Clinical trial NCT03527264
Conditions: Cervical Cancer
Keywords: cervical cancer Stage IB Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IVA
Sponsor: Brown University
Start date: 2018-11-08; Completion date: 2020-11-13
Enrollment: 4 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of the investigational drug in combination with radiation to learn whether the drug(s) works in treating a specific disease. In this study, researchers are studying three treatment arms, each using standard chemotherapy, with the drug cisplatin and radiation and the drug Nivolumab. Each treatment Arm will test the addition of Nivolumab at a different time point

Detailed description:

Arms: arm 1: Nivolumab during Chemo/RT with whole pelvic RT arm 2: Nivolumab during Chemo/RT with extended field arm 3: Chemoradiation followed by Nivolumab Maintenance arm 4: Nivolumab during chemoradiation and then as maintenance
Interventions: intervention 1: Nivolumab induction intervention 2: Cisplatin intervention 3: Radiation intervention 4: Nivolumab with chemoradiation intervention 5: Nivolumab maintenance
Intervention descriptions: intervention 1: 2 doses Nivolumab 240mg IV intervention 2: 40 mg/m2 of cisplatin: Dosing on Days: 1, 8, 15, 22, 29, 36 beginning on day 1 of radiation therapy. intervention 3: Total dose of 45 Gy in 25 fractions at 180 cGy/fx

Whole pelvic or extended field intervention 4: Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered concomitantly during chemoradiation and beginning day 1 of Radiation. intervention 5: Nivolumab 480 mg IV every 4 weeks for 2 years

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
 
Page 1 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 2/6/18, 
2/7/18, 2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/6/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 4/23/18, 
5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment #4 
5/11/2020 
BrUOG 355 
BMS: CA209-9LX 
 
 
TITLE:  BrUOG 355: A Pilot Feasibility study incorporating Nivolumab to tailored radiation 
therapy with concomitant cisplatin in the treatment of patients with cervical cancer  
 
Coordinating Center: 
 
 
Brown University Oncology Group (BrUOG) 
 
*Principal Investigator (PI): 
Don S. Dizon, MD 
 
Lifespan Cancer Institute 
 
Rhode Island Hospital 
 
Don_Dizon@Brown.edu 
 
 
 
 
Agent(s): Nivolumab (supplied by Bristol-Myers Squibb) 
 
This study is financially supported by Bristol-Myers Squibb and in part by LifeCycle 
 
IND #: 139716 
Amendment #1 7/9/18 
Amendment # 2 12/12/18 
Amendment #3 4/6/2020 
Amendment #4 5/11/2020 
 
 
 
 
 
 
 
 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
2 
SCHEMA 
 
 
 
 
 
Cervical Cancer 
Stage IB2-IVA 
Biopsy proven 
Nivolumab 240mg IV 
Stratification by RT field 
Extended field RT 
planned 
Whole pelvic RT 
WEEK 1 
WEEK3 
Biopsy 
(Due 
Week 
4-5) 
Cohort 3: Chemoradiation + Nivolumab 
240mg IV (Q2W x3) followed by 
Nivolumab Maintenance 480mg IV 
(Q4W x 2 yrs) 
Cohort 2: Chemoradiation followed by 
Nivolumab Maintenance 480 mg IV 
(Q4W x 2yrs) 
Cohort 1A: RT* 
Cohort 1B: RT* 
Cohort 1: Chemoradiation + Nivolumab 
240mg IV (Q2WX3) 
RT*: See section 5.7 
Cohort 1a: EFRT RT +/- HDR/LDR brachytherapy. Parametrial boost is 
per MD discretion 
Cohort 1b: WPRT +/- HDR/LDR brachytherapy.  Parametrial boost is per 
MD discretion 
Cohort 2/3: EBRT RT +/- HDR/LDR brachytherapy or IMRT +/- 
HDR/LDR brachytherapy.  Parametrial boost is per MD discretion 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
3 
TABLE OF CONTENTS 
 
SCHEMA 
......................................................................................................................2 
1 
OBJECTIVES ..............................................................................................6 
1.1 
Study Design ............................................................................................................6 
1.2 
Primary Objectives...................................................................................................6 
1.3 
Secondary Objectives...............................................................................................6 
1.4 
Exploratory Objectives ............................................................................................6 
2 
BACKGROUND .........................................................................................6 
2.1 
Study Disease(s).......................................................................................................6 
2.2 
Nivolumab................................................................................................................7 
2.3 
Rationale ..................................................................................................................9 
2.4 
Correlative Studies Background ..............................................................................9 
3 
PARTICIPANT SELECTION (3.1, 3.2, 3.3 must all be confirmed) ..........9 
3.1 
Eligibility Criteria ....................................................................................................9 
3.2 
Exclusion Criteria ..................................................................................................10 
3.3 
Clinical Staging Evaluation: Each item below is required to be 
documented if done or not with reason by treating physician and all 
assessments/tests with results are required to be submitted with 
registration .............................................................................................................12 
3.4 
Inclusion of Women and Minorities ......................................................................12 
4 
REGISTRATION PROCEDURES ...........................................................12 
5 
TREATMENT PLAN ................................................................................13 
5.1 
BIOPSY: ................................................................................................................13 
5.2 
ALL PATIENT TREATMENT .............................................................................13 
5.3 
Nivolumab..............................................................................................................13 
5.4 
COHORT ASSIGNMENT: ...................................................................................14 
5.5 
Nivolumab administration .....................................................................................15 
5.6 
Definitive Chemoradiation Plan ............................................................................17 
5.7 
Radiation specifications .........................................................................................18 
6 
DOSING DELAYS/DOSE MODIFICATIONS Cisplatin/Radiation .......28 
6.1 
Prior to dosing with cisplatin any day, the following criteria must be met 
(please refer to Nivolumab requirements to dose as well if dosing on 
applicable day is for both drugs): ...........................................................................28 
6.2 
Radiation therapy: ..................................................................................................29 
7 
RESCUE MEDICATIONS AND SUPPORTIVE CARE .........................30 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
4 
7.1 
Supportive Care Guidelines ...................................................................................30 
7.2 
Criteria for Taking a Participant Off Protocol Therapy .........................................33 
7.3 
Duration of Follow Up ...........................................................................................34 
7.4 
General Concomitant Medication and Supportive Care Guidelines ......................34 
8 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ....35 
8.1 
Expected Toxicities ................................................................................................35 
8.2 
Adverse Event Characteristics ...............................................................................36 
8.3 
Definitions..............................................................................................................37 
8.4 
Monitoring of Adverse Events and Period of Observation ....................................39 
8.5 
BRUOG ADVERSE EVENT REPORTING REQUIREMENTS .........................39 
8.6 
Pregnancies ............................................................................................................40 
8.7 
Serious Adverse Event Reporting Procedures .......................................................40 
8.8 
Types of Report: Guidelines for sites to report:.....................................................42 
8.9 
BrUOG Responsibility Regarding Reporting: .......................................................43 
8.10  IND Annual ...............................................................................................................44 
8. 11 Adverse event updates/IND safety reports ...............................................................44 
9 
PHARMACEUTICAL INFORMATION ..................................................45 
9.1 
Nivolumab..............................................................................................................45 
10 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ................50 
11 
STUDY CALENDAR ...............................................................................51 
12 
MEASUREMENT OF EFFECT................................................................53 
12.1 
Antitumor Effect – Solid Tumors ..........................................................................53 
13 
REGULATORY CONSIDERATIONS .....................................................60 
13.1 
Protection of Human Subjects ...............................................................................60 
13.2 
Compliance with the Protocol and Protocol Revisions: ........................................60 
13.3 
Protocol amendments or changes in study conduct: ..............................................60 
14 
DATA MONITORING / QUALITY ASSURANCE/ RECORD 
RETENTION 
                                                                                                                    61 
14.1 
Good Clinical Practice: ..........................................................................................61 
14.2 
Patient Confidentiality: ..........................................................................................61 
14.3 
Protocol Compliance:.............................................................................................61 
14.4 
On-site Audits: .......................................................................................................62 
14.5 
Drug Accountability: .............................................................................................62 
14.6 
Premature Closure of the Study: ............................................................................62 
14.7 
Record Retention: ..................................................................................................62 
15 
DATA SAFETY AND MONITORING BOARDS ...................................63 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
5 
16 
STATISTICAL CONSIDERATIONS.......................................................63 
16.1 
Study Design/Endpoints.........................................................................................63 
16.2 
Sample Size, Accrual Rate and Study Duration ....................................................64 
16.3 
Stratification Factors ..............................................................................................64 
16.4 
Analysis of Primary Endpoints ..............................................................................65 
16.5 
Analysis of Secondary Endpoints ..........................................................................65 
16.6 
Reporting and Exclusions ......................................................................................65 
17 
PUBLICATION PLAN .............................................................................65 
18 
REFERENCES ..........................................................................................65 
APPENDIX A Eligibility CheCKLIST .........................................................................................67 
APPENDIX B: Agreement to Participate in a Research Study and Authorization for Use and 
Disclosure of Information ..............................................................................................................70 
APPENDIX C 
PERFORMANCE STATUS CRITERIA ..................................................88 
APPENDIX D 
I-O AE ALGORITHMS ............................................................................89 
 
 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
6 
1 
OBJECTIVES 
 
1.1 
Study Design 
1.1.1 This is a pilot study to assess the feasibility and toxicity of incorporating nivolumab 
with definitive chemoradiation for newly diagnosed cervical cancer.  
1.2 
Primary Objectives 
1.2.1 To determine the feasibility of the incorporation of nivolumab with weekly cisplatin 
and extended field (EFRT) or whole pelvic radiation therapy (WPRT) in women with 
cervical cancer.   
1.2.2 To determine the feasibility of the regimen through assessment of acute toxicities.  
1.2.3 Estimate the distribution of progression free survival for three years after study entry 
 
1.3 
Secondary Objectives 
1.3.1 To determine site of recurrence, loco-regional versus distant within three years of study 
entry  
1.3.2 To estimate the frequency of chronic toxicities experienced within three years after 
study entry. 
1.4 
 Exploratory Objectives  
1.4.1 To assess if there is an association between progression free survival, PD-L1 
expression, and serum Chitinase 3-like 1 (Chi3l1) in cervical cancer treated with 
definitive chemoradiation and nivolumab. 
2 
BACKGROUND 
 
2.1 
Study Disease(s) 
 
Women with locally advanced cervical cancer include those with FIGO stage IB2 (a clinically 
visible cervical lesion of 4cm or larger), stage II (invasion beyond the uterus but not to pelvic 
sidewall or lower third of the vagina), stage III (tumor extension to the pelvic sidewall and/or 
involvement of the lower third of the vagina, and/or associated with hydronephrosis or a 
nonfunctioning kidney), and stage IVA disease (tumor extension to the bladder, rectum, or 
beyond the true pelvis).1 For these patients, prognosis ranges greatly with five-year overall 
survival ranging from 89% (with stage IB disease) to 22% (with stage IVA disease) using 
contemporary standard therapies.2  


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
7 
 
For these women, seminal trials defined that standard treatment requires cisplatin-based 
chemoradiation (chemo-RT).3 Despite this, it is well recognized that prognosis following 
definitive chemo-RT remains very much dependent on disease stage and nodal involvement. In 
addition, the reality is that, despite the routine use of chemoradiation, many patients are not 
cured.  
 
The prognostic impact of stage and nodal disease was shown in one recent review of 139 patients 
which included 48% had stage IIB disease and 18% had  para-aortic node (PAN) involvement 
(PAN+), defined at laparoscopic lymphadenectomy.4 Following definitive chemoradiation, the 
median OS for the whole group was 68 months. For PAN+ patients, however, median OS was 21 
months (versus 77 months if PAN-). On regression analysis, PAN+ and large tumor size 
(T>5cm, which constitutes stage IB or IIB disease) both were found to be independent and 
significant risk factors for poor survival. In a 2010 individual patient meta-analysis conducted by 
the Cochrane group, the overall benefit of chemoradiation was confirmed, with a 19% relative 
reduction in the risk of death with chemoradiation compared to RT alone, translating in to an 
absolute survival benefit of 6% at five years.5 However, in real-world terms, the estimates of 
overall survival at 5 years was 66% with chemoRT versus 60% with RT alone, indicating that 
almost 40% will die of their disease despite treatment. In addition, the magnitude of the benefit 
associated with chemoradiation was found to depend on FIGO stage: estimated absolute survival 
benefit was 10, 7, and 3% at five years for patients with stage 1b-2a, 2b, versus 3-4a (which 
includes those with PAN involvement), respectively.  
 
These results illustrate the lack of advancement in the contemporary curative intent treatment 
strategies for newly diagnosed cervical cancer since 2000. It also illustrates that much progress is 
still needed to cure more patients of this disease.  
 
The potential role of immunotherapy in cervical cancer is based on the causative role of HPV 
infection in this disease. There are data to support the theory that the host immunological status 
and HPV-induced immune evasion are responsible for persistent HPV infection and the 
subsequent development of cervical cancer.6 HPV infection invokes a cellular immune response, 
and regulatory T cells appear to play a role in local immune suppression in HPV-associated 
tumors.7 Finally, recent results from The Cancer Genome Atlas on cervical cancer has identified 
amplification of known immune targets, specifically CD274 (which encodes the PD-L1 
checkpoint protein) and PDCD1LG2 (which encodes the PD-L2 immune checkpoint protein).8 
 
2.2 
Nivolumab 
 
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody 
(HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-1) 
cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative 
regulatory molecule expressed by activated T and B lymphocytes.1 Binding of PD-1 to its 
ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
8 
lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as 
self-antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced 
using standard mammalian cell cultivation and chromatographic purification technologies. The 
clinical study product is a sterile solution for parenteral administration. It is approved for use in 
multiple countries including the United States (US, Dec-2014), the European Union (EU, Jun-
2015), and Japan (Jul-2014). 
 
The PK, clinical activity, and safety of nivolumab have been assessed in subjects with non-small 
cell lung cancer (NSCLC), melanoma, clear-cell renal cell carcinoma (RCC), and classical 
Hodgkin Lymphoma (cHL) in addition to other tumor types. This updated Investigator Brochure 
(IB) references the most recent US Prescribing Information (USPI) and EU Summary of Product 
Characteristics (SmPC) as the basis for the current state of knowledge on nivolumab for use in 
humans.  
 
Nivolumab monotherapy is approved in multiple countries, including the US and EU, for 
unresectable or metastatic melanoma, previously treated metastatic NSCLC, and previously 
treated advanced RCC; it is also approved for the treatment of cHL in the US. Nivolumab is 
being investigated both as monotherapy and in combination with chemotherapy. 
 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 12,300 subjects treated to date. 
For monotherapy, the safety profile is similar across tumor types. There is no pattern in the 
incidence, severity, or causality of AEs to nivolumab dose level. In Phase 3 controlled studies, 
the safety profile of nivolumab monotherapy is acceptable in the context of the observed clinical 
efficacy, and manageable using established safety guidelines. Clinically relevant AEs typical of 
stimulation of the immune system were infrequent and manageable by delaying or stopping 
nivolumab treatment and timely immunosuppressive therapy or other supportive care. 
In several ongoing clinical trials, the safety of nivolumab in combination with other therapeutics 
such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies is being 
explored. Most studies are ongoing and, as such, the safety profile of nivolumab combinations 
continues to evolve. 
Nivolumab has demonstrated promising activity in refractory cervical cancer according to results 
from CheckMate 358 presented at the ASCO Annual Meeting, 2017.9 Conventional second-line 
options for recurrent or metastatic cervical cancers results in a median PFS of around 2 to 4 
months and an objective response rate of 0% to 14%. Hollebecque and colleagues evaluated data 
from 24 patients (median age, 51 years) with cervical  (n = 19) or vaginal or vulvar cancer (n = 
5) treated in CheckMate 358, an ongoing multicohort study of five virus-associated cancers. The 
study included PD-L1–unselected adults with relapsed and metastatic gynecologic cancers with 
an ECOG performance score of 0 to 1 who had received two or fewer prior systemic therapies 
All patients who underwent HPV testing were positive, with 41.7% of patients having an 
unreported HPV status. Ten patients had PD-L1 expression above 1%. Patients received 240 mg 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
9 
nivolumab every 2 weeks until progression or unacceptable toxicity. ORR and safety served as 
primary endpoints; secondary endpoints included duration of response, PFS and OS. Median 
follow-up was 31 weeks (range, 6-38). Researchers reported an ORR of 20.8%, which included 
one complete response (4.2%) and four partial responses (16.7%). Twelve patients (50%) 
achieved stable disease, for a disease control rate of 70.8%. All response occurred in patients 
with cervical cancer (ORR, 26.3%) and occurred regardless of PD-L1 or HPV status. 
2.3 
Rationale 
 
Given the emerging understanding on the importance of immune mechanisms in cervical cancer, 
including the recent findings in the TCGA project, we propose to evaluate the safety of adding 
nivolumab to definitive chemoradiation for cervical cancer.  
 
2.4 
Correlative Studies Background 
 
All patients will have tumor tissue from the diagnosis (or else, obtained prior to treatment) 
available, prior to study treatment, for exploratory correlative studies, which will be performed at 
a later date. In order to evaluate the tumor and the surrounding microenvironment, an optional 
second tumor biopsy attempt as outlined in the Schema is built in to the study, following 
induction doses of nivolumab (prior to start of chemoradiation).  
 
The aim of such studies will be to identify potentially predictive biomarkers of benefit for 
patients with cervical cancer treated with nivolumab and standard chemoradiation. Data from 
these investigations will be evaluated for associations with response, survival (OS, PFS) and/or 
safety (adverse event) data. Biomarkers analysis may include PD-L1 expression, and tumor 
mutation burden.  We may explore the prognostic significance of  Chitinase 3-like 1 (Chi3l1), 
which we have recently demonstrated to have prognostic significance following immune 
checkpoint inhibitors in lung cancer. It is anticipated that advances in the understanding of 
biomarkers for immune checkpoint inhibitors will be forthcoming over the next few years 
emphasizing the need for tissue storage for future collaborative studies.  
 
 
3 
PARTICIPANT SELECTION (3.1, 3.2, 3.3 MUST ALL BE CONFIRMED) 
 
3.1 
Eligibility Criteria  
 
3.1.1 Age ≥  18 years.  Cervical cancer is rarely seen in women under 18 years.   
 
3.1.2 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) 
 
3.1.3 Patients with histologically confirmed advanced cervical cancer (any cell type): FIGO 
Clinical stages IB2, IIA, IIB, IIIA, IIIB, IVA. All patients must have tissue from the diagnostic 
biopsy submitted prior to enrollment for both pathologic confirmation of the diagnosis (if done 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
10 
outside of a BrUOG institution) and for specimen collection. Pathology must be reviewed by 
gynecological pathologist. NOTE: Patients with positive or negative pelvic and/or para-aortic 
lymph nodes by histologic confirmation or by radiological evaluation are eligible. 
 
NOTE: Histologic or cytologic evaluation of PA nodes is highly recommended in the presence of 
enlarged lymph nodes on imaging (CT or PET/CT). In such cases, FNA or laparoscopic 
sampling are acceptable. 
3.1.4 Participants must have normal organ and marrow function as defined below: 
 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
total bilirubin 
within normal institutional limits. A value below the 
LLN is acceptable if confirmed appropriate by the treating MD 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
− 
creatinine 
Within normal institutional limits 
-     hemoglobin  
            >9.0g/dL 
3.1.5 Neuropathy (sensory and motor) ≤ CTCAE v4.0 grade 1 
 
3.1.6 Patients with ureteral obstruction should undergo stent or nephrostomy tube placement 
prior to study entry. Any side effects or complications associated with stent placement that, in 
the opinion of the treating investigator, puts the patient at increased risk for treatment-related 
toxicity, must be resolved completely prior to study enrollment.  
 
3.1.7 Patients of child-bearing potential must have a negative serum pregnancy test prior to study 
entry (within 7 days prior to initiation of study treatment) and be practicing an effective form of 
contraception during study treatment and for 24 months  (2 years) thereafter.  
 
3.1.8 Women should not breast-feed while on this study 
 
3.1.9 Patients must not be receiving any other investigational agent 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent document. 
 
3.1.11 All patients with a history of hearing loss are required to have an audiogram within 28 
days prior to initiating protocol therapy. If patient does not have a history of hearing loss this 
must be documented by treating physician. Audiogram with results required to be submitted to 
BrUOG. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Participants with visceral metastases, including brain metastases. 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
11 
3.2.2 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
hepatitis, active rheumatologic or collagen vascular disease, symptomatic congestive heart 
failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. Patients with active 
HIV disease not controlled on antiretroviral therapy are also excluded.  
 
NOTE: Participants with active or a history of Hepatitis B or C infection as follows: 
 
• Active hepatitis B (positive hepatitis B surface antigen [HBsAg] or hepatitis C virus 
(HCV) (positive HCV RNA) are not eligible to participate.  
• HBV carriers or those participants requiring antiviral therapy are not eligible to 
participate. 
• Participants positive for HCV antibody are eligible only if PCR is negative for HCV 
RNA. If PCR is positive, they are not eligible to participate. 
• Past HBV infection or resolved HBV infection are may be eligible on this trial provided 
the following criteria are met prior to randomization: Positive for hepatitis B core 
antibody (HBcAb), the absence of hepatitis B surface antigen (HBsAg), and no 
detectable HBV DNA in serum.  
 
3.2.3 Patients who have received previous pelvic or abdominal radiation, cytotoxic 
chemotherapy, or previous therapy of any kind for this or any other malignancy. 
 
