inhibition will become a standard of care for the first-
line management of locally advanced or metastatic UC.  
In January 2020, the phase 3 JAVELIN Bladder 100 trial was announced to have met its primary 
endpoint of OS at the planned interim analysis, which was subsequently published (16). In this 
study, patients with previously untreated locally advanced or metastatic UC whose disease did 
not progress on 4-6 cycles of induction platinum-containing chemotherapy were randomized to 
maintenance avelumab until progressive disease or intolerable toxicity plus best supportive care 
(BSC) or BSC alone. In April 2020, the FDA granted breakthrough therapy designation for 
avelumab for first-line maintenance treatment of locally advanced or metastatic UC. 
1.3 
Clinical data evaluating early ICI discontinuation  
There is emerging clinical evidence that patients with various tumor histologies who stop ICI 
treatment earlier than anticipated may still derive benefit beyond treatment discontinuation. In 
a post-hoc analysis of CheckMate 069, a double-blind phase 2 study in which patients with 
treatment-naïve unresectable stage III or IV melanoma were randomized 2:1 to receive 
nivolumab plus ipilimumab followed by nivolumab maintenance versus placebo plus 
ipilimumab followed by placebo maintenance, 35 patients (37%) in the nivolumab plus 
ipilimumab arm discontinued treatment for treatment-related adverse events (17). The median 
number of nivolumab and ipilimumab doses received in the patients who discontinued treatment 

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was each 3. At a minimum follow-up of 2 years, these 35 patients had similar objective ORR, 
disease progression rate, PFS and OS compared to the overall population randomized to 
nivolumab plus ipilimumab (17).  
In KEYNOTE-001, 61 advanced melanoma patients treated with pembrolizumab achieved 
complete response (CR) and stopped treatment at a median of 23 months. Of these patients, 59 
(97%) maintained their CRs at a median off-treatment period of 10 months (18). In the pivotal 
phase 3 KEYNOTE-006 study which demonstrated superiority of pembrolizumab over 
ipilimumab in advanced melanoma, patients who were randomized to the pembrolizumab arms 
(10mg/kg q2wk or 10mg/kg q3wk) continued treatment for up to 2 years or until disease 
progression or intolerable toxicity (19). A total of 556 patients received pembrolizumab, 104 
(19%) of whom completed 2 years of pembrolizumab. 102 (98%) of patients who completed 2 
years of pembrolizumab were alive at a median of 9.7 months, and the median PFS was not 
reached (20).  
In a multicenter retrospective cohort of 19 metastatic renal cell carcinoma (RCC) patients treated 
with an anti-PD-1 or anti-PD-L1 antibody who achieved radiographic response and discontinued 
treatment for immune-related adverse events, 8 (42%) patients continued to have durable 
response and remained off treatment for a median of 20 months (range 7-72) (21). More recently, 
a multicenter retrospective study of 20 patients with various advanced solid malignancies, 
including metastatic urothelial carcinoma, who discontinued anti-PD-1 or anti-PD-L1 inhibitor 
treatment after achieving SD, PR or CR demonstrated durable disease control after treatment 
discontinuation (22).   
Taken together, these data suggest that sustained clinical response can still be achieved with 
early treatment discontinuation. It is worthwhile to note that the only randomized prospective 
study to date that evaluated treatment duration of a PD1/PD-L1 inhibitor, CheckMate 153, 
challenged this concept (23). In this study, patients with advanced or metastatic non-small cell 
lung cancer (NSCLC) who had received at least one prior systemic therapy and remained on 
treatment at 1 year were randomized to continue or stop nivolumab, regardless of response status 
at the time of randomization. When the subset of patients who had SD/PR/CR at randomization 
were evaluated for efficacy (163 of 220 randomized), PFS and OS were found to be longer for 
those who continued nivolumab. However, the study had several limitations. Patients with PD 
were included and randomized. Further, the primary endpoint of the study was incidence of 
high-grade AEs, and was not powered for efficacy analyses. Therefore, more definitive studies 
with careful patient selection and adequate statistical design are needed to answer the clinically 
important question of optimal duration of immune checkpoint inhibition. 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
To compare overall survival (OS)   

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2.2 
Major Secondary Objectives 
2.2.1 
To compare progression free survival (PFS) by RECIST 1.1 criteria 
2.2.2 
To compare PFS by irRECIST criteria 
2.2.3 
To determine treatment-free interval (TFI) after ICI discontinuation (Arm B) 
2.2.4 
To determine the rate of response by RECIST 1.1 criteria after ICI rechallenge (Arm B)  
2.2.5 
To assess adverse events in each study arm by CTCAE 5.0 
2.3 
Biomarker Objectives 
The following correlative study outline is provided to justify biospecimen collection. 
Investigators will submit correlative studies complete protocols including the correlative study 
objectives, endpoints, sample size, statistical analysis plan including power calculations, etc., 
once the clinical trial has completed at least 50% accrual and the correlative study appears 
feasible. 
2.3.1 
To evaluate archival tumor biomarkers associated with attaining an initial complete 
response (CR), partial response (PR), or SD (Arm A and B). 
2.3.2 
To evaluate archival tumor biomarkers associated with time to progression after ICI 
discontinuation and radiographic response after treatment rechallenge (Arm B) 
2.3.3 
To explore peripheral biomarkers associated with clinical outcomes (Arms A and B). 
2.3.4 
To evaluate baseline tumor-specific cell-free methylated DNA (cfMeDNA) and circulating 
tumor DNA (ctDNA) association with treatment-free interval (Arm B) and PFS (both arms 
separately and together). 
2.3.5 
To evaluate changes in tumor-specific cfMeDNA and ctDNA as a biomarker for early 
detection of disease progression prior to radiographic progression (Arm A and B). 
2.3.6 
To evaluate normal organ-specific cfMeDNA as a biomarker for early detection of 
immune-related adverse events (irAE) (Arm A and B). 
2.4 
Quality of Life (QOL) and Health Economics Objectives 
2.4.1 
To compare quality-adjusted survival using EQ-5D-5L (primary) and PROMIS PROPr 
(exploratory) 
2.4.2 
To compare global QOL using EORTC QLQ-C30 
2.4.3 
To compare patient-reported fatigue using PROMIS-Fatigue 
2.4.4 
To compare healthcare utilization 
2.4.5 
To compare incremental cost effectiveness and cost utility ratios 
2.4.6 
To compare financial toxicity 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  

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3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled 
diabetes mellitus or cardiac disease which, in the opinion of the treating physician, 
would make this protocol unreasonably hazardous for the patient. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin 
cancers or cervical carcinoma in situ. Patients are not considered to have a “currently 
active” malignancy if they have completed therapy and are free of disease for ≥ 2 years. 
Patients with NCCN very low or low risk prostate cancer on active surveillance without 
evidence of progression to higher risk disease for ≥ 2 years are allowed. 
In addition: 
• 
Women and men of reproductive potential should agree to use an appropriate method 
of birth control throughout their participation in this study due to the teratogenic 
potential of the therapy utilized in this trial. Appropriate methods of birth control 
include abstinence, oral contraceptives, implantable hormonal contraceptives or double 
barrier method (diaphragm plus condom). 
3.2 
Pre-registration Eligibility Criteria  
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
A female of childbearing potential is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 
12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive 
months). 
___ 
3.2.1 
Documentation of Disease 
Histologic Documentation: Histologically or cytologically confirmed urothelial 
carcinoma (UC) with predominantly transitional-cell features. 
Stage: Locally advanced or metastatic disease prior to starting immune checkpoint 
blockade 
Tumor Site: Bladder, renal pelvis, ureter, urethra, or prostate 

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___ 
3.2.2 
Patients must have received at least one cycle of current active treatment with 
standard of care (SOC) FDA approved PD-1/L1 immune checkpoint inhibitor (ICI)-
containing therapy for locally advance or metastatic UC. 
___ 
3.2.3 
No history of tuberculosis, active hepatitis B (HBV) or hepatitis C (HCV), or 
uncontrolled human immunodeficiency virus (HIV) 
Patients with resolved HBV infection, defined as positive hepatitis B core antibody (anti-
Hb) and negative hepatitis B surface antigen (HbsAg), are eligible. 
Patients with positive HCV antibody are eligible if HCV RNA PCR is negative. 
Patients with HIV who are compliant with highly active antiretroviral therapy (HAART) 
and have normal CD4 count and undetectable viral load are eligible. 
___ 
3.2.4 
No history of allogeneic organ transplantation 
___ 
3.2.5 
No current immunosuppressive medication exceeding 10mg/day of 
prednisone or its equivalent 
Patients with pre-existing or treatment-emergent autoimmune or inflammatory disorders 
which do not require systemic immunosuppressive treatment exceeding 10mg/day of 
prednisone or its equivalent may be included.  
___ 
3.2.6 
No female patients who are pregnant or breastfeeding, or male or female 
patients of reproductive potential who are not willing to employ effective birth 
control, because this study involves investigational agents whose genotoxic, mutagenic, 
and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for 
women of childbearing potential only, a negative urine or serum pregnancy test pregnancy 
test done ≤ 14 days prior to registration is required. 
3.3 
Registration Eligibility Criteria  
___ 
3.3.1 
Patients without progressive disease per RECIST v 1.1 guidelines (i.e., with an 
ongoing CR, PR or SD) following completion of 12-18 months of ICI treatment.  
___ 
3.3.2 
No toxicity from ICI therapy that makes continuation of treatment clinically 
unacceptable  
___ 
3.3.3 
Adequate bone marrow and organ functions to continue PD-1/L1 ICI as judged by 
the treating physician 
___ 
3.3.4 
Age ≥ 18 years  
___ 
3.3.5 
ECOG Performance Status 0-2 
___ 
3.3.6 
CNS metastasis is allowed if radiographically stable, clinically asymptomatic, and 
prior local therapy (if received) was completed > 6 months before registration 
4.0 
PATIENT REGISTRATION 
4.1 
Cancer Therapy Evaluation Program Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
In addition, persons with a registration type of Investigator 

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(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
    
RCR utilizes five person registration types. 
• 
IVR—MD, DO, or international equivalent; 
• 
NPIVR—advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
• 
AP—clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System [RUMS], OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• 
Associate (A)—other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB)—individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering 
their practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
For questions, please contact the 
RCR Help Desk by email at 
 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU Regulatory Support System 
(RSS). 

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4.2 
CTSU Site Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at 
the site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, 
but 
sites 
are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
 to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email address or calling 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) 
and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
4.2.1 
Additional site registration requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
4.2.2 
Downloading Site Registration Documents  
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted based on person and site roster assignment. To participate, the 
institution and its associated investigators and staff must be associated with the LPO or a 
Protocol Organization (PO) on the protocol. One way to search for a protocol is listed 
below: 

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• 
Log in to the CTSU members’ website 
using your CTEP-
IAM username and password; 
• 
Click on Protocols in the upper left of the screen 
- Enter the protocol number in the search field at the top of the protocol tree, or 
- Click on the By Lead Organization folder to expand, then select Alliance, and 
NCI protocol number [A031901]. 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load automatically 
to the CTSU.) 
4.2.3 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log on to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
4.2.4 
Checking your Site’s Registration Status  
Site’s registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory  at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
4.3 
Patient Pre-registration Requirements 
Patients can be pre-registered to A031901 at any point after one cycle of therapy and at least 
one scan showing CR, PR, or SD. Patients with progressive disease may not be pre-registered. 
Patients who have received 12-18 months of immunotherapy therapy and meet both pre-
registration and registration eligibility criteria may be pre-registered and registered at the same 
time. 
4.3.1 
Informed consent 
The patient must be aware of the neoplastic nature of his/her disease and willingly consent 
after being informed of the procedure to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current human 
protection committee approval of this protocol and a consent form is required prior to 
patient consent and registration. 

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Patients with impaired decision-making capacity may be enrolled on this study, where 
institutional policy and IRB of record allow.  
4.4 
Patient Registration Requirements 
4.4.1 
Informed consent 
The patient must be aware of the neoplastic nature of his/her disease and willingly consent 
after being informed of the procedure to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current human 
protection committee approval of this protocol and a consent form is required prior to 
patient consent and registration. 
Patients with impaired decision-making capacity may be enrolled on this study, where 
institutional policy and IRB of record allow.  
4.4.2 
Patients will be registered to A031901 between 12-18 months after starting immune 
checkpoint inhibitor therapy. 
4.4.3 
Patient questionnaire booklets 
Patient questionnaire booklets are to be ordered prior to the registration of any patients. 
Patient completed booklets can be ordered by downloading and completing the CTSU 
supply request form (located under the site registration documents section of the A031901 
CTSU web site) and submitting it through the CTSU regulatory portal. Samples of the 
booklets are found in Appendix I, which are to be used for reference and IRB submission 
only. They are not to be used for patient completion. 
4.5 
Patient Pre-registration and Registration Procedures 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations:  Must be an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer 
in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned 
the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  

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• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
Access OPEN at 
or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
For any additional questions, contact the CTSU 
Help Desk at 
 
4.6 
Registration to Substudies and Companion Studies 
4.6.1 
Registration to substudies described in Section 14.0  
There are two substudies within Alliance A031901. These studies must be offered to all 
patients registered to Alliance A031901 (although patients may opt to not participate). 
These substudies do not require separate IRB approval. The substudies included within 
Alliance A031901 are: 
• 
Quality of Life and Health Economics Studies in A031901: Alliance A031901-
HO1 (Section 14.1) 
• 
Correlative Science Studies in A031901: Alliance A031901-ST1 (Section 14.2) 
If a patient answers “yes” to “I choose to take part in the Quality of Life and Cost study 
and will fill out these forms,” Question #1 in the model consent, they have consented to 
participate in the substudy described in Section 14.1. The patient should be registered to 
Alliance A031901-HO1 at the same time they are registered to the treatment trial 
(A031901). Questionnaires should be submitted per Section 6.4.   
If a patient answers “yes” to “I agree that my samples and related information may be used 
for the laboratory studies described above,” Question #2 in the model consent, they have 
consented to participate in the substudy described in Section 14.2. The patient should be 
registered to Alliance A031901-ST1 at the same time they are registered to the treatment 
trial (A031901). Samples should be submitted per Section 6.2. 
4.7 
Stratification Factors and Treatment Assignments for Registered Patients 
4.7.1 
Stratification Factors 
Line and type of therapy: 
o Chemotherapy followed by ICI maintenance 
o ICI monotherapy first-line 
o ICI monotherapy second-line and beyond 
4.7.2 
Treatment Assignments  
The factors defined in Section 4.6.1 will be used as stratification factor. 
After the patient has been registered into the study, the values of the stratification factor 
will be recorded, and the patient will be assigned to one of the following treatment groups 
using the Pocock and Simon dynamic allocation procedure which balances the marginal 
distributions of the stratification factor between the treatment groups.  
1. Arm A: continuation of ICI treatment 
2. Arm B: discontinuation of ICI treatment 

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5.0 
STUDY CALENDAR 
Pre-study Testing Intervals 
The pre-study testing intervals are guidelines only. Laboratory and clinical parameters during 
treatment are to be followed using individual institutional guidelines and the best clinical judgment 
of the responsible physician. It is expected that patients on this study will be cared for by physicians 
experienced in the treatment and supportive care of patients on this trial.  
When calculating days of tests and measurements, the day a test or measurement is done is considered 
Day 0. Therefore, if a test were done on a Monday, the Monday one week later would be considered 
Day 7. 
To be completed ≤ 28 DAYS  before registration: All laboratory studies, history and physical.  
To be completed ≤ 42 DAYS before registration: Any X-ray, scan of any type or ultrasound which 
is utilized for tumor measurement per protocol  
To be completed ≤ 60 DAYS  before registration: Any baseline exams used for screening, or any 
X-ray, scan of any type or ultrasound of uninvolved organs which is not utilized for tumor 
measurement.  
5.1 
Arm A Study Calendar (For patients who are randomized to continue ICI treatment) 
 
 

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Prior to Registration* 
Every cycle (+/- 7 
days)** 
Post treatment 
follow up*** 
Tests & Observations 
 