3.2.4 Patients who have circumstances that will not permit completion of this study or the 
required follow-up as per the treating physician 
  
3.2.5 Patients with a history of other invasive malignancies, with the exception of non-melanoma 
skin cancer are excluded if there is any evidence of other malignancy being present within the 
last three years (2 years for invasive breast cancer). However, patients with a malignancy that is 
non-likely to require treatment, as per the treating physician, in the next 2 years, such as a 
completely resected, early stage breast cancer, or other malignancies treated with curative intent 
are eligible. Patients are also excluded if their previous cancer treatment contraindicates this 
protocol therapy. 
 
3.2.6 Prior treatment with immunotherapy for any cancer, including immune checkpoint 
inhibitors or anti-CTLA4 agents  
 
3.2.7 Patients with renal abnormalities, such as pelvic kidney, horseshoe kidney, or renal 
transplantation, that would require modification of radiation fields as documented by treating 
physician 
 
3.2.8 Participants with an active, known or suspected autoimmune disease. Participants with type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
12 
expected to recur in the absence of an external trigger are permitted to enroll. 
 
3.2.9 Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of day 1 of treatment. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease 
 
3.3 
Clinical Staging Evaluation: Each item below is required to be documented if 
done or not with reason by treating physician and all assessments/tests with results are 
required to be submitted with registration 
 
Patients will undergo clinical staging as permitted by FIGO rules. To be documented by treating 
physician 
Assessment of adenopathy demonstrated on CT or PET scans by fine needle aspiration (FNA), 
extraperitoneal lymph node biopsy, or laparoscopic sampling (see section 3.4) is recommended.  
Cystoscopy, proctoscopy, and barium enema are optional prior to entry onto study, although they 
should be obtained in those patients with clinical symptoms and/or physical findings highly 
suspicious of recto-vaginal and/or vesico-vaginal fistula. To be documented by treating physician 
if done (submit) or if not done confirming not required. 
3.4 
Inclusion of Women and Minorities 
 
Women of all races and ethnic groups are eligible for this trial. 
 
4 
REGISTRATION PROCEDURES 
All patients will be registered through the Brown University Oncology Research Group Central 
Office. Eligibility Checklist with supporting documentation, On Study Form and the signed 
Patient Consent Form must be faxed to the BrUOG Central Office, Fax: (401) 863-3820, at the 
time of registration and prior to patient treatment. 
 
Details of patient’s study participation should be documented in clinic/file notes. The Brown 
University Oncology Research Group will provide case report forms, included in the appendix, 
for the recording and collection of data. In the event of corrections, each correction will be 
initialed and dated by the person making the correction. The investigator will sign the case 
reports to indicate that, to his/her knowledge, they are complete and accurate. Case report forms, 
flow sheets, off-study forms and follow-up forms should emailed to:  
 
Brown University Oncology Research Group, 
Brown University 
Box G-R 001 
Providence, RI 02912 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
13 
BrUOG@brown.edu 
All support data must be sent in with the corresponding BrUOG forms. It is the treating 
physician’s responsibility to review all data submitted to the BrUOG Central Office for accuracy 
and completeness and he/she must sign the off study form.  Sites are to be sure that elements to 
support all inclusion and exclusion criteria are submitted and that all assessments from the 
schedule of evaluations are submitted for registration.  
 
5 
TREATMENT PLAN 
 
5.1 
BIOPSY: 
 
There are 2 specimens anticipated for collection, as outlined in the schema. NOTE: Only the 
diagnostic specimen is required. The second biopsy (following two doses of neoadjuvant therapy 
prior to start of planned chemoradiation) is optional.  
 
The first specimen must be obtained or ordered (if from outside institution) prior to enrollment. 
This may consist of the biopsy obtained for diagnostic purposes. All tissue submitted from 
outside of a BrUOG institution must be reviewed at Rhode Island Hospital for pathologic 
confirmation of the diagnosis.  
 
The second biopsy is an optional research only core needle biopsy and will not be required as 
part of participation in this trial. If patients agree to proceed, an attempt at the biopsy will be 
obtained following the first two doses of Nivolumab (see 5.3 below) in each patient, which must 
be scheduled (and attempted) within 2 weeks of the final Nivolumab dose (week 4-5). The type 
of biopsy will be determined by the treating physician. Note, if there is evidence of primary 
cervical lesion, the biopsy may be obtained at the discretion of the treating gynecologic 
oncologist. However, the treating physician may proceed with a biopsy in Interventional 
Radiology if determined to be a better modality of collection. 
 
If the biopsy is non-diagnostic or otherwise not technically feasible, patients will be allowed to 
continue on study.  
 
All collected specimens will be utilized for correlative testing for future exploratory analyses to 
assess biomarkers associated with treatment using nivolumab in cervical cancer.  
 
5.2 ALL PATIENT TREATMENT 
5.3 
Nivolumab 
All patients will receive two doses of nivolumab prior to the start of definitive chemoradiation.  
During induction and for those receiving concurrent nivolumab with chemoradiation, this study 
will use a fixed dose of nivolumab 240 mg every 2 weeks during RT, with each 2 week period 
constituting a cycle. The cycle window will be +/- 3 days (See section 5.5).  


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
14 
 
For patients assigned to maintenance nivolumab (cohorts 2 and 3), nivolumab will be 
administered at a fixed dose of 480 mg every 4 weeks, with each 4-week period constituting 
cycle. The cycle window will be +/- 3 days 
 
5.4 
COHORT ASSIGNMENT: 
 
All patients will continue on treatment within 14 days (+/- 7 days) following the final dose of 
nivolumab pre-chemoradiation in one of three cohorts: 
 
Cohorts will be enrolled consecutively with all patients being enrolled to cohort 1 (8 patients) 
after-which enrollment to cohort 2 will open (to enroll 4 patients). Once safety is confirmed in 
those cohorts, enrollment to cohort 3 will open and enroll the remaining patients up to a total of 
24 evaluable patients. 
 
- 
Cohort ONE: Nivolumab during chemoradiation (total, 8 patients) 
 
o Definitive radiation therapy fields will be determined by the treating 
radiation oncologist. 
o Two groups of patients (4/group) will be evaluated dependent on the 
chemoradiation field, with the field determined and documented in 
advance by the treating radiation oncologist:  
 
 COHORT 1A: Patients receiving EFRT  +/- HDR/LDR 
brachytherapy. Parametrial boost is per MD discretion 
 COHORT IB: Patients receiving WPRT +/- HDR/LDR 
brachytherapy.  Parametrial boost is per MD discretion  
o Nivolumab 240mg IV every 14 days (+/- 3 days) for 3 doses, administered 
concomitantly during chemoradiation and beginning day 1 of Radiation. 
Dosing days of nivolumab will be flexible to align with cisplatin dosing. 
 
o Standard cisplatin dosing will be utilized during treatment (40 mg/m2 
weekly for maximum of 6 doses) 
- 
Cohort TWO: Chemoradiation followed by Nivolumab maintenance for 2 years 
(total, four patients) 
 
o Patients will proceed with definitive chemoradiation alone.  
o 2-3 weeks following completion, patients will begin Nivolumab 480 mg 
IV every 4 weeks (+/- 3 days) for a planned duration of 2 years. 
- 
Cohort THREE: Nivolumab 240mg IV during chemoradiation and then as 
nivolumab monotherapy 480mg IV (beginning no more than 4 weeks post CRT) 
for 2 years (total, approximately 12 patients to enroll allow for total study 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
15 
enrollment of up to total 24 patients on study)  
 
o Patients will receive nivolumab during definitive chemoradiation (as in 
cohort one) followed by nivolumab alone (as in cohort two). Pending 
safety data of cohort one, patients may be stratified by the radiation field, 
as in cohort One.  
 
5.5 
Nivolumab administration 
 
Nivolumab is to be administered as an approximate 30-minute IV infusion. For details on 
prepared drug storage, preparation, and administration, please refer to the Nivolumab 
Investigator Brochure (IB). 
 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding polyethersulfone membrane in-line filter at 240 mg. It is not to be 
administered as an IV push or bolus injection. Nivolumab injection can be infused undiluted (10 
mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to 
protein concentrations as low as 1 mg/mL. Care must be taken to assure sterility of the prepared 
solution as the product does not contain any antimicrobial preservative or bacteriostatic agent.  
At the end of the infusion, flush the line with an adequate amount of normal saline.     
 
5.5.1 DOSE DELAYS FOR NIVOLUMAB (see section 6 for radiation and cisplatin 
dose modifications and requirements) 
 
There will be no dose reduction of nivolumab in this protocol.  
During Chemo/RT:  
 
For patients receiving definitive chemoradiation plus nivolumab (cohorts one and three), 
standard treatment parameters will apply toward administration of weekly cisplatin and/or 
radiation therapy. If a dose of cisplatin is held on a treatment week where nivolumab is 
scheduled, that dose of nivolumab should be skipped and not made up.  
 
Nivolumab (All Cohorts): 
 
Non-Immune mediated: All toxicities- heme or non-heme- felt to have some causality to 
nivolumab must resolve to < grade 2 (excluding weight loss, weight gain, and alopecia) or to 
baseline prior to a patient receiving a subsequent dose (of Nivolumab). Any dose of nivolumab 
not administered will be skipped and not made up.  
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
16 
Immune mediated: Adverse events (both serious and non-serious) associated with nivolumab 
may represent immunologic etiology. Nivolumab must be held for  suspected immune-mediated  
toxicities  or severe/life-threating AEs of particular interest (in Section 7.0) and immune-related 
toxicities (in Appendix D). Please review both Sections (7 and Appendix D) prior to infusion of 
nivolumab in any patient in whom immune-mediated toxicity is suspected.   
 
If the investigator is unsure if a particular toxicity at least possibly represents an immune 
mediated toxicity to nivolumab, the treating physician should follow section 7 and appendix D 
and treat as immune mediated, until it is confirmed as not being immune mediated. Consultation 
with BrUOG is suggested in such situations. BrUOG will share information about the situation 
with the BrUOG Reviewer and PI and provide the site guidance, as available. 
 
Removal from study (all cohorts): 
 
Patients must discontinue nivolumab permanently for the following:  
 
• Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment 
• Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding   
• Any treatment delay resulting in no nivolumab dosing for > 6 weeks.  
• Patients who discontinue nivolumab during definitive chemoradiation (cohorts one and 
three)  
• Grade 4 drug-related endocrinopathy adverse events such as adrenal insufficiency, ACTH 
deficiency, hyper- or hypothyroidism, or glucose intolerance, hypophysitis. 
• > Grade 4 hepatic AEs 
• > Grade 4 skin toxicity (per Appendix D can delay or discontinue for grade 3. Must come 
off, as per this bullet for grade 4 skin) 
• ALL OTHER treatment related grade 3/4 treatment related events with the following 
exceptions: 
  
 Grade 4 neutropenia ≤ 7 days;  
 Grade 4 lymphopenia or leukopenia;  
 isolated Grade 4 electrolyte imbalances/abnormalities that are not 
associated with clinical sequelae and are corrected with supplementation/ 
appropriate management within 72 hours of their onset;  
 Grade 3 hepatic AEs that return to Grade 2 or less within 5 days Of note, 
this overrides Appendix D 
 Skin toxicity < grade 3 that improves with steroid therapy. NOTE: Any 
rash consistent with Stevens-Johnson Syndrome or Toxic Epidermal 
Necrolysis requires permanent discontinuation of nivolumab.  
 Grade 3 renal toxicity (as per Appendix D) 
If Nivolumab is discontinued, the patient is to be taken off study. The total treatment patient 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
17 
received will be collected, but once patient is off study, all treatment is per standard of care and 
does not need to follow-BrUOG 355. 
 
In situations when RT is not given (held for toxicity or other reasons (weather, machine is down, 
holiday), cisplatin and Nivolumab should not be given and should also be held. 
 
If Nivolumab is held on a day Cisplatin is due and the patient meets criteria to receive Cisplatin 
and Radiation then every attempt should be made to administer Cisplatin and radiation, while 
holding Nivolumab.  
 
Every attempt should be made for all patients to complete radiation therapy (even if cisplatin and 
nivolumab are held) 
 
5.6 
Definitive Chemoradiation Plan 
 
Standard therapy guidelines for definitive chemoradiation in cervical cancer will be utilized 
during this trial. All patients will receive tailored pelvic (if para-aortic nodes are negative) and/or 
extended field, pelvis+para-aortic, radiation therapy (if para-aortic nodes are involved) with a 
plan for daily delivery of RT (Monday-Friday) for approximately 6 weeks (which may include 
brachytherapy). 
 
Cisplatin:  
40 mg/m2 of cisplatin (maximum total dose of 70 mg/week and maximum BSA=1.75m2)  
 
Dosing on Days: 1, 8, 15, 22, 29, 36 (preferably on Mondays or Tuesdays). The only exception 
allowed is to account for holidays or unexpected events that warrant closure of the radiation 
oncology or infusion center, in which case treatment is allowed within the next fully operational 
day. For example, if D8 falls on a holiday, treatment with cisplatin (and with nivolumab if 
scheduled) should occur on next day, which will be counted as D8 with all subsequent days 
rescheduled to allow for a 7-day interval between dosing.   
- 
Cisplatin should be infused over approximately 1 hour, beginning on day 1 of 
radiation therapy.   
 
One hour before cisplatin administration, 500-1000 ml of normal saline should be infused 
intravenously, as per institutional standard of care. 
 
Appropriate antiemetics should be administered prior to cisplatin. Additional fluid may be given 
as needed for symptomatic support. Premedications for nausea and vomiting prophylaxis should 
follow institutional guidelines.  
 
Immediately after completion of the cisplatin infusion, an additional 500-1000 ml normal saline 
should be infused over one hour. It is highly recommended that KCl 20-40 meq and MgSO4 2 
grams be added to the normal saline in the post hydration fluid given that hypomagnesemia and 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
18 
hypokalemia are associated with cisplatin therapy. This is the minimum fluid administration 
recommendation and more fluid may be given at the discretion of the treating physician 
and institutional standard of care should be followed. 
 
On days when Cisplatin and Nivolumab are administered the same day, Nivolumab is to be 
administered first, followed by the normal saline flush of the line.  
 
After Nivolumab administration, administer one hour of normal saline (500-1000 ml), 1 hour of 
Cisplatin, then 1 hour of normal saline (500-1000 ml). It is highly recommended KCl 20-40 meq 
and MgSO4 2 grams added. Radiation would then commence post completion of Cisplatin and 
normal saline.  
 
5.7 
Radiation specifications 
 
This protocol requires photon external beam radiation therapy (EBRT), either 3D conventional 
radiation therapy (3D- CRT) or intensity modulated radiation therapy (IMRT) techniques 
followed by low dose rate (LDR) or high dose rate (HDR) brachytherapy. Radiation therapy 
must be completed within 60 days of initiation. Four-field box 3D-CRT and IMRT are 
pretreatment stratification variables. 
 
• For 3D-CRT, the prescription dose is 45 Gy in 25 fractions at 1.8 Gy/fraction with an 
optional parametrial boost of 5.4 Gy in three fractions at 1.8 Gy/fraction. EBRT should 
be given once daily Monday-Friday, 5 fractions per week.  
 
• For IMRT, the prescription dose is 45 Gy in 25 fractions at 1.8 Gy/fraction, unless a 
simultaneous integrated boost (SIB) is used for gross nodal disease. For SIB cases, the 
primary target will receive 47.6 Gy in 1.7 Gy/fraction and the gross nodal PTV 
(PTV_Boost) will receive 1.93-2.12 Gy per fraction, depending on bowel tolerance. 
IMRT should be given once daily Monday-Friday, 5 fractions per week.  
 
• For brachytherapy, the prescription doses are 27.5 - 30 Gy for HDR. 
 
Cohort 1A - Extended-Field Radiation Therapy (EFRT) - EFRT will be used for patients with 
any positive common iliac LN requiring extension of the superior border of the radiation 
field above the L4-L5 inter-space as detailed in Section 5.7.1. 
 
Cohort 1B -Whole Pelvic Radiation Therapy (WPRT) - WPRT will be used for patients 
without evidence of high common iliac LN necessitating EFRT.  The traditional whole pelvic 
radiation field borders are as detailed in Section 5.7.1.  
 
 
5.7.1 Treatment technology 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
19 
Conventional 3D RT (4-field box) 
 
Conventional 3D plans will consist of a 4-field box arrangement using AP/PA and Right/Left 
lateral fields. Conventional RT must use 4-25 MV photons. It is permissible i) to use bone 
landmarks to draw field borders as described below or ii) to use 3D planning with explicit targets 
as outlined in section 5.2.3. Custom cerrobend blocks or MLCs are acceptable for field shaping. 
 
If bone landmarks are used, use the following portals: 
 
• Superior border: L4-L5 interspace. For patients with positive high common iliac LN, an 
extended field will be used such that the superior border will extend above L4-L5 inter-
space to cover additional para-aortic LN at least 3cm above the superior-most extent of 
gross nodal disease.  
• Lateral border: 1-2 cm lateral to the border of the true pelvis  
• Inferior border: Obturator foramen or 3 cm inferior to the lowest extent of disease, 
whichever is lower  
• Anterior border: line from pubic symphysis to 1.5 cm anterior to common iliac nodes at 
L4-5. At least 0.5 cm anterior of the L4-L5 vertebral bodies should be included in the 
field in order to adequately encompass the low para-aortic region.  
• Posterior border: draw border 1.0 cm posterior to the sacrum from S1-S4  
• Custom blocking to shield femoral heads. Do not block the obturator foramen or within 1 
cm of the common iliac nodes 
 
Opposed lateral pelvic fields are used using the same isocenter as the anterior and posterior 
pelvic fields. The superior and inferior borders will be the same as for the anterior and posterior 
fields. 
 
The inferior extent or vaginal extension of disease should be marked so that the inferior border of 
disease can be documented. Uninvolved normal tissues may be blocked although the position of 
the uterus should be contoured to ensure adequate coverage. 
 
For patients who underwent lymph node dissection: If clips are present to document the position 
of the lymph nodes, these should be used as a guide when anterior blocks are designed to shield 
small bowel. When shielding bowel, at least 3 cm should not be blocked anterior to the L4 and 
L5 vertebral bodies in order to adequately encompass the low para-aortic region. 
 
IMRT 
IMRT plans may include static field arrangements (e.g. 5-9 fields), modulated arc therapy, or 
Tomotherapy. Pseudo-step-wedge intensity modulation (PSWIM) or volumetric modulated arc 
therapy (VMAT) techniques are permitted. IMRT should use 6-15 MV photons. 
 
Parametrial boost 
After conventional RT or IMRT delivery, a parametrial boost can be delivered at the treating 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
20 
physician’s discretion. The parametrial boost will use an AP/PA field arrangement. The superior 
border should be reduced to include only the true pelvis and the upper border of the true pelvis is 
defined as 1 cm above the inferior aspect of the sacroiliac joint. The inferior border remains the 
same as in the pelvis fields. A parametrial central field block is a minimum of 4 cm wide. 
 
Brachytherapy 
Patients will be treated using HDR brachytherapy for all patients treated on this protocol. 
Tandem and ring or tandem and ovoids will be used for intact cervix brachytherapy. Interstitial 
brachytherapy such as with a Vienna applicator is allowed at the discretion of the treating 
physician. A tandem and cylinder or tandem alone is allowed only for patients where tandem and 
ring or ovoid application is not possible due to extent of disease or poor anatomy (e.g., 
obliterated fornices).  
 
Use of IMRT or other external beam techniques in place of brachytherapy to boost gross cervical 
disease is discouraged. If deemed necessary or essential for the patient’s care (e.g., if a patient 
refuses brachytherapy), reasons for not performing brachytherapy should be documented. 
 
5.7.2 Immobilization and simulation 
 
Conventional RT  
CT simulation is required. Field outlines should be drawn electronically on Digitally 
Reconstructed Radiographs (DRRS) produced from the CT simulation information. Localization 
or block-check-images of simulated fields are to be obtained in a simulator and/or treatment 
machine. Digital pictures of all treatment portals with the patient in the treatment position are to 
be submitted for quality assurance review. All treatment fields, whether formed by cerrobend 
blocks or multi-leaf collimation, should be independently checked against the corresponding 
DRRs. Prone positioning with bowel exclusion devices (e.g. belly boards) is allowed. 
 
3D planning is at the physician’s discretion. If 3D planning is being done, a CT simulation scan 
is required with a slice thickness ≤ 3.0 mm for the regions extending at least 4cm above and 
below target volumes. Patients can be simulated supine or prone. All subjects will have a 
customized immobilization device (e.g., Alpha Cradle or Vac-Loc) fabricated at the time of 
simulation. A full bladder is required at the time of simulation and treatment. Intravenous 
contrast is recommended to visualize vessels better. Oral or rectal contrast is not recommended 
for treatment planning. 
 
IMRT 
All subjects will undergo a CT (or PET/CT) simulation scan in the supine position using a slice 
thickness ≤ 3.0 mm and large field-of-view pelvic protocol. A customized immobilization device 
fabricated at the time of simulation is required. It is recommended that CT scans be obtained 
from the T12 vertebral body to 5 cm below the ischial tuberosities. For patients undergoing 
CBCT with each fraction, it is recommended that the isocenter be placed along the patient’s 
midline 1.5 cm caudal to the inferior border of the sacroiliac joint. Otherwise, isocenter 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
21 
placement is left to the discretion of the treating physician. It is recommended to use a consistent 
bladder filling state (e.g. always full or always empty) for simulation and treatment. It is 
recommended for patients not to be simulated or treated with a full rectum as this may result in 
poor setup reproducibility. Bowel preparatory agents (enema, stool softeners, etc.) may be 
applied at the discretion of the physician. Oral contrast is optional. Radio-opaque cervical 
markers or implanted fiducials are optional 
The volume irradiated will include the totality of the gross disease locally and regionally, as 
visualized by CT scan, the whole uterus, paracervical, parametrial and uterosacral ligaments as 
well as the areas of the obturator, hypogastric, external and internal iliac lymph nodes. In patients 
treated with extended fields the para-aortic regions with a minimum margin of 2 cm should be 
included. A margin of 2-3 cm should be given around the gross disease and 1.5-2 cm around 
uninvolved lymph nodes. 
 
Brachytherapy 
For 3D brachytherapy planning, all subjects will undergo a CT (or PET/CT) simulation scan 
using a slice thickness ≤ 3.0 mm with brachytherapy applicators and dummy sources in. It is 
recommended that CT scans contain the entire brachytherapy applicators and the critical 
structures such as bladder and rectum. 
 
Maintaining applicator position is required from the time of applicator insertion to simulation 
and treatment. Before a CT scan, a Foley catheter is inserted into the bladder and the balloon 
must be filled with 7 cc of radio-opaque fluid to define the bladder reference point in treatment 
planning. 
 
For volume-directed brachytherapy, pelvic MRI (≤ 3 mm slice thickness) is required with either 
the first or second insertion. An MRI-compatible applicator is required to perform volume-
directed brachytherapy. Subsequent insertions may use CT or MRI for planning. 
 
5.7.3 Target volumes, margins, and compliance criteria 
 
The structures marked as “Required” in the table must be contoured and documented in the 
Radiation Oncology Treatment Plan. 
 
Conventional RT (4-field box) 
For a 4-field box treatment without 3D planning, contouring target volumes is not required. For 
3D plans, target volumes and margins will be the same as for IMRT described below. The only 
difference between 3D plans and IMRT contours is that patients treated with 3D planning will 
not have an ITV option. 
 
IMRT 
Pelvic MRI and/or PET fusion with the CT simulation scan is recommended to aid target 
delineation. Fusion should be optimized to match the MRI/PET scans to the treatment position. 
The Gross Tumor Volume (GTV), Clinical Target Volume (CTV) and Planning Target Volume 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
22 
(PTV) will be contoured on all CT slices in which the structures exist. 
Standard 
Description 
Specification 
Gross Tumor Volume (GTV) 
Required dose = 45 Gy 
The GTV is defined as all 
known gross disease determined 
from radiographic studies, 
clinical information, physical 
examination, endoscopic 
examination, and biopsy results. 
Cervical Tumor Volume 
(CTV) 
Required dose = 45 Gy 
The CTV will be divided in to 3 
sub regions: CTV1, CTV2, 
CTV3. CTV1 will consist of the 
gross tumor, cervix, and uterus. 
CTV2 will consist of the 
parametria and superior third of 
the vagina (or half of the vagina, 
if the vagina is clinically 
involved). CTV3 will include 
the common, external, and 
internal iliac and presacral 
lymph nodes. The upper border 
of the CTV3 should not extend 
above the confluence of the 
common iliac arteries with the 
aorta (i.e., aortic bifurcation), 
and should begin no  
lower than superior border of 
L5. The nodal CTV (CTV3) will 
be obtained by ensuring an 
approximately 7 mm margin 
around the vessels, plus 
extension to include any 
adjacent visible lymph nodes, 
lymphoceles, or pertinent 
surgical clips. The presacral 
nodes should be contoured until 
the superior border of the S3 
vertebral body is reached; below 
this point the nodal volume can 
be separated into two structures. 
The external iliac nodes should 
be contoured to the superior 
aspect of the femoral head. 
CTV3 should be modified to 
exclude bone, muscle, and 
bowel. The CTV should not 
extend inferior to the ischial 
tuberosities. 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
23 
CTV (for SIB schemes) 
Required dose = 47.6 Gy 
Same as above 
CTVn boost (for boost) 
Required dose = 54.0 to 59.4 
Gy 
Gross pelvic nodes 
ITV 
Total dose = 45 Gy 
Patients should be simulated 
with both a full and empty 
bladder (i.e., 2 simulation 
scans). CTV1-CTV3 and PTV1-
PTV3 should be delineated as 
described above on the plan 
used for treatment (either the 
full or empty bladder scan), and 
CTV1 should be delineated on 
both scans. The CTV1 from 
both scans should be fused 
together to generate the ITV. A 
7 mm margin should be applied 
to generate PTV4. PTV4 should 
be fused with PTV1-PTV3 to 
generate the final PTV.  
Pelvic Tumor Volume (PTV) 
Required dose = 45 Gy 
Around CTV1, a 15 mm 
uniform expansion should be 
used. Around CTV2, a 10 mm 
uniform expansion should be 
used. Around CTV3 (and 
CTV_boost, if applicable), a 5 
mm uniform expansion should 
be used. These expansions will 
generate PTV1, PTV2, and 
PTV3, respectively. PTV1-3 
will be fused to generate the 
PTV . 
PTV-skin 
IF applicable only: 
PTV-3mm from skin surface 
The PTV should be manually or 
automatically trimmed up to 3 
mm from the skin surface, if 
necessary, to spare skin. 
However, the CTV still needs to 
be included entirely within the 
PTV . 
PTV-boost 
Required dose = 54 to 59.4 
Gy 
5 mm uniform expansion around 
CTV_Boost  
 
Brachytherapy (point-directed) 
The definition of all points (A, B, Bladder, Rectum and Vaginal Surface) will be in accordance 
with the 1985 ICRU Report #38: Dose and Volume Specifications for Reporting Intracavitary 
Therapy in Gynecology. 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
24 
Brachytherapy (volume-directed) 
The MRI based target delineation can be reused by superimposition in the process of contouring 
on CT, if for subsequent fractions of brachytherapy only CT can be used with the applicator in 
place. No planning margins will be added to the CTV. 
 
Standard name 
Description 
Specification 
GTV  
Required dose = 27.5-30 Gy 
Macroscopic tumor (if present) 
at time of brachytherapy  
CTV 
GTV + whole cervix + 
presumed extra cervical tumor 
extension  
Compliance criteria: 
 
 
Per protocol 
Variation 
(Acceptable) 
Deviation 
(Unacceptable)* 
Overall Treatment 
time 
≤ 60 days 
≤ 66 days 
>66 days 
 
Patients who require a treatment delay of RT for 7 consecutive days or longer will be removed 
from this protocol. The decision to continue standard chemoradiation will be left to the treating 
physician. See Section 6.2. 
 
5.7.4 Definition of critical structures and margins 
The structures marked as “Required” in the table must be contoured and documented with the 
treatment plan. Structures marked as “Required when applicable” must be contoured and 
documented only when applicable.  
Conventional RT (4-field box) 
For a 4-field box treatment without 3D planning, contouring critical structures is not required. 
For 3D plans, critical structures and margins will be the same as for IMRT described below. 
 
IMRT 
Location 
Specification 
External (Required) 
Normal tissues will be contoured on the CT  
simulation scan. The tissue within the skin surface 
and outside all other critical normal structures and 
the PTV should be contoured on every slice and 
designated as “External. 
Bowel space (Required) 
Bowel Space will be contoured beginning from 
the axial slice situated 1 cm superior to the 
superior-most slice containing PTV (if bowel is 
not present at this level, the bowel contour will 
start from its most superior extent), and will 
continue to its most inferior extent in the pelvis. 
The Bowel Space will include the outermost 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
25 
extent of the bowel loops plus any space within 
the abdominal cavity the bowel may occupy. 
Individual loops of bowel should not be contoured 
separately. Bowel Space will be outlined on each 
axial CT slice. Rectum should be contoured 
separately from bowel.  
Rectum (Required) 
The outer rectal wall will be contoured and filled 
in, treating the organ as a solid continuous 
structure, and will be defined from the level of the 
sigmoid flexure to the anus. 
Bladder (Required) 
The outer bladder wall will be contoured and 
filled in, treating the organ as a solid continuous 
structure. 
Bone marrow (Required) 
The outer bone contour will be delineated and 
filled in, treating the bone marrow as a solid 
continuous structure. The regions contoured will 
include the os coxae, L4 and L5 vertebral bodies, 
entire sacrum, acetabulae, and proximal femora. 
The caudal-most extent of the bone marrow 
contour should be at the level of the ischial 
tuberosities. 
Active Bone Marrow (Required) 
Active or functional BM will be a subset of the 
entire BM volume (delineated in Bone Marrow), 
as determined by 18F-FDG-PET/CT. Active BM 
will be defined as the sub region of total BM with 
a standardized uptake value (SUV) greater than 
the mean value over the total BM volume. 
Automatic segmentation using commercially 
available software will be used to define the 
functional BM volume, which will be used as an 
avoidance structure for IMRT planning.  
Femur (left and right, separately) (Required) 
The outer contours of the left and the right 
femoral head will be delineated and filled in, 
treating each separately as its own solid 
continuous structure. Do not include the femoral 
neck. 
 
Brachytherapy 
Standard 
Specification 
Bladder (Required) 
The outer bladder wall is contoured. Calculated at 
the center (in the superior-inferior plane on AP 
view) of a contrast-filled balloon of a Foley 
catheter and closest to the applicator system on a 
lateral view. 
Rectum (Required) 
The outer rectal wall is contoured from above the 
anal sphincter to the level of transition into the 
sigmoid. 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
26 
 
5.7.5 Dose Prescription 
 
Conventional RT 
For Conventional RT, the prescription dose of 45 Gy at 1.8 Gy/fraction will be delivered to the 
isocenter which is defined as the intersection of the four beams. EBRT is preferably given once 
daily Monday-Friday, for 5 fractions per week. A three consecutive day parametrial boost may 
be optionally given in the sixth week. 
 
IMRT 
Standard 
Dose (Gy) 
Fraction size (# 
fractions) 
Technique 
PTV 
45 
1.8 (25) 
Exactly 95% of PTV 
receives ≥ 45 Gy  
PTV (for SIB) 
47.6 
1.7 (28) 
Exactly 95% of PTV 
receives ≥ 47.6 Gy  
PTV boost (for SIB) 
54.0-59.4 
1.93-2.12 (28) 
Exactly 95% of PTV 
receives ≥ 54=58.4 Gy 
 
Parametrial boost.  
After the delivery of 45 Gy, at the discretion of the treating physician, a parametrial boost of 5.4 
Gy at 1.8 Gy/fraction may be delivered to mid-plane given by AP/PA fields and the center of the 
unblocked portion of the field. 
 
Lymph Node Boost 
After the delivery of 45 Gy WPRT/EFRT +/- parametrial boost, a nodal boost may be delivered 
to any grossly positive lymph node (PET SUV > 2.5, LN > 15mm short axis diameter on 
CT/MRI, or histologically positive).  Nodal boosts should be delivered to a final dose of 54-59.4 
Gy in keeping with bowel tolerance at the discretion of the treating physician.   
 
HDR Brachytherapy 
In point-directed approach, the doses of 27.5 - 30 Gy and 35 - 40 Gy will be delivered to the 
point A for HDR. The HDR brachytherapy dose can be prescribed to a high-risk clinical target 
volume (CTV) as volume-directed approach, but point A dose must be documented. 
 
Total EBRT (Gy) 
# Fractions 
HDR Point A 
dose/fraction (Gy) 
Total HDR  point 
A Dose (Gy) 
Total Point A 
EQD2-Gy10 
45 
4 
7 
28 
83.9 
45 
5 
5.5 
27.5 
79.8 
45 
5 
6 
30 
84.3 
47.6 
4 
7 
28 
86.1 
47.6 
5 
5.5 
27.5 
81.9 
47.6 
5 
6 
30 
86.4 
HDR-Point A determined implant or volume directed approach 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
27 
In general, HDR insertions should start during the fourth week and be separated by a minimum 
of 48 hours and no more than 2 insertions should be performed per week. Iridium-192 is the 
preferred source for HDR brachytherapy. External beam radiation and brachytherapy may not be 
administered on the same day. Radiation therapy must be completed within 6 weeks of its 
initiation. 
 
5.7.6 Treatment planning priorities and instructions 
Critical structures and target priorities are listed in order of decreasing importance: 
 
EBRT 
1. Bowel 
2. Bone marrow 
3. Rectum 
4. Bladder 
5. Femurs 
 
If max dose constraints are exceeded, the following solution can be entertained: For conventional 
RT with 3D planning, use the field in field technique to decrease hot spots and to reduce the 
bowel dose when MLCs are used. 
 
Brachytherapy 
 
1. Rectum 
2. Bladder 
3. Sigmoid 
 
If dose constraints of critical structures are exceeded, the following solution can be entertained: 
For volume-directed brachytherapy, if the treatment planning system provides a manual 
optimization option, optimize the plan manually to reduce dose to the critical structures as long 
as D90 of CTV meets target volume constraints. 
 
 
5.7.7 Dose Calculations 
 
The primary data set for dose calculations is CT. In the case in which contrast is present during 
the treatment planning CT, the density of the contrast should be overridden to a representative 
background electron density. Heterogeneity corrections should be applied. The dose grid size 
should be ≤ 3 mm in all directions, which means that the CT slice thickness should be ≤ 3 mm. 
 
For IMRT plans, patient specific QA is required. QA is performed by delivering the plan onto a 
phantom and measuring the dose using an ion chamber array or other 2D/3D device. Measured 
dose distribution will be compared to planned dose distribution using a Gamma criterion of 3% 
dose difference and 3 mm distance to agreement. The pass rate should be at least 90% measured 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
28 
for the entire plan. 
 
5.7.8 Daily treatment localization/Image-guided radiation therapy (IGRT) 
 
Conventional RT (4-field box) 
Skeletal imaging using an electronic portal imaging device (EPID) or film portal imaging should 
be performed at least weekly to verify setup accuracy. IGRT technique such as orthogonal kV or 
volumetric imaging such as Cone Beam CT (CBCT) can also be used for weekly setup 
verification. 
 
IMRT 
Daily IGRT is required for this protocol when the IMRT treatment technique is used. Any form 
of online imaging is acceptable, such as MV or kV planar imaging, MVCT or MV CBCT, kV 
CBCT, CT on rails, etc. The AAPM recommendations stated above for verifying coincidence of 
the imaging and treatment beam reference points must be adhered to for daily use of IGRT. At 
the time of simulation, it is recommended to place the isocenter along the patient’s midline 1.5 
cm caudal to the inferior border of the sacroiliac joint. In general, the CT or CBCT will be used 
for setup verification using bone landmarks only and not for soft tissue alignment. Small soft 
tissue shifts (≥3 mm) are acceptable. Otherwise, the treating physician may elect to postpone 
treatment or re-simulate. 
 
5.7.9 Re-planning 
 
Re-planning (such as to account for changes in tumor volume) is allowed. If re-planning is 
necessary, the new treatment plan should meet the same criteria as the initial plan, as if the new 
plan were delivered for the entire treatment course. The new treatment plan should be submitted 
for central review according to the same process as the initial plan. 
 
 
 
 
 
6 
DOSING DELAYS/DOSE MODIFICATIONS CISPLATIN/RADIATION 
 
6.1 
Prior to dosing with cisplatin any day, the following criteria must be met (please 
refer to Nivolumab requirements to dose as well if dosing on applicable day is for 
both drugs): 
 
• ANC > 1000/mcl  
• Platelet count > 50,000/mcl 
*If patient experienced a ANC< 1,000 or a PLT count < 50,000 consider drawing CBC twice 
weekly (not required)  
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
29 
The following table will be used for dose adjustment: 
 
Cisplatin dosing table 
Starting dose all patients 
Dose -1 
Dose -2 
40 mg/m2 (maximum 
70mg/week BSA 1.75m2) 
30 mg/m2 (maximum 
60mg/week) 
25mg/m2 (maximum 
50mg/week) 
*All dose reductions are permanent and each patient can only have 2 dose reductions before 
needing to come off study  
 
For all patients undergoing chemoradiation, all non-hematological related toxicities must be < 
grade 2 to continue with cisplatin, with the following notes:  
 
• Hold chemoradiation for GI toxicities (including diarrhea, nausea, vomiting) > grade 3, 
may resume only when < grade 1 
 
• Creatinine < 2.0mg/dL 
 
If it is > 2.0mg/dL draw CrCl and consider renal ultrasound.  
If CrCl is > 50 ml/min, continue therapy.  
If CrCl is < 50 ml/min, hold treatment and check CrCl weekly.  
When the CrCl is > 50 ml/min, or the serum creatinine < 2.0 mg/dl, resume therapy at 
one dose level reduction.  
Persistence of CrCl < 50 ml/min or serum creatinine > 2.0 mg/dl for > two weeks 
patient’s study therapy with Nivolumab will be stopped. However, patients will 
continue on definitive chemoradiation as standard of care, off protocol, as directed by 
their treating physician. 
 
• Neurotoxicity (including neuropathy and paresthesia) < grade 2 
 
If patient experiences a grade 3-4 neurotoxicity patient will be removed from study 
 
     Refer to section 7 for more information on supportive care 
 
In situations when RT is not given (held for toxicity or other reasons (weather, machine is down, 
holiday), cisplatin and Nivolumab should not be given and should also be held. 
If Nivolumab is held on a day Cisplatin is due and the patient meets criteria to receive Cisplatin 
and Radiation then every attempt should be made to administer Cisplatin and radiation, while 
holding Nivolumab.  
 
Every attempt should be made for all patients to complete radiation therapy (even if cisplatin and 
nivolumab are held) 
 
6.2 
Radiation therapy: 
 
Prior to Radiation administration a patient must be confirmed as having: 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
30 
• ANC> 500/mcl  
• Platelets > 50,000/mcl 
• GI toxicities < grade 2 
• Bladder toxicities < grade 2 
 
Radiation therapy will not be interrupted for uncomplicated hematological toxicity. For purposes 
of this trial, complicated hematologic toxicity is defined as:  
 
• Grade 4 neutropenia- hold radiation until neutropenia is grade 3 or less  
Grade 3-4 thrombocytopenia, hold radiation until thrombocytopenia is grade 2 or less 
RT should be held until ANC > 500/mcl and platelets > 50,000/mcl. Radiation should then be 
restarted, even if cisplatin (and nivolumab) are held.  
 
An uncomplicated hematological toxicity is any hematological toxicity that does not meet the 
above criteria.  
 
Refer to section 7 for more information on supportive care 
   
Other toxicities:  
 
RT should be held for ≥ grade 3 GI toxicities (including diarrhea, nausea, vomiting).  
 
Every attempt should be made for all patients to complete radiation therapy (even if cisplatin and 
nivolumab are held). Patient who require a hold of RT due to toxicity for 7 consecutive days or 
longer will be removed from protocol. See 5.7.1 for definition of deviations for RT delays. 
 
In situations when RT is not given (held for toxicity or other reasons (weather, machine is down, 
holiday), cisplatin and Nivolumab should not be given and should also be held. 
 
If Nivolumab is held on a day Cisplatin is due and the patient meets criteria to receive Cisplatin 
and Radiation then every attempt should be made to administer Cisplatin and radiation, while 
holding Nivolumab.  
 
7 
RESCUE MEDICATIONS AND SUPPORTIVE CARE 
 
7.1 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below. 
 
Where appropriate, these guidelines include the use of oral or intravenous 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 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
31 
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 are recommended when the 
investigator determines the events to be related to nivolumab. 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. These procedures should be performed at the 
discretion of the investigator and are not mandated by the protocol. 
 
7.1.1. Diarrhea/Colitis 
 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  
 
• For patients who are being treated with nivolumab during chemoradiation:  
 
o If diarrhea/colitis occurs prior to initiation of nivolumab or can be attributed 
to chemoradiation, then subjects should be advised to drink liberal quantities 
of clear fluids and will receive standard management for diarrhea with 
loperamide, low residue diet and Lomotil if needed. If sufficient oral fluid 
intake is not feasible, fluid and electrolytes should be substituted via IV 
infusion. For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis.  
 
o If diarrhea/colitis occurs after subject has received any administration of 
nivolumab, then it is critically important to evaluate the subject for immune-
related diarrhea/ colitis. The diarrhea/colitis is likely to be immune-related if it 
has any of the following characteristics:  
 
 Bloody or mucous stools   
 Cramping occurs at a timepoint not typical for chemoRT (i.e., in first 2 
weeks of treatment or after completion of external beam RT) 
 
• If the event meets these criteria (immune mediated), then it should be treated as 
follows: 
 
o All subjects who experience 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.  
o For Grade 2 diarrhea/colitis that is felt to be possibly, probably, or likely 
related to nivolumab, administer oral corticosteroids consistent with Appendix 
D (GI Adverse Event Management Algorithm). Delay treatment as per 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
32 
appendix D. 
o For Grade 3 diarrhea/colitis that is felt to be possibly, probably, or likely 
related to nivolumab and that persists > 1 week, treat with 1-2 mg/kg/day 
methylprednisolone IV (or equivalent). Discontinue nivolumab permanently. 
If opportunistic infection suspected, begin antibiotics promptly. If warranted, 
consider lower endoscopy. If improves, continue steroids until grade 1 then 
taper over at least a month, pending symptoms. If symptoms persist up to 5 
days later, add infliximab 5 mg/kg (if no contraindication).  
o For Grade 4 diarrhea/colitis, treat with 1-2 mg/kg/day methylprednisolone IV 
(or equivalent). Discontinue nivolumab permanently. If opportunistic 
infection suspected, begin antibiotics promptly.  
 