 
 
History and physical, weight, 
ECOG PS 
X 
X 
X 
Height 
X 
 
 
Vital signs (Pulse, BP, RR, 
O2 saturation) 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
Registration Fatigue/Uniscale 
Assessment 
X(1) 
 
 
Laboratory Studies 
 
 
 
Complete Blood Count, 
Differential, Platelets 
X 
X 
X 
Serum Creatinine,  
X 
X 
X 
Albumin, glucose 
X 
X 
X 
AST, ALT, Alk. Phos, Bili 
X 
X 
X 
TSH w/ reflex fT4 ‡ 
X 
X 
 
Serum or Urine HCG 
X(2) 
 
 
Staging 
 
 
 
Brain Imaging (MRI or CT) 
A 
A 
A 
CT/MRI chest/abd/pelvis 
B(3) 
B 
B 
Bone Scan 
C 
C 
C 
Correlative Studies: For those who consent to participate 
QOL/cost assessment 
See Section 6.4. 
Tissue and Blood samples 
See Section 6.2. 
* 
Labs completed prior to registration may be used for day 1 of cycle 1 tests if obtained ≤ 7 days 
prior to treatment. For subsequent cycles, labs, tests and observations may be obtained ≤ 48 hours 
prior to day of treatment.  
** 
Cycle definition is based on ICI cycle length (see Section 7.2). 
*** 
For participants who progress, have started a new treatment, or have withdrawn consent: 
Physical exam, laboratory, and imaging assessments are required within 4 weeks after the end of 
treatment. Thereafter, survival information is required every 6 months ( 4 weeks) until 5 years 
following registration, death, withdrawal of consent, or the end of the study, whichever occurs first. 
Survival information may be collected during clinic visit, phone, or medical record review. 
For participants who discontinue treatment for reasons other than disease progression: 
Physical examination, laboratory, and imaging assessments are required every 12 weeks  4 weeks 

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until radiographic progression, initiation of new treatment, or up to 5 years following registration. 
Once a participant has progressed or initiated a new treatment, the participant will be followed for 
survival every 6 months ( 4 weeks) until 5 years following registration, death, withdrawal of 
consent, or the end of the study, whichever occurs first. Survival information may be collected 
during clinic visit, phone, or medical record review. See also Section 12.0. 
‡ 
Free T4 will only be collected if TSH is abnormal, or if there is clinical suspicion of an AE 
related to the endocrine system. 
1 
To be completed after registration and prior to treatment.  
2 
For women of childbearing potential (see Section 3.3), obtain within  ≤14 days prior to registration. 
3 
Baseline scans can include either: 1) a CT, spiral CT, or MRI, or 2) an FDG-PET scan and 
diagnostic CT. Both IV and oral contrast should be used unless contraindicated, with slide thickness 
of 5 mm or less. Supporting documentation is to be submitted, per Section 6.1.1.  
A. Brain imaging is required only if there is indication of brain metastases at baseline or if signs or 
symptoms suggestive of brain metastases develop. Participants with a history of brain metastasis 
should have surveillance MRI with and without gadolinium contract approximately every 12 weeks 
( 4 weeks), or sooner if clinically indicated. 
B. Tumor assessments will occur every 12 weeks ( 4 weeks) until evidence of progression or relapse. 
The same imaging method should be used at screening/baseline. Confirmatory scans should also 
be obtained 4-8 weeks following documentation of objective progression when possible (see 
Section 11.0).  
C. Bone scan is required only if there is indication of bone metastases at baseline or if signs or 
symptoms suggestive of bone metastases develop. 
5.2 
Arm B Study Calendar (for patients who are randomized to discontinue ICI treatment) 
 
 

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Prior to 
Registration* 
Clinical 
Monitoring**  
Day 1 of Each cycle post-
progression (Treatment 
rechallenge)** 
Tests & Observations 
 
 
 
History and physical, 
weight, and ECOG PS 
X 
X 
X 
Height 
X 
 
 
Vital signs (Pulse, BP, 
RR, O2 saturation) 
X 
X 
X 
Adverse Event 
Assessment 
X 
X 
X 
Registration 
Fatigue/Uniscale 
Assessment 
X(1) 
 
 
Laboratory Studies 
 
 
 
Complete Blood Count, 
Differential, Platelets 
X 
X 
X 
Serum Creatinine  
X 
X 
X 
Albumin, Glucose 
X 
X 
X 
AST, ALT, Alk. Phos., 
Bili 
X 
X 
X 
Serum or Urine HCG 
X(2) 
 
 
Staging 
 
 
 
Brain Imaging (MRI or 
CT) 
A 
A 
A 
CT/MRI chest/abd/pelvis 
B (3) 
B 
B 
Bone Scan 
C 
C 
C 
Correlative Studies: For those who consent to participate 
QOL/cost assessment 
See Section 6.4. 
Tissue and Blood samples See Section 6.2. 
 
* 
Labs completed prior to registration may be used for day 1 of cycle 1 tests if obtained ≤ 7 days 
prior to start of disease monitoring. For subsequent cycles during monitoring, labs, tests and 
observations may be obtained ≤ 72 hours prior to day of next cycle.  
** 
 For participants who discontinue ICI treatment after randomization to Arm B: Participants 
are required to undergo physical examination and imaging assessments every 12 weeks ( 4 
weeks), from date of last scans, until evidence of progression or relapse. Labs and AE 
assessments are required every cycle ( 3 days); however, labs may be done with telephone call 
to review results within 48 hours of completion (without clinic visit), and AE assessments may be 

A031901 
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Update 03 
done via telephone call. Once a participant has progressed, the ICI-containing treatment may be 
restarted at the discretion of the treating physician (see below; treatment rechallenge). Once a 
participant has progressed after treatment discontinuation and started a new treatment different 
from treatment rechallenge, they will be followed for survival every 6 months ( 4 weeks) until 5 
years following registration, death, withdrawal of consent, or the end of the study, whichever 
occurs first. Survival information may be collected during clinic visit, phone, or medical record 
review. 
For participants who progress after treatment discontinuation and restart ICI (treatment 
rechallenge): Participants who have received ICI monotherapy may be restarted on the same ICI 
treatment at the discretion of the treating physician. Participants who had received ICI maintenance 
treatment, either 4-6 cycles of platinum-containing chemotherapy followed by ICI maintenance if 
CR/SD/PD or ICI monotherapy may be restarted at the discretion of the treating physician. The 
interval between the scan showing disease progression and treatment rechallenge should be < 30 
days if no confirmatory scan is obtained, or < 60 days if a confirmatory scan is obtained. During 
treatment rechallenge, labs, tests and observations may be obtained ≤ 48 hours prior to day of 
treatment. Physical examination and laboratory assessments are required every cycle until 
radiographic progression, initiation of new treatment, or up to 5 years following registration. Tumor 
assessments will occur every 12 weeks ( 4 weeks) until evidence of progression. Once a 
participant has progressed or initiated a new treatment after ICI rechallenge, the participant will be 
followed for survival every 6 months ( 4 weeks) until 5 years following registration, death, 
withdrawal of consent, or the end of the study, whichever occurs first. Survival information may 
be collected during clinic visit, phone, or medical record review. 
For participants who start a treatment after ICI discontinuation without evidence of disease 
progression, or have withdrawn consent: Physical exam, laboratory, and imaging assessments 
are required within 4 weeks before starting the non-protocol treatment (including new treatment or 
resuming ICI treatment). Thereafter, survival information is required every 6 months ( 4 weeks) 
until 5 years following registration, death, withdrawal of consent, or the end of the study, whichever 
occurs first. Survival information may be collected during clinic visit, phone, or medical record 
review. 
1 
To be completed within 21 days after registration. 
2 
For women of childbearing potential (see Section 3.3), obtain within ≤ 14 days prior to 
registration. 
3 
Baseline scans can include either: 1) a CT, spiral CT, or MRI, or 2) an FDG-PET scan and 
diagnostic CT (with both IV and oral contrast unless contraindicated), and the CT acquired with 5 
mm or less slice thickness. Supporting documentation is to be submitted, per Section 6.1.1 
A 
Brain imaging is required only if there is an indication of brain metastases at baseline or if signs or 
symptoms suggestive of brain metastases develop. Participants with a history of brain metastasis 
should have surveillance MRI with and without gadolinium contract approximately every 12 
weeks, or sooner if clinically indicated. 
B 
Tumor assessments will occur every 12 weeks ( 4 weeks) until evidence of progression or relapse. 
The same imaging method should be used at screening/baseline. Confirmatory scans should also 
be obtained 4-8 weeks following documentation of objective progression when possible (see 
Section 11.0).  
C 
Bone scan is required only if there is indication of bone metastases at baseline or if signs or 
symptoms suggestive of bone metastases develop. 
 

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6.0 
DATA AND SPECIMEN SUBMISSION 
6.1 
Data Collection and Submission 
6.1.1 
Data submission schedule 
A Data Submission Schedule (DSS) is available on the Alliance study webpage, within the 
Case Report Forms section. The data submission schedule is also available on the CTSU 
site within the study-specific case report forms folder. 
6.1.2 
Medidata Rave 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and 
role assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid and active CTEP-IAM account; and  
• 
Assigned a Rave role on the relevant LPO or PO roster at the enrolling site: Rave 
CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
o Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role must hold an Associates (A) registration type. 
Refer to 
 for registration types 
and documentation required. 
If the study has a Delegation of Tasks Log (DTL), individuals requiring write access to 
Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
e-mail from iMedidata. To accept the invitation, site staff must log in to the Select Login 
using their CTEP-IAM username and password, 
and click on the accept link in the upper right-corner of the iMedidata page. Site staff will 
not be able to access the study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), 
and can be accessed by clicking on the link in the upper right pane of the iMedidata screen. 
If an eLearning is required and has not yet been taken, the link to the eLearning will appear 
under the study name in iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study in Rave will be granted, 
and a Rave EDC link will display under the study name.  
Site staff who have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will also receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on the 
CTSU website in the Rave section under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave 

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is available on the CTSU members’ website in the Data Management > Rave section at 
or by contacting the CTSU Help Desk at 
or by e-
mail at 
   
6.1.3 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports modules are available 
to access details and reports of unanswered queries, delinquent forms, and timeliness 
reports. Review the DQP modules on a regular basis to manage specified queries and 
delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 
6.1.4 
Supporting documentation to be submitted to the Alliance 
This study requires supporting documentation for diagnosis, treatment, response, and 
progression. Supporting documentation will include the following and must be submitted 
at the following time points: 
• 
Pathology report documenting urothelial carcinoma (submit within 30 days 
following registration) 
• 
Progress notes or medication records documenting systemic therapy for locally 
advanced or metastatic UC (submit within 30 days following registration) 
• 
Imaging reports and progress notes corresponding to all submissions, including 
documentation of no evidence of progressive disease after completion of 12-18 
months of ICI treatment (submit within 30 days following registration), disease 
response, and disease progression (submit within 30 days of event). 
Supporting documentation is to be submitted via Medidata Rave. 
6.2 
Specimen collection and submission  
The following correlative study outline is provided to justify biospecimen collection. 
Investigators will submit correlative studies complete protocols including the correlative study 
objectives, endpoints, sample size, statistical analysis plan including power calculations, etc., 
once the clinical trial has completed at least 50% accrual and the correlative study appears 
feasible. 

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The Alliance A031901 Correlative Science Manual (CSM) contains instructions for specimen 
collection, processing and shipping. The manual can be found on the BioMS and CTSU 
websites. Questions regarding the CSM should be address to the contacts specified in the 
manual. 
For patients registered to substudy A031901-ST1: All participating institutions must ask patients 
for their consent to participate in the correlative substudies planned for Alliance A031901-ST1, 
although patient participation is optional. Biomarker studies will be performed. Rationale and 
methods for the scientific components of these studies are described in Section 14.0. For patients 
who consent to participate, tissue and blood will be collected at the following time points for 
these studies: 
 
After registration 
Week 12 
At progression 
 
For patients registered to A031901-ST1, submit the following: 
Paraffin block/cores of 
tumor tissue 
X 
 
 
Plasma and buffy coat 
(EDTA/lavender top) 
2 x 10 mL 
2 x 10 mL 
2 x 10 mL 
6.3 
Digital radiation therapy data submission using Transfer of Images and Data (TRIAD) 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s (ACR) image 
exchange application. TRIAD provides sites participating in clinical trials a secure method to 
transmit images. TRIAD anonymizes and validates the images as they are transferred. 
6.3.1 
TRIAD Access Requirements 
• 
A valid CTEP-IAM account.  
• 
Registration and Credential Repository (RCR) registration type of: Associate (A), 
Associate Plus (AP), Non-Physician Investigator (NPIVR), or Investigator (IVR) 
registration type. Refer to the CTEP Registration Procedures section for 
instructions on how to request a CTEP-IAM account and complete registration in 
RCR.  
• 
TRIAD Site User role on an NCTN or ETCTN roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have access 
to TRIAD and may submit images for credentialing purposes, or for enrollments to which 
the provider is linked in OPEN. 
6.3.2 
TRIAD Installations 
To submit images, the individual holding the TRIAD Site User role will need to install the 
TRIAD application on their workstation. TRIAD installation documentation is available at 
 
This process can be done in parallel to obtaining your CTEP-IAM account and RCR 
registration. 
For questions, contact TRIAD Technical Support staff via email 
 
 

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6.3.3 
Image Submission  
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible. 
DICOM tag dates and times cannot be altered prior to submission as they are used to put 
submissions into context regarding patient treatment. 
Additional changes to DICOM tags prior to submission impede further technical analysis 
and should be avoided whenever possible. 
DICOM images uploading is preferred to be submitted using TRIAD, however these 
methodologies are supported: 
a) TRIAD-based (a PC with internet access and TRIAD software installation will be 
needed) 
b) Web transfer-based (a PC with internet access and a web browser will be needed) 
c) FTP transfer-based (a PC with internet access and any FTP software will be 
needed) 
d) Mail/CD Shipment-based (only if electronic transfer approaches cannot be 
achieved) 
Questions regarding image submissions can be send to 
 
Detailed Steps of Data Submission 
Collection of images is required. Images will be collected digitally for central archiving and 
curation. Imaging studies will be collected digitally for the following time points: 
1. Pre-study  
a. Every effort should be made to deposit pre-ICI and post-ICI radiological 
assessments (e.g. CT, MRI, FDG-PET, bone scan, and/or MRI/CT brain). 
i. Pre-ICI scans consist of scans performed immediately prior to initiation of 
ICI therapy. 
ii. Post-ICI scans consist of scans performed after initiation of ICI therapy, 
during the 12-18 months of treatment prior to study screening. 
2. Baseline 
a. CT, spiral CT, or MRI, OR FDG-PET scan and diagnostic CT of the 
chest/abdomen/pelvis 
i. Requires IV and oral contrast unless contraindicated 
ii. Requires 5mm slice thickness for the CT 
b. MRI or CT of the brain 
i. Required if there is an indication of brain metastases at baseline or if signs 
or symptoms suggestive of brain metastases develop 
ii. Required if patients have a history of brain metastases 
iii. Requires sequences done with and without gadolinium contrast unless 
contraindicated 
c. Bone scan of the whole body 
i. Required only if there is an indication of bone metastases at baseline or if 
signs or symptoms suggestive of bone metastases develop 
3. Restaging 
a. Same chest/abdomen/pelvis imaging as acquired at baseline 

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b. Same brain imaging as acquired at baseline or if signs/symptoms suggestive of 
metastases develop 
c. Same bone imaging as acquired at baseline or if signs/symptoms suggestive of 
metastases develop 
4. Progression after randomization (Arm A and B) and Progression after ICI rechallenge (Arm 
B only) 
5. Rechallenge restaging (Arm B only) 
a. Same chest/abdomen/pelvis imaging as acquired at baseline 
b. Same brain imaging as acquired at baseline or if signs/symptoms suggestive of 
metastases develop 
c. Same bone imaging as acquired at baseline or if signs/symptoms suggestive of 
metastases develop 
6. Rechallenge progression (Arm B only) 
The complete imaging data set in digital DICOM format will be submitted electronically to the 
Imaging and Radiation Oncology Core at Ohio (IROC Ohio) within no more than 3 business 
days upon the image acquisition completeness. BMP files, JPG files, or hard copies (films) are 
not acceptable. The raw data of the entire study should be saved until the imaging data is 
accepted by IROC Ohio  
Sites need to de-identify the patient data using institutional procedures to remove patient name 
and medical record number while preserving the Alliance patient ID number (e.g., 112136) and 
protocol number (e.g., ALLIANCE031901), respectively.  
DICOM tag dates and times cannot be altered prior to submission as they are used to put 
submissions into context regarding patient treatment. 
Additional changes to DICOM tags prior to submission impede further technical analysis and 
should be avoided whenever possible. 
Imaging data should be submitted electronically to IROC Ohio via TRIAD, Web Transfer or 
FTP Transfer: 
1. TRIAD based data transfer   
The standard TRIAD based data transfer approach will be provided separately through 
IROC efforts via the specific trial e-mail 
 per the 
request by participating sites before their first data submission. 
2. Web Transfer 
 
 
 
Any PCs with internet access and web browser (e.g., Chrome, Edge, Internet Explorer, 
Mozilla Firefox) can be used to web transfer DICOM images and other required files to 
IROC Ohio. The standard Web Transfer information will be provided separately 
through the specific trial e-mail 
 per the request by 
participating sites before their first data submission.  
3. FTP Transfer  
 
Any FTP software can be used to initiate access to the secure FTP Server of IROC Ohio. 
The standard FTP access information will be provided separately through the specific 
trial e-mail 
per the request by participating sites 
before their first data submission.  
4. Mail/CD Shipment   
Only if electronic data transfer approaches cannot be achieved, the de-identified images 
in digital DICOM format can be burned to a CD and mailed to IROC Ohio. Submit only 
one patient’s images per CD, with the patient’s Alliance ID number, study type, date of 

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scans, and name of submitting institution. 
 