 
7.1.2. Nausea/Vomiting 
Nausea and/or vomiting during the course of chemoradiation is expected and should be 
treated symptomatically by anti-emetic and anti-diarrheal medications, and dietary 
modifications. Every effort should be made to control diarrhea by dietary restriction and 
anti-peristaltic drugs.  
 
o For Grade 1-2 nausea/vomiting with the onset of concomitant cisplatin and 
radiation therapy may be expected. Patients may receive the investigator’s choice 
of drugs for the control of nausea and vomiting associated with the cisplatin 
administration. Intractable nausea and vomiting beyond the first few days after 
cisplatin chemotherapy should arouse suspicion of other causes such as bowel 
obstruction. Consider sending stool sample for Clostridia difficile toxin. 
 
o For Grade 3-4 nausea/vomiting, subjects 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. IV antiemetics may be required, 
as indicated by institutional guidelines. Treatment with cisplatin and/or radiation 
therapy should be delayed until symptoms abate to <grade 3. In circumstances 
where cisplatin is delayed, nivolumab dose should be skipped and not made up.  
 
o For patients who are delayed, every effort should be made to reinitiate 
chemoradiation within a week.  


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
33 
7.1.3. Suggested Management for Renal Adverse Effects 
Increased frequency with dysuria may occur in some patients. This may be treated 
symptomatically with anti-spasmodics and increased fluid intake. Urinary tract infection 
should be ruled out if the symptoms persist.  
 
Persistence of CrCl less than 50 ml/min or serum creatinine greater than 2.0 mg/dl for more 
than two weeks requires discontinuation of protocol treatment, see section 6.1. Selective 
renal tubular defects are sometimes observed. Hypocalcemia with hypomagnesemia and 
hypokalemia are common and potentially severe. Replacement of magnesium, calcium, and 
potassium are usually effective. Severe tubular defects, although rare, may require chronic 
replacement therapy. Diagnostic tests for alternative mechanisms of hypocalcemia (for 
example, GI or metabolic) are suggested. 
 
RT related holds for > 7 days will require removal from protocol treatment. If creatinine rises 
to greater than 2.0 mg/dl, obtain creatinine clearance (CrCl). Consider renal ultrasound. If 
CrCl is greater than or equal to 50 ml/min, continue therapy. If CrCl is less than 50 ml/min, 
hold treatment and check CrCl weekly. When the CrCl is greater than or equal to 50 ml/min, 
or the serum creatinine is less than 2.0 mg/dl, resume therapy at one dose level reduction.  
 
7.1.4. Neurologic adverse effects 
Neurotoxicity from cisplatin therapy is primarily seen as paresthesias, but may also result in 
hearing loss and/or vestibular symptoms due to toxicity to the eighth (VIII) cranial nerve. 
Cisplatin induced neurotoxicity may be related to cumulative dose and thus severe toxicity 
can be largely avoided by careful monitoring prior to each treatment.  
 
Patients should be removed from study for Grade 3-4 neurotoxicity. 
 
7.2 
Criteria for Taking a Participant Off Protocol Therapy 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. For patients receiving nivolumab during chemoradiation, treatment with nivolumab 
must be held if cisplatin is also held.  
 
In the absence of treatment delays due to adverse event(s), treatment with nivolumab may 
continue as indicated in each cohort or until one of the following criteria applies: 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Participant demonstrates non-compliance with treatment regimen and/or required 
study evaluations 
• 
Participant decides to withdraw from the protocol therapy 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
• 
Any required toxicity reason as noted in prior sections of the protocol requiring the 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
34 
patient stop treatment 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
7.3 
Duration of Follow Up 
All Patients will be followed for three years from the end of study treatment. All patients who are 
removed for toxicity will be followed unless they withdraw consent for follow-up.  
 
7.4 
General Concomitant Medication and Supportive Care Guidelines 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented 
source documents as concomitant medication. 
 
Permitted Supportive/Ancillary Care and Concomitant Medications 
 
• Analgesics 
• Antibiotics 
• Anticonvulsants 
• Antiemetics 
• Anticoagulants 
• Antihistamines  
• Corticosteroids +/- mineralocorticoid component  
• Hydration 
• Immunosuppressive agents – other  
• Infliximab  
• Mycophenolate mofetil  
• Nutritional supplementation 
• Interventional use of growth factors is allowed if deemed necessary by the 
Investigator but only to treat grade 4 neutropenia or febrile neutropenia only when 
radiation therapy is held. G-CSF and GM-CSF are not allowed during radiation 
therapy. Erythropoietin use is discouraged in accordance with ASCO guidelines.  
 
Prohibited therapies 
 
• Chronic systemic corticosteroids or other immunosuppressive agents for conditions 
other than for hypersensitivity or immune adverse effects associated with nivolumab 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
35 
as specified in the protocol. 
Patients in this study may use standard vaccines.  Where possible, routine vaccination 
for influenza, pneumococcal pneumonia should be given prior to the start of therapy 
but may be administered during treatment when clinically indicated. Vaccination 
should be given when there is enough separation to distinguish any vaccine reactions 
from drug toxicity.  NOTE: There is no experience using live attenuated vaccination 
during nivolumab therapy, so live vaccine should be used cautiously during 
treatment. 
Concomitant systemic or local anti-cancer medications or treatments are prohibited. 
• G-CSF and GM-CSF are not allowed during radiation therapy. Erythropoietin is 
discouraged in accordance with FDA guidelines.  
 
8 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs and the characteristics of an observed AE will 
determine whether the event requires expedited reporting in addition to routine reporting. 
 
8.1 
Expected Toxicities 
 
Adverse Event List(s) for Nivolumab 
 
Categorization of AEs Potentially Associated with Nivolumab 
 
In order to characterize AEs of special clinical interest that are potentially associated with the use 
of nivolumab, the Sponsor identified select AEs based on the following 4 guiding principles: 
• AEs that may differ in type, frequency, or severity from AEs caused by non-
immunotherapies 
• AEs that may require immunosuppression (e.g., corticosteroids) as part of their 
management 
• AEs whose early recognition and management may mitigate severe toxicity 
• AEs for which multiple event terms may be used to describe a single type of AE, thereby 
necessitating the pooling of terms for full characterization 
 
Based on these guiding principles and taking into account the types of AEs already observed 
across studies of nivolumab monotherapy, endocrinopathies, diarrhea/colitis, hepatitis, 
pneumonitis, nephritis, and rash are currently considered to be select AEs. Multiple event terms 
that may describe each of these are grouped into endocrine, GI, hepatic, pulmonary, renal, and 
skin select AE categories, respectively. The list of AEs belonging to select AE categories may 
evolve as more safety information becomes available in the nivolumab program. 
 
Hypersensitivity/infusion reactions were also analyzed along with the select AE categories 
because multiple AE terms may be used to describe these events, and therefore, pooling of terms 
provides a more complete characterization of the events. Hypersensitivity/infusion reactions do 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
36 
not, otherwise, meet criteria to be considered select AEs. 
Serious Adverse Events Reported from Clinical Trials with Nivolumab Monotherapy 
As of June 2017, the following serious AEs have been reported in clinical studies in which 
nivolumab was given as monotherapy. The frequency of ADRs is defined using the following 
convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 
1/100); rare (≥ 1/10,000 to < 1/1,000); and very rare (< 1/10,000). For further information, 
including SAEs that are rarely associated, please reference the IB. 
 
The following common SAE is associated: pneumonitis, diarrhea 
 
The following uncommon SAEs by system organ class are associated: 
• Endocrine: Adrenal insufficiency, Hypothyroidism 
• Gastrointestinal: Abdominal pain, Colitis, Diarrhea, Nausea, Pancreatitis, Vomiting 
• General and Administrative Site Conditions: Mucosal inflammation, Pyrexia 
• Hepatobiliary: Abnormal hepatic function 
• Immune system: Hypersensitivity 
• Injury, Poisoning and Procedural Complications: Infusion-related reaction 
• Metabolism and Nutrition: Dehydration, Hyperglycemia 
• 
Neurologic: demyelinating polyneuropathy, myasthenic syndrome 
• Renal and Urinary: Acute renal failure, Tubulointerstitial nephritis 
• Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, Hypoxia, Interstitial lung 
disease, Lung infiltration, Respiratory failure 
 
Nonserious Adverse Events Reported from Clinical Trials with Nivolumab Monotherapy 
 
As of June 2017, the following nonserious AEs have been reported in clinical studies in which 
nivolumab was given as monotherapy. The frequency of ADRs is defined using the following 
convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 
1/100); rare (≥ 1/10,000 to < 1/1,000); and very rare (< 1/10,000). 
 
The following very common nonserious AEs are associated: Fatigue, Diarrhea 
The following common nonserious AEs are associated: Arthralgia, Asthenia, Cough, Decreased 
appetite, Pyrexia, Rash, Nausea, Pruritus 
 
A complete list of adverse events observed with nivolumab are detailed in the Investigator’s 
Brochure (IB). 
 
8.2 
Adverse Event Characteristics 
This study will utilize the descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 for grading all adverse events. 
All appropriate treatment areas should have access to a copy of the CTCAE version 4.03. A copy 
of the CTCAE version 4.03 can be downloaded from the CTEP web site (http://ctep.cancer.gov).  
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
37 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily have to 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of Nivolumab, cisplatin or radiation, whether or not considered related to 
Nivolumab, cisplatin or radiation. This includes any newly occurring event or previous condition 
that has increased in severity or frequency since the administration of drug. 
 
During clinical trials, adverse events can be spontaneously reported or elicited during open-
ended questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, 
subjects should not be questioned regarding the specific occurrence of one or more adverse 
events.) 
 
Adverse events (AEs) will be recorded in the case report form for the duration of the trial, 
regardless of whether or not the event(s) are considered related to trial medication.  
 
8.3 
Definitions 
An adverse event is any new, undesirable medical experience or change of an existing condition 
that occurs during or after treatment, whether or not considered product-related. 
 
8.3.1 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Suspected adverse reaction: 
BrUOG, for the sponsor-investigator, is required to report in an IND safety report any suspected 
reaction to the study treatment that is both serious and unexpected.  
 
As per 21 CFR 312.32 (a), the FDA has defined a suspected adverse reaction as any adverse event 
where there is reasonable possibility that the drug may have caused the adverse event. A 
reasonable possibility means there is evidence suggesting a causal relationship between the drug 
and the adverse event.  
 
A suspected adverse reaction outlines the possibility of the causal relationship between the event 
and the drug, whereas an adverse reaction means the drug caused the event.  
 
8.3.2 Serious Adverse Events (SAE) 
 
An adverse event occurring at any dose that results in any of the following outcomes (CFR 
312.32): 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
38 
• death 
• is life-threatening  
• inpatient hospitalization or prolongation of existing hospitalization excluding those for study 
drug administration, transfusional support, disease staging/re-staging procedures, 
concomitant radiotherapy, thoracentesis / paracentesis, or placement of an indwelling 
catheter, unless associated with other serious events. 
• persistent or significant disability or incapacity, 
• congenital anomaly / birth defect.  
 
The definition of serious adverse event (experience) also includes important medical event. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These should 
also usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse. A new diagnosis 
of cancer during the course of treatment should be considered an important medical event. 
 
Unexpected adverse event 
An adverse event that is not mentioned in the Investigator's Brochure or package insert or the 
specificity or severity of which is not consistent with the investigator's brochure or package 
insert. 
 
Life-threatening 
Any adverse drug experience that places the patient or subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred.  It does not include a reaction that, had 
it occurred in a more severe form, might have caused death. 
 
Events requiring reporting as an Important Medical Event: 
 
 Potential drug induced liver injury (DILI) is also considered an important medical 
event.  
 
Potential drug induced liver injury is defined as:  
o ALT and/or AST elevation > 3 times upper limit of normal (ULN) 
AND 
o Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) 
AND 
o No other immediately apparent possible causes of AT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
39 
chronic or acute liver disease, or the administration of other drug(s) known to be 
hepatotoxic. 
Wherever possible, timely confirmation of initial liver related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs. 
• Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE.  
• Although pregnancy, overdose, and cancer (a second primary, excluding non-melanoma 
skin cancer) are not always serious by regulatory definition, these events must be handled 
as SAEs. 
o Pregnancy: see section for information 
o An overdose is defined as the accidental or intentional administration of any dose 
of a product that is considered both excessive and medically important. All 
occurrences of overdose must be reported as an SAE. 
 
NOTE: The following hospitalizations are not considered SAEs: 
 
− 
a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered “important medical event” or event life 
threatening)  
− 
elective surgery, planned prior to signing consent and which would have been 
documented to BrUOG at time of registration (otherwise it will be a SAE) 
− 
admissions as per protocol for a planned medical/surgical procedure per study 
− 
routine health assessment requiring admission for baseline/trending of health status 
(ie, routine colonoscopy)  
− 
medical/surgical admission for purpose other than remedying ill health state and was 
− 
planned prior to entry into the study. Appropriate documentation is required in these 
cases and which would have been documented to BrUOG at time of registration 
admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (ie, lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative) 
  
8.4 
Monitoring of Adverse Events and Period of Observation 
Adverse events, both serious and non-serious, and deaths that occur during the patient’s study 
participation will be recorded in the source documents.   
 
8.5 
BRUOG ADVERSE EVENT REPORTING REQUIREMENTS  
Investigators are required by Federal Regulation to report adverse drug reactions. Questions 
regarding drugs as used in this study should be directed to the Brown University Oncology 
Research Group (BrUOG) Central Office, Phone: (401) 863-3000 Fax (401) 863-3820, which 
will in turn notify the Principal Investigator. 
 
All adverse events and special reporting situations, whether serious or non-serious, related or 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
40 
unrelated, will be reported from the time a signed and dated ICF is obtained until 30 days after 
the last treatment (Nivolumab, cisplatin, radiation, whichever is last), or until the subject 
withdraws consent from study participation (declines participation) or at the time patient 
becomes a screen failure, whichever occurs first. 
 
8.6 
Pregnancies 
Pregnancies occurring while the subject is on study drug or within 30 days (+1 week) after the 
subject’s last treatment (Nivolumab, cisplatin, radiation, whichever is last) are considered 
expedited reportable events.  If the subject is on active treatment, the treatment is to be 
discontinued immediately.  The pregnancy must be reported to the Brown University Oncology 
Research Group, by the site, immediately (within 24 hours of the site being made aware), via the 
site completed BMS pregnancy reporting Form and a 3500A MedWatch form (site to submit to 
BrUOG), and BrUOG will in turn report to BMS immediately (within 1 working day and once in 
receipt of the site submitted SAE forms). Pregnancies and suspected pregnancies (including a 
positive pregnancy test regardless of age or disease state) of a female subject occurring while the 
subject is on treatment (Nivolumab, cisplatin, radiation), or within 30 days (+1 week) of the 
subject’s last treatment (Nivolumab, cisplatin, radiation, whichever is last), are considered 
immediately reportable events. Treatment is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to BMS Drug Safety 
immediately by facsimile, email, or other appropriate method (to be done by BrUOG), using the 
required reporting forms (Forms to be completed by site and sent to BrUOG). 
 
The Investigator will follow the subject until completion of the pregnancy, and must notify BMS 
(by informing BrUOG) of the outcome as specified below.  The Investigator will provide this 
information as a follow-up to the initial report. If the outcome of the pregnancy meets the criteria 
for immediate classification as a SAE (i.e., spontaneous abortion [any congenital anomaly 
detected in an aborted fetus is to be documented], stillbirth, neonatal death, or congenital 
anomaly), the Investigator should follow the procedures for reporting SAEs (i.e., report the event 
to BrUOG who will then report to BMS by facsimile or email within 1 working day of being 
made aware of the event via the sites formal submission of the SAE pregnancy forms). 
 
The patient should be referred to an obstetrician/gynecologist experienced in reproductive 
toxicity for further evaluation and counseling. 
 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 30 days that the Investigator suspects to be 
related to the in utero exposure to the study drug should also be reported. In the case of a live 
“normal” birth, BMS should be advised as soon as the information is available (BrUOG will 
advise BMS once information is submitted to BrUOG). 
 
8.7 
Serious Adverse Event Reporting Procedures  
All pregnancies or suspected pregnancies, including suspected fetal exposure or neonatal deaths 
must be reported to the Brown University Oncology Research Group immediately (within 24 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
41 
hours of being made aware of the event). BrUOG will report all pregnancies to BMS within 1 
working day, and once being made aware of the event once in receipt of the site submitted 
required reports. All other SAEs are to be announced via email to BrUOG within 24 hours of 
being made aware of the event and the site has 5 business days (from being made aware of the 
event) to send the written MedWatch 3500A report to BrUOG, who will then report the SAE to 
BMS product safety within 1 working day of being in receipt of the completed and signed 
Medwatch report (submitted to BrUOG from the site).  Initial SAE information and all 
amendments or additions must be recorded on an SAE Form and faxed or emailed to BMS (to be 
done by BrUOG).  
 
BMS Drug Safety Contact Information: (to be reported to by BrUOG) 
 
BMS SAE EMAIL ADDRESS: Worldwide.Safety@BMS.com 
A copy of the fax transmission or email confirmation of the SAE report to BMS should be 
attached to the SAE and retained with the study records at BrUOG.  
 
The principal investigator (or his designee) has the obligation to report all serious adverse events 
to the Brown University Oncology Research Group’s (BrUOG) office who in return will report 
to the FDA, BMS, and all sites participating in the trial.  All SAE reports will be forwarded to 
BMS Product Safety by BrUOG. All events must be reported by the investigator utilizing the 
Form FDA 3500A (MedWatch Form).  Sites must alert BrUOG to SAEs within 24 hours of 
being made aware of the event via phone or email, and the site will have 5 business days (from 
when site was made aware of the event) to submit formal signed report via the 3500A. BrUOG 
will then alert BMS within 1 business day of being in receipt of the signed Medwatch report. 
BrUOG will submit a SAE memo and Medwatch 3500A to the FDA within the reporting time 
frames. 
 
The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s), if available.  Information not 
available at the time of the initial report (e.g., an end date for the adverse event or laboratory 
values received after the report) must be documented on a follow-up report.   
 
A final report to document discharge from hospital (or end of important medical event) is 
required.   
 
All deaths during treatment or within 30 days following completion of active protocol treatment 
(Nivolumab, cisplatin, radiation, whichever is last) must be formally reported to BrUOG within 5 
business days of being made aware of the event or as soon as the investigator is made aware of 
the event. If the death is thought to be related to the study treatment (Nivolumab, cisplatin, 
radiation), deaths must be reported to BrUOG within 24 hours of the investigator being made 
aware of the event. 
 
All adverse events and special reporting situations, whether serious or non-serious, related or 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
42 
unrelated, will be reported from the time a signed and dated ICF is obtained until 30 days after 
the last treatment (Nivolumab, cisplatin, radiation, whichever is last), or until the subject 
withdraws consent from study participation (declines participation) or at the time patient 
becomes a screen failure, whichever occurs first. 
Every adverse event, serious or non-serious, must be assessed by the investigator with regard to 
whether it is considered immune-mediated. 
 
Serious adverse events occurring more than 30 days (+1 week) after study discontinuation need 
only be reported if a relationship to the study treatment (Nivolumab, cisplatin, radiation) is 
suspected.  
 
8.8 
Types of Report: Guidelines for sites to report: 
Telephone report:  For SAE’s contact the BrUOG office within 24 hours of learning of a SAE. 
For SAE notification: (initial and follow-up) contact BrUOG Central Office (401) 863-3000 (or 
via email), with 24 hour noticed prior to submitting a SAE report. 
 
Written report: Send the signed Medwatch 3500A form (and BMS pregnancy reporting form 
for pregnancies if applicable) within 5 business days of being made aware of the event to the 
BrUOG Central Office by email. For Follow-up reports, please submit the signed Medwatch 
3500A when new information has become available and the event can be closed out. 
 
Brown University Oncology Research Group 
Phone: (401) 863-3000, Fax: (401) 863-3820 
Emails: BrUOG@brown.edu 
 
All deaths during treatment or within 30 days following completion of active protocol treatment 
(Nivolumab, cisplatin, radiation, whichever is last) must be reported within 5 business days 
(from when site was made aware of the event) or as soon as the investigator is made aware of the 
event. If the death is thought to be related to the study treatment (Nivolumab, cisplatin, 
radiation), deaths must be reported to BrUOG within 24 hours of the investigator being 
made aware of the event. SAEs post 30 days since last dose of drug (+1 week) that are 
thought to be possibly related to study treatment (Nivolumab, cisplatin, radiation, whichever 
is last) must be reported to BrUOG within the 5 business day time frame noted above. 
 
MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of 
the MedWatch 3500A form: 
• Treatment regimen (dosing frequency, combination therapy): if related to treatment 
regimen add to section C suspect product, if not related to any, add to concomitant 
section noting Lot #  
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome, if known 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
43 
• Action taken with Nivolumab, cisplatin, radiation as a result of the SAE and 
expectedness (based on IB and consent) 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each investigational 
product (nivolumab) and suspect medication/treatment (cisplatin and radiation) and if 
event(s) is/are immune mediated 
• Site to be clear to outline which events are being reports as serious 
• Must be typed 
• **It is required that sites put the following numbers on the MedWatch form for 
tracking: 
o CA209-9LX 
o BrUOG 355 
A final report to document discharge from hospital (or resolution of important medical 
event) is required. 
 
Follow-up information:   
For any follow-up SAE report, submit a new MedWatch 3500A report; do not resubmit the 
initial report with any additions. The follow-up report must be submitted to BrUOG with subject 
identifiers (subject number, initials, and date of birth), protocol description and number (BrUOG 
355 and CA209-9LX), suspect drug, a brief summary of previously reported SAE information, 
and any new information, including modification of prior events, causality, new serious events, 
discharge date, etc. 
A final report documenting discharge date from the hospital is required. 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of a 
serious adverse event according to institutional policy.   
 
8.9 
BrUOG Responsibility Regarding Reporting:  
The sponsor-investigator by way of BrUOG, the sponsor representative and central coordinating 
office, is required to promptly review all information relevant to the safety of the drug (21 CFR 
312.32(b)).  
 
Safety Reporting for IND Holders 
In accordance with 21 CFR 212.32, Sponsor-Investigator of the study conducted under an IND 
must comply with following safety-reporting requirements:  
 
The BrUOG Central Office will notify by fax all drug reaction reports to the FDA, the Principal 
Investigator, and the participating sites (who will in turn notify their local IRBs) as soon as 
possible but no later than 15 calendar days after initial receipt of the signed information, 
submitted to BrUOG by the site, as per regulatory requirements.  
 
BrUOG, for the sponsor-investigator, is required to report in an IND safety report any suspected 
reaction to the study treatment that is both serious and unexpected (21 CFR 312.32 (c)(1)(i)). It is 
required that events that are suspected, serious and unexpected, be reported to the FDA via an 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
44 
IND safety report. 
 
BrUOG will fax reports to the FDA for IND Safety Reports: to the CDER DOP1 fax number at: 
(301)-796-9845 
 
SAEs will be reported as an amendment to the IND (if applicable) within 15 days of sponsor 
notification. The FDA will all receive a simultaneous copy via facsimile of all adverse events 
filed with the FDA (which will be sent to the Medwatch fax line for IND exemption or to the 
division fax if there is an IND). A copy of the form will be kept by the BrUOG Central Office.   
• “IND safety report” for 15-day reports  
• “Follow-up IND safety report” for followup information  
• “7-day IND safety report” for unexpected fatal or life threatening adverse reaction reports 
 
 
Fax: 1-800-FDA-0178 (1-800-332-0178) For IND exempt study or for IND study the SAE 
will be sent to Center Drug Evaluation Division fax line that has responsibility for review of 
IND): CDER DOP1: (301)-796-9845 
 
Mail: For IND studies BrUOG will send the SAE as an amendment to the IND as well 
 
All SAEs that are serious and reasonably or probably related to the use of Nivolumab will 
be faxed to: BMS 
 
BrUOG will alert BMS to an SAE within 1 business day of being in receipt of the complete 
signed site submitted documentation. 
 
All written IND Safety Reports submitted to the FDA by the Sponsor-Investigator must also be 
faxed to BMS, as well as any pregnancy occurring in association with use of a BMS Product to:  
 
BrUOG will send to: BMS SAE Email Address: Worldwide.Safety@BMS.com 
BMS SAE Facsimile Number:  +1 609-818-3804 
 
8.10  IND Annual Reports, for IND study only 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual 
report is provided to the FDA within 60-days of the IND anniversary date.  21 CRF 312.33 
provides the data elements that are to be submitted in the report.  The Annual Report should be 
filed in the study's Regulatory Binder, and a copy provided to BMS as a supporter of this study  
 
8. 11 Adverse event updates/IND safety reports 
BMS shall notify the Brown University Oncology Research Group (BrUOG) via an IND Safety 
Report of the following information: 
• Any AE associated with the use of study drug in this study or in other studies that is both 
serious and unexpected. 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
45 
• Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
BrUOG will then notify the sites who shall notify their IRB/EC promptly of these new serious 
and unexpected AE(s) or significant risks to subjects. 
 
 
 
 
9 
PHARMACEUTICAL INFORMATION 
 
9.1 
Nivolumab 
 
9.1.1 Description 
Nivolumab is an anti-PD-1Mab with a molecular weight of 146,221 daltons. Nivolumab targets the 
programmed death–1 (PD-1, cluster of differentiation 279 [CD279]) cell surface membrane 
receptor. PD-1 is a negative regulatory receptor expressed by activated T and B lymphocytes. 
Binding of PD-1 to its ligands, programmed death–ligand 1 (PD-L1) and 2 (PD-L2), results in the 
down-regulation of lymphocyte activation. Nivolumab inhibits the binding of PD-1 to PD-L1 and 
PD-L2.  Inhibition of the interaction between PD-1 and its ligands promotes immune responses 
and antigen-specific T-cell responses to both foreign antigens as well as self-antigens. 
 
Nivolumab Injection is a clear to opalescent, colorless to pale yellow liquid; light (few particulates 
may be present. The drug product is a sterile, non-pyrogenic, single-use, isotonic aqueous solution 
formulated in sodium citrate, sodium chloride, mannitol, diethylenetriamine pentacetic acid 
(pentetic acid) and polysorbate 80 (Tween® 80), pH 6.0. 
 
9.1.2 Form 
Nivolumab Injection is a clear to opalescent, colorless to pale yellow liquid; light (few) 
particulates may be present. The drug product is a sterile, non-pyrogenic, single-use, isotonic 
aqueous solution formulated in sodium citrate, sodium chloride, mannitol, diethylenetriamine 
pentacetic acid (pentetic acid) and polysorbate 80 (Tween® 80), pH 6.0. 
 
Nivolumab is supplied by Bristol-Myers Squibb and distributed as 100 mg vials (10 mg/mL) with a 
0.7 mL overfill.  It is supplied in 10 mL type I flint glass vials, with butyl rubber stoppers and 
aluminum seals. 
 
9.1.3 Storage and stability 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) vials of nivolumab injection must be stored at 
2ºC to 8ºC (36ºF to 46ºF) and protected from light and freezing. 
 
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Container 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
46 
 The administration of nivolumab infusion must be completed within 24 hours of preparation. If 
not used immediately, the infusion solution may be stored under refrigeration conditions (2°C to 
8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at 
room temperature (20ºC to 25ºC, 68ºF to 77ºF) and room light. The maximum of 8 hours under 
room temperature and room light conditions includes the product administration period. 
 
Shelf life 
Unopened vial 2 years. 
After opening: 
From a microbiological point of view, once opened, the medicinal product should be infused or 
diluted and infused immediately. 
After preparation of infusion 
From a microbiological point of view, the product should be used immediately. 
 
If not used immediately, chemical and physical in-use stability of OPDIVO has been 
demonstrated for 24 hours at 2ºC to 8ºC protected from light and a maximum of 8 hours at 20°C-
25°C and room light (this 8-hour period of the total 24 hours should be inclusive of the product 
administration 
 
9.1.4 Compatibility 
No incompatibilities between Nivolumab injection and polyvinyl chloride (PVC), non-PVC/non-
DEHP (di[2-ethylhexyl]phthalate) IV components, or glass bottles have been observed. 
 
9.1.5 Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
9.1.6 Availability 
Nivolumab is an investigational agent and will be supplied free of charge from Bristol-Myers 
Squibb. 
 
9.1.7 Preparation 
Visually inspect the drug product solution for particulate matter and discoloration prior to 
administration.  Discard if solution is cloudy, if there is pronounced discoloration (solution may 
have a pale-yellow color), or if there is foreign particulate matter other than a few translucent-to-
white, amorphous particles. 
 
Note: Mix by gently inverting several times.  Do not shake. 
 
Aseptically withdraw the required volume of nivolumab solution into a syringe, and dispense 
into an IV bag.  If multiple vials are needed for a subject, it is important to use a separate sterile 
syringe and needle for each vial to prevent problems such as dulling of needle tip, stopper coring, 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
47 
repeated friction of plunger against syringe barrel wall. Do not enter into each vial more than 
once.  Do not administer study drug as an IV push or bolus injection 
 
Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose 
Injection solution. It is acceptable to add nivolumab solution from the vials into an appropriate 
pre-filled bag of diluent.  
 
Note: Nivolumab infusion concentration must be at or above the minimum allowable 
concentration of 0.35 mg/mL (see most up to date IB for reference)  
 
Note: It is not recommended that so-called “channel” or tube systems are used to transport 
prepared infusions of nivolumab. 
Attach the IV bag containing the nivolumab solution to the infusion set and filter. 
At the end of the infusion period, flush the line with a sufficient quantity of approved diluents. 
After nivolumab (BMS-936558-01) has been prepared for administration, the total storage time 
(combination of refrigeration and room temperature) is not to exceed 24 hours 
 
Please refer to the current Investigator Brochure. Due to parameters surrounding the use time of 
nivolumab, the time of preparation should be noted in the Pharmacy Source documents 
[accountability logs] or in study files as required for investigator sponsored research [FDA and 
GCP]. 
 
9.1.8 Administration 
The administration of BMS-936558-01 injection prepared for dosing nivolumab infusion must be 
completed within 24 hours of preparation. If not used immediately, the infusion solution may 
be stored under refrigeration conditions (2°C to 8°C, 36°F to 46°F) for up to 24 hours, and a 
maximum   of 8 hours of the total 24 hours can be at room temperature   (20°C to 25°C, 
68°F to 77°F) and room light. The maximum of 8 hours under room temperature and room 
light conditions includes the product administration period. 
 
Nivolumab will be given every two weeks at a dose of 240 mg to be administered as a 30 minute 
IV infusion. In maintenance the dose is 480mg to be administered as per the Investigator 
Brochure as a 30 minute IV infusion. 
 
When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat dose), nivolumab injection can be 
infused undiluted or diluted so as not to exceed a total infusion volume of 160 mL. 
 
There are no premedications recommended for nivolumab on the first cycle. There will be no 
dose modifications allowed. 
 
Subjects should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, subjects should be managed according to the Protocol. 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
48 
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
subject tolerates the treatment. 
 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) 
 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding polyethersulfone membrane in-line filter at the protocol-specified 
doses and infusion time. It is not to be administered as an IV push or bolus injection. Nivolumab 
injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, 
USP or 5% Dextrose Injection, USP to protein concentrations as low as 0.35 mg/mL. Care must 
be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. No incompatibilities between nivolumab and 
polyvinyl chloride (PVC), non-PVC/non-DEHP (di(2-ethylhexyl) phthalate) IV components, or 
glass bottles have been observed. 
 
9.1.9 Ordering 
It is possible that sites may have more than one clinical study on the same drug ongoing at the 
same time. It is imperative that only drug product designated for this protocol be used for this 
study 
 
If concerns regarding the quality or appearance of the investigational product arise, do not 
dispense the investigational product, and contact BMS immediately.  
 
Please allow for 5-7 business days for the shipment of drug. 
 
Initial Orders  
• Following submission and approval of the required regulatory documents, BrUOG will 
activate each site, which will allow a supply of nivolumab (when applicable) to be ordered by 
the investigational pharmacist via the BrUOG 355 drug order form. 
• It is required that the box “request for initial drug supply” be checked, the investigator address 
be confirmed as correct (if pre-populated) or populated (if blank), and that the # of vials being 
requested be documented on the form.  
• Once complete, email the form to the email addresses on the drug order form: 
distribution.allentown@thermofisher.com and Cc bruog@brown.edu. 
• Nivolumab:  
o Nivolumab will be supplied in 100 mg vials. 
o The initial order should be limited to 20 vials. Allow 5 business days for shipment of 
drug from BMS receipt of the Drug Request Form. Drug is protocol specific, but not 
patient specific. All drug product will be shipped by courier in a temperature-controlled 
container. It is possible that sites may have more than one nivolumab clinical study 
ongoing at the same time. It is imperative that only drug product designated for this 
protocol number be used for this study. 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
49 
• When drug is received, it is required that an email be sent to bruog@brown.edu to alert BrUOG 
the order was received.  
• Take note that drug should be transferred to +2°C/+8°C storage immediately upon receipt 
• Pharmacy supplies not provided by BMS:  Empty IV bags/containers, approved diluents, In-
line filters and infusion tubing 
 
Re-Supply 
• Drug re-supply request should be requested using the BrUOG 355 drug order form and 
allowing for 5-7 business days for drug shipment.  Deliveries will be made Tuesday through 
Friday. 
• When assessing need for resupply, institutions should keep in mind the number of vials used 
per treatment dose. Drug is not patient-specific. Be sure to check with your pharmacy regarding 
existing investigational stock to assure optimal use of drug on hand. 
• It is required that the box “request for resupply” be checked, the investigator address be 
confirmed as correct (if pre-populated) or populated (if blank), and that the # of vials being 
requested be documented on the form.  
• Once complete, email the form to the email addresses on the drug order form: 
distribution.allentown@thermofisher.com and Cc bruog@brown.edu. 
• When drug is ordered it is required that an email be sent to bruog@brown.edu to alert BrUOG 
to the placed order.  
• When drug is received, it is required that an email be sent to bruog@brown.edu to alert BrUOG 
the order was received.  
 
Drug Excursions 
• Drug excursions should be reported immediately to BMS on the form provided with the 
study-specific drug order form. Please cc bruog@brown.edu on all drug excursion emails 
 
Questions on drug expiration, delayed shipments etc: 
• Send an email to distribution.allentown@thermofisher.com and cc sashin.bhuta@bms.com, 
Rashmi.gadkari@bms.com, and bruog@brown.edu 
• For questions on drug destruction please refer to 9.1.11 as this needs to be communicated 
directly with BrUOG only 
 
9.1.10 Accountability 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
9.1.11 Destruction and Return 
At the end of the study, unused supplies of nivolumab will be destroyed according to institutional 
policies once BrUOG confirms and approves destruction. BrUOG will obtain approval to destroy 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
50 
from BMS.  Destruction will be documented in the Drug Accountability Record Form and the 
form will be routed to BrUOG. 
 
Each participating hospital and pharmacy must submit, up front and throughout the trial, the 
most up to date drug destruction policy, to BrUOG.  
 
Drug that is used (partially used vial for examples), can be destroyed in real-time as per the 
pharmacy destruction policy and do not need to be tracked on the accountability log.  
 
Expired drug: Contact BrUOG to provide the number of expired vials and the current 
accountability logs. BrUOG will obtain approval to destroy drug and will communicate approval 
the pharmacy. BrUOG will then require submission of the drug accountability log, documenting 
the drug destruction of expired material. 
 
10 BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
The aim of such studies will be to identify potentially predictive biomarkers of benefit for 
patients with cervical cancer treated with nivolumab and standard chemoradiation. Data from 
these investigations will be evaluated for associations with response, survival (OS, PFS) and/or 
safety (adverse event) data. Biomarkers analysis may include PD-L1 expression, and tumor 
mutation burden.  We may explore the prognostic significance of  Chitinase 3-like 1 (Chi3l1), 
which we have recently demonstrated to have prognostic significance following immune 
checkpoint inhibitors in lung cancer. It is anticipated that advances in the understanding of 
biomarkers for immune checkpoint inhibitors will be forthcoming over the next few years 
emphasizing the need for tissue storage for future collaborative studies.  
 
Tissue: 
 
Diagnostic: 
For patients with diagnostic tissue at Rhode Island Hospital, The Miriam Hospital or Women and 
Infants Hospital, tissue should remain in the Pathology Department until correlative testing is 
imminent. At that time, all patient’s tissue will be requested for sectioning (20 unstained slides of 
4uM thickness) or a FFPE.  
 
For patients with diagnostic tissue outside of the system (defined above): Tissue will be 
requested from patient’s baseline diagnostic sample or most recent biopsy. Samples are to be 
labeled with study number (BrUOG 355), patient initials, patient study number and time point. 
 
Formalin-fixed paraffin embedded (FFPE) tumor tissue block or at least 20 unstained slides 
(charged) of 4 uM thickness will be required to be sent to the Clinical Research Center (CRC) at 
Rhode Island Hospital. 
 
Lifespan Clinical Research Center 
1 Hoppin Street, 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
51 
Coro West, Room 3.461, 
Providence RI, 02903 
 
For tissue from research only (optional) biopsy: 
The research staff is to contact their respective pathology department point of contact (it is 
required to submit de-identified email chain with data to BrUOG), at least 24 hours prior to 
collection of a research only biopsy. Following the sites institutional policies & procedures, the 
specimen will be prepped, cassetted, processed, and embedded.  The block will then be sectioned 
at 4µM, 20 sections and placed on charged slides. The tissue must be labeled with study number 
(BrUOG 355), patient initials, patient study number and time point. The tissue will then be sent 
for storage at the CRC for future testing. 
 
Lifespan Clinical Research Center 
1 Hoppin Street, 
Coro West, Room 3.461, 
Providence RI, 02903 
LCRCLab@lifespan.org 
 
 
11 STUDY CALENDAR 
Baseline evaluations are to be conducted within 28 days prior to start of protocol therapy, unless 
otherwise specified.  Scans and x-rays must be done <4 weeks (28 days) prior to the start of 
therapy.   
Assessments must be performed within 3 days prior to each treatment dosing day. Study 
assessments (required to be completed and resulted prior to any drug administration) and agents 
should be administered within + 3 days of the protocol-specified date, unless otherwise noted. 
*The day an assessment (PE, labs, scan etc) is completed is day 0 for counting for example 
labs drawn on Friday can be used for Monday dosing as this is within 3 days* 
 
Baseline evaluations are to be conducted within 28 days prior to start of protocol therapy, unless 
otherwise specified below.  Scans must be done <28 days prior to the start of therapy. 
Baseline labs are required within 14 days of registration. HCG is 7 days.  
Parameter 
Pre- 
Study to be 
sent to BrUOG 
with results 
prior to 
registration 
WeeklyaI 
within 3 days 
prior to dosing 
day 1 each 
week. 
Monthlyb 
required within 
3 days prior to 
day 1 of each 
cycle 
Off study 
(post 
completion 
of whole 
cycle)j +1 
week 
30 days 
post last 
treatment 
(+1 
week)j 
Follow-up 
Informed 
consent(within 30 
days of day 1) *pts 
are to be re-
consented if ICF 
will be outside 30 
day window 
X 
 
 
 
 
 
Diagnostic 
pathology 
X- no time 
frame 
 
 
 
 
 
FNA 
X- no time 
 
 
 
 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
52 
frame k 
History & Physical  
X 
X 
X 
X 
X 
 
Concurrent meds 
X 
X 
X 
X 
 
 
Toxicity 
Assessment 
XD 
X 
X 
X 
X 
 
Vitals M 
X 
X 
X 
X 
 
 
Performance status 
X 
X 
X 
X 
 
 
Imaging 
evaluation(CT 
C/A/P preferred) 
Xf 
 
 
Xf 
Xf 
Xf 
Tumor 
measurement 
X 
 
 
X 
 
X 
CBC (Including 
differential) 
Xd 
Xe 
X 
X 
 
 
Chemistries (CMP, 
CA/Mg/PO4) 
Xd 
X 
X 
X 
 
 
Amylase and lipase 
Xd 
X 
X 
X 
 
 
Liver Function tests 
(AST, ALT, Alk 
Phos, LDH) 
Xd 
X 
X 
X 
 
 
EKG 
X 
 
 
 
 
 
Pregnancy test 
Xg 
Xg 
Xg 
 
 
 
Audiogram 
Xh 
 
Xh 
Xh 
 
 
Thyroid Function 
Tests (TSH, Free 
T4, T3) 
X 
 
X 
X 
 
 
Viral studies (CD4 
count – only 
required for patients 
who are HIV 
positive to certify 
eligibility, see 
exclusion 3.2.2 for 
timeframes and 
requirements.; 
HBsAg, , HCV Ab, 
if positive HCV Ab 
then order HCV 
RNA testing) 
X 
 
 
 
 
 
Tumor Biopsy 
Xc 
 
 
 
 
 
Radiation 
 
 
XN 
 
 
 
Cystoscopy, 
proctoscopy, barium 
enema 
X- optional but 
if done must 
submit 
 
 
 
 
 
CMP=Glucose, Calcium, Albumin, Total Protein, Sodium, Potassium, CO2, Chloride, BUN, Creatinine, ALP, 
ALT, AST, Bilirubin (total), amylase and lipase 
a. 
Obtain during cycles 1 and 2 Nivolumab (all cohorts) and chemoradiation therapy. Amylase and Lipase are 
required within 3 days of dosing with Nivolumab, with cycles 1 and 2 and q 2 weeks during chemoradiation 
therapy. 
b. Obtain for those patients receiving maintenance nivolumab treatment, prior to dosing each cycle 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
53 
c. 
The first tumor biopsy may come from the diagnostic procedure where the diagnosis of cervical cancer was 
made. For patients who consent, a second biopsy should be attempted within 7 days after second dose of 
nivolumab in all patients, prior to chemoradiation. 
d. Must be obtained within 14 days prior to initiation of protocol treatment 
e. If grade 4 neutropenia is documented, monitor CBC twice weekly until resolved to ≤ grade 3 
f. CT C/A/P is the preferred method of imaging. CT C/A/P must be obtained at the completion of chemoradiation (+ 
14 days), 6 months later (+/- 14 days) and then q 6 months (+/- 14 days) for up to 3 years or until confirmation of 
PD.  If an alternative imaging modality is used at baseline, the same imaging technique must be used throughout the 
study duration.  
g. Serum pregnancy test (women of childbearing potential) required within 7 days prior to day 1, Also required 
every 4 weeks (+/- 1 week) while on-study. Cycle 1 day 1: required HCG for all women of child bearing potential 
within 24 hours (1 day) prior to dosing day 1 cycle 1 only and confirmation of negative HCG test required to be sent 
to BrUOG. Patients with a positive test are required to be taken off study prior to any dosing on study. 
h. Required in all patients with a history of hearing loss. Must be obtained within 28 days prior to initiating 
protocol therapy. Repeat during treatment as clinically indicated. 
I.If screening labs are performed greater than 14 days prior to Cycle 1 Day 1, labs must be repeated on Cycle 1 Day 
1 and must meet eligibility criteria. The patient may not start on study treatment until Cycle 1 Day 1 labs meet 
eligibility criteria. If screening labs are performed within 14 days prior to Cycle 1 Day 1, and meet eligibility 
criteria, labs do not need to be repeated on Cycle 1 Day 1 unless the investigator believes they are likely to have 
changed significantly. History, AE & concomitant medication assessment, vitals and performance status can be used 
from screening for cycle 1 day 1 if they were within the 14 day screening period (14 days from day 1). A physical 
exam within 7 days prior to cycle 1 day 1 can be utilized. 
j. Off-study evaluation to occur post completion of entire cycle. Follow-up visits or other contact are required in 
order to identify SAEs during the 30 days (+1 weeks) following the end of study treatment (Nivolumab, cisplatin or 
radiation), respectively. SAEs need to be reported after 30 days if the SAE is thought to be related to study 
treatment.  
k. patients who have positive or suspicious para-aortic nodes on lymphangiography, CT scan, or ultrasound 
examinations will undergo a fine needle aspiration (FNA), extraperitoneal lymph node biopsy, or laparoscopic 
sampling 
L. Survival and disease status will be collected approximately every 6 months (+/- 1 month)  for 3 years. DURING 
COVID 19, study follow-up may be done virtually if it is in the best interests for the patient and her safety. 
Virtual follow-up will be documented by the research team if performed.  
M. Vital signs include: Weight, height (baseline only required), Blood pressure, heart rate, temperature, and Pulse 
oximetry oxygen saturation 
N Site to submit end of treatment Radiation Oncology note summarizing all treatment  
 
12 MEASUREMENT OF EFFECT 
12.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response at the completion 
of definitive chemoradiation (+ 14 days) and then six months later (+/- 14 days). Following this, 
all patients will be followed every 6 months (+/- 14 days) for up to three years. The same 
imaging modality should be used at each time point in this study. For purposes of this trial, 
imaging should consist of a CT Chest/Abdomen/Pelvis (CT/CAP).  
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
54 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
Definitions 
 
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan (preferred), MRI, or calipers by clinical exam.  All 
tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  NOTE: bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 
disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all 
considered non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
55 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (inclusive of cervical masses and palpable lymph nodes) and ≥10 mm in 
diameter as assessed using calipers.    
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
56 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. the low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with RECIST measurements and will not 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
57 
be used on this trial.  
 