 
Submit these data to:  
 
 
  
  
 
 
 
 
 
 
 
 
 
Once the imaging data submission is done, send an e-mail to IROC Ohio at the specific trial 
email 
to inform that the study has been submitted from the 
institution. IROC Ohio will notify site and ALLIANCE A031901 imaging committee within 2 
business days of the data receipt, and then, within 3 business days following the data receipt, of 
the quality check report.  
Any questions or problems about the data submission to IROC Ohio email 
 for help. 
6.4 
Submission of Patient Completed Measures 
Patient-completed questionnaire booklets for this study are to be ordered prior to the registration 
of any patients (see Section 4.3). Samples of questionnaire booklets are available in Appendix 
II for reference and IRB submission only. They are not to be used for patient completion. 
Booklets must be given to patients to complete and patients should be instructed to return the 
booklets to site staff either in person or by mail and site staff will enter patient responses into 
Medidata Rave. The booklets should be completed within a +/- 2 week window at each time 
point. At visits in which booklets are to be completed, the booklet should be given to the patient 
before any discussion of the patient’s health status or test results. Booklet administration 
schedule is provided below.  
Form 
At 
registration 
6 months 
12 months 
18 months 
24 months 
For patients registered to A031901-HO1, submit patient-completed questionnaires* at the following time points: 
EQ-5D-5L 
X 
X 
X 
X 
X 
EORTC QLQ-C30 
X 
X 
X 
X 
X 
PROMIS-29+2 v2.1 (PROPr) (includes 
PROMIS-Fatigue) 
X 
X 
X 
X 
X 
Healthcare Utilization 
X 
X 
X 
X 
X 
COST-FACIT 
X 
X 
X 
X 
X 
* 
See Appendix I for the EQ-5D-5L, EORTC QLQ-C30, PROMIS-29+2 v2.1 (PROPr), 
healthcare utilization and COST-FACIT questionnaires for IRB submission and review 
only. Note that the PROMIS-Fatigue is embedded within the PROMIS-29+2 v2.1 (PROPr). 
Patients must complete the questionnaires in booklet format. 
The forms may be completed in person in the clinic or remotely via telephone calls with the 
patient. 

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Verbal administration of the measures for visually impaired patients is permitted if the measure 
and verbal administration of the measure is conducted in a language understandable to the 
patients.  
6.4.1 
Patient Language Considerations 
All of the QOL and healthcare utilization measures are available in both English and 
Spanish. Patients not speaking one of those languages should not be registered to the 
A031901 HO-1 substudy.  
7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 7 days of registration.  
For questions regarding treatment, please see the study contacts page.  
7.1 
Protocol Therapy 
This is a randomized trial. Patients will be randomized to continuing PD-1/L1 ICI treatment vs 
discontinuing ICI. Patients should continue ICI treatment during study screening. 
Patients randomized to Arm A will continue to receive ICI. Following randomization, the next 
dose of ICI should be administered based on the cycle length of ICI they are receiving. For 
example, a patient receiving pembrolizumab (cycle length = 21 days) randomized to Arm A on 
4/01/2021 whose last dose of pembrolizumab was administered on 3/15/21 should receive the 
next cycle of pembrolizumab on 4/05/2021 (+/- 3 days). 
At disease progression patient should be treated at the discretion of the treating physician. 
Patients randomized to Arm B will discontinue treatment with the ICI. Following 
randomization to Arm B, the last dose of ICI should be administered within 1 cycle length of 
randomization. For example, a patient receiving pembrolizumab (cycle length = 21 days) 
randomized to Arm B on 4/01/21 should receive their last dose of pembrolizumab between 
3/11/21 and 4/22/21. 
At disease progression patients will have the option to restart ICI-containing treatment. 
For questions regarding treatment, please see the study contacts page.  
7.2 
ICI choices 
The following applies to all ICI choices: 
• 
A +/- 3 day treatment window 
• 
Treatment may be delayed for up to a maximum of 8 week from the last dose. A dose 
will be considered delayed if the delay is exceeding 3 days (i.e., ≥ 4 days from scheduled 
dosing date). The reason for the dose delay will be captured on the treatment forms. 
Investigators will choose one of the below ICI treatments for the duration of the trial. The 
following rules apply: 
• 
Pembrolizumab (Cycle = 21 or 42 days): To be administered by IV over 30 minutes 
at 200 mg every 21 days OR at 400 mg every 42 days. 
• 
Nivolumab (Cycle = 28 days): To be administered by IV over 30 minutes at 240 mg 
every 14 days or 480 mg every 28 days. 
• 
Atezolizumab (Cycle = 21 days): To be administered by IV at 1200 mg every 21 days. 
The first infusion should be given over 60 minutes, if tolerated well, subsequent 
infusions may be given over 30 minutes. 

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• 
Avelumab (Cycle = 28 days): To be administered by IV over 60 minutes at 800 mg 
every 14 days. Premedication is not required but may be administered based upon 
clinical judgement and presence/severity of prior infusion reactions. 
8.0 
DOSE AND TREATMENT MODIFICATIONS  
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Patients should not receive any other systemic treatment which would be considered 
treatment for the primary neoplasm or impact the primary endpoint.  
8.1.2 
Patients should receive full supportive care while on this study.   
This includes blood product support, antibiotic treatment, and treatment of other newly 
diagnosed or concurrent medical conditions. All blood products and concomitant 
medications such as antidiarrheals, analgesics, and/or antiemetics received from the first 
day of study treatment administration until 30 days after the final dose will be recorded in 
the medical records. 
Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined in Section 8.2. Where appropriate, these guidelines 
include the use of oral or IV treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids. 
Several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out other 
causes such as metastatic disease or bacterial or viral infection, which may require 
additional supportive care.  
8.1.3 
Treatment with hormones or other chemotherapeutic agents may not be administered 
except for steroids given for immune-related toxicities (e.g., colitis); hormones 
administered for non-disease-related conditions (e.g., insulin for diabetes); premedication 
for hypersensitivity reactions (e.g., premedication for iodinated contrast allergy before CT 
scan) and intermittent use of dexamethasone as an antiemetic.  
8.1.4 
Antiemetics may be used at the discretion of the attending physician, except for the 
steroids above. 
8.1.5 
Palliative radiation therapy during protocol therapy may be administered. Patients 
who receive palliative radiation but otherwise do not have evidence of disease progression 
are allowed to remain on protocol until evidence of radiographic progression. Patients 
randomized to Arm A may continue ICI, and patients randomized to Arm B my remain off 
ICI until progression. Decision to hold ICI during palliative radiation is at the discretion of 
the treating physician.   
8.1.6 
Alliance Policy Concerning the Use of Growth Factors 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations.  The use of growth factors should follow 
published guidelines of the American Society of Clinical Oncology Clinical Practice 
Guideline Update.  J Clin Oncol 33: 3199-3212, 2015 and American Society of Clinical 
Oncology – American Society of Hematology Clinical Practice Guideline Update on the 
Use of Epoetin and Darbepoetin in Adult Patients with Cancer.  J Clin Oncol 28:4996-
5010, 2010. 

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8.1.7 
Hypersensitivity/infusion reactions 
Treat hypersensitivity and infusion reactions to study treatment per institutional standards. 
8.2 
Dose Modifications 
For patients randomized to ICI treatment continuation in Arm A and patients who progress after 
treatment discontinuation and subsequently undergo treatment rechallenge in Arm B, dose 
interruptions are permitted. However, dose reductions and escalations are not allowed.  
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Patients should be placed back on study therapy within 1-cycle length of the 
scheduled interruption (e.g., 3 weeks for pembrolizumab 200mg Q3W). The reason for 
interruption should be documented in the patient's study record. 
Adverse events associated with PD-1/L1 inhibitors may represent an immunologic etiology. 
These AEs may occur shortly after the first dose or several months after the last dose of treatment 
(i.e. after treatment discontinuation). In general, the approach to suspected treatment-related 
AEs is similar across different PD-1/L1 agents as well as any involved organ system. Subjects 
should have a thorough diagnostic work-up to evaluate potential drug- and non-drug-related 
diagnoses. For suspected ICI-related AEs, based on the severity of the event, management with 
immunosuppressants may be necessary. In general, dose delays (for patients on active treatment) 
and observation are adequate for low-grade AEs. For moderate- and high-grade AEs, 
immunosuppression with corticosteroids should be utilized. Once the AE has begun to improve, 
corticosteroids can be tapered over approximately 3 weeks to 6 weeks (depending on the severity 
of the AE). Safety management algorithms for organ-specific AEs are found  below to serve as 
general guidance. 
AER reporting may be required for some adverse events (See Section 9.0) 
8.2.1 Dose Modification and Supportive Care Guidelines for PD-1/L1 ICI-related Adverse 
Events 
Adverse events (both nonserious and serious) associated with pembrolizumab exposure 
may represent an immunologic etiology.  These AEs may occur shortly after the first dose 
or several months after the last dose of treatment.  Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as described in this section. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays).  Patients should be placed back on study therapy within 3 weeks 
of the scheduled interruption.  The reason for interruption should be documented in the 
patient's study record. 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are also outlined in the table in this section.  Where 
appropriate, these guidelines include the use of oral or IV treatment with corticosteroids as 
well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids.  Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased.  For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care.  The treatment guidelines 

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are intended to be applied when the investigator determines the events to be related to 
pembrolizumab. 
Note:  If after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of the evaluation of the event. 
Clinicians should refer to the package insert for further guidance on specific drug dose 
modifications. 
Table: Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
and Infusion Reactions Associated with Pembrolizumab  
General instructions: 
1. For non-endocrine-related severe and life-threatening irAEs, investigators should consider the 
use of IV corticosteroids followed by oral steroids.  Other immunosuppressive treatment 
should begin if the irAEs are not controlled by corticosteroids.  Some non-endocrine irAEs do 
not require steroids.  For example, celiac disease induced by pembrolizumab can be controlled 
by diet alone. 
2. For non-endocrine-related toxicities, pembrolizumab must be permanently discontinued if the 
irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last 
pembrolizumab treatment.  
3. Generally, when corticosteroids are used, investigators should begin a taper when the irAE is 
≤Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld due to a non-endocrine irAE, pembrolizumab may 
generally resume after the irAE has decreased to ≤Grade 1 after a corticosteroid taper. 
irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab  
Corticosteroid and/or 
other therapies  
Monitoring and 
follow-up  
Pneumonitis  
Grade 2 
Withhold  
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
 
Monitor participants 
for signs and 
symptoms of 
pneumonitis 
Evaluate 
participants with 
suspected 
pneumonitis 
with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 

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Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
Patients who do not 
respond to 
corticosteroids 
should be seen by a 
gastroenterologist 
for confirmation of 
the diagnosis and 
consideration of 
secondary immune 
suppression 
 
 
Monitor participants 
for signs and 
symptoms of 
enterocolitis 
(i.e., diarrhea, 
abdominal pain, 
blood or mucus 
in stool with or 
without fever) 
and of bowel 
perforation (i.e. 
peritoneal signs 
and ileus) 
Specifically assess 
for celiac 
disease 
serologically, 
and exclude 
Clostridium 
difficile 
infection 
Participants with 
≥Grade 2 
diarrhea 
suspecting 
enterocolitis 
should consider 
GI consultation 
and performing 
endoscopy to 
rule out 
enterocolitis and 
assess mucosal 
severity 
Participants with 
diarrhea/colitis 
should be 
advised to drink 
liberal quantities 
of clear fluids. If 
sufficient oral 
fluid intake is 
not feasible, 
fluid and 
electrolytes 
should be 
substituted via 
IV infusion 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 

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AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
Administer 
corticosteroids 
(initial dose of 
0.5 to 1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
Monitor with liver 
function tests 
(consider 
weekly or more 
frequently until 
liver enzyme 
value returned 
to baseline or is 
stable) 
Grade 3 b or 4 
c 
Permanently 
discontinue 
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 

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Type 1 diabetes 
mellitus 
(T1DM) or 
Hyperglycemia 
Grade 1 or 2 
Continue 
 
Investigate for 
diabetes.  In the 
absence of 
corticosteroids 
or diabetes 
medication non-
adherence, any 
grade 
hyperglycemia 
may be an 
indication of 
beta-cell 
destruction and 
pembrolizumab-
induced diabetes 
akin to type 1 
diabetes.  This 
should be 
treated as a 
Grade 3 event.  
Given this risk, 
exercise caution 
in utilizing non-
insulin 
hypoglycemic 
agents in this 
setting.  After a 
thorough 
investigation of 
other potential 
causes, which 
may involve a 
referral to an 
endocrinologist, 
follow 
institutional 
guidelines.   
Monitor glucose 
control. 

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New onset 
T1DM 
(evidence of 
-cell failure) 
or  
Grade 3 or 4 
hyperglycemia 
Withhold d 
Resume 
pembrolizumab 
when symptoms 
resolve and 
glucose levels 
are stable 
Initiate treatment with 
insulin 
If patient is found to 
have diabetic 
ketoacidosis or 
hyperglycemic 
hyperosmolar 
syndrome, treat as 
per institutional 
guidelines with 
appropriate 
management and 
laboratory values 
(e.g. anion gap, 
ketones, blood pH, 
etc.) reported 
 
Monitor for glucose 
control 
Strongly consider 
referral to 
endocrinologist 
Obtain C-peptide 
level paired with 
glucose, 
autoantibody 
levels (e.g. 
GAD65, islet 
cell 
autoantibodies), 
and hemoglobin 
A1C level 
 
Hypophysitis 
Grade 2 
Withhold 
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated 
Monitor for signs 
and symptoms 
of hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency) 
Provide adrenal 
insufficiency 
precautions 
including 
indications for 
stress dose 
steroids and 
medical alert 
jewelry 
Strongly consider 
referral to 
endocrinologist 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Consider 
withholding. 
Resume 
pembrolizumab 
when symptoms 
are controlled, 
and thyroid 
function is 
improving 
Treat with nonselective 
beta-blockers (e.g., 
propranolol) or 
thionamides as 
appropriate 
Initiate treatment with 
anti-thyroid drug 
such as 
methimazole or 
Monitor for signs 
and symptoms 
of thyroid 
disorders 
Strongly consider 
referral to 
endocrinologist 
 

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Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
carbimazole as 
needed 
Hypothyroidism 
Grade 2, 3 or 
4 
Continue 
Initiate thyroid 
replacement 
hormones (e.g., 
levothyroxine or 
liothyronine) per 
standard of care 
Monitor for signs 
and symptoms 
of thyroid 
disorders 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
Administer 
corticosteroids 
(prednisone 
1 to 2 mg/kg or 
equivalent) 
followed by taper 
Monitor changes of 
renal function 
Strongly consider 
referral to 
nephrologist 
Grade 3 or 4 
Permanently 
discontinue 
Cardiac Events 
(including 
myocarditis, 
pericarditis, 
arrhythmias, 
impaired 
ventricular 
function, 
vasculitis) 
Asymptomatic 
cardiac 
enzyme 
elevation with 
clinical 
suspicion of 
myocarditis 
(previously 
CTCAE v4.0 
Grade 1), or 
Grade 1 
Withhold 
Based on severity of 
AE administer 
corticosteroids 
 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes 
Strongly consider 
referral to 
cardiologist and 
cardiac MRI 
Consider 
endomyocardial 
biopsy 
If event resolves to 
Grade 1 or 
better, taper 
corticosteroids 
over ≥1 month 

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Grade 2, 3 or 
4 
Permanently 
discontinue 
Initiate treatment with 
corticosteroids 
equivalent to 1-2 
mg/kg/day IV 
methylprednisolone 
and convert to 1-2 
mg/kg/day oral 
prednisone or 
equivalent upon 
improvement 
If event does not 
improve within 48 
hours after 
initiating 
corticosteroids, 
consider adding an 
immunosuppressive 
agent 
Initiate treatment per 
institutional 
guidelines and 
consider 
antiarrhythmic 
drugs, temporary 
pacemaker, 
extracorporeal 
membrane 
oxygenation 
(ECMO), 
ventricular assist 
device (VAD), or 
pericardiocentesis 
as appropriate 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes 
Strongly consider 
referral to 
cardiologist and 
cardiac MRI 
Consider 
endomyocardial 
biopsy 
If event resolves to 
Grade 1 or 
better, taper 
corticosteroids 
over ≥1 month 
Exfoliative 
Dermatologic 
Conditions 
Suspected 
SJS, TEN, or 
DRESS 
Withhold 
Based on severity of 
AE administer 
corticosteroids 
Ensure adequate 
evaluation to 
confirm etiology 
or exclude other 
causes 
Strongly consider 
referral to 
dermatologist 
Consider skin 
biopsy for 
evaluation of 
etiology 
Confirmed 
SJS, TEN, or 
DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent 
Grade 2 
Withhold 
Ensure adequate 
evaluation to 

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Grade 3 
Withhold or 
discontinue 
based on the 
event e  
Based on severity of 
AE administer 
corticosteroids 
confirm etiology 
or exclude other 
causes 
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
 
 
Infusion-Related Reactions 
Infusion 
Reactions 
NCI CTCAE 
Grade 
Treatment  
Premedication at 
subsequent dosing 
Mild reaction; 
infusion 
interruption not 
indicated; 
intervention not 
indicated 
  
Grade 1 
Increase monitoring of vital signs as 
medically indicated until the 
participant is deemed medically stable 
in the opinion of the investigator. 
None 

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Infusion 
Reactions 
NCI CTCAE 
Grade 
Treatment  
Premedication at 
subsequent dosing 
Requires 
therapy or 
infusion 
interruption but 
responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, 
narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for 
≤24 hrs. 
Grade 2 
• 
Stop Infusion. 
• 
Additional appropriate medical 
therapy may include but is not 
limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
• 
Increase monitoring of vital 
signs as medically indicated 
until the participant is deemed 
medically stable in the opinion 
of the investigator. 
• 
If symptoms resolve within 1 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion 
rate (e.g. from 100 mL/hr. to 50 
mL/hr.). Otherwise dosing will 
be held until symptoms resolve 
and the participant should be 
premedicated for the next 
scheduled dose. 
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug treatment 
Participant 
may 
be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion 
of 
study 
intervention with: 
Diphenhydramine 50 
mg PO (or equivalent 
dose of antihistamine). 
Acetaminophen 500-
1000 mg PO (or 
equivalent dose of 
analgesic). 

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Infusion 
Reactions 
NCI CTCAE 
Grade 
Treatment  
Premedication at 
subsequent dosing 
Prolonged (i.e., 
not rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
recurrence of 
symptoms 
following initial 
improvement; 
hospitalization 
indicated for 
other clinical 
sequelae (e.g., 
renal 
impairment, 
pulmonary 
infiltrates) 
 
 
 
Grade 3 
• 
Stop Infusion. 
• 
Additional appropriate medical 
therapy may include but is not 
limited to: 
• 
Epinephrine** 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids (e.g. 
methylprednisolone 2 
mg/kg/day or dexamethasone 
10 mg every 6 hours) 
• 
Increase monitoring of vital 
signs as medically indicated 
until the participant is deemed 
medically stable in the opinion 
of the investigator. 
• 
Hospitalization 
may 
be 
indicated. 
**In cases of anaphylaxis, epinephrine 
should be used immediately. 
Participant is permanently discontinued 
from further study drug treatment. 
 
No subsequent dosing. 
 
Life-
threatening; 
pressor or 
ventilator 
support 
indicated 
 
Grade 4 
Admit participant to intensive care unit 
(ICU) and initiate hemodynamic 
monitoring, mechanical ventilation, 
and/or IV fluids and vasopressors as 
needed. Monitor other organ function 
closely. 
Manage constitutional symptoms and 
organ toxicities as per institutional 
practice. 
Follow Grade 3 recommendations as 
applicable. 
No subsequent dosing. 
 

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Infusion 
Reactions 
NCI CTCAE 
Grade 
Treatment  
Premedication at 
subsequent dosing 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common 
Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; 
ECMO=extracorporeal membrane oxygenation; GI=gastrointestinal; ICU=intensive care unit; IO=immuno-oncology; 
ir=immune related; IV=intravenous; MRI=magnetic resonance imaging; PO=per os; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal; VAD=ventricular 
assist device. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; 
bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the 
investigator or treating physician. If control achieved or ≤Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: encephalitis and other clinically 
important irAEs (e.g. vasculitis and sclerosing cholangitis). 
 
Appropriate resuscitation equipment should be available at the bedside and a physician readily 
available during the period of drug administration. For further information, please refer to the 
Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
 
Neurological Toxicities 
 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
• Continue pembrolizumab. 
• Investigate etiology. 
• Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 2 
• Withhold pembrolizumab for up to 12 weeks after event onset. a 
• Investigate etiology and refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• For general immune-mediated neuropathy: 
o If event resolves to Grade 1 or better, resume 
pembrolizumab. b 
o If event does not resolve to Grade 1 or better while 
withholding pembrolizumab, permanently discontinue 
pembrolizumab. c 
• For facial paresis: 
o If event resolves fully, resume pembrolizumab. b 
o If event does not resolve fully while withholding 
pembrolizumab, permanently discontinue 
pembrolizumab. c 

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Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 3 or 4 
• Permanently discontinue pembrolizumab. c  
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
• Permanently discontinue pembrolizumab. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 
mg/kg/day oral or IV prednisone. 
a Pembrolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day 
oral prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefit−risk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before pembrolizumab can be resumed. 
c Resumption of pembrolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge patients 
with pembrolizumab should be based on investigator's assessment of benefit−risk and 
documented by the investigator (or an appropriate delegate). 
 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
• 
Continue pembrolizumab unless symptoms worsen or 
do not improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
• 
Permanently discontinue pembrolizumab.  
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
• 
Permanently discontinue pembrolizumab. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 

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Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
• Permanently discontinue pembrolizumab. a 
• Refer patient to neurologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 
mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month. 
a Resumption of pembrolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge patients 
with pembrolizumab should be based on investigator's assessment of benefit−risk and 
documented by the investigator (or an appropriate delegate). 
 
 
 

 
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Neurological Toxicities 
 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
• 
Continue pembrolizumab. 
• 
Investigate etiology. 
• 
Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, including 
facial paresis, Grade 2 
• 
Withhold pembrolizumab for up to 12 weeks after event onset. a 
• 
Investigate etiology and refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
For general immune-mediated neuropathy: 
o If event resolves to Grade 1 or better, resume 
pembrolizumab. b 
o If event does not resolve to Grade 1 or better while 
withholding pembrolizumab, permanently discontinue 
pembrolizumab. c 
• 
For facial paresis: 
o If event resolves fully, resume pembrolizumab. b 
o If event does not resolve fully while withholding 
pembrolizumab, permanently discontinue pembrolizumab. c 
Immune-mediated 
neuropathy, including 
facial paresis, Grade 3 
or 4 
• 
Permanently discontinue pembrolizumab. c  
• 
Refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
Myasthenia gravis and 
Guillain-Barré 
syndrome (any grade) 
• 
Permanently discontinue pembrolizumab. c 
• 
Refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day 
oral or IV prednisone. 
a Pembrolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral prednisone.  
The acceptable length of the extended period of time must be based on an assessment of benefit−risk 
by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 10 
mg/day oral prednisone before pembrolizumab can be resumed. 
c Resumption of pembrolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challenge patients with 
pembrolizumab should be based on investigator's assessment of benefit−risk and documented by the 
investigator (or an appropriate delegate). 
 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
• 
Continue pembrolizumab unless symptoms worsen or do not 
improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
• 
Permanently discontinue pembrolizumab.  
• 
Investigate etiology and refer patient to a neurologist. 

 
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Event 
Management 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
• 
Permanently discontinue pembrolizumab. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
Event 
Management 
Immune-mediated 
meningoencephalitis, all 
grades 
• 
Permanently discontinue pembrolizumab. a 
• 
Refer patient to neurologist. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone and convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
1 month. 
a Resumption of pembrolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re-challenge patients with 
pembrolizumab should be based on investigator's assessment of benefit−risk and documented by the 
investigator (or an appropriate delegate). 
 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events 
(CTCAE), 
Version 
5.0. 
The 
CTCAE 
is 
available 
at 
 
Attribution 
to 
protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further details 
on AE reporting procedures.  
9.1 
Routine Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. 
9.1.1 
Rave-CTEP-AERS integration 
The Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS) 
Integration enables evaluation of post-baseline Adverse Events (AE) entered in Rave to 
determine whether they require expedited reporting, and facilitates entry in CTEP-AERS 
for those AEs requiring expedited reporting.    
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period and used to collect 
AEs that start during the period or persist from the previous reporting period. The CRA 

 
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will enter AEs that occur prior to the start of treatment on a baseline form that is not 
included in the Rave-CTEP-AERS integration. AEs that occur prior to enrollment must 
begin and end on the baseline Adverse Events form and should not be included on the 
standard Adverse Events form that is available at treatment unless there has been an 
increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• 
The reporting period (course/cycle) is correct; and 
• 
AEs are recorded and complete (no missing fields) and the form is query free 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting. A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs that 
meet reporting requirements. The CRA completes the report by accessing CTEP-AERS via 
a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
In the rare occurrence, that Internet connectivity is lost, a 24-hour notification is to be  faxed 
to the Alliance office at 
Once Internet connectivity is restored, the 24-hour 
notification that was faxed in must be entered immediately into CTEP-AERS using the 
deep link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
• 
Study specific documents: Protocols > Documents> Education and Promotion; and   
• 
Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information> User Guides. 
NCI requirements for SAE reporting are available on the CTEP website:  
• 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available 
at 
 
9.1.2 
Solicited adverse events 
The following adverse events are considered "expected" and their presence/absence should 
be solicited, and severity graded, at baseline and for each cycle of treatment. 
 
CTCAE v5.0 Term 
CTCAE v5.0 System Organ Class 
(SOC) 
Pneumonitis 
Respiratory, thoracic and mediastinal 
disorders 
Hyperthyroidism 
Endocrine disorders 
Colitis 
Gastrointestinal disorders 

 
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Acute kidney injury 
Renal and urinary disorders 
Alanine aminotransferase increased  
Investigations 
Aspartate aminotransferase increased 
Investigations 
Rash maculo-pupular 
Skin and subcutaneous tissue disorders 
Papulopustular rash 
Infections and infestations 
Bullous dermatitis 
Skin and subcutaneous tissue disorders 
9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 
Alliance Statistics and Data Center. Questions about routine reporting should be directed to the 
Data Manager. 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on 
Case Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) Adverse Events: Other CRF - Applies to AEs occurring between registration and within 
30 days of the patient’s last treatment date, or as part of the Clinical Follow-Up Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. The descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5 will be utilized for AE reporting.  The CTCAE 
is 
identified 
and 
located 
on 
the 
CTEP 
website 
at: 
 
All 
appropriate 
treatment areas should have access to a copy of the CTCAE. All reactions determined to be 
“reportable” in an expedited manner must be reported using the Cancer Therapy Evaluation 
Program Adverse Event Reporting System (CTEP-AERS). 
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
 
 

 
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9.3.1 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 
10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
 

 
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9.3.2 
Expedited AE reporting timelines defined 
• 
“24 hours; 5 calendar days” – The investigator must initially report the AE via 
CTEP-AERS ≤ 24 hours of learning of the event followed by a complete CTEP-
AERS report ≤ 5 calendar days of the initial 24-hour report. 
• 
“10 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
≤ 10 calendar days of the investigator learning of the event.  
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under an IND. 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
9.3.3 
Additional Instructions or Exclusions to CTEP-AERS Expedited Reporting 
Requirements  
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
Treatment expected adverse events include those listed in Section 10.0 and in the package 
insert. 
CTEP-AERS reports should be submitted electronically. 
Exclusions 
Grade 1-3 nausea or vomiting and hospitalization resulting from such do not require AERS 
reporting, but should be reported via routine AE reporting 
Grade 3 nausea or vomiting does not require AERS reporting, but should be reported via 
routine AE reporting.  
Death 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
Pregnancy loss and neonatal death 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any Pregnancy loss should be 
reported expeditiously, as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and 
perinatal conditions SOC. A Pregnancy loss should NOT be reported as a Grade 5 event 

 
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under the Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-AERS 
recognizes this event as a patient death. 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 
New Malignancies 
All new malignancies must be reported via CTEP-AERS whether or not they are thought 
to be related to either previous or current treatment. All new malignancies should be 
reported, i.e. solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors.  
Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology, history or prior tumors, prior treatment/current treatment including duration, 
any associated risk factors or evidence regarding how long the new malignancy may have 
been present, when and how the new malignancy was detected, molecular characterization 
or cytogenetics of the original tumor (if available) and of any new tumor, and new 
malignancy treatment and outcome, if available. 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event:  
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS)  
• 
Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via Rave.  
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting unless otherwise specified. 
9.4 
Adverse Event Lists for Commercial Agents 
Refer to the package inserts for the comprehensive list of adverse events. 
Pembrolizumab: Fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, 
rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain 
Nivolumab: Fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, 
dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, 
pyrexia, headache, abdominal pain, and vomiting 
Atezolizumab: Fatigue, nausea, cough, dyspnea, and decreased appetite. 
Avelumab: Fatigue, fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased 
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10.0 
DRUG INFORMATION 
10.1 
General Considerations 
All study agents are to be administered at the registering institution. 
A list of the adverse events and potential risks associated with the commercial agents 
administered in this study can be found in Section 9.4. 
The total administered dose of chemotherapy may be rounded up or down within a range of 10% 
of the actual calculated dose. 
If the Group credited for enrollment is a non-Alliance Group, then other requirements from the 
credited Group may apply. 
10.2 
Pembrolizumab (NSC #7766864, MK-3475) 
Formulation 
Pembrolizumab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to 
slightly yellow solution for intravenous use.  Each vial contains 100 mg of pembrolizumab in 4 mL 
of solution.  Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-
histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP. 
Storage 
Store intact vials between 2°C - 8°C (36°F - 46°F).  Do not freeze.  Protect from light by storing in 
the original box.   
Stability 
Administer prepared solutions immediately after preparation.  If not administered immediately, 
prepared solutions may be stored refrigerated for up to 24 hours.  Pembrolizumab solutions may 
be stored at room temperature for a cumulative time of up to 6 hours.  This includes room 
temperature storage of liquid drug product solution in vials, room temperature storage of 
infusion solution in the IV bag, and the duration of infusion. 
Preparation 
Pembrolizumab solution for infusion must be diluted prior to administration.  Allow the required 
number of vials to equilibrate to room temperature.  Do not shake the vials.  Do not use if opaque 
or extraneous particulate matter other than translucent to white proteinaceous particles is observed.  
Do not use if discolored.  To prepare the infusion solution add the dose volume of pembrolizumab 
to an infusion bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, 
USP.  Gently invert the bag 10-15 times to mix the solution.  The final concentration must be 
between 1 mg/mL to 10 mg/mL. 
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC (polyolefin), EVA, or PE 
lined polyolefin. 
Administration 
Administer diluted solution by IV over 30 minutes through an intravenous line containing a sterile, 
non-pyrogenic, low protein binding 0.2 micron to 5 micron in-line or add-on filter. Do not co-
administer other drugs through the same infusion line. 
Adverse Events 
Consult the package insert for the most current and complete information. 