Response Criteria 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
58 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
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 for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
59 
objective progression even after discontinuation of treatment. 
For Participants 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 preferred 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 
 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
Progression-Free Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation. 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
60 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported. 
 
13 REGULATORY CONSIDERATIONS 
This research study is sponsored by the Principal Investigator, Dr. Don Dizon, in collaboration 
with Brown University Oncology Research Group (BrUOG), which will serve as the central 
coordinating office for the study. This study is supported by BMS (the makers of Nivolumab). 
 
13.1 Protection of Human Subjects 
The Investigator must ensure that patients or their legally acceptable representatives are clearly 
and fully informed about the purpose, potential risks and other critical issues regarding clinical 
trials in which they volunteer to participate.  Preparation of the consent form is the responsibility 
of the Investigator and must include all elements required by CFR 21 Part 50.25 and the local 
IRB. 
 
13.2 Compliance with the Protocol and Protocol Revisions: 
The study must be conducted as described in this approved protocol.   
All revisions to the protocol must be created by Brown University Oncology Research Group, 
and approved by BMS.  The Investigator should not implement any deviation or change to the 
protocol without prior review and documented approval/favorable opinion from the IRB/IEC and 
BMS of an Amendment, except where necessary to eliminate an immediate hazard(s) to study 
patients. 
 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to Brown University Oncology Research Group, and BMS.  If the revision is an 
Administrative Letter, Investigators must inform their IRB(s)/IEC(s).  
 
The Investigator must ensure that patients or their legally acceptable representatives are clearly 
and fully informed about the purpose, potential risks and other critical issues regarding clinical 
trials in which they volunteer to participate.  Preparation of the consent form is the responsibility 
of the Investigator and must include all elements required by CFR 21 Part 50.25 and the local 
IRB. 
 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative prior to study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent will comply 
with ICH-GCP and all applicable regulatory requirement(s). 
 
13.3 Protocol amendments or changes in study conduct:  
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be created the Brown University Oncology Research Group, BMS and the 
investigator before implementation. Amendments significantly affecting the safety of subjects, 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
61 
the scope of the investigation or the scientific quality of the study require additional approval by 
the IRB at each study center.  A copy of the written approval of the IRB must be provided to 
Brown University Oncology Research Group, and BMS 
• Examples of amendments requiring such approval  
• Increases in drug dose or duration of exposure of subjects 
• Significant changes in the study design (e.g. addition or deletion of a control group) 
• Increases in the number of invasive procedures 
• Addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Brown University Oncology Research Group and BMS in the 
interests of preserving the safety of all patients included in the trial.  If an immediate change to 
the protocol is felt to be necessary by the investigator and is implemented for safety reasons 
Brown University Oncology Research Group and BMS must be notified and the IRB at the 
center must be informed immediately.  
14 DATA MONITORING / QUALITY ASSURANCE/ RECORD RETENTION 
14.1 
Good Clinical Practice:  
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and in the US Code of Federal Regulations.  The 
investigator will be thoroughly familiar with the appropriate use of the drug as described in the 
protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations.   
 
14.2 
Patient Confidentiality:  
In order to maintain patient privacy, all data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
The investigator will grant monitor(s) and auditor(s) from BMS or its designees and regulatory 
authority (ies) access to the patient’s original medical records for verification of data gathered on 
the data capture records and to audit the data collection process.  The patient’s confidentiality 
will be maintained and will not be made publicly available to the extent permitted by the 
applicable laws and regulations. 
 
14.3 
Protocol Compliance:   
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB/IEC and the appropriate regulatory authority(ies).  Changes to the protocol 
will require approval from BMS and written IRB/IEC approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
patients.  The IRB/IEC may provide, if applicable regulatory authority (ies) permit, expedited 
review and approval/favorable opinion for minor change(s) in ongoing studies that have the 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
62 
approval /favorable opinion of the IRB/IEC.  The investigator will submit all protocol 
modifications to BMS and the regulatory authority (ies) in accordance with the governing 
regulations. Any departures from the protocol must be fully documented in the source 
documents.   
 
14.4 
On-site Audits:  
Regulatory authorities, the IRB and/or BMS clinical quality assurance group may request access 
to all source documents, data capture records, and other study documentation for on-site audit or 
inspection.  Direct access to these documents must be guaranteed by the investigator, who must 
provide support at all times for these activities. 
 
14.5 
Drug Accountability:  
Accountability for the drug at all study sites is the responsibility of the principal investigator.  
The investigator will ensure that the drug is used only in accordance with this protocol.  Drug 
accountability records indicating the drug’s delivery date to the site (if applicable), inventory at 
the site (if applicable), use by each patient, and return to BMS for disposal of the drug (if 
applicable and if approved by BMS) will be maintained by the clinical site.  Accountability 
records will include dates, quantities, lot numbers, expiration dates (if applicable), and patient 
numbers.   
 
All material containing Nivolumab will be treated and disposed of as hazardous waste in 
accordance with governing regulations. 
 
14.6 
Premature Closure of the Study:  
This study may be prematurely terminated, if in the opinion of the investigator or BMS, there is 
sufficient reasonable cause.  Written notification documenting the reason for study termination 
will be provided to the investigator or BMS by the terminating party.   
 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate 
• Insufficient adherence to protocol requirements 
• Insufficient complete and/or evaluable data 
• Plans to modify, suspend or discontinue the development of the drug 
• Should the study be closed prematurely, all study materials must be returned to BMS 
14.7 Record Retention:  
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).   
 
The Brown University Oncology Research Group, as coordinator of this study, is responsible for 
ensuring proper conduct of the study with regard to protocol adherence and the validity of the 
data recorded on the case report forms. The Principal Investigator (Don Dizon, M.D.) and Brown 
University Oncology Research Group will monitor this study. The case report forms will be 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
63 
monitored against the submitted documents for accuracy, completeness, adherence to the 
protocol and regulatory compliance.  
 
U.S. FDA regulations (21CFR312.62[c] require all records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consents 
forms, laboratory test results and medication inventory records, must be retained by the Principal 
Investigator for 2 years after marketing application approval. If no application is filed, these 
records must be kept 2 years after the investigation is discontinued and the FDA and the 
applicable local health authorities are notified. BMS will notify the Principal Investigator if an 
application is filed.  
 
15 DATA SAFETY AND MONITORING BOARDS 
All trials initiated by the Brown University Oncology Research Group (BrUOG) are subject to 
oversight by the Data Safety Monitoring Board (DSMB).  This board meets two times per year 
with any additional meetings scheduled when needed.  The responsibilities are as follows: 
• Familiarize themselves with the research protocol (s)  
• The DSMB reviews trial performance information such as accrual information.   
• Review interim analyses of outcome data and cumulative toxicity data summaries to 
determine whether the trial should continue as originally designed, should be changed, or 
should be terminated based on these data.   
• The DSMB also determines whether and to whom outcome results should be released 
prior to the reporting of study results. 
• All adverse events are reviewed by the committee, with assurances that these have been 
in fact sent for review to all pertinent IRBs. 
• Review of reports of related studies to determine whether the monitored study needs to be 
changed or terminated. 
• Review major proposed modifications to the study prior to their implementation (e.g., 
termination, dropping an arm based on toxicity results or other reported trial outcomes, 
increasing target sample size). 
• Following each DSMB meeting, provide the study leadership with written information 
concerning findings for the trial as a whole related to cumulative toxicities observed and 
any relevant recommendations related to continuing, changing, or terminating the trial.  
 
The study leadership will provide information on cumulative toxicities and relevant 
recommendations to the local principal investigators to be shared with their IRB’s. 
16 STATISTICAL CONSIDERATIONS 
 
16.1  Study Design/Endpoints 
The primary endpoint of this pilot study is to assess the acute toxicity of combining nivolumab 
with definitive chemoradiation. For the purposes of the study, acute toxicities will be those 
having onset during or within 30 days of completing treatment. For those receiving nivolumab as 
maintenance treatment, it will also include those events occurring during or within 30 days of 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
64 
treatment completion.  
 
16.1.1. Safety review 
A safety review for each cohort will be conducted. For cohort 1, safety analysis will occur at the 
end of chemoradiation. For patients in cohort 2 (who receive nivolumab following 
chemoradiation), evaluation for safety will occur 4 weeks following initiation of maintenance 
nivolumab. For patients in cohort 3, safety analyses will occur at the end of chemoradiation and 
after maintenance therapy has completed.  
 
Criteria that will determine safety will include: 
- Grade 3 or higher adverse events that persists for 14 days or longer despite dose-
holds and/or maximal medical support. This excludes uncomplicated 
neutropenia and any laboratory abnormalities deemed by the treating clinician 
as having no clinical significance 
- Inability to complete chemoradiation within 8 weeks 
 
The BrUOG overall PI, the Women & Infants’ Hospital site PI (once study is activated), and the 
Medical Director of BrUOG will review safety data as described to make determinations of 
feasibility. Enrollment to cohort 2 will not be dependent on the safety review for cohort 1. 
However, the safety review will be completed for cohort 2, before enrollment begins in cohort 3.  
 
If more than 25% of patients (more than 2 patients in cohort 1 or more than 1 patient in cohort 2) 
experience a grade 3 or higher adverse event that persists for 14 days or longer, despite dose-
holds and/or maximal support, the treatment will be considered not feasible and the next cohort 
will not be opened.  
If more than 25% of patients (more than 2 patients in cohort 1 or more than 1 patient in cohort 2) 
are unable to complete chemoradiation within 8 weeks, the treatment will be considered not 
feasible and the next cohort will not be opened.  
 
16.2 
Sample Size, Accrual Rate and Study Duration 
For this feasibility study, the planned sample size is 24 patients (8 in cohorts 1 (1A and 1B)), 4 in 
cohort 2, and up to 12 in cohort 3 to enroll a maximum of 24 evaluable patients in the trial). The 
total sample size may need to be adjusted to allow for replacement of participants who withdraw 
prior to completion of the third week of chemoradiation, as these are the only reasons for 
replacement. It is anticipated that 4 patients will be enrolled per month for an approximate 
accrual period of 9 months. All patients who begin protocol therapy will be included in the 
evaluation of toxicity for 30 days post last treatment, unless patient withdraws from study.   
 
16.3 
Stratification Factors 
For those treated with nivolumab during chemoradiation (Cohort 1) stratification will be guided 
by radiation field. Cohort 1A will consist of patients receiving whole pelvic RT, while Cohort 1B 
will consist of patients receiving extended field RT. No further stratification is anticipated for 
Cohorts 2 and 3. However, enrollment in Cohort 3 may be revised pending outcomes in Cohort 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
65 
1.  
 
16.4 
Analysis of Primary Endpoints 
Time-to-event endpoint of progression free survival at 3 years will be described using the 
method of Kaplan-Meier, and presented with 90% confidence intervals. Patients that are alive 
without disease progression at time of analysis are censored at the date of last disease evaluation. 
Acute Treatment-related toxicities that occur during and within six months of study treatment 
will be summarized by maximum grade and by term using CTCAE v4.0 and reported with 90% 
binomial exact confidence intervals. Acute toxicities will be used to determine the feasibility 
within each cohort. 
 
16.5 
Analysis of Secondary Endpoints 
 
Recurrence patterns within three years of study entry will be described for each cohort, to 
determine whether there is a difference in patterns (locoregional versus distant). 
 
Chronic treatment-related toxicities will be summarized by maximum grade, experienced beyond 
six months of completion of radiation therapy.  
 
16.6 
Reporting and Exclusions 
 
Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
Evaluation of the Primary Efficacy Endpoint 
 
All of the participants who met the eligibility criteria and who receive at least one dose of study 
drug will be included in the main intent-to-treat analysis of the response rate.  
 
17 PUBLICATION PLAN 
The results should be made public within 12 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than 12 
months after the end of the study.  
18 REFERENCES 
 
1. AJCC Cancer Staging Manual. (Springer). 
2. Quinn, M. A. et al. Carcinoma of the cervix uteri. FIGO 26th Annual Report on the Results of 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
66 
Treatment in Gynecological Cancer. Int. J. Gynaecol. Obstet. Off. Organ Int. Fed. Gynaecol. 
Obstet. 95 Suppl 1, S43-103 (2006). 
3. Dizon, D. S. et al. State of the science in cervical cancer: where we are today and where we 
need to go. Cancer 120, 2282–2288 (2014). 
4. Benito, V. et al. Should the Presence of Metastatic Para-aortic Lymph Nodes in Locally 
Advanced Cervical Cancer Lead to More Aggressive Treatment Strategies? J. Minim. Invasive 
Gynecol. (2017). doi:10.1016/j.jmig.2017.01.016 
5. Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (CCCMAC). Reducing 
uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient 
data meta-analysis. Cochrane Database Syst. Rev. Online CD008285 (2010). 
doi:10.1002/14651858.CD008285 
6. Sasagawa, T., Takagi, H. & Makinoda, S. Immune responses against human papillomavirus 
(HPV) infection and evasion of host defense in cervical cancer. J. Infect. Chemother. Off. J. 
Jpn. Soc. Chemother. 18, 807–815 (2012). 
7. Patel, S. & Chiplunkar, S. Host immune responses to cervical cancer. Curr. Opin. Obstet. 
Gynecol. 21, 54–59 (2009). 
8. Cancer Genome Atlas Research Network. Integrated genomic and molecular characterization 
of cervical cancer. Nature (2017). doi:10.1038/nature21386 
9. Hollebecque, A. et al. An open-label, multicohort, phase I/II study of nivolumab in patients 
with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic 
(R/M) cervical, vaginal, and vulvar cancers. J. Clin. Oncol. 35, 5504–5504 (2017). 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
67 
APPENDIX A ELIGIBILITY CHECKLIST 
 
BrUOG 355: A Pilot Feasibility study incorporating Nivolumab to tailored radiation therapy with 
concomitant cisplatin in the treatment of patients with cervical cancer  
 
Inclusion criteria (UNLESS OTHERWISE SPECIFIED, ALL CRITERIA MUST BE 
FULFILLED WITHIN 28 days (labs are 14 days)OF ENROLLMENT): 
 
_________(y/n) Age ≥  18 years.  Cervical cancer is rarely seen in women under 18 years.   
 
_________(y/n) ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) 
 
_________(y/n) Patients with histologically confirmed advanced cervical cancer (any cell type): 
FIGO Clinical stages IB2, IIA, IIB, IIIA, IIIB, IVA.  
 
_________(y/n) All patients must have tissue from the diagnostic biopsy submitted prior to 
enrollment for both pathologic confirmation of the diagnosis (if done outside of a BrUOG 
institution) and for specimen collection. Pathology must be reviewed by gynecological 
pathologist.NOTE: Patients with positive or negative pelvic and/or para-aortic lymph nodes by 
histologic confirmation or by radiological evaluation are eligible. 
 
_________(y/n) Participants must have normal organ and marrow function as defined below: 
_________(y/n) absolute neutrophil count ≥1,500/mcL 
_________(y/n) platelets ≥100,000/mcL 
 
 
 
_________(y/n) total bilirubin within normal institutional limits 
_________(y/n) AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal 
_________(y/n) creatinine Within normal institutional limits 
 
_________(y/n) hemoglobin > 9.0g/dL 
_________(y/n) Neuropathy (sensory and motor) ≤ CTCAE v4.0 grade 1 
 
_________(y/n) Patients with ureteral obstruction should undergo stent or nephrostomy tube 
placement prior to study entry. Any side effects or complications associated with stent placement 
that, in the opinion of the treating investigator, puts the patient at increased risk for treatment-
related toxicity, must be resolved completely prior to study enrollment.  
 
_________(y/n) Patients of child-bearing potential must have a negative serum pregnancy test 
prior to study entry (within 7 days prior to initiation of study treatment) and be practicing an 
effective form of contraception during study treatment and for 24 months  (2 years) thereafter.  
 
_________(y/n) Women should not breast-feed while on this study 
 
_________(y/n) Patients must not be receiving any other investigational agent 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
68 
_________(y/n) Ability to understand and the willingness to sign a written informed consent 
document. 
 
_________(y/n) All patients with a history of hearing loss are required to have an audiogram 
within 28 days prior to initiating protocol therapy. If patient does not have a history of hearing 
loss this must be documented by treating physician. Audiogram with results required to be 
submitted to BrUOG. 
Exclusion: 
_________(y/n) Participants with visceral metastases, including brain metastases. 
 
_________(y/n) Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, hepatitis, active rheumatologic or collagen vascular disease, symptomatic congestive 
heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. HIV disease not 
controlled on antiretroviral therapy are also excluded. See exclusion for hepatitis information. 
 
_________(y/n) Patients who have received previous pelvic or abdominal radiation, cytotoxic 
chemotherapy, or previous therapy of any kind for this or any other malignancy. 
 
_________(y/n) Patients who have circumstances that will not permit completion of this study or 
the required follow-up as per the treating physician 
  
_________(y/n) Patients with a history of other invasive malignancies, with the exception of 
non-melanoma skin cancer are excluded if there is any evidence of other malignancy being 
present within the last three years (2 years for invasive breast cancer). However, patients with a 
malignancy that is non-likely to require treatment, as per the treating physician, in the next 2 
years, such as a completely resected, early stage breast cancer, or other malignancies treated with 
curative intent are eligible. Patients are also excluded if their previous cancer treatment 
contraindicates this protocol therapy. 
 
_________(y/n) Prior treatment with immunotherapy for any cancer, including immune 
checkpoint inhibitors or anti-CTLA4 agents  
 
_________(y/n) Patients with renal abnormalities, such as pelvic kidney, horseshoe kidney, or 
renal transplantation, that would require modification of radiation fields as documented by 
treating physician 
 
_________(y/n) Participants with an active, known or suspected autoimmune disease. 
Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, 
skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to enroll. 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
69 
_________(y/n) Participants with a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications 
within 14 days of day 1 of treatment. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease 
 
*See section 3.3 in eligibility* 
It is required that all elements be submitted  
 
Signed informed consent: The patient must be aware of the neoplastic nature of his/her disease and must 
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. 
 
The support documentation, per the requirements under the study parameters section of this study, as well 
as the consent form and this checklist, must be faxed to the BrUOG Central Office at the time of 
registration.  Please check if “Enclosed”, state reason when “Not Enclosed,” or check if "Not Applicable."  
 
1) Eligibility Form  
 
Enclosed __Not Enclosed   
___ Not Applicable  __ 
2) Heme/Onc initial note 
Enclosed __Not Enclosed   
___ Not Applicable  __ 
3) Pathology Report(s)         
Enclosed __Not Enclosed   
___ Not Applicable  __ 
4) MRI/CT Report(s)   
Enclosed __Not Enclosed   
___ Not Applicable  __ 
5) Lab Source Document         
Enclosed __Not Enclosed   
___ Not Applicable  __ 
6) ICF signature page 
 
7) Other documentation 
 
It is required that each item from the schedule of evaluation be submitted to BrUOG along with 
confirmation via source to match each inclusion and confirm each exclusion criteria. 
 