 
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10.3 
Nivolumab (NSC #748726, BMS-936558, MDX1106) 
Formulation 
Nivolumab is available in 40 mg/4 mL (10 mg/mL), 100 mg/10 mL (10 mg/mL) and 240 
mg/24 mL (10 mg/mL) single dose vials. 
Storage 
Vials of nivolumab injection must be stored at 2°- 8°C (36°- 46°F) and protected from light and 
freezing. The unopened vials can be stored at room temperature (up to 25°C, 77°F) and room light 
for up to 48 hours. 
Preparation 
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose. Prepare an infusion with a final concentration ranging 
from 1 mg/mL to 10 mg/mL. The total volume of infusion must not exceed 160 mL.  For patients 
with body weight <40 kg, do not exceed a total volume of infusion of 4 mL/kg of body weight.  
Mix diluted solution by gentle inversion. Do not shake. 
Administration 
The administration of undiluted and diluted solutions of nivolumab must be completed within 
24 hours of preparation.  If not used immediately, the infusion solution may be stored up to 24 
hours in a refrigerator at 2°-8°C (36°-46°F) and a maximum of 8 hours of the total 24 hours can 
be at room temperature (up to 25°C, 77°F) and room light.  The maximum 8-hour period under 
room temperature and room light conditions includes the product administration period. 
CAUTION:  The single-use dosage form contains no antibacterial preservative or bacteriostatic 
agent.  Therefore, it is advised that the product be discarded 8 hours after initial entry.  
Route of Administration: Intravenous infusion over 30 minutes. Do not administer as an IV push 
or bolus injection. 
Method of Administration: Administer through a 0.2 micron to 1.2 micron pore size, low-protein 
binding in-line filter. 
Adverse Events 
Consult the package insert for the most current and complete information. 
10.4 
Atezolizumab (NSC #783608, MPDL3280A) 
Formulation 
Atezolizumab Injection is available in 840 mg/14 mL (60 mg/mL) and 1200 mg/20 mL (60 
mg/mL) single use vials.  The solution is colorless to slightly yellow solution. 
Storage 
2°C-8°C (36°F-46°F) Vial contents should not be frozen or shaken and should be protected from 
direct sunlight. 
Stability 
CAUTION:  No preservative is used in atezolizumab; therefore, the vial is intended for single 
use only. Discard any unused portion of drug remaining in a vial. 
Preparation 

 
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The prescribed dose of atezolizumab should be diluted in 0.9% NaCl and infused through a 0.2 
micrometer in-line filter.  Dilute to a final concentration between 3.2 mg/mL and 16.8 mg/mL. 
The IV bag may be constructed of PVC, PO, or PE; the IV infusion line may or may not contain 
a sterile, non-pyrogenic, low-protein binding in-line filter (pore size of 0.2–0.22 micron).  
The prepared solution may be stored either: 
• 
At room temperature for up to 6 hours from the time of preparation.  This includes room 
temperature storage of the  infusion in the infusion bag and time for administration of 
the solution.  
• 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from time 
of preparation.   
Do not freeze or shake the infusion. 
Administration 
Route of Administration: IV infusion 
Method of Administration: Atezolizumab is administered as an intravenous infusion over 60 
minutes. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 
minutes. Do not administer atezolizumab as an intravenous push or bolus. No premedication is 
indicated for administration of Cycle 1 of atezolizumab. Patients who experience an infusion 
related reaction with Cycle 1 of atezolizumab may receive premedication with antihistamines 
or antipyretics/analgesics (e.g. acetaminophen) for subsequent infusions. 
Drug Interactions 
Cytochrome P450 enzymes as well as conjugation/glucuronidation reactions are not involved in 
the metabolism of atezolizumab. No drug interaction studies for atezolizumab have been 
conducted or are planned. There are no known interactions with other medicinal products or 
other form of interactions. 
Adverse Events 
Consult the package insert for the most current and complete information. 
10.6 
Avelumab (NSC #799232)  
Formulation 
Avelumab is a clear and colorless to slightly yellow concentrate for solution supplied as a single-
dose vial of 200 mg/10 mL (20 mg/mL) and containing D-mannitol, glacial acetic acid, 
polysorbate 20, sodium hydroxide, and water for injection, and supplied in glass vials closed 
with a rubber (not made with natural rubber latex) stopper and sealed with an aluminum crimp 
seal closure fitted with a removable plastic cap. 
Storage 
Store intact vials at 2-8 ºC (36-46 ºF) in the original container and protected from light.  Do not 
freeze or shake the vial. 
Stability 
Refer to package labeling for expiration. The diluted drug product should be protected from 
light and can be stored up to 4 hours at room temperature (up to 25 ºC) or up to 24 hours at 2-8 
ºC. If refrigerated, allow the diluted drug product to come to room temperature before 
administration. 

 
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CAUTION:  No preservative is used in avelumab; therefore, the vial is intended for single use 
only. Discard any unused portion of drug remaining in a vial. 
Preparation 
Avelumab must be diluted prior to administration. Inspect the vials for particulate matter and 
discoloration. Withdraw the required volume of avelumab from the vial(s) and inject it into a 
250 mL infusion bag containing 0.9% sodium chloride injection or 0.45% sodium chloride 
injection. Gently invert the bag to mix and avoid foaming or excessive shearing. Inspect the 
solution to ensure it is clear, colorless, and free of visible particles. 
Administration 
Patients should be pre-medicated with an antihistamine and with acetaminophen prior to the first 4 
infusions. Premedication should be administered for subsequent avelumab doses based upon 
clinical judgement and presence/severity of prior infusion reactions. 
Administer the diluted solution as an intravenous infusion over 60 minutes through an intravenous 
line containing an in-line 0.2-micron low protein binding filter. Do not co-administer other drugs 
through the same intravenous line. 
Adverse Events 
Consult the package insert for the most current and complete information. 
11.0 
MEASUREMENT OF EFFECT 
11.1 
RECIST 1.1 and iRECIST Criteria 
Response and progression will be evaluated in this study using RECIST 1.1 criteria (25) and 
iRECIST criteria (26) (See study objectives in Section 2.0). After randomization, disease should 
be re-evaluated every 12 weeks   4 weeks until evidence of progression or relapse (see study 
calendar in Section 5.0). Imaging assessment will be time-based and not cycle-based.  
Baseline scans can include either: 1) a CT, spiral CT, or MRI, or 2) an FDG-PET scan and 
diagnostic CT. Both IV and oral contrast should be used unless contraindicated, with slide 
thickness of 5 mm or less. Supporting documentation is to be submitted, per Section 6.1.1. 
Confirmatory scans should be obtained 4-8 weeks following documentation of objective 
progression when possible (i.e., clinically stable, without worsening PS or increase in disease-
related symptoms). Response assessment should include assessment of all sites of disease, and 
use the same imaging method as was used at baseline. 
Brain imaging and bone scan are required only if there is indication of brain or bone metastases 
at baseline or if signs or symptoms suggestive of brain or bone metastases develop, respectively. 
These should follow the same schedule as other cross section imaging (see Sections 5 and 6.3.) 
11.1.1 RECIST 1.1 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 (<1 cm).  
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 

 
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demonstrate an absolute increase of at least 5 mm (0.5 cm). (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. 
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 [<1 cm] 
short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e. Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation 
is Required* 
CR 
CR 
No 
CR 
4 wks 
confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
4 wks 
confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at 
least once 4 
wks from 
baseline** 
PD 
Any 
Yes or No 
PD 
No prior SD, 
PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
* See RECIST 1.1 manuscript (25) for further details on what is evidence of a new lesion. 
** Required only for non-randomized trials with response as primary endpoint. Confirmation of 
progression is strongly encouraged 4-8 weeks after documentation of PD for this study and should be 
performed whenever possible (i.e. clinically stable). 

 
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*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e. Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
*”Non-CR/Non-PD” is referred over “stable disease” for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised. 
11.1.2 iRECIST Criteria 
The mechanism of action of immune modulating agents, with activation of anti-tumor 
immune response, has been postulated to lead to unusual patterns of response. Some 
patients whose disease met criteria for disease progression based on traditional RECIST 
criteria (i.e. increase in sum of measures of target lesions, unequivocal increase in non-
target disease, or appearance of new lesions) were noted to have late responses that are 
deep and durable. The iRECIST criteria has been developed which allows responses not 
typically observed in traditional systemic therapies (26). Key comparisons of RECIST 1.1 
and iRECIST criteria are summarized below. 
 
 
RECIST 1.1 
iRECIST 
Definitions of measurable and 
non-measurable disease; 
numbers and site of target 
disease 
Measurable lesions are 10 mm 
or more in long diameter (15 
mm for nodal lesions); 
maximum of 5 lesions (2 per 
organ); all other disease 
considered not-target (must be 
10 mm of longer in short axis 
for nodal disease) 
No change; however, NEW 
lesions are evaluated  as per 
RECIST 1.1 but are recorded 
separately on the CRF (but not 
included in the sum of lesions 
for target lesions identified at 
baseline) 
CR, PR or SD 
Cannot have met criteria for PD 
prior to CR, PR or SD 
May have had iUPD (1 or more 
instances), but not iCPD, prior 
to iCR, iPR or iSD 
New lesions 
Results in PD. Recorded but not 
measured 
Results in iUPD but iCPD is 
only assigned based on this 
category if at next assessment 
• Additional NL appear or 
• Increase in size of NLs (≥5 
mm for sum of NLT or any 
increase in NLNT) 

 
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NLs, where none have 
previously been recorded can 
also confirm iCPD 
Consideration of clinical status 
Not included in assessment 
Clinical stability* is considered 
in whether treatment is 
continued after iUPD 
 
Abbreviations: NT = non-target, T = target; NL = new lesions; NLT = new lesion target; NLNT = new 
lesion non target; iUPD = unconfirmed immune PD; iCPD = confirmed immune PD; SOM= sum of 
measures. iCR = immune complete response; iPR = immune partial response; iSD = immune stable 
disease 
* Clinical stability requires no worsening in performance status, no clinically relevant increase in disease 
related symptoms (e.g. pain, dyspnea) felt related to disease progression, and no requirement for 
intensified management of disease related symptoms including increased analgesia, radiation, or palliative 
care. 
12.0 
END OF TREATMENT/INTERVENTION 
12.1 
Duration of Protocol Treatment  
Protocol treatment is to continue until disease progression. Please see the study calendar 
(Section 5) and the treatment section (Section 7) for treatment and following up time periods. 
12.2 
Criteria for Discontinuation of Protocol Treatment 
Protocol treatment may continue until one of the following criteria applies: 
• 
Disease progression (radiographic by RECIST 1.1 criteria or clinical) 
• 
Intolerable treatment-related adverse event (Arm A only) 
• 
Intercurrent illness that prevents further administration of treatment (Arm A only) 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator (Arm A only) 
• 
Patient non-compliance 
• 
Pregnancy: All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or late 
menstrual period) at any time during study participation. The investigator must 
immediately notify CTEP in the event of a confirmed pregnancy in a patient 
participating in the study. The investigator must immediately notify CTEP in the event 
of a confirmed pregnancy in a patient participating in the study. 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
12.3 
Follow-up  
12.3.1 Duration of Follow-up  
Patients will be followed for survival for 5 years, until death, withdrawal of consent, or the 
end of the study, whichever occurs first (see Section 5.0). 

 
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12.3.2 Follow-up for Patients who Stop Study Treatment Early  
- Follow up for patients in Arm A who stop treatment due to reasons other than disease 
progression (e.g. toxicity): Patients will be followed with physical examination, laboratory, 
and imaging assessments until radiographic progression, initiation of new treatment, or up 
to 5 years following registration (See Section 5.0). 
- Follow up for patients in Arm A who receive non-protocol therapy: Physical exam, 
laboratory, and imaging assessments are required within 4 weeks after the end of study 
treatment. Thereafter, survival information is required every 6 months until 5 years 
following registration, death, withdrawal of consent, or the end of the study, whichever 
occurs first (See Section 5.0).  
- Follow up for patients in Arm B who receive non-protocol therapy (e.g. restart ICI 
treatment or new treatment prior to disease progression): Physical exam, laboratory, and 
imaging assessments are required within 4 weeks before starting non-protocol treatment. 
Thereafter, survival information is required every 6 months until 5 years following 
registration, death, withdrawal of consent, or the end of the study, whichever occurs first 
(See Section 5.0).  
12.4 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
12.5 
Managing ineligible patients and registered patients who never receive protocol 
intervention  
Definition of ineligible patient 
 A study participant who is registered to the trial but does not meet all of the eligibility criteria 
is deemed to be ineligible.  
Follow-up for ineligible patients who continue with protocol treatment 
Patients who are deemed ineligible after registering may continue protocol treatment, provided 
the treating physician, study chair, and executive officer agree there are no safety concerns if 
the patient continues protocol treatment. All scans, tests, and data submission are to continue as 
if the patient were eligible. Notification of the local IRB may be necessary per local IRB 
policies. 
Follow-up for ineligible patients who discontinue protocol treatment 
For patients who are deemed ineligible after registering to the trial, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for 
those patients who are eligible and who discontinue study treatment. 
Follow-up for patients who are registered, but who never start study treatment 
For all study participants who are registered to the trial but who never receive study intervention 
(regardless of eligibility), the follow-up requirements are for patients who are eligible and who 
discontinue study treatment.  