Most recent IRB approval date of protocol (whether this be the initial, latest amendment or CR):  
 
 
  
 
Date of treatment day 1 (Nivolumab):____________ 
 
Hospital where patient will be treated with Oncologist:  
 
 
 
Name of treating physician: _____________ 
 
Hospital/location where radiation will be administered:_____________ 
 
Name of Radiation Oncologist:__________________________ 
 
Was tissue at diagnosis from outside hospital? _________(y/n) 
 
If yes, document tissue was requested with date:______________ 
Confirm received and confirm by local gynecologic pathologist and pathology report of review of the 
outside sample with this registration: _________(y/n) 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
70 
Your signature:  
 
 
 
 
 
 
 
APPENDIX B: AGREEMENT TO PARTICIPATE IN A RESEARCH STUDY AND 
AUTHORIZATION FOR USE AND DISCLOSURE OF INFORMATION 
 
BrUOG 355: A Pilot Feasibility study incorporating Nivolumab to tailored radiation therapy with 
concomitant cisplatin in the treatment of patients with cervical cancer  
 
 
You are being asked to take part in a research study.  All research studies carried out at 
<INSERT HOSPTIAL NAME> are covered by rules of the Federal government as well as rules 
of the State and <INSERT HOSPTIAL NAME>.  Under these rules, the researcher will first 
explain the study, and then he or she will ask you to participate.  You will be asked to sign this 
agreement that states that the study has been explained, that your questions have been answered, 
and that you agree to participate. 
 
The researcher will explain the purpose of the study. He or she will explain how the study will be 
carried out and what you will be expected to do.  The researcher will also explain the possible 
risks and possible benefits of being in the study.  You should ask the researcher any questions 
you have about any of these things before you decide whether you wish to take part in the study.  
This process is called informed consent. 
 
This form also explains the research study.  Please read the form and talk to the researcher about 
any questions you may have.  Then, if you decide to be in the study, please sign and date this 
form in front of the person who explained the study to you. You will be given a copy of this form 
to keep. 
 
Nature and Purpose 
 
Your doctors are participating in this research study sponsored by the Principal Investigator, Dr. 
Don Dizon, in collaboration with Brown University Oncology Research Group (BrUOG), which 
will serve as the central coordinating office for the study. Bristol-Myers Squibb, a 
pharmaceutical company, is financially supporting this research study by providing the study 
drug, Nivolumab, and funding for the study. 
 
You are invited to take part in a clinical trial, a type of research study, because you have locally 
advanced cervical cancer that you have not previously received treatment for. Your doctor will 
explain standard options specific to your cancer type that are available outside of this clinical 
trial, but it may include standard available chemotherapy or other targeted treatment. 
 
This research study is a Phase II clinical trial.  Phase II clinical trials test the safety and 
effectiveness of the investigational drug in combination with radiation to learn whether the 
drug(s) works in treating a specific disease.  “Investigational” means that the agent in this trial 
has not been approved for use in the treatment of this particular tumor type. 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
71 
 
In this study, your doctors are studying three treatment arms, each using standard chemotherapy, 
with the drug cisplatin and radiation and the drug Nivolumab. Each treatment Arm will test the 
addition of Nivolumab at a different time point. This will be explained below. Your doctors will 
be comparing the arms to see if one is more effective and less toxic than the other. While some 
patients with locally advanced cervical cancer will be cured by standard treatment with cisplatin 
and radiation, in many patients, the cancer comes back after that treatment, and so we are hoping 
that the addition of nivolumab will make the standard treatment more effective. Nivolumab is 
believed to work by preventing the cancer from blocking the immune system from attacking it, 
which may help fight the cancer. We are unsure if the addition of adding nivolumab to standard 
treatment will improve the effectiveness of cisplatin and radiation, but this is being studied. 
 
The FDA (the U.S. Food and Drug Administration) has not approved nivolumab for cervical 
cancer, but Nivolumab is approved for other cancers, such as advanced melanoma. The treatment 
of using the chemotherapy drug cisplatin and radiation is standard for the treatment of your 
disease. The primary objective of the study is to determine if nivolumab can be safely given in 
combination with cisplatin and pelvic radiation in patient with cervical cancer.  
 
How Many People will take part in the Study?  
It is expected that up to 24 people will take part in this research study.  
 
Explanation of Procedures   
 
What will happen if I take part in this research study?  
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests, while on the study.  They are part of regular cancer care.  
 
• A medical history, which includes questions about your health, current medications, and 
any allergies. 
• Performance status, which evaluates how you are able to carry on with your usual 
activities.  
• An assessment of your tumor including the chest, abdomen and pelvis, by CT 
(Computerized Tomography) scan 
• Blood tests. about 4 teaspoons of blood will be taken to assess your organ function.  
• Pregnancy test (blood), if you are a female of child-bearing potential will be performed 
both 7 days prior to the start of treatment and again within 1 day prior to the start of 
treatment. 
• Electrocardiogram (ECG), which measures the electrical activity of your heart 
• Audiogram, a test to check your hearing may be done if you are found to have a history 
of hearing loss. This will be done as one of the drugs being used with radiation, cisplatin, 
has been known to cause hearing loss. 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
72 
• Cystoscopy (a test to examine the lining of your bladder), proctoscopy (a procedure 
to examine your anus, rectum and sigmoid colon) and barium enema (an X-ray to 
look for changes in your large intestine), may all be done depending on the stage of 
your disease  
• Tissue: A sample of your tumor from your initial diagnosis or the most recent biopsy 
procedure will be requested by your study doctor. Researchers at Rhode Island Hospital, 
will examine your tumor tissue to see how the study treatment may affect your cancer. 
 
While on study: 
There are three treatment groups in this study. Patients will be enrolled to one group at a time. 
Neither you nor your doctor may choose which Arm you are enrolled to or which treatment you 
get. Your doctor will tell you which Arm and treatment you have been assigned. 
 
The first group of patients will only get nivolumab during their chemoradiation, the second 
group of patients  will only get it for the 2 years after they complete the standard chemoradiation, 
the third group, assuming patients from the first 2 groups tolerated treatment well, will get the 
nivolumab both during chemoradiation and for the 2 years following it.  
 
All patients in all treatment groups, will receive two doses of nivolumab prior to the start of 
chemotherapy and radiation.  
 
Following the two doses of nivolumab, you have the option to consent for the collection of a 
second biopsy. Depending on the location of your cancer your doctor will choose what type of 
biopsy is best for you, such as a biopsy performed in clinic or a CT guided biopsy (a procedure 
using a very thin needle and syringe to withdraw tissue from a tumor with the help of a CT scan). 
This is not a required biopsy.  
 
___ YES I consent to the second research biopsy 
 
___ NO I do not want to have the second research biopsy 
 
All patients will receive standard chemotherapy drug cisplatin with radiation. Cisplatin will be 
given by IV over about 1 hour once a week for 6 weeks beginning day 1 of radiation. Radiation 
will be given 5 days a week (preferably beginning on a Monday) for 6 weeks.  
 
Arm 1: Will include about 8 patients.  
 
A cycle is about 2 weeks long. 
 
There will be 2 groups of patients in Arm 1: about 4 patients will receive external beam radiation 
and about 4 patients will receive a targeted radiation called intensity modulated radiotherapy 
(IMRT). The radiation field will be determined by your Radiation Oncologist depending on your 
disease.  


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
73 
 
Treatment in Arm 1 includes Nivolumab with standard chemotherapy (drug cisplatin) and 
radiation.  
Nivolumab will be given once every 2 weeks into your vein (by intravenous infusion) beginning 
day 1 of radiation for 3 cycles (3 doses).  
• Pre-medications: You may be pre-medicated with drugs to reduce the chance of having 
a reaction to the study treatment. If you tolerate the study treatment without a reaction, 
then pre-medications may be changed by your doctor. 
 
Arm 2: Arm 2 will include about 4 patients. Enrollment to Arm 2 will open once all patients 
have been enrolled in Arm 1.  
 
In the Arm 2, patients will receive standard chemotherapy (drug cisplatin) and radiation. The 
radiation field will be determined by your Radiation Oncologist depending on your disease. 
 
Approximately 2-3 weeks post the completion of chemotherapy and radiation Nivolumab will be 
given once every 4 weeks into your vein (by intravenous infusion) for 2 years (about 24 doses). 
 
• Pre-medications: You may be pre-medicated with drugs to reduce the chance of having 
a reaction to the study treatment. If you tolerate the study treatment without a reaction, 
then pre-medications may be changed by your doctor. 
 
Arm 3: Once Arms 1 and 2 have been completed the study doctors will review the safety of the 
treatment and enrollment to Arm 3 will be opened. Arm 3 will enroll about 12 patients.  
 
Treatment in Arm 3 includes Nivolumab with standard chemotherapy (drug cisplatin) and 
radiation. Nivolumab will be given once every 2 weeks (3 doses) into your vein (by intravenous 
infusion) beginning day 1 of radiation. The radiation field will be determined by your Radiation 
Oncologist depending on your disease. 
 
Once chemotherapy and radiation ends, patients will then receive Nivolumab once every 4 weeks 
into your vein (by intravenous infusion) for 2 years (about 24 doses). 
 
All patients: Study Visit: Weekly 
This visit will involve the following: 
• Clinical Exams:  During this visit you will have a physical exam and you will be asked 
questions about your general health and specific questions about any problems that you 
might be having and any medications you may be taking. 
• Performance status, which evaluates how you are able to carry on with your usual 
activities.  
• Safety evaluation 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
74 
• Blood tests (approximately 3 tablespoons),  
 
 
All patients: Study visit: Monthly 
• Clinical Exams:  During this visit you will have a physical exam and you will be asked 
questions about your general health and specific questions about any problems that you 
might be having and any medications you may be taking. 
• Performance status, which evaluates how you are able to carry on with your usual 
activities.  
• Safety evaluation 
• Blood tests (approximately 3 tablespoons), inclusive of a pregnancy test for women of 
child-bearing potential 
• Audiogram: for patients with a history of hearing loss 
 
All Arms: End of Treatment  
 
This visit will involve the following: 
• Clinical Exams:  During this visit you will have a physical exam and you will be asked 
questions about your general health and specific questions about any problems that you 
might be having and any medications you may be taking. 
• Performance status, which evaluates how you are able to carry on with your usual 
activities.  
• Safety evaluation 
• Blood tests (approximately 3 tablespoons) 
• An assessment of your tumor CT scan (or other scan if determined to be more 
beneficial by your study doctor or your insurance) of your chest, abdomen and pelvis 
used to assess the response of your disease. 
• Audiogram: for patients with a history of hearing loss 
• At approximately 30 days after your final treatment, you will have another visit to assess 
any problems you may be having that may be related to your treatment  
 
All Arms: Follow-up  
 
After completion of treatment you will be seen by your doctor approximately every 6 months for 
3 years. You will continue to be followed by a CT scan of the chest, abdomen and pelvis 
approximately every 6 months during follow-up. These scans will stop if your cancer progresses. 
 
Can I stop being in the study?  
Yes. You can decide to stop at any time.  Tell your doctor if you are thinking about stopping or 
decide to stop.  He or she will tell you how to stop safely.   
 
It is important to tell your doctor if you are thinking about stopping so any risks from the 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
75 
discontinuation of treatment can be evaluated. Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you.  
 
Your doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped.  
 
Costs for participating in this study  
Some of the services you will receive are being performed only because you are participating in 
this research study.  Examples of these ‘research only’ services include the drug Nivolumab. The 
drug will be will be provided by BMS, the makers of the drug, at no charge and will not be billed 
to you or your health insurance company. Also, the second optional biopsy, and its storage, 
which may be attempted post the first two doses of Nivolumab is a ‘research only’ service. Your 
insurance nor you will be charged for any costs associated with the research only biopsy.  
 
Other services you will receive during this research study are considered "routine clinical 
services" that you would have received even if you were not in the research study. 
 
These include all study doctor visits, blood tests, drugs used to reduce side effects, doctor visits, 
all blood tests, pregnancy tests, radiation, cisplatin, audiogram, the infusion of  the study drug 
Nivolumab, disease related testing (such as a cystoscopy etc), CT scans, MRIs, PET scans and 
EKGs.  Therefore, all of the services listed in this paragraph will be billed to your health 
insurance company, but you will be responsible for paying any deductibles, co-payments, or co-
insurance that are a normal part of your health insurance plan. If you do not have health 
insurance or your insurance does not cover these services, you will be responsible for those 
costs. 
 
Contact Information: If you have any questions regarding this study, you may contact your 
site’s Principal Investigator, <INSERT NAME AND CONTACT> 
 
Discomforts and Risks 
There are risks to taking part in any research study. One risk is that you may get a study drug that 
does not help treat your disease or that makes your condition or disease worse.  Another risk is 
that there may be side effects.   
 
All cancer treatments can have side effects, which can range from mild and reversible to severe, 
long lasting and possibly life-threatening.  There is a great deal of variability among side effects 
of different cancer treatments and between individuals.  In a research study, all of the risks or 
side effects may not be known before you start the study. You need to tell your doctor or a 
member of the study team immediately if you experience any side effects.  
 
Everyone in the research study will be watched carefully for side effects.  You will be monitored 
during the administration of study drugs to keep track of your blood counts and organ function, 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
76 
particularly your kidney and liver function.  If you experience side effects, they may go away 
after you stop taking the study drug.  Some side effects can be mild; but others can be long 
lasting and may never go away.  Some may be life-threatening or fatal.  
 
Since the effect of the study drug taken with other medications may not be known, it is important 
that you tell the research doctor about all prescription and non-prescription drugs, herbal 
preparations and nutritional supplements that you are taking or planning to take.  
 
During the research study, you will be notified of newly discovered side effects or significant 
findings, which may affect your health or willingness to participate.  You may be asked to sign a 
new consent form that shows that you have been informed of new information relating to this 
research study. 
Taking part in this study may lead to time away from work. 
 
Nivolumab is an immunotherapy drug. Nivolumab is an agent involved in the inhibition of 
“immune checkpoints,” and may result in severe and possibly fatal immune-mediated side 
effects probably due to activation and growth of immune cells (T-cells).  By stimulating the 
immune system, it is possible that the immune system could attack and damage normal organs 
and tissues. Immune-mediated side effects have been reported in patients receiving Nivolumab.  
In clinical trials, most side effects were reversible and managed by stopping Nivolumab 
temporarily, administration of corticosteroids and supportive care. While rare, immune mediated 
side effects may also occur after stopping Nivolumab. These are considered late onset immune 
mediated toxicities, which may begin even months after stopping treatment. Your doctor will 
closely monitor you after you stop treatment and provide supportive care as necessary.  There 
are also some side effects which may not yet be known. There is a small risk of death 
 
Nivolumab: 
Frequent - Greater than 10% chance this will happen 
• Diarrhea 
• Nausea 
• Fatigue 
• Rash 
• Itchiness  
 
Occasional – Between 1 and 10% chance this will happen  
• Thyroid gland abnormalities. May cause fatigue, weight gain, fluid retention, sensitivity 
to cold & mental apathy. Can be serious or life threatening.  
• Elevated blood sugar  
• Bowel inflammation. This could result in severe diarrhea and may require hospitalization 
for treatment. Severe and prolonged diarrhea can be  life-threatening.  
• Inflammation or ulceration of the mouth and lining of the digestive tract  
• Vomiting  


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
77 
• Abdominal pain  
• Constipation  
• Dry mouth  
• Fevers  
• Swelling of the face, body, arms, or legs (edema).  
• Abnormally high levels of enzymes produced by the liver meaning your liver is not 
functioning properly. Although this is usually mild and reversible, this can be serious or 
life threatening. 
• Reaction to the drug infusion, including flushing, shortness of breath, dizziness, chest 
pain, or other symptoms.  
• Infections  
• Blood abnormalities, including low blood phosphate, magnesium, potassium, or sodium 
levels. These may require repletion or correction of abnormal blood test values.  
• Blood test abnormalities, including increase in lipase or amylase, which may reflect 
inflammation of the pancreas.  
• Decreased appetite  
• Joint or muscle pain or stiffness  
• Tingling, burning, or numbness in hands and feet  
• Headache  
• Dizziness  
• Kidney failure which is when both of your kidneys fail and your body holds fluid which 
can be serious or life threatening. Your blood pressure rises and harmful wastes build up 
in your body. When this happens, you may need to be hospitalized or else be placed in 
dialysis.  
• Shortness of breath  
• Cough  
• Loss of color (pigment) from areas of skin  
• Skin reactions, including hives, redness, and dry skin. Rarely, a skin reaction may be 
severe and result in extensive skin blistering (Stevens Johnson syndrome). This can be a 
life-threatening event.  
• Hair thinning or loss  
• Elevated blood pressure  
• Inflammation of the lungs which can cause shortness of breath and difficulty breathing. If 
severe, this can be life threatening. 
• Muscle or joint pain 
 
 
Rare – Less than 1% chance this will happen  
• Changes in heart rhythm, resulting in a fast or irregular heartbeat. Certain types of 
irregular heartbeats can be serious or life-threatening.  
• Adrenal gland abnormalities, which may cause you to feel weak.  


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
78 
• Pituitary gland abnormalities, which may cause headaches, change in eyesight, increased 
thirst, and increased frequency passing urine.  
• Diabetes. This is an elevated blood sugar that can occur when your body is not able to 
regulate blood sugar levels normally. Elevated blood sugar levels may be life-threatening 
and may require hospitalization for treatment.  
• Inflammation of the eyes. This may result in decreased or blurry vision.  
• Inflammation of the pancreas. This could become severe and cause nausea and vomiting, 
fever and rapid heart rate. This could require hospitalization and may be life threatening.  
• Inflammation of the airways. This can result in cough or shortness of breath.  
• Swollen lymph nodes  
• Autoimmune disorders, including Guillain-Barre syndrome, which can be associated with 
progressive muscle weakness or paralysis.  
• Inflammation or loss of the lining of the brain and spinal cord, which may cause 
neurological damage including confusion, hallucinations, difficulty walking or using 
arms  
• Myasthenia gravis, when the body’s immune system attacks muscle nerve cell receptors 
causing weakness in the muscles. This can be severe or life-threatening.  
• Abnormal brain function due to brain inflammation (encephalitis), which can be 
potentially life-threatening or fatal.  
• Inflammation of the blood vessels, which could cause possible bleeding and/or bruising. 
• Cardiac issues, including the risk of heart inflammation, or myocarditis 
 
 
Lung Inflammation (pneumonitis):  It is possible that nivolumab may cause inflammation of 
the tissues of the lung.  This adverse effect has been reported infrequently in patients treated with 
nivolumab.  While many patients with x-ray or CT abnormalities have not developed any 
symptoms, some patients have developed mild to severe symptoms and in rare cases, death has 
occurred as a result of their lung inflammation.  Signs and symptoms of lung inflammation may 
include difficulty breathing, pain or discomfort while breathing, chest pain, cough, shortness of 
breath, increased rate of breathing, fever, low blood oxygen levels, or fatigue.   
   
Your study doctor and nurse will watch you closely for changes in your ability to breathe and for 
other signs or symptoms that might show you are developing this type of lung inflammation and 
will perform regular tests including physical exams, measurement of oxygen levels through non-
invasive testing (i.e., pulse oximeter), blood tests, chest x-rays and/or CT scans. 
 
Please inform your study doctor or nurse AT ONCE if you experience any of the following: 
• Any new or increased shortness of breath; 
• Any new or increased chest pain; 
• Any new or increased pain/difficulty while breathing; 
• Any new or increased cough or any significant change in your type of cough; for example 
any new or increased mucous or blood in your cough;   


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
79 
• Any change in the amount of oxygen you require; 
• Any fever, fatigue, or other symptoms that occur at the same time as any changes to your 
breathing or other lung symptoms.  
 
If you start to develop symptoms, your study doctor will ask you to return to the clinic for 
additional tests, which could include a physical exam, measurement of oxygen levels, blood 
tests, chest x-rays, and/or CT scans. You will be monitored very closely for changes in your 
overall lung symptoms, monitoring may require hospitalization. You may require specific 
treatment in order to control pneumonitis. You may also be seen by a special doctor called a 
pulmonologist, who has special training to be an expert in how your lungs work. 
 
Prolonged treatment with medicines that suppress inflammation, sometimes needed to manage 
the side effects of nivolumab treatment, may lower your body’s ability to fight off certain 
infections (i.e., opportunistic infections). These infections may require treatment with antibiotic 
or antifungal medications and may be fatal. 
 
Reproductive Risks From nivolumab  
 
Because the drug in this study can affect an unborn baby, you should not become pregnant while 
on this study. 
 
If you are a woman of childbearing potential you must practice an effective method of birth 
control while receiving study treatment.  For women of child-bearing potential, you should not 
attempt pregnancy while participating in this research study and for 2 years after.  
Ask your study doctor for more information regarding preventing pregnancy during the study 
treatments. 
 
You should not nurse your baby while on this study. If you are premenopausal, your periods are 
likely to stop temporarily and may stop permanently due to the study treatments, which may lead 
to symptoms of menopause, such as hot flashes, and the inability to become pregnant, which may 
be permanent. If you are concerned about this, ask your study doctor about options for 
preserving your reproductive choices, which may include referral to a specialist in this field.   
 
By signing this document you are acknowledging that you understand and agree to the 
information presented in this Reproductive Risk section. 
 
Risks from cisplatin 
 
Risks and side effects related to cisplatin include those which are listed below.   
  
Likely:  
• Decreased white blood cell count, which may increase risk of infection 
• Decreased red blood cell, also called anemia, which may cause tiredness, weakness, and 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
80 
shortness of breath 
• Decreased platelet counts, which may increase risk of bleeding 
• Nausea 
• Vomiting 
• Decreased appetite 
• Abnormal kidney function 
• Hearing loss and/or ringing in ears  
  
Less likely but serious:  
• Numbness/tingling in hands and feet, difficulty walking  
• Electrolyte imbalances (decreased calcium, magnesium)  
• Vision problems  
• Allergic reaction  
• Abnormal liver function  
  
Rare:  
• Rash  
• Hair loss  
• Secondary leukemia  
• Abnormal heart function  
• Loss of appetite   
  
Risks from Radiation Therapy 
 
Risks and side effects related to radiation therapy include those which are listed below.   
  