 
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13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
This is a prospective multicenter, randomized, open-label, non-inferiority phase 3 study 
evaluating the optimal duration of immune checkpoint blockade in patients with locally 
advanced or metastatic UC. Eligible patients must not have PD per RECIST v1.1 guidelines 
(i.e., with an ongoing CR, PR or SD) following completion of 12 to 18 months of ICI treatment. 
Allocation to the two study arms will be performed using stratified randomization as described 
in Section 4.6. Patients will be randomized 1:1 to continuation of standard of care ICI until 
disease progression or intolerable toxicity (Arm A) or discontinuation of ICI treatment (Arm B). 
Patients who progress after treatment discontinuation in Arm B will have the option of restarting 
the same ICI treatment. This trial implements a non-inferiority design with the primary endpoint 
of overall survival. Formal interim analysis will be conducted for harm after 25% and 50% of 
OS events, and the study will be monitored for treatment assignment compliance and feasibility 
every 6 months. 
13.2  Study Endpoints 
13.2.1 Primary Endpoint 
The primary endpoint is overall survival (OS), which is measured from randomization until 
death due to any cause. Patients who are lost to follow-up or are not known to be deceased 
at the time of analysis will be censored at the time of last patient contact. 
13.2.2 Secondary Endpoints 
Progression-free survival (PFS): This will be assessed using RECIST 1.1 criteria. This 
will be the time from randomization until disease progression as assessed by RECIST 1.1 
or death due to any cause. Patients who are alive and without documented progression will 
be censored at the time of last disease evaluation. 
Immune-related progression-free survival (iPFS): This will be assessed using iRECIST 
criteria. This will be the time from randomization until disease progression as assessed by 
irRECIST criteria or death due to any cause. Patients who are alive and without 
documented progression by iRECIST will be censored at the time of last disease 
evaluation. 
Treatment-free interval (TFI): This is only defined for Arm B (ICI discontinuation) 
patients and is the time from last dose of ICI to initiation of a subsequent systemic treatment 
or death. Patients who are alive and have not started a treatment at the time of analysis will 
be censored at the time of last follow-up. 
Rate of response after ICI rechallenge: This is only defined for Arm B (ICI 
discontinuation) patients. Response after re-initiation of ICI after the first disease 
progression that occurs after randomization will be assessed using RECIST 1.1. 
Adverse events: These will be assessed using CTCAE v5.0. 
13.3 
Subgroup Analysis 
Subgroup analysis may be conducted in the following groups for efficacy endpoints including 
OS, PFS, and iPFS. 
• 
Response at randomization: CR or PR vs SD 
• 
Type of ICI therapy: Chemotherapy followed by ICI maintenance versus ICI 
monotherapy first-line versus ICI monotherapy second-line and beyond 

 
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• 
Age: <65 yr vs. 65 yr 
• 
Sex: Male vs. Female 
• 
ECOG performance status: 0 or 1 versus 2 
• 
Smoking status: current versus former versus never or unknown 
• 
Histology: transitional cell versus mixed 
• 
Location of primary tumor: upper tract versus lower tract 
• 
Liver metastases (prior to ICI treatment): Yes versus No 
13.4 
Sample Size Calculation 
The sample size was determined with East (v6.4.1) under the following assumptions: 
• 
accrual rate: 15 patients per month 
• 
arm A 24-month OS rate = 50% 
• 
exponential distribution for OS events 
• 
non-inferiority margin, HR = 1.2 (Arm B 24-month OS = 43.5%) 
• 
alpha (one-sided) = 0.05 
• 
power = 80% 
• 
two-interim analysis for harm after 25% and 50% of OS events 
This requires a total sample size = 988 evaluable patients (494 in each arm). The sample size 
will be inflated by 5% to account for patients who withdraw from study prior to starting the 
protocol, so the target accrual is 1038 patients (or 519 randomized to each arm). In order to 
accrue the 988 evaluable patients a total of 4500 patients will need to be pre-registered. 
13.5 
Accrual time and study duration 
The anticipated accrual rate is approximately 15 patients per month. Assuming the study 
proceeds after interim analysis for harm, the maximum expected accrual period is 69 months. 
Patients will be followed for OS for up to 5 years following registration; therefore, the maximum 
total study duration (including OS follow-up) is 129 months.  
13.6 
Primary Analysis Plan 
Interim analysis for harm/futility: There will be two interim analyses for overall survival. The 
first will occur after 25% of deaths (186 deaths) have occurred. This will determine the potential 
for patient harm. A recommendation will be made to the DSMB to stop the trial for harm if the 
OS for the discontinuation arm (Arm B) is statistically inferior to the control arm (Arm A) at a 
one-sided significance level of 0.05. The second interim analysis will be for futility and will 
occur after 50% of deaths (372 deaths) have occurred. The Wieand rule will be used and the 
trial will halt for futility if the observed HR is greater than or equal to 1.2 (the non-inferiority 
margin) (26). 
Final Analysis: The final analysis will occur after 744 deaths have been observed. It will be an 
intention-to-treat analysis and will contain all randomized patients with follow-up data. The 
analysis will test for non-inferiority. If the one-sided 95% CI for the HR contains 1.2, the 
treatment approach will be declared inferior. The point estimate for the HR and corresponding 
one-sided 95% CI will be generated with a stratified Cox regression (using the trial stratification 
factors) that has treatment arm as an exploratory variable. 

 
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13.7 
Secondary Analysis Plans 
A key secondary analysis will be to repeat the primary analysis for the per-protocol population. 
This will only include eligible patients who were treated according to their randomized 
assignment. It will exclude patients who withdrew after randomization and prior to receiving 
protocol treatment.  
For the secondary time-to-event endpoints, stratified Cox models will be used to compare the 
outcomes between the two treatment groups. This includes PFS and iPFS. The subgroup 
analyses will be done using a stratified Cox model that includes the treatment arm assignment 
as an explanatory variable and a separate model will be generated for each level for the subgroup 
of interest.  
Tumor responses will be determined for patients on Arm B who had disease progression and re-
initiated ICI. The best confirmed tumor response (assessed via RECIST) will be summarized as 
frequency and relative frequency. The proportion of patients who achieved a tumor response (a 
CR or PR) will be determined with a binomial point estimate with 95% confidence interval. In 
addition, an analysis will be done that compares the best confirmed tumor response prior to trial 
entry to that achieved after ICI re-challenge with a contingency table. A chi-square test (or 
Fisher’s exact test) will be used to determine whether there is an association between the best 
tumor response prior to trial enrollment and that achieved upon ICI re-challenge. 
Adverse events will be summarized with frequencies and relative frequencies. The maximum 
grade for an AE will be recorded for each patient. The number (percent) of patients that 
experience each observed adverse event will be summarized. In addition, the proportion of 
patients that experience a grade 3+, grade 4+, and grade 5 adverse event will be summarized as 
the number and percent of patients. The primary summary will be regardless of attribution. We 
will also do an analogous summary for the adverse events that were deemed at least possibly 
related to treatment.  
13.8 
Data and Safety Monitoring 
The study team and DSMB will monitor the study for compliance and feasibility every 6 months. 
For the continuation arm (Arm A), if time to treatment discontinuation (censored for 
discontinuation for unacceptable toxicities) is appreciably faster than PFS (there is a 2 month or 
greater difference in the estimated of the median time to treatment discontinuation and median 
PFS), the study may be stopped for lack of compliance. In the discontinuation arm (Arm B), if 
median treatment free interval (TFI) is less than 6 months, the study may be stopped for lack of 
feasibility. The proportion of patients who withdraw from study prior to protocol initiation will 
also be monitored. If after 100 patients are accrued this proportion is 0.15 or greater, the study 
may be stopped due to unacceptability. 
In addition, the DSMB will monitor the trial for safety and whether the trial is meeting its accrual 
goals in a satisfactory manner. 
For studies assigned Demography monitoring and enrolling patients via OPEN: 
Required submission of patient demographic data for this study will be submitted automatically 
via OPEN.   
Note: Serious adverse events must be submitted via CTEP-AERS per protocol guidelines. 
13.9 
Inclusion of Women and Minorities 
Minorities will be eligible for this study without alteration in eligibility criteria. From prior 
knowledge, gender or race/ethnicity differences in the intervention effect are not expected. 
Based on previous data from advanced renal carcinoma patients enrolled on CALGB 90206, the 

 
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accrual targets in individual cells are not large enough to perform subgroup analysis by the two 
treatment groups. This table is based on the accrual profile of urothelial carcinoma patients 
enrolled to 3 Alliance studies (CALGB 90601 (N-506), A031701 (N=69) and A031501 
(N=425)), the Alliance does not anticipate accrual from some subgroups. Therefore, overall 
accrual to the study will not be extended to meet individual subgroup accrual targets. However, 
we plan to perform exploratory analyses within gender, racial, and ethnic groups. Both men and 
women of all races and ethnic groups are eligible for this study. 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
1 
2 
2 
2 
7 
Asian 
2 
12 
2 
2 
18 
Native Hawaiian or 
Other Pacific 
Islander 
2 
2 
2 
2 
8 
Black or African 
American 
8 
19 
2 
2 
31 
White 
188 
648 
24 
106 
966 
More Than One 
Race 
2 
2 
2 
2 
8 
Total 
203 
685 
34 
116 
1038 
 
• 
Ethnic Categories: 
 
• 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
• 
Not Hispanic or Latino 
• 
Racial Categories 
 
• 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
• 
Asian – a person having origins in any of the original peoples of the Far East, Southeast 
Asia, or the Indian subcontinent including, for example, Cambodia, China, India, Japan, 
Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: 
Individuals from the Philippine Islands have been recorded as Pacific Islanders in 
previous data collection strategies.)  
• 
Black or African American – a person having origins in any of the black racial groups 
of Africa.  
• 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original 
peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
• 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 

 
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14.0 
CORRELATIVE AND COMPANION STUDIES  
There will be 2 substudies and all patients are encouraged to participate.  
14.1 
Quality of Life and Health Economics (Alliance A031901-HO1) 
14.1.1 Background 
The primary objective for this trial is to assess whether discontinuation of ICI (Arm B) 
versus continued ICI (Arm A) therapy leads to non-inferior overall survival. In terms of 
quality of life, it is hypothesized that the discontinuation of therapy leads to improved 
overall quality of life, better quality-adjusted survival, and less fatigue. If indeed this trial 
demonstrates that the discontinuation of therapy versus continued therapy results in non-
inferior overall survival and better quality of life, then these results will directly impact 
patient care. Therefore, quality of life is an essential component of this trial.  
We hypothesize that early discontinuation of ICI in patients will translate into several 
benefits, including decreased healthcare utilization, improved QOL, less financial toxicity 
and decreased healthcare costs.  
14.1.2 Objectives 
Primary Objective 
To compare quality-adjusted survival between patients who discontinue ICI therapy vs. 
receive continuous therapy using EQ-5D-5L.  Hypothesis: Therapy discontinuation leads 
to better quality-adjusted survival (defined by combining health utilities at baseline, 6, 12, 
18, and 24 months with overall survival) compared to continuous therapy. 
Secondary Objectives 
• 
To compare overall QOL as measured by the EORTC QLQ-C30 at each time point 
between patients who discontinue therapy vs. receive continuous therapy.  
Hypothesis: Therapy discontinuation leads to better quality of life compared to 
continuous therapy. 
• 
To compare patient-reported fatigue as measured by PROMIS-Fatigue at each time 
point between patients who discontinue therapy vs. receive continuous therapy.  
Hypothesis: Therapy discontinuation leads to less fatigue compared to continuous 
therapy.  
• 
To compare healthcare utilization. Hypothesis: Therapy discontinuation leads to 
decreased healthcare utilization. 
• 
To compare incremental cost-effectiveness and cost-utility ratios. Hypothesis: 
Therapy continuation is much more costly but no more effective. 
• 
To compare financial toxicity between patients who discontinue therapy vs. those 
who received continuous therapy. Hypothesis: Therapy discontinuation leads to 
less financial toxicity. 
Exploratory QOL Objective: To compare quality-adjusted survival as measured using 
EQ-5D-5L versus PROMIS-Preference (PROPr).  
14.1.3 Methods 
QOL 
EQ-5D-5L: This is a 6-item validated utility assessment instrument. The first part consists 
of 5 items covering 5 dimensions including: mobility, self-care, usual activities, 

 
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pain/discomfort, and anxiety/depression. Each dimension can be graded on 5 levels. Health 
states are defined by the combination of the leveled responses to the 5 dimensions, 
generating 243 health states to which unconsciousness and death are added. The sixth item 
is a visual analogue scale for overall health. The 5-item index score is transformed into a 
health utility score between 0, “Worst health state,” and 1, “Best health state.” For this 
study, health utilities (at baseline, 6, 12, 18 and 24 months) for each patient will be 
combined with overall survival to calculate quality-adjusted survival. 
EORTC QLQ-C30: The EORTC QLQ-C30 is one of the most commonly-used QOL 
instruments in cancer patients, and includes 30 questions broadly applicable to all cancer 
patients. This instrument is chosen because it has been used in multiple NCTN trials. The 
instrument assesses 5 functional domains (physical, role, cognitive, emotional, social) and 
8 symptoms (fatigue, pain, nausea/vomiting, dyspnea, loss of appetite, insomnia, 
constipation, diarrhea), together with financial problems and global quality of life.  
PROMIS Fatigue: Because fatigue is an important aspect of immunotherapy and there is 
only a limited assessment of fatigue in EORTC QLQ-C30, PROMIS Fatigue (27) is added 
to study this outcome in more detail. The PROMIS fatigue measures 4 items. An initial 
item pool of 58 fatigue experience and 54 fatigue impact items were developed. The 
psychometric properties of these items were evaluated in a sample of 450 individuals from 
the general US population using classical test theory indices, monotonicity, and scalability. 
Of note, the 4 questions of PROMIS Fatigue are included in the PROMIS-29 questionnaire 
(see below). 
PROMIS-29+2 v2.1 (PRORr): The PROMIS-29+2 v2.1 includes 29 items from the 
PROMIS-29 v2.1 plus 2 Cognitive Function Abilities items to enable calculation of a 
preference score (PROMIS--Preference, PROPr). The preference scores summarize health-
related quality of life on a 0 (as bad as dead) to 1 (perfect or ideal health) scale based on 
PROMIS T-scores for Cognitive Function Abilities, Depression, Fatigue, Pain 
Interference, Physical Function, Sleep Disturbance, and Ability to Participate in Social 
Roles and Activities (28). The PROMIS-29+2 v2.1 items were selected from PROMIS 
item banks and calibrated using item response theory. The PROMIS item banks and short 
forms demonstrate high reliability and validity in the general population and in populations 
with chronic health conditions (29). 
Time points of QOL assessment: All instruments will be assessed at baseline (within 21 
days of registration), 6, 12, 18 and 24 months. QOL assessment should continue after 
disease progression. 
Health Economics 
Resource Utilization: Resource utilization analysis will take a 2-year horizon. To permit 
maximum generalizability, data collection will focus on resource utilization rather than 
costs. Information about treatment delivery, complication management, and post-trial 
treatments will be captured for all patients through medical record review as part of the 
clinical trial. Because this study will evaluate the impact of discontinuing immune 
checkpoint inhibitor therapy among responding patients, knowledge of post-trial therapy 
is crucial for interpretation of both clinical and economic outcomes. Data will be obtained 
from the following sources:  
Resource utilization 
Form 
Immunotherapy dose administered, number of 
cycles 
Treatment 
form 
(on-study) 
Completed by CRA 

 
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Post-study anti-neoplastic treatments 
Post-study treatment form 
List anti-neoplastic treatments 
including cytotoxic, biologic and 
immunotherapy 
treatments 
received from the end of study 
treatment to 24 months or death. 
List each drug with stop and start 
date. If a drug is discontinued for 
>=2 months and then restarted, 
then indicate STOP on date of 
last administration and then 
include a new start. Doses and 
cycles not required. 
Clinic assessments, ER visits, hospitalizations and 
length of stay, radiation treatment and ICU days  
Participant Health Care Resource 
Utilization Form, completed by 
the patient at the same time as the 
QOL forms 
Data also collected by CRA at 12 
and 
24 
months 
post-
randomization to capture health 
resource utilization based on 
medical record review 
Survival 
Follow-up form 
Completed by the CRA 
Utilities 
EQ-5D 
Completed by the patient at the 
same time as QOL forms 
Financial toxicity 
COST-FACIT 
Completed by the patient at the 
same time as the QOL forms 
 
Cost estimates will be obtained by applying standard 2020 Medicare reimbursement rates 
to each item of resource utilization. Economic results will be presented in a disaggregated 
fashion, i.e., cost = resource utilization x unit cost, where the units of resource use (e.g., 
number of hospital days) for each resource will be multiplied by the appropriate cost 
multiplier and summed for each arm of the study. This allows the potential for re-analysis 
using any cost inputs. Utilities will be captured prospectively on all patients participating 
in the QOL evaluation with the EQ-5D.  
Survival: Survival is the primary endpoint of the clinical trial. Any survival differences 
found in the trial will be measured as the area between the survival curves for the purposes 
of the economic evaluation. 
Economic analysis will be performed at the completion of the phase 3 portion of the study 
in accordance with the methodological guidelines set forth by the Second Panel on Cost 
Effectiveness in Health and Medicine (30). If the non-inferiority OS margin is met, 

 
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incremental cost-effectiveness and cost-utility ratios will be calculated. If non-inferiority 
margin is not met, a cost comparison analysis will be conducted. Financial toxicity 
comparisons will be conducted regardless of the primary OS results. 
To capture resource utilization and financial toxicity directly from patients, at each time 
point that QOL is evaluated, patients will also be asked about major health care episodes 
that are known cost drivers. Patients will be asked about the number of clinic visits to 
emergency departments, the number of hospitalizations and the duration of each 
hospitalization including ICU days. Forms will solicit information about other acute cost 
drivers including stays in skilled nursing facilities, rehabilitations centers and major 
operations. Patients will be asked to provide categorical estimates of their direct medical 
costs for prescription drugs and for transportation. They will also be asked about the 
financial impact of their medical care using the COST-FACIT questionnaire, a patient-
reported outcome measure that describes the financial distress experiences by cancer 
patients (31, 32). 
At 12 months (or at death, whichever is earlier) and 24 months (or death, whichever is 
earlier), the study data coordinator will complete a medical record review to capture 
resource utilization for the post-randomization study period.   
14.1.4 Statistical Methods 
QOL 
All questionnaires will be scored according to published scoring algorithms, including 
recommendations for addressing missing items within a scale. An intent-to-treat approach 
will be used for all analyses. To evaluate between-arm differences in quality-adjusted 
survival, each patient’s quality-adjusted survival will be calculated using the area under the 
curve approach (without discounting) based on health utilities derived from the EQ-5D-
5Lat baseline, 6, 12, 18 and 24 months. When calculating quality-adjusted survival, the 
patient’s health utility from an earlier assessment will be assumed to be maintained until 
the patient’s next assessment, censoring date, or death (whichever occurs first). Quality-
adjusted survival will be compared across arms using a two-sided log-rank test with a 
nominal significance level of α = .05. All data through the follow-up of the earliest 
censored patient will be used in the quality-adjusted survival analysis. A population-based 
approach will also be used such that the area under the curve of a quality-adjusted survival 
curve (i.e., mean health utility multiplied by the proportion of patients surviving based on 
Kaplan-Meier estimates) is the mean quality-adjusted survival for the population. Mean 
quality-adjusted survival will be compared between arms using a bootstrap approach (33). 
As an exploratory analysis, between-arm differences in quality-adjusted survival will be 
evaluated while calculating each patient’s quality-adjusted survival based on health utilities 
derived from the PROPr (rather than the EQ-5D-5L). The same procedures described above 
will be used, and results will be compared when deriving patients’ health utilities from the 
EQ-5D-5L versus the PROPr. These comparisons (between the EQ-5D-5L and PROPr) 
will be used to validate the PROPr and to inform future methodological decisions in the 
cooperative group setting. To our knowledge, the PROPr has not been implemented and 
validated in a large phase III trial like A031901. 
To evaluate between-arm mean differences in patient-reported quality of life at each time 
point, a mixed model will be estimated for patient-reported quality of life as assessed by 
the EORTC QLQ-C30 over the entire study period. The mixed model will include a fixed 
intercept; fixed effect for time, arm, and arm by time interaction; and residual covariance 
matrix based on the observed covariances. An unstructured residual covariance matrix will 

 
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initially be used, though alternative structures will be investigated with final selection 
based on convergence of the mixed model and minimization of the Akaike information 
criterion. The stratification factor used in the randomization as well as baseline patient 
characteristics and prognostic factors may be included in the mixed model as covariates. 
Estimates from the mixed model will be used to construct a 95% confidence interval for 
the mean difference in patient-reported quality of life between arms at each time point. 
Contrasts estimated via the mixed model will involve a two-sided t-test with a nominal 
significance level of α = .05. There will be no adjustment for multiple testing for the 
secondary QOL objectives.  
To evaluate between-arm differences in patient-reported quality of life at each time point, 
a mixed model will be estimated for patient-reported quality of life as assessed by the 
EORTC QLQ-C30 over the entire study period. The mixed model will include a fixed 
intercept; fixed effect for time, arm, and arm by time interaction; and residual covariance 
matrix based on the observed covariances. An unstructured residual covariance matrix will 
initially be used, though alternative structures will be investigated with final selection 
based on convergence of the mixed model and minimization of the Akaike information 
criterion. The stratification factor used in the randomization as well as baseline patient 
characteristics and prognostic factors may be included in the mixed model as covariates. 
Estimates from the mixed model will be used to construct a 95% confidence interval for 
the mean difference in patient-reported quality of life between arms at each time point. 
Contrasts estimated via the mixed model will involve a two-sided t-test with a nominal 
significance level of α = .05.  
The proportion of, and reported reasons for, missing data will be presented by time point 
and arm. Correlation analysis and logistic regression analysis will be used to examine 
whether baseline patient characteristics and prognostic factors predict missingness. A 
sensitivity analysis will be conducted to assess the robustness of the results across various 
assumptions about the missing data. 
Power: To evaluate between-arm differences in quality-adjusted survival, 829 evaluable 
patients from among the 1,037 randomized patients on the parent protocol (i.e., allowing 
10% of patients to decline consent and 10% of patients to miss booklets due to reasons 
other than death) provide 83% power to detect a difference in quality-adjusted survival 
between arms based on a two-sided log-rank test, nominal significance level of α = .05, 
and median quality-adjusted survival of 15.6 and 19.2 months in Arms A and B, 
respectively. Median quality-adjusted survival for Arms A and B were approximated by 
multiplying median overall survival (i.e., 24 months based on the 24-month overall survival 
rate of 50%) by health utilities of .65 and .80, respectively (i.e., 24 months × .65 = 15.6 
months in Arm A, 24 months × .80 = 19.2 months in Arm B). 
To evaluate between-arm differences in patient-reported quality of life at each time point, 
the number of evaluable patients ranges from 310 to 663 when allowing 10% of patients to 
decline consent, 10% of patients to miss booklets due to reasons other than death, and 16% 
(at 6 months) to 50% (at 24 months) of patients to not survive based on a 24-month overall 
survival rate of 50% in Arms A and B. Power ranges from 62% (at 24 months) to 91% (at 
6 months) to detect a mean difference in patient-reported quality of life between arms based 
on a two-sided t-test estimated via a mixed model with 5 assessments per patient, nominal 
significance level of α = .05, intraclass correlation of .50, and population standardized 
mean difference of 0.20 (i.e., a small effect size based on Cohen’s conventions) (34). For 
a population standardized mean difference of 0.35 (i.e., between a small and moderate 
effect size based on Cohen’s conventions) (34), power exceeds 95% at all time points (i.e., 
6, 12, 18, or 24 months) to detect a mean difference in patient-reported quality of life 

 
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between arms. The same power calculations apply when evaluating between-arm 
differences in patient-reported fatigue at each time point. 
Health Economics 
Resource utilization analysis will take a 2-year horizon and will evaluate major cost drivers 
using structured case report forms. Major cost drivers will include the following categories: 
immunotherapy drug cost, cytotoxic chemotherapy or targeted therapy drug costs, surgical 
procedures, radiation treatments, ED visits, hospital days, ICU days, outpatient clinic visits, 
other prescription costs, and transportation costs. Cost data will be derived from both 
medical record review, much of which overlaps with the review needed to ascertain adverse 
events, and patient reporting, to capture events occurring at the study site as well as events 
occurring elsewhere; in the event of discrepancies in cost estimated between medical 
record and patient reporting, the higher of the two estimates will be used. Unit costs will 
be assigned based on Medicare reimbursement rates for beneficiaries in fee for service 
programs for the year 2020. Costs will be standardized to a single year using the medical 
component of the Consumer Price Index. Economic analysis will be performed at the 
completion of the phase 3 portion of the study in accordance with the methodological 
guidelines set forth by the Second Panel on Cost Effectiveness in Health and Medicine 
(30). If the non-inferiority OS margin is met, incremental cost-effectiveness and cost-utility 
ratios will be calculated. If non-inferiority margin is not met, a cost comparison analysis 
will be conducted. If cost-utility analyses are calculated they will be performed as follows: 
1. Compare the Costs between Arm A and Arm B: 
Sum up for Arm A and for Am B: Mean costs of on-study immunotherapy+ mean costs of 
post-study anti-neoplastic therapy+mean costs of on-study care+mean costs of post-study 
care + mean on-study prescription drug costs. All estimates will be rounded to the nearest 
$10. Cost will then be defined as the difference in the sum of mean costs between the two 
arms ($CostsA-$CostsB=$CostsA-B). 
2. Compare Life Years between Arm A and B: The area under the survival curves at 24 
months for arm A versus B will be used to estimate the difference in life expectancy. (LYA-
LYB=LYA-B). 
3. Estimate the Quality Adjusted Life Year difference between Arm A and Arm B by 
multiplying the EQ5D utility weights for Arm A and B respectively by the LYs for each 
arm. 
QALYA-QALYB=QALYA-B 
4. Estimate the Incremental Cost-Effectiveness Ratio using the formula: 
$CostsA-B /LYA-B 
5. Estimate the Incremental Cost-Utility Ratio using the formula: 
$CostsA-B /QALYA-B 
Perform Sensitivity Analyses: Estimates of each parameter, including cost, utility, and life 
year estimates will be varied (+/- 1 standard deviation above and below the mean), and the 
impact of these changes on the incremental cost-effectiveness ratio and incremental cost-
utility ratio will be calculated.  
The intervention will be considered cost-effective for at a willingness-to-pay threshold of 
$100,000 per (quality-adjusted) life-year gained. 

 
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6. Compare financial toxicity between Arm A and B (This analysis will be performed 
regardless of the primary OS results.) 
To measure patient-reported financial toxicity, the FACIT-COST will be administered at 
registration and at 6, 12, 18, and 24 months.  It will be scored according to its published 
scoring algorithm, including recommendations for addressing missing items within the 
scale. To evaluate between-arm mean differences in patient-reported financial toxicity at 
each time point, a mixed model will be estimated for patient-reported financial toxicity as 
assessed by the FACIT-COST over the entire study period. The mixed model will include 
a fixed intercept; fixed effect for time, arm, and arm by time interaction; and residual 
covariance matrix based on the observed covariances. An unstructured residual covariance 
matrix will initially be used, though alternative structures will be investigated with final 
selection based on convergence of the mixed model and minimization of the Akaike 
information criterion. The stratification factor used in the randomization as well as baseline 
patient characteristics and prognostic factors may be included in the mixed model as 
covariates. Estimates from the mixed model will be used to construct a 95% confidence 
interval for the mean difference in patient-reported financial toxicity between arms at each 
time point. Contrasts estimated via the mixed model will involve a two-sided t-test with a 
nominal significance level of α = .05. 
Power: To evaluate between-arm mean differences in patient-reported financial toxicity at 
each time point, the number of evaluable patients ranges from 310 to 663 when allowing 
10% of patients to decline consent, 10% of patients to miss booklets due to reasons other 
than death, and 16% (at 6 months) to 50% (at 24 months) of patients to not survive based 
on a 24-month overall survival rate of 50% in Arms A and B. Power ranges from 62% (at 
24 months) to 91% (at 6 months) to detect a mean difference in patient-reported financial 
toxicity between arms based on a two-sided t-test estimated via a mixed model with 5 
assessments per patient, nominal significance level of α = .05, intraclass correlation of .50, 
and population standardized mean difference of 0.20 (i.e., a small effect size based on 
Cohen’s conventions) (34). For a population standardized mean difference of 0.35 (i.e., 
between a small and moderate effect size based on Cohen’s conventions) (34), power 
exceeds 95% at all time points (i.e., 6, 12, 18, or 24 months) to detect a mean difference in 
patient-reported financial toxicity between arms. 
14.2 
Correlative Science (Alliance A031901-ST1) 
The following correlative study outline is provided to justify biospecimen collection. 
Investigators will submit correlative studies complete protocols including the correlative study 
objectives, endpoints, sample size, statistical analysis plan including power calculations, etc., 
once the clinical trial has completed at least 50% accrual and the correlative study appears 
feasible. 
14.2.1 DNA-based biomarkers from tissue 
DNA will be extracted from archival tumor specimens for whole exome sequencing 
(WES).  A number of genetic and molecular features in pre-treatment biopsy specimens 
have been associated with responses to checkpoint inhibitor-based immunotherapy (35), 
including high tumor mutational burden (TMB) and neoantigen load. In addition, high 
TMB with low burden of copy number loss (36) (and particularly intact PTEN (36, 37) has 
been associated with response to immunotherapy.  The association between these baseline 
genomic features to clinical outcomes will be evaluated, including attaining CR versus less 
than CR (e.g., PR or SD) at study entry, time to progression after treatment discontinuation, 
and recaptured response after treatment rechallenge. 

 
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14.2.2 RNA-based biomarkers from tissue 
A number of studies have shown that gene expression profiles from tumor tissue are 
associated with response to immunotherapeutics (38-41). We will perform RNA 
sequencing from archival tumor specimens and evaluate the association between published 
gene expression signatures including T-cell inflamed gene expression profile, with clinical 
outcomes. We will also explore the association between expression of other 
genes/pathways with clinical outcomes.   
14.2.3 PD-L1 immunohistochemistry 
In urothelial carcinoma, PD-1/L1 inhibitor monotherapy have demonstrated superior 
clinical efficacy in PD-L1+ tumors compared to PD-L1- tumors in platinum-refractory 
mUC patients. While OS benefit with pembrolizumab was observed for both PD-L1 high 
and PD-L1 low tumors compared to investigators choice of chemotherapy, the degree of 
benefit was greater in patients with PD-L1 high tumors on subgroup analysis (8). In the 
first-line setting, interim OS analysis of IMvigor130 demonstrated that in the PD-L1 IC0/1 
subgroup, survival favored platinum-containing chemotherapy earlier but atezolizumab 
later. Conversely, in the PD-L1 IC2/3 subgroup, survival favored atezolizumab. These 
results indicate that PD-L1 expression is associated with increased benefit from immune 
checkpoint blockade (14). We plan to evaluate the correlation between PD-L1 expression 
in archival tumor specimens with clinical outcomes, including PFS and OS in both arms. 
In Arm B, PD-L1 expression will also be associated with duration of response after 
treatment discontinuation, and response rate after treatment rechallenge. 
14.2.4 Characterization of Immune Infiltrate by Immunohistochemistry 
The dynamic nature of anti-tumor immune response and intricacy of immune regulation 
indicate that evaluation of multiple components within the tumor microenvironment is 
likely to more accurately portray the complete tumor microenvironment and better predict 
clinical outcomes. We plan to characterize the immune microenvironment through 
multiplex immunohistochemistry evaluating PD-L1 expression and immune cell subsets, 
including CD3, CD8 and FoxP3 T cells.  Density of pre-treatment CD8+ immune infiltrate 
(43) and CD8+ T cell to CD3+/FoxP3+ regulatory T-cell ratio have been associated with 
favorable outcomes with immunotherapy (44), and we will assess the association of these 
features with clinical outcomes in our study.   
14.2.5 Cell-free methylated DNA and circulating tumor DNA from Blood 
Cell-free methylated DNA immunoprecipitation and high-throughput sequencing 
(cfMeDIP-Seq) is a robust and sensitive methodology for profiling of methylation patterns 
in cell-free DNA (cfDNA). Recently, cancer (and tissue) specific epigenetic alterations 
have been identified in a sensitive and accurate manner, including in UC (45). This 
technology provides the opportunity to detect minimal residual disease (MRD) after 
treatment, as well as early detection of disease progression.  
Circulating tumor DNA (ctDNA) can be differentiated from germ-line cell-free DNA 
through tumor-specific somatic genomic alterations and can be collected non-invasively 
from a single blood draw. ctDNA has potential to be a biomarker of tumor burden in 
multiple solid tumor types. The Phase 3 IMvigor011 trial evaluating adjuvant atezolizumab 
in patients with muscle-invasive bladder cancer failed to meet its primary endpoint; 
however, prospective ctDNA analysis showed that patients with ctDNA-positive disease 
had significantly improved clinical outcomes with adjuvant atezolizumab compared to 
observation (45). Furthermore, a phase 2 study evaluating patients with advanced solid 

 
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tumors treated with pembrolizumab showed that baseline ctDNA level as well as changes 
in ctDNA level with treatment correlates with PFS and OS after immunotherapy (46).  
In this study, tumor-specific cfMeDNA and ctDNA will be evaluated as potential indicator 
of MRD. Detection of cfMeDNA and ctDNA at baseline will be correlated with treatment-
free interval after treatment discontinuation, and conversion of undetectable to detectable 
cfMeDNA to ctDNA, as well as quantification of ctDNA, will be evaluated as an early 
indicator of disease progression prior to radiographic progression. Tissue-specific 
cfMeDNA profiles will be evaluated as an early indication of immune-related organ 
toxicity. 
14.2.6 Statistical Considerations 
Associations between tumor markers from the primary tumor and clinical outcomes will 
be evaluated via logistic regression for the tumor response outcome, i.e. attaining CR 
versus less than CR (e.g., PR or SD). Association between markers and time to event 
outcomes will be evaluated with Cox proportional hazards models if the outcome is a time-
to-event endpoint (e.g. PFS, OS, TFI). When appropriate, the models will include treatment 
arm as a covariable (e.g. when the analysis is using all patients). The treatment variable 
will not be used in analyses that uses Arm B patients only (e.g. TFI). The analysis of the 
association of changes in cfMeDNA and PFS (Arm A and B) and TFI (Arm B only) will 
only include patients who have a baseline cfMeDNA value and at least one follow-up 
cfMeDNA value obtained prior to the study visit where a progression event was 
determined. This analysis will be done using a multivariable Cox model. The model will 
include the baseline cfMeDNA value as well as a time-dependent variable that indicates 
the difference in cfMeDNA from baseline at the follow-up visit. For example, if the 
baseline value was 10 and a follow-up value was 15, the change from baseline variable 
would be 5. This analysis will be done separately for Arm A and B for PFS, and for Arm 
B only for TFI and repeated for all patients. The Cox model would contain the treatment 
arm and would also contain the treatment-arm by cfMeDNA change value interaction term.  
 