Likely:  
• Tanning or reddening of the skin which is exposed to the radiation beam 
• Burning or pain during urination or defecation  
• Diarrhea  
• Permanent pubic hair loss  
  
Less likely but serious:  
• Damage to the small or large intestine or rectum or ureter or bladder which may require 
medications, hospitalization for management, or rarely a surgical procedure to repair  
  
Rare:  
• Nerve damage which may cause numbness or weakness in the legs  
  
Other unknown side effects can occur with the combination of immunotherapy and standard 
chemoradiation, but you will be monitored for them.    
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
81 
Other risks:  
Antiemetics (anti-nausea medications): Various medications used to prevent nausea and 
vomiting may cause drowsiness, dry mouth, diarrhea, constipation, headache, restlessness, 
agitation, anxiety, dizziness, involuntary tremors, skin rash, and possible allergic reaction. 
You will receive pre-medication to reduce the risk of infusion/injection reactions on your 
treatment days. Overall, the pre-medications you will be given are well tolerated. 
 
Venipuncture (inserting a needle into a vein to obtain blood or give medication): May cause 
inflammation, pain, bruising, bleeding, or infection. 
 
When you receive chemotherapy by vein, there is a slight risk that some of the drug may leak out 
around the needle at the injection site. A skin burn may result. Most skin burns are treatable and 
heal well. 
 
In order to monitor the side effects, your physician will examine you frequently and obtain 
laboratory tests (blood tests, chest x-rays, or CT scans as needed) to determine the effects of your 
treatment and alter the drug dosages if necessary. 
 
Risk of CT imaging: CT imaging uses x-rays. The radiation dose associated with this procedure 
is estimated to be a small fraction of the annual permissible dose to an x-ray technologist. There 
is no significant risk from this amount of radiation. 
There may be other side effects that have not been reported. If you have any unusual symptoms, 
you should report them immediately to your doctor or nurse. 
 
Benefits 
We do not know if taking part in this study will help you. This study may help researchers learn 
information that could help people in the future. 
 
Alternative Therapies 
 
Taking part in this research study is voluntary. Instead of being in this research 
study, you have other options which may include the following: 
 
• Receive standard treatment. Your doctor will discuss with you specific 
standard treatment options. 
• Take part in another research study if there is one available. 
• Receive no therapy specific to your cancer. 
• Comfort care, also called palliative care. This type of care may help to reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat the 
cancer directly, but instead tries to treat the symptoms. 
 
Please talk to the research doctor about your options before you decide whether 
you will take part in this research study. 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
82 
 
Refusal/Withdrawal 
It is up to you whether you want to be in the study.  You are not required to enroll or participate.  
If you decide to participate, you can always change your mind and quit at any time.  If you 
decide not to be in the study, or if you quit later, you will still be able to get the health care 
services you normally get.  If you join, but later on the researcher or your doctor feels being in 
the study is no longer good for you, they may choose to take you out of the study before it is 
over.  If new information becomes available that might change your mind about whether you 
want to stay in the study the researcher will share this information with you as soon as possible. 
If you make the decision to withdraw from this study (stop taking study medication) for any 
reason, tell your doctor immediately. You will be asked to sign a form indicating whether you 
give your permission for your doctor and the research staff to continue to collect and submit 
follow-up information on your health status from your physicians and medical record. After 
signing the form, you still have the right to change your mind, at any time, regarding follow-up 
after withdrawal. 
 
Medical Treatment/Payment in Case of Injury 
A research injury is any physical or mental injury or illness caused by being in the study. If you 
are injured by a medical treatment or procedure you would have received even if you were not in 
the study that is not a research injury. To help avoid research injury and added medical expenses, 
it is very important to follow all study directions carefully. If you do experience a research 
injury, <INSERT HOSPITAL NAME> or the study doctor can arrange medical treatment for 
you. Such treatment will be paid for as described below.  
 
Medical treatment will be available if you suffer a research related injury; however, you and/or 
your health insurance company will be charged for this treatment. The study will not pay for this 
medical treatment. Neither Dr. Don Dizon nor BrUOG, the coordinating center, have money set 
aside to reimburse you for medical bills from treatment of a research related injury or otherwise 
compensate you in the event of a study-related injury.  
 
If you have insurance and have a research injury that is not covered by the study, it is possible 
that some or all of the cost of treating you could be billed to your insurer. If your health 
insurance will not cover such costs, it is possible you would have to pay out of pocket. In some 
cases, <INSERT HOSPITAL NAME>  might be able to help you pay if you qualify for free care 
under <INSERT HOSPITAL NAME>  policy. However, <INSERT HOSPITAL NAME>  has 
no policy to cover payment for such things as lost wages, expenses other than medical care, or 
pain and suffering. 
 
Rights and Complaints 
Signing this form does not take away any of your lawful rights. If you have any complaints about 
this study, or would like more facts about the rules for research studies, or the rights of people 


 
 
Br U O G 3 5 5: 7/ 8/ 1 7, 7/ 1 1/ 1 7, 7/ 2 0/ 1 7, 8/ 7/ 1 7, 8/ 8/ 1 7, 8/ 1 4/ 1 7, 8/ 1 6/ 1 7, 8/ 2 1/ 1 7, 8/ 2 2/ 1 7, 8/ 2 4/ 1 7, 8/ 2 8/ 1 7, 9/ 5/ 1 7, 
9/ 6/ 1 7, 9/ 8/ 1 7, 9/ 1 1/ 1 7, 1 1/ 7/ 1 7, 1 1/ 8/ 1 7, 1 1/ 1 9/ 1 7 a p pr o ve d D D, 1 1/ 2 0/ 1 7, 1 2/ 1 2/ 1 7, 1 2/ 1 4/ 1 7, 1/ 2 9/ 1 8, 2/ 1/ 1 8, 
2/ 6/ 1 8, 2/ 7/ 1 8, 2/ 8/ 1 8, 2/ 9/ 1 8, 2/ 1 2/ 1 8, 2/ 1 3/ 1 8, 3/ 8/ 1 8 all re vie ws, 3/ 9/ 1 8, 3/ 1 3/ 1 8, 3/ 1 4/ 1 8, 3/ 1 5/ 1 8, 4/ 1 9/ 1 8, 
4/ 2 3/ 1 8, 5/ 2 9/ 1 8, 6/ 5/ 1 8, A me n d me nt # 1 7/ 9/ 1 8, A me n d me nt # 2 1 2/ 1 2/ 1 8, A me n d me nt # 3, 4/ 6/ 2 0 2 0, A me n d me nt 
# 4 5/ 1 1/ 2 0 2 0  
 
8 3  
w h o ta ke part i n r esearc h st u dies y o u ma y c o nt act <I N S E R T C O N T A C T N A M E O F I R B > 
 
C o nfi de nti alit y  
  
 
Y o ur res ear c h rec or ds will be treate d as pri vate healt h care rec or ds a n d will be pr otecte d 
acc or di n g t o <I N S E R T H O S PI T A L N A M E > pri vac y practices a n d p olicies t hat are b ase d o n 
state a n d fe d eral la w. I n partic ular, f e deral la w re q uires us t o get y o ur per missi o n t o use or 
discl ose (release y o ur i nf or mati o n t o s o me o ne o utsi de of <I N S E R T H O S PI T A L N A M E >) y o ur 
healt h i nf or mati o n f or r esearc h p ur p oses. If y o u si g n t his f or m y o u a gree t o be i n t his researc h 
st u d y a n d y o u p er mit t he use a n d discl os ure of y o ur healt h i nf or mati o n f or t he p ur p ose of 
c o n d ucti n g t h e res ear c h, pr o vi di n g treat me nt, c ollecti n g p a y me nt a n d r u n ni n g t he b usi ness of t h e 
h os pital. T his per missi o n has n o e x pirati o n date. Y o u ma y wit h dra w fr o m t he st u d y at a n y ti me. 
H o we ve r, if y o u d o n ot wa nt t he res earc hers t o use or discl ose a n y f urt her i nf or mati o n i n t his 
st u d y y o u m ust ca ncel per missi o n i n writi n g a n d ma y d o s o at a n y ti me. If y o u ca ncel y o ur 
per missi o n, y o u will st o p ta ki n g part i n t he st u d y a n d n o ne w i nf or mati o n wil l be c ollecte d a b o ut 
y o u. H o w e ver, if y o u ca n cel y o ur per missi o n, it will n ot a p pl y t o acti o ns alrea d y ta ke n or 
i nf or mati o n alrea d y c ollecte d a b o ut y o u b y t he h os pital or t he researc h ers b ef ore y o u ca n cele d 
y o ur p er missi o n.  
Ge ner all y, t he e ntire r esearc h  r ec or d a n d a n y me di cal rec or ds hel d b y t he h os pital ma y be us e d 
a n d release d f or res ear c h p ur p oses. T he f oll o wi n g pe o ple or b usi nesses/c o m pa nies mi g ht use, 
releas e, or r ecei v e s uc h i nf or mati o n:  
 T he researc h er a n d t h eir s u p p ort staff;  
 T he st u d y s p o ns or a n d Pri nci pal I n v esti gat or Dr. D o n Diz o n a n d Br U O G, T he Br o w n 
U ni versit y O n c ol o g y Res earc h Gr o u p a n d its re prese ntati ves, i ncl u di n g B M S t he fi na ncial 
s u p p orter of t his trial a n d t he ma ker of Ni v ol u ma b 
 D oct ors, n urses, la b or at ories a n d ot hers w h o pr o vi de ser vices t o y o u i n c o n necti o n wit h t his 
st u d y;  
 T he c o m pa n y or secti o n of t he U. S. g o v er n me nt t hat is pa yi n g f or t h e st u d y a n d ot h ers t he y 
hire t o o versee, a d mi nister, or c o n d u ct t he res earc h;  
 T he  U nite d States F o o d a n d Dr u g A d mi nistrati o n, t he De part me nt of Healt h a n d H u ma n 
Ser vices, t he Office of I ns pect or Ge n eral, a n d t he Office of Ci vil Ri g hts;  
 Pe o ple w h o v ol u nteer t o be patie nt a d v ocates or researc h v ol u nteer pr otect ors;  
 Me m bers of t he h os pital's a d mi nistrati ve staff res p o nsi ble f or re vie wi n g, a p pr o vi n g a n d 
a d mi nisteri n g cli nical tri als a n d ot her healt hcare or researc h acti vities.  
 
  
 
T h ere are ti mes w h e n t he la w mi g ht re q uire or p er mit <I N S E R T H O S PI T A L N A M E >  t o rel ease 
y o ur h ealt h i nf or mati o n wit h o ut y o ur per missi o n. F or e x a m ple, <I N S E R T S T A T E > la w re q uires 
researc hers a n d healt h care w or k ers t o re p ort a b us e or ne glect of c hil dre n t o t he De part me nt of 
C hil dre n, Y o ut h a n d Fa milies ( D C Y F) a n d t o re p ort a b use or ne gl ect of p e o ple a ge 6 0 a n d ol d er 
t o t he De part me nt of El d erl y Aff airs. 
All resear c hers a n d healt h care pr o vi ders are re q uire d t o pr otect t he pri vac y of y o ur healt h care 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
84 
information. Other people and businesses/organizations that are not health care providers are not 
required by law to do that so it is possible they might re-release your information.  
You have the right to refuse to sign this form and not participate in the research. Your refusal 
would have no effect on your treatment, charges billed to you, or benefits at any <INSERT 
HOSPITAL NAME> health care site. If you do not sign, you will not be able to enroll in the 
research study and will not receive treatment as a study participant.  
 
If you decide to quit the study after signing this form (as described in Section 6) no new 
information will be collected about you unless you gave us permission to do so. However, the 
hospital or the researchers may continue to use information that was collected before you quit the 
study to complete analysis and reports of this research. 
 
 
 
Additionally, a description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. law. This Web site will not include 
information that can identify you. At most, the Web site will include a summary of the results. 
You can search this Web site at any time.  
If after you have signed this form you have any questions relating to your rights, please contact 
<INSERT IRB CONATACT INFORMATION> 
 
 
about your privacy rights see the <INSERT HOSPITAL NAME> which has or will be given to 
you. 
Research authorization for use and disclosure of information.   
The purpose of this section of the document is to provide you with some more information about 
how the information learned about you during the study will be used and shared. 
We understand that your medical information is very personal and we will work hard to keep it 
private. If you sign this form you consent to participate in this research study and are giving us 
permission to use and share your personal health information in the ways described in this form.   
Understandings and notifications 
 
The main purpose of permitting the use and release of your information is to allow the research 
project to be conducted and to ensure that the information relating to that research is available to 
all parties who may need it for research purposes.  Your information may also be used as 
necessary for your research-related treatment, to collect payment for your research-related 
treatment (when applicable), and to run the business operations of the hospital. 
 
All health care providers are required to protect the privacy of your information.  However, most 
persons or entities (i.e., businesses, organizations) that are not health care providers are not 
bound by law to protect the privacy of your information.  You understand that if the person or 
entity that receives your information is not a health care provider bound to protect your privacy, 
such person or entity might re-release your health information.  
 
 
You have the right to refuse to sign this form.  If you do not sign this form, none of your health 
care outside the study, or the payment for your health care, or your health care benefits will be 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
85 
affected.  However, if you do not sign this form, you will not be able to enroll in the research 
study described in this form, and you will not receive treatment as a study participant.  
If you sign this consent form, you may withdraw from the study at any time.  However, if you do 
not want the researchers to use or disclose any further information in this study you must cancel 
permission in writing and may do so at any time. If you cancel your permission, you will stop 
taking part in the study and no new information will be collected about you.  However, if you 
cancel your permission, it will not apply to actions already taken or information already collected 
about you by the hospital or the researchers before you canceled your permission.  This 
information or action may be needed to complete analysis and reports of this research. This 
permission will never expire unless you cancel it.  To cancel this permission, please write to Don 
Dizon, MD c/o the Medical Oncology Clinical Research Office at Rhode Island Hospital, 593 
Eddy Street, APC Building Rm. 131, Providence, RI 02903. 
If after you have signed this form you have any questions relating to your rights, please contact 
<INSERT IRB CONTACT> 
 
Uses and releases covered by this authorization (permission) 
Who will release, receive, and/or use your information?  This form will allow the following 
person(s), class(es) of persons, and/or organization(s)* to release,  use, and receive the 
information listed below in connection with this Study, or as required by law: 
 
Every research site for this study, including this hospital, and including each site's 
research staff and medical staff 
 
Health care providers who provide services to you in connection with this study 
 
Laboratories and other individuals and organizations that analyze your health 
information in connection with this study, in accordance with the study’s protocol 
 
The following research sponsors and the people and companies that they use to 
oversee, administer, or conduct the research: The Principal Investigator and sponsor Don Dizon, 
MD, BrUOG, the group coordinating the study (or their advisers), and BMS, the makers of the 
drugs being used and the financial supporter of the trial 
 
The United States Food and Drug Administration, the Department of Health and 
Human Services, the Office of Inspector General, and the Office of Civil Rights 
 
The members and staff of the Institutional Review Board(s) or Ethics Committee(s) 
that approves this study 
 
Principal Investigator and other Investigators 
 
Study Coordinator 
 
Additional members of the Research Team 
 
The Patient Advocate or Research Volunteer Protector: _____________________ 
 
Members of the hospital's administrative staff responsible for administering clinical 
trials and other research activities 
 
Contract Research Organization (A contract research organization is an independent 
organization that agrees to oversee and make possible, various aspects of the clinical research 
process for the research sponsor.) 
 
Data and Safety Monitoring Boards and others that monitor the conduct of the Study, 
for example a Clinical Events Committee 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
86 
 
The members and staff of the hospitals affiliated Privacy Board (if such a board is 
used) 
 
Others: 
 
 
 
 
 
_____________________________ 
* If, during the course of the research, one of the companies or institutions listed above merges 
with or is purchased by another company or institution, this permission to use or release 
protected health information in the research will extend to the new company or institution.  
 
 The entire research record and any medical records held by the hospital may be used and 
released.   
 The following information: _____________________________________________ 
 
 
GINA STATEMENT  
This study involves ‘genetic testing’ as defined by the Genetic Information Nondiscrimination 
Act of 2008 (GINA). GINA generally makes it illegal for health insurance companies, group 
health plans, and most employers to discriminate against you based on your genetic 
information.  There are some limitations to GINA’s protections (it does not apply to all insurers 
or employers, nor does it apply to all genetic information, such as information related to a 
genetic disease that you already have).  In addition to GINA’s protections regarding the ultimate 
use to which your genetic information is put, <INSERT HOSPITAL NAME>’s privacy policies 
generally protect the privacy of such information and restrict its release outside of <INSERT 
HOSPITAL NAME>, unless you specifically authorize its disclosure or unless disclosure 
without your authorization is permitted under applicable privacy laws.  
 
Optional Participation in Specimen Banking (optional biopsy) 
You are agreeing to participate in this research study by signing this form (the “Main Study”) 
tissue samples will be collected from you, which will be referred to here as your ‘Specimen.’  In 
addition to being analyzed as part of the Main Study, your Specimen may be useful for future 
research purposes.  Your signature on this consent form will document you to agree to this study 
are willing to allow your Specimen to be saved or ‘banked’ for use in future research studies. 
You give permission for your Specimen to be stored in a specimen bank indefinitely, until it is 
no longer usable. The Specimen may also be used to create a cell line, which would also be 
stored for an indefinite period of time. Along with the specimens, portions of your personal 
health information collected as part of the Main Study will also be stored.  Your Specimen and 
personal health information may be stored and analyzed at Lifespan; or, they may be shared with 
researchers at other institutions or companies that may store them and use them for their own 
research.  It is very unlikely that any future research performed using your Specimen would 
benefit you directly.  However, the research may provide important medical knowledge that in 
the future could help other patients with your medical condition or other medical problems.     
 
At this time, we do not know what future research studies may be done using your Specimen.  
Such research studies may include genetic tests that would analyze your DNA, RNA or other 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
87 
gene products, like proteins and metabolites.  These genetic tests may be done by Lifespan, or 
they may be done by other researchers with whom your Specimen and data have been shared.  
Because any genetic testing of your Specimen would be for research purposes, the results would 
have no clear implications for your health or medical condition, or that of your family members.  
Any testing results would not be made available to you or to any insurance company, your 
employer, your family, or any physician who treats you in the future.       
 
There is a very remote possibility that your Specimen and some associated data may become part 
of a process or product that ultimately has commercial value.  For instance, the Specimen could 
be used to establish a cell line (a group of cells that are able to reproduce, sometimes 
indefinitely) that could be patented and licensed.  There are no plans to provide financial 
compensation to you should this occur. 
 
If you decide at some time in the future that you no longer wish your stored Specimen to be used 
in future studies, you have the right to request that the Specimen be withdrawn from the 
specimen bank.  However, withdrawal cannot be guaranteed and may be impossible.  For 
example, it is possible that the Specimen might no longer be identifiable as belonging to you, or 
it may have been used up, or it may already have been shared with other institutions or 
companies for their own research.  To request withdrawal of your Specimen, please write to: 
Don Dizon, MD 593 Eddy Street APC1 Providence, RI 02903. 
 
If you are willing to allow your Specimen to be banked for future research purposes, please 
indicate your consent by signing below. Please note this refers to the optional biopsy. 
 
___________________________________________  
 
________          
Signature of study volunteer/authorized representative  
 
Date          
 
SIGNATURE 
I have read this informed consent and authorization form.  ALL OF MY QUESTIONS HAVE 
BEEN ANSWERED, AND I WANT TO TAKE PART IN THIS RESEARCH STUDY. 
By signing below, I give my permission to participate in this research study and for the described 
uses and releases of information.  I also confirm that I have been now or previously given a copy 
of the <INSERT HOSPITAL NAME> Privacy Notice 
 
 
 
 
The Researcher is required to provide a copy of this consent to you.  
 
_________________________________________ ________          ____________ 
Signature of study volunteer/authorized representative* Date         and    Time when signed 
 
 
 
This informed consent document expires on ______________.   
DO NOT sign this document after this expiration date 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
88 
I was present during the consent PROCESS AND signing of this agreement by the study 
volunteer or authorized representative 
 
__________________________________________ 
 
______________ 
Signature of witness (required if consent  
 
 
Date 
is presented orally or at the request of the IRB)  
 
 
 
 
 
 
 
 
__________________________________________ 
 
______________ 
Signature of Translator 
 
 
 
 
 
Date 
 
___________________________________________ ________          __________ 
Signature of researcher or designate  
 
 
Date         and    Time when signed 
 
* If signed by agent other than study volunteer, please explain below. 
______________________________________________________________________________ 
 
APPENDIX C 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
20 
Very sick, hospitalization indicated. 
Death not imminent. 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
89 
self-care.  Totally confined to bed 
or chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX D 
I-O AE ALGORITHMS 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
90 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
91 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
92 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
93 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
94 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
95 
 


 
 
BrUOG 355: 7/8/17, 7/11/17, 7/20/17, 8/7/17, 8/8/17, 8/14/17, 8/16/17, 8/21/17, 8/22/17, 8/24/17, 8/28/17, 9/5/17, 
9/6/17, 9/8/17, 9/11/17, 11/7/17, 11/8/17, 11/19/17 approved DD, 11/20/17, 12/12/17, 12/14/17, 1/29/18, 2/1/18, 
2/6/18, 2/7/18,2/8/18, 2/9/18, 2/12/18, 2/13/18, 3/8/18 all reviews, 3/9/18, 3/13/18, 3/14/18, 3/15/18, 4/19/18, 
4/23/18, 5/29/18, 6/5/18, Amendment # 1 7/9/18, Amendment # 2 12/12/18, Amendment #3, 4/6/2020, Amendment 
#4 5/11/2020 
 
96