 

 
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3. Lu L, Xu X, Zhang B, et al. Combined PD-1 blockade and GITR triggering induce a potent 
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4. Guo Z, Wang X, Cheng D, et al. PD-1 blockade and OX40 triggering synergistically protects 
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6. Park JH, Riviere I, Gonen M, et al. Long-Term Follow-up of CD19 CAR Therapy in Acute 
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urothelial carcinoma (IMvigor 130): a multicentre, randomized, placebo-controlled phase 3 trial. 
Lancet 2020; 395:1547-1557. 
15. Alva A, Csoszi T, Ozguroglu M, et al. LBA23 - Pembrolizumab (P) combined with 
chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): 
KEYNOTE-361. Annals of Oncology (2020) 31 (suppl_4): S1142-S1215 
16. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic 
urothelial carcinoma. N Engl J Med 2020; 383:1218-1230. 
17. Hodi FS, Postow MA, Chesney JA, et al. Overall survival in patients with advanced melanoma 
(MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to toxicity 
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18. Robert C, Ribas A, Hamid O, et al. Three-year overall survival for patients with advanced 
melanoma treated with pembrolizumab in KEYNOTE-001. J Clin Oncol 34, 2016 (suppl; abstr 
9503). 
19. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced 
Melanoma.N Engl J Med 2015; 372:2521-32. 
20. Robert C, Long GV, Schachter J, et al. Schachter J, et al. Long-term outcomes in patients (pts) 
with ipilimumab (ipi)-naive advanced melanoma in the phase 3 KEYNOTE-006 study who 
completed pembrolizumab (pembro) treatment. J Clin Oncol 35, 2017 (suppl; abstr 9504). 
21. McKay RR, Martini D, Moreira RB, et al. Outcomes of PD-1/PD-L1 responders who discontinue 
therapy for immune-related adverse events (irAEs): Results of a cohort of patients (pts) with 
metastatic renal cell carcinoma (mRCC). J Clin Oncol 35, 2017 (suppl 6S; abstract 467). 
22. Myint Z, Arays R, Raajasekar A, et al. Long-term outcomes in patients after discontinuation of 
PD1/PDL1 inhibitors. J Clin Oncol 36, 2018 (suppl; abstr e15086). 
23. Waterhouse DM, Garon EB, Chandler J, et al. Continuous versus 1-year fixed-duration 
nivolumab in previously treated advanced non-small cell lung cancer: CheckMate 153. J Clin 
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24. Eisenhauer EA1, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
25. Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol 2017; 18:e143-e152. 
26. Korn EL, Freidlin B. Interim monitoring for non-inferiority trials: minimizing patient exposure to 
inferior therapies. Ann Oncol 2018. 29:573-577. 
27. Cella D, Lai J, Jensen SE, et al. PROMIS Fatigue Item Bank Had Clinical Validity Across 
Diverse Chronic Conditions. J Clin Epidemiol 2016; 73:128-34.  
28. Dewitt B, Feeny D, Fischhoff B, et al. Estimation of a preference-based summary score for the 
Patient-Reported Outcomes Measurement Information System: The PROMIS-Preference 
(PROPr) Scoring System. Med Decis Making. 2018; 38:683-698. 
29. Cella D, Riley W, Stone A, et al, PROMIS Cooperative Group. The Patient-Reported Outcomes 
Measurement Information System (PROMIS) developed and tested its first wave of adult self-
reported health outcome item banks: 2005-2008. J Clin Epidemiol. 2010; 63:1179-1194. 
30. Sanders GD, Neurmann PJ, Basu A, et al. Recommendations for Conduct, Methodological 
Practices, and Reporting of Cost-Effectiveness Analyses: Second Panel on Cost-Effectiveness in 
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31. De Souza JA, Yap BJ, Hlubocky FJ. The development of a financial toxicity patient-reported 
outcome in cancer: the COST measure. Cancer. 2014;120:3245-53. 
32. De Souza JA, Yap BJ, Wroblewski K et al. Measuring financial toxicity as a clinically relevant 
patient-reported outcome: the validation of the Comprehensive Score for Financial Toxicity 
(COST). Cancer. 2017;123:476-84. 
33. Billingham LJ, Abrams KR, Jones DR. Methods for the analysis of quality-of-life and survival 
data in health technology assessment. Health Technol Assess. 1999;3(10). 
34. Cohen J. Statistical Power Analysis for the Behavorial Science. 2nd ed. Hillsdale, NJ: Lawerence 
Erlbaum Associates; 1988.  
35. Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based 
immunotherapy. Lancet Oncol. 2016;17:e542-e551. 
36. Roh W, Chen PL, Reuben A, et al. Integrated molecular analysis of tumor biopsies on sequential 
CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci Transl Med. 
2017;9(379). 
37. Peng W, Chen JQ, Liu C, et al. Loss of PTEN Promotes Resistance to T Cell-Mediated 
Immunotherapy. Cancer Discov. 2016;6:202-16. 
38. Grivas P, Castellano DE, O’Donnell PH, et al. Association between stromal/TGF-β/EMT gene 
expression signature and response to pembrolizumab monotherapy in cisplatin-ineligible patients 

 
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with locally advanced (unresectable) or metastatic urothelial carcinoma. J Clin Oncol 37, 2019 
(suppl 7S; abstr 433). 
39. Powels T, Loriot Y, Ravaud A, et al. Atezolizumab (atezo) vs. chemotherapy (chemo) in 
platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): Immune 
biomarkers, tumor mutational burden (TMB), and clinical outcomes from the phase III 
IMvigor211 study. J Clin Oncol 36, 2018 (suppl 6S; abstr 409). 
40. Ayers M, Lunceford J, Nebozhn M, et al. IFN-γ-related mRNA profile predicts clinical response 
to PD-1 blockade. J Clin Invest. 2017;127:2930-2940. 
41. Chen PL, Roh W, Reuben A, et al. Analysis of Immune Signatures in Longitudinal Tumor 
Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune 
Checkpoint Blockade. Cancer Discov. 2016;6:827-37. 
42. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 Blockade Induces Responses by Inhibiting 
Adaptive Immune Resistance . Nature 2014; 515:568-71. 
43. Feng Z, Puri S, Moudgil T, et al. Multispectral imaging of formalin-fixed tissue predicts ability to 
generate tumor-infiltrating lymphocytes from melanoma. J Immunother Cancer. 2015;3:47. 
44. Nuzzo PV, Spisak S, Solymosi N et al. Circulating cell-free methylated DNA (cfmeDNA) to 
predict postoperative recurrence in patients with muscle-invasive bladder cancer (MIBC). J Clin 
Oncol 37, 2019 (suppl 7S; abstr 454). 
45. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial 
carcinoma. Nature 2021; 595:432-437. 
46. Bratman SV, Yang SYC, lafolla MAJ, et al. Personalized circulating tumor DNA analysis as a 
predictive biomarker in solid tumor patients treated with pembrolizumab. Nat Cancer 2020;1:873-
881. 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX I 
REGISTRATION FATIGUE/UNISCALE ASSESSMENT 
 
At patient registration, this form is to be administered by a nurse/CRP, completed by the patient, and 
entered into Medidata Rave at the time of registration. 
 
If needed, this appendix can be adapted to use as a source document.  A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
 
 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Fatigue 
 
 
 
 
 
 
 
Fatigue as bad as it can be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as it can be 
 
 
 
 
 
 
 
As good as it can be 
 
 

 
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APPENDIX II: QOL AND HEALTH ECONOMICS FORMS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health Questionnaire 
 
 
English version for the USA 
 
 
 

 
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Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems walking 
❑ 
I have slight problems walking 
❑ 
I have moderate problems walking 
❑ 
I have severe problems walking 
❑ 
I am unable to walk 
❑ 
SELF-CARE 
 
I have no problems washing or dressing myself 
❑ 
I have slight problems washing or dressing myself 
❑ 
I have moderate problems washing or dressing myself 
❑ 
I have severe problems washing or dressing myself 
❑ 
I am unable to wash or dress myself 
❑ 
USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities) 
 
I have no problems doing my usual activities 
❑ 
I have slight problems doing my usual activities 
❑ 
I have moderate problems doing my usual activities 
❑ 
I have severe problems doing my usual activities 
❑ 
I am unable to do my usual activities 
❑ 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
❑ 
I have slight pain or discomfort 
❑ 
I have moderate pain or discomfort 
❑ 
I have severe pain or discomfort 
❑ 
I have extreme pain or discomfort 
❑ 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
❑ 
I am slightly anxious or depressed 
❑ 
I am moderately anxious or depressed 
❑ 

 
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I am severely anxious or depressed 
❑ 
I am extremely anxious or depressed 
❑ 
 
 

 
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The worst health 
you can imagine 
 
 
 
 
We would like to know how good or bad your health is TODAY. 
This scale is numbered from 0 to 100. 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
Mark an X on the scale to indicate how your health is TODAY. 
Now, please write the number you marked on the scale in the box below. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The best health you 
can imagine 
YOUR HEALTH TODAY = 
10
0
20
30
40
50
60
80
70
90
100 
5
15
25
35
45
55
75
65
85
95

 
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EORTC QLQ-C30 (version 3) 
We are interested in some things about you and your health. Please answer all of the questions yourself by 
circling the number that best applies to you. There are no "right" or "wrong" answers. The information 
that you provide will remain strictly confidential. 
 
Please fill in your initials: 
 
Your birthdate (Day, Month, Year): 
 
Today's date (Day, Month, Year): 
31 
 
1. 
Do you have any trouble doing strenuous activities, 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 

 
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14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the  following  questions  please  circle  the  number  between   1  and  
7  that   best applies to you 
29. How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 

 
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1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
 
 
 
 
 
 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
 
 

 
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Healthcare Utilization Form 
 
Dear Study Participant: 
We want to understand what resources patients treated on this clinical trial need. We know that 
some of your care may be at the center where you receive your treatments on this clinical trial. 
You may also experience the need for treatment elsewhere. Please think back over the past 6 
months about health care services that you have needed. Consider services you have received no 
matter what hospital or clinic you went to. You do not need exact dates. Your best estimates 
are fine. You can ask a family member or caregiver to help you complete this form. 
Thinking back over the past 6 months, since __________ (date of last assessment) , please 
complete the following form: 
 
1. Did you require any overnight stays in a 
hospital? 
❑ NO.   
      If NO: Skip to question #3. 
 
❑ YES. 
       If YES: How many days did you spend in  
       the hospital?    
 
       ________ 
2. Did you spend any time in the Intensive 
Care Unit (ICU)? 
❑ NO.   
      If NO: Skip to question #3. 
 
❑ YES. 
       If YES: How many days did you spend in  
       the ICU? 
        
       _________ 
3. Did you have any operations? 
❑ NO.   
      
 
❑ YES. 
       If YES: Which operation(s)? 
        
       ____________________ 
4. Did you have any visits to an emergency 
department/acute or urgent care center? 
❑ NO.   
      
 
❑ YES. 
       If YES: How many visits did you make to  
       an emergency department/acute or urgent  
       care center? 

 
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       ___________ 
5. Did you spend any days in a 
rehabilitation or skilled nursing facility? ❑ NO.   
      
 
❑ YES. 
       If YES: How many days did you spend in  
       a rehabilitation or skilled nursing facility?  
        
       ___________ 
6. Did you have any outpatient medical 
procedures include cystoscopy, stents, 
insertion of tubes or drains, other than 
any listed under question #3 above? 
❑ NO.   
      
 
❑ YES. 
       If YES: Which procedure(s) did you have?  
        
       _____________________ 
7. Did you have any radiation treatment? 
❑ NO.   
      
 
❑ YES. 
       If YES: How many days of radiation  
       treatment did you have? 
        
       ___________ 
8. How many outpatient visits did you 
make to see your cancer doctors 
(surgeons, medical oncologists, or 
radiation oncologists) and their practice 
assistants?  
 
 
 
_________ 
9. How many outpatient visits did you 
make to see other kinds of doctors (such 
as primary care physicians, pain or 
palliative care physicians, or non-cancer 
related specialists)? 
 
 
 
 
 
_________ 
10. About how much did you spend paying 
out-of-pocket for your outpatient 
prescription medications? 
❑ $0 
 
❑ < $200 
 
❑ $200 - $499 
 
❑ $500 - $999 

 
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❑ $1000 - $5000 
 
❑ $5000 - $10,000 
 
❑ > $10,000 
 
11. About how much did you spend paying 
for transportation to travel back and 
forth to get your cancer treatments? 
Include estimates for transportation 
including gas, parking and any hotel 
stays you may have needed 
❑ $0 
 
❑ < $200 
 
❑ $200 - $499 
 
❑ $500 - $999 
 
❑ $1000 - $5000 
 
❑ $5000 - $10,000 
 
❑ > $10,000 
 
 
 
 

 
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COST-FACIT VERSION 2 
 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
FT1 
I know that I have enough money in savings, retirement, 
or assets to cover the costs of my treatment
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
FT2 
My out-of-pocket medical expenses are more than I 
thought they would be
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
FT3 
I worry about the financial problems I will have in the 
future as a result of my illness or treatment
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
FT4 
I feel I have no choice about the amount of money I 
spend on care
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
FT5 
I am frustrated that I cannot work or contribute as much 
as I usually do
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
FT6 
I am satisfied with my current financial situation
 .......................................................................................... 
0 
1 
2 
3 
4 
FT7 
I am able to meet my monthly expenses
 .......................................................................................... 
0 
1 
2 
3 
4 
FT8 
I feel financially stressed
 .......................................................................................... 
0 
1 
2 
3 
4 

 
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FT9 
I am concerned about keeping my job and income, 
including work at home
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
FT10 
My cancer or treatment has reduced my satisfaction with 
my present financial situation
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
FT11 
I feel in control of my financial situation
 .......................................................................................... 
0 
1 
2 
3 
4 
FT12 
My illness has been a financial hardship to my family 
and me
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
English (Universal) 
26 September 2017 
Copyright 2014, FACIT and The University of Chicago 
 

 
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APPENDIX III:  PATIENT CLINICAL TRIAL WALLET CARD 
 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of your 
healthcare providers and keep 
it with you in case you go to 
the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:        
Study Drug(S):        
 
 
 
 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